- Email: [email protected]
The cerebellum in fear and anxiety-related disorders
Accepted Manuscript The cerebellum in fear and anxiety-related disorders
Josep Moreno-Rius PII: DOI: Reference:
S0278-5846(17)31056-4 doi:10.1016/j.pnpbp.2018.04.002 PNP 9379
To appear in:
Progress in Neuropsychopharmacology & Biological Psychiatry
Received date: Revised date: Accepted date:
31 December 2017 29 March 2018 4 April 2018
Please cite this article as: Josep Moreno-Rius , The cerebellum in fear and anxiety-related disorders. The address for the corresponding author was captured as affiliation for all authors. Please check if appropriate. Pnp(2018), doi:10.1016/j.pnpbp.2018.04.002
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
The cerebellum in fear and anxiety-related disorders Josep Moreno-Rius* Department of Pharmacology and Toxicology, University of Innsbruck, Innsbruck, Austria *Corresponding author:
PT
Department of Pharmacology and Toxicology, University of Innsbruck, Innrain 80-82, A-
AC C
EP T
ED
MA
NU
SC
RI
6020 Innsbruck, Austria. [email protected]
ACCEPTED MANUSCRIPT
ABSTRACT Fear and anxiety-related disorders are highly prevalent psychiatric conditions characterized by avoidant
and
fearful
reactions
towards
specific
stimuli
or
situations,
which
are
disproportionate given the real threat such stimuli entail.
PT
These conditions comprise the most common mental disorder group. There are a high proportion of patients who fail to achieve remission and the presence of high relapse rates
RI
indicate the therapeutic options available are far from being fully efficient. Despite an
SC
increased understanding the neural circuits underlying fear and anxiety-related behaviors in the last decades, a factor that could be partially contributing to the lack of adequate
NU
therapies may be an insufficient understanding of the core features of the disorders and
MA
their associated neurobiology.
Interestingly, the cerebellum shows connections with fear and anxiety-related brain areas and
ED
functional involvement in such processes, but explanations for its role in anxiety disorders are lacking.
EP T
Therefore, the aims of this review are to provide an overview of the neural circuitry of fear and anxiety and its connections to the cerebellum, and of the animal studies that directly
AC C
assess an involvement of the cerebellum in these processes. Then, the studies performed in patients suffering from anxiety disorders that explore the cerebellum will be discussed. Finally, we’ll propose a function for the cerebellum in these disorders, which could guide future experimental approaches to the topic and lead to a better understanding of the neurobiology of anxiety-related disorders, ultimately helping to develop more effective treatments for these conditions. Keywords: Anxiety; cerebellum; fear; prediction; anticipation.
ACCEPTED MANUSCRIPT
1. Introduction Fear and anxiety-related disorders comprise a group of conditions characterized by exaggerated emotional aversive responses to situations that don’t suppose a real threat. These
PT
disorders represent the most prevalent type of psychiatric illness (Ravindran and Stein, 2010), and their annual costs have been estimated to reach 75 billion € in 2010 (Olesen et al., 2012).
RI
In addition to the economic impact, it’s documented and recognized that patients suffering
SC
from these conditions also show a high degree of functional impairment and a decrease in life quality (Barrera and Norton, 2009). Moreover, a great number of patients fail to achieve
NU
remission, and, among the ones who do, relapse rates are very high (Yonkers et al., 2003).
MA
Although some differences exist (Tovote et al, 2015), the neural circuitries of fear and anxiety-related behavior show substantial overlap in several cortical and subcortical brain
ED
areas including limbic structures, such as amygdala or hippocampus (Liberzon and Martis, 2006), prefrontal cortical areas (Hilbert et al, 2014), midbrain structures as the periaqueductal
EP T
grey (Dejean et al., 2015) or raphe nuclei (Graeff, 2004), and other more recently identified contributors, such as dopaminergic areas (Small et al., 2016).
AC C
The literature and research on fear and anxiety has not paid much attention to the cerebellum. The cerebellum contains more neurons than the rest of the brain (Herculano-Houzel, 2009). Despite being traditionally associated to motor functions, an increasing number of recent findings have pointed to the possibility that functions unrelated to motor domains could require the cerebellum. Indeed, several studies now support the cerebellar implication in some of the brain functions involved in anxiety disorders, such as memory (Sacchetti et al., 2004) and prediction (Blakemore and Sirigu, 2003).
ACCEPTED MANUSCRIPT
Basic studies show the cerebellum to be connected with fear and anxiety-related areas, such as the amygdala (Farley et al., 2016), midbrain structures such as the periaqueductal grey (Koutsikou et al., 2014), the raphe nuclei (Kaufman et al., 1996), and the VTA (Oades and Halliday, 1987) and also prefrontal cortical areas (Kelly and Strick, 2003, Watson et al.,
PT
2014). Moreover, a number of studies performed in rodents assessing the contribution of the cerebellum to fear and anxiety-related behaviors also support the notion of the cerebellum
RI
being an important part of their underlying neural circuitries (Sacchetti et al., 2007; Otsuka et
SC
al., 2016).
As of today, multiple neuroimaging studies have reported differential activation, connectivity
NU
patterns and volumes in the cerebellum when anxiety patients are compared with healthy
MA
controls (Ke et al., 2016; Talati et al., 2015; Etkin et al., 2009; Konishi et al., 2014). Nevertheless, due to the traditional views of the cerebellum as a structure exclusively devoted
ED
to motor functions, there’s a lack of explanations on its role even in studies that report differential activity in patients and controls, so the functional significance of such cerebellar
EP T
activation in anxious patients remains unknown. Based on the aforementioned reasons, this work aims to review evidence about the
AC C
involvement of the cerebellum in the fear-related neural circuitry as well as in anxiety disorders, and to propose a hypothesis for its role. First, the neurocircuitry of anxiety-related conditions and its connections to the cerebellum is described. Afterwards, animal studies involving the cerebellum in fear and anxiety-related behaviors are discussed. Then, we review neuroimaging studies performed in anxious patients in which differential activation of the cerebellum was shown. Finally, a hypothesis to clarify the function cerebellar activation might play in pathological anxiety states is proposed. Hopefully, this work will help guiding future experimental approaches to the topic.
ACCEPTED MANUSCRIPT
2. Distinctions between fear and anxiety and relevance of animal models for the human disorders. Although a classical differentiation between fear and anxiety states that fear is a response
PT
directed towards external, definite or factual threatening stimuli, and anxiety is often defined
RI
as a response towards internal, vague and conflictual stimuli, this distinction has frequently been criticized and attempted to redefine because of providing little clarity both at the level of
SC
preclinical studies as well as in pathological human conditions (Gray, 1982; Perusini and
NU
Fanselow, 2015). For example, at the level of preclinical studies, it is well accepted that a paradigm such as cued fear conditioning reflects fear-like responses and the elevated plus
MA
maze (EPM) allows to measure anxiety-related behaviors. Nonetheless, according to the source of the potential threat, these two paradigms present an external allocation of the
ED
threatening stimuli. Further analyzing these two paradigms, now regarding how much of a factual threat is eliciting the threat-related behaviors, in the EPM, the threat-related behavior
EP T
reflected in avoiding open arms in which, if the animals perform a wrong movement while in there, may fall down from an important height, is considered as a nonfactual/conflictual
AC C
threat, whereas in the cued fear conditioning paradigm, in the session in which fear-like behavior uses to be assessed, such behavior is elicited by a cue which indeed, is, once training has finished, signals lack of threat and there is no possibility of harm to the animal, which again, does not seem to support a real usefulness of the previously mentioned definitions. In addition, later attempts of establishing such a differentiation, such as the one by Gray and McNaughton (2002), also proved to be unsuccessful. These authors defend that the proof that fear and anxiety are different entities is that fear-related behaviors are insensitive to anxiolytic drugs, but recent evidence contradicts this assumption (Gunduz-Cinar et al., 2016; Smith et
ACCEPTED MANUSCRIPT
al., 2012). Moreover, such a fear/anxiety distinction shows itself as confusing when the definitions and criteria for defining the disorders associated with these behavioral responses to threat are consulted. A clarifying example of this is provided by Perusini and Fanselow (2015). They report that even in the Diagnostic and Statistical Manual of Mental Disorders
PT
(DSM)’s chapter of anxiety disorders “the descriptions are unclear, inconsistent and often define one in terms of the other”. Specific phobia, classified within the anxiety disorders in
RI
the DSM is described as “a marked or persistent fear of clearly discernible and differentiated
SC
objects or situations” shows how unclear the fear/anxiety differentiation resembles even in diagnostic manuals. The fact that it is also stated in DSM’s definition of specific phobia that
NU
“exposure to the phobic stimuli immediately provokes an anxiety response” is also showing a
MA
discrepancy between the association of anxiety and non-discrete threats favored by the classical distinction. The very same picture emerges when the criteria for Social Anxiety Disorder are consulted, and other disorders classified within this chapter, a panic attack is
ED
defined as “feelings of intense fear or discomfort”.
In light of these discrepancies, the author
EP T
favors the consideration of fear and anxiety as different points within the continuum of threatrelated responses, rather than considering them two discrete entities. According to this view,
AC C
paradigms such as the EPM would allow to measure mild threat-related responses which can also be considered to reflect personality-like traits in experimental animals, whereas fear conditioning paradigms would be generating more vigorous threat-related responses. Within the range of human behaviors, exaggerated threat-like responses such as the ones observed in fear and anxiety-related disorders would be located in the upper extreme of the continuum, and proportional anxiety-related reactions such as enhanced anxious activation before a university exam could be located within the lower extreme of the continuum. Therefore, and in order to avoid
possible misunderstandings derived from conceptualizing fear and anxiety
ACCEPTED MANUSCRIPT
as categorically distinct, the author refers to these behaviors as “threat-related behaviors” or “fear and anxiety-related behaviors” and to the associated pathological conditions as “fear and anxiety-related disorders”. This conceptualization also enables to consider PTSD within this group as it might be the most paradigmatic disorder associated with threat-related behaviors.
PT
Another point that needs to be stressed in order to clarify the usefulness of fear and anxietyrelated animal models and the attempts of translating the animal findings to the human
RI
condition is to remark the common features the animal models and fear and anxiety-related
SC
disorders in humans. As mentioned before, it is the authors’ opinion that according to the intensity of the threat-related behaviors susceptible to appear and being measured in animal
NU
paradigms, the fear conditioning paradigm seems to be closer than other options to the
MA
pathological fear and anxiety-related conditions in human beings. Another feature that strengthens the consideration of fear conditioning paradigms as relevant for the discussed
ED
disorders is the fact that in both cases, threat-related behaviors are elicited by/developed towards stimuli or situations which, normally, are not threatening. And last but not least, it is
EP T
also worth to remark that the fear conditioning paradigm presents, in addition to the component of face validity that comes from the aforementioned similarity in developing
AC C
threat-like responses towards something that normally is not threatening, predictive validity in the sense that pharmacological treatments for fear and anxiety-related disorders are effective in reducing threat-related behaviors in fear conditioning paradigms and vice versa (GunduzCinar et al., 2016; Smith et al., 2012), and also construct validity, as demonstrated by involvement of common brain areas both in fear and anxiety-related disorders and in fear conditioning.
A brief description of these common areas affected in the human conditions
and animal paradigms, as well as their connections to the cerebellum, is presented in the following section.
ACCEPTED MANUSCRIPT
3. The circuitry of fear and anxiety and its connections to the cerebellum. Converging evidence coming from animal and clinical studies has increased our knowledge of the brain areas involved in fear and anxiety behaviors. We will succinctly describe the areas involved in fear and anxiety and their connections to the cerebellum, as excellent reviews on
PT
anxiety-related neural circuitry have been recently issued (Tovote et al., 2015; Taylor and Whalen, 2015; Calhoon and Tye, 2015).
RI
One of the core components of the anxiety circuitry is the amygdala. This limbic group of
SC
nuclei, a critical site for the aversive learning-associated plasticity, shows abnormal activation and connectivity patterns in anxious patients (Etkin et al., 2009; Wolff et al., 2014). The
NU
prefrontal cortex and its subdivisions, including the ventromedial part and the anterior
MA
cingulate cortex also seem to play different roles in fear-related behaviors and disorders (Carrion et al., 2009; Peters et al., 2010). Another cortical zone such as the insula, responsible interoception
and
multimodal sensory
processing,
presents
comparable evidence
ED
for
supporting its inclusion as part of this circuitry (Klumpp et al., 2012; Alves et al., 2013).
EP T
Similarly, the participation of the hippocampus in the circuitry of anxiety, a brain structure thought to be exclusively involved in spatial memory and navigation is now supported by
AC C
both clinical and preclinical evidence (Jatzko et al., 2006; Zhang et al., 2017). The periaqueductal gray, a midbrain structure responsible for returning neural signals related to aversive stimuli to the peripheral nervous system, also participates of fear and anxiety-related circuitries as indicated by patient and animal studies (Watson et al., 2016; Harricharan et al., 2016). An equivalent amount of findings also involves the raphe nuclei within these brain circuits. The main source of serotonergic neurons in the brain seems to be essential component of the structures mediating fear and anxiety-related responses (Spindelegger et al., 2009; An et al., 2016). The ventral tegmental area, the region in which the dopaminergic cell
ACCEPTED MANUSCRIPT
bodies are located, traditionally regarded as a reward processing and valuating area can also be considered as part of this circuitry in light of several lines of evidence (Pignatelli et al., 2017; Cha et al., 2014). The same could be applied to the striatum. Being classically involved in motivated behavior as well as in motor abilities, its connections and recent findings in
PT
animals and patients favor the inclusion of this structure in the anxiety circuitry (Norris et al., 2016; Felmingham et al., 2014). previously
mentioned
areas’
neuromodulators.
activity
is
strongly
modulated
by
several
This is of special relevance from a clinical
SC
neurotransmitters and
brain
RI
The
perspective, given that the available non-behavioral treatments of fear and anxiety-related
NU
disorders are essentially pharmacological compounds targeting those systems. Most of these
MA
treatments present a series of inconveniences such as being effective only in short-term reduction of symptoms, delayed onset of action and lack of targeting the cause of the anxiety-
ED
related symptoms among others. Nonetheless, the use of such chemicals has shed light on the neurotransmitter systems which are involved in fear and anxiety-related behaviors and
EP T
disorders within the aforementioned brain areas. One of the neurotransmitter systems involved is the GABAergic system. It is well known that drugs enhancing GABA
AC C
transmission are effective in reducing abnormal fear and anxiety-related behaviors in both experimental animals and humans (Ballenger et al., 1998; Rickels and Rynn, 2002; Toth et al., 2012). The serotonergic system also seems to be involved, as drugs enhancing serotonergic transmission are effective in relieving anxiety symptoms in patients (Cascalenda and Boulenger, 1998), and it is also the case for fear and anxiety-related paradigms in rodents (Toth et al., 2012; Gunduz-Cinar et al., 2016).
Similar evidence favors the involvement of
noradrenergic transmission. Norepinephrine itself or drugs enhancing norepinephrine function are able to induce panic attacks in humans (Pyke and Greenberg, 1986), and modulating the
ACCEPTED MANUSCRIPT
activity of the noradrenergic system affects fear and anxiety-related behaviors in rodents as well (Davies et al., 2004; Davis et al., 1979). Another neuromodulation system which is involved in anxiety is the endocannabinoid system. It is well known that the moderate doses of exogenous cannabinoids such as the ones present in marijuana produces anxiolytic effects
PT
in humans (Sethi et al., 1986), and this feature is paralleled by analogous effects in rodent models of fear and anxiety (Fokos and Panagis, 2010; Rubino et al., 2007). Glutamatergic
RI
neurotransmission may be similarly involved as well, as modulating it via pharmacological
SC
means alters fear and anxiety-related behaviors in rodents (Brodkin et al., 2002; Walker and Davis, 2002), and some of the compounds modulating this neurotransmitter system show
NU
promising effects in patients afflicted from fear and anxiety-related conditions (Hofmann et
MA
al., 2015).
Importantly, it is nowadays demonstrated that all the previously mentioned brain areas seem
ED
to be connected to the cerebellum. Animal studies proving the existence of connections between cerebellum and both cortical and subcortical areas involved in fear and anxiety, reciprocal connections
with
brain
areas
which
are the main source of
EP T
including
neurotransmitters involved these behaviors (Snider, 1950; Snider and Maiti, 1976; Kaufman
AC C
et al., 1996; Kelly and Strick, 2003; Berntson and Torello, 1982; Bishop and Ho, 1985; Watson et al., 2009; 2014; Farley et al., 2016) are reinforced by human neuroimaging studies that confirm these cerebrocerebellar relationships. In this regard, a functional relationship between cerebellum and different areas within the cortex, such as anterior cingulate cortex (Addis et al., 2016; Moulton et al., 2011; Sang et al., 2012; Zeng et al., 2012), insula (Addis et al., 2016; Habas et al., 2009; Moulton et al., 2011; Sang et al, 2012), and inferior frontal gyrus (Addis et al., 2016; Moulton et al., 2011; Tomasi and Volkow, 2011) has been shown. Other subcortical structures such as amygdala (Leutgeb et al., 2016; Sang et al., 2012; Zeng et al.,
ACCEPTED MANUSCRIPT
2012), hippocampus (Onuki et al., 2015; Sang et al., 2012; Zeng et al., 2012), raphe nuclei (Beliveau et al., 2015), ventral tegmental area (Carnell et al., 2014; Etkin et al., 2009; Kline et al, 2016; Kwon et al., 2014) and striatum (Cauda et al., 2011; Cservenka et al., 2014; Koehler et al., 2013) also seem to present a comparable relationship with the cerebellum.
PT
The aforementioned studies provide strong cross-species neuroanatomical evidence pointing to, although not proving, that the cerebellum may play a functional role in anxiety-related
RI
behaviors and disorders. Such a role has been demonstrated in experiments conducted in
SC
rodent models, which allow performing transient or permanent modifications of brain structure and function as well as studying the associated changes at molecular resolution. In
NU
the forthcoming section, we will discuss the studies that show this functional involvement for
MA
the cerebellum in paradigms aiming to measure fear and anxiety-related behaviors. 4. The cerebellum in fear and anxiety-related behaviors.
ED
When studying fear and anxiety-like behaviors in rodents, basic scientists make use of paradigms in which either a noxious stimulus is applied or a moderately aversive environment
EP T
that the animal can avoid is presented. As previously discussed, the latter type is thought to measure anxiety-like responses inferred from the avoidance of the aversive environment,
AC C
whereas the former are supposed to represent fear behaviors. The first study showing an involvement of the cerebellum in fear-related behaviors was the one conducted by Moruzzi in 1947. The author reported that sham rage elicited by cortical removal could
be temporarily blocked by cerebellar stimulation, but this cerebellar
manipulation led to increased rage-like symptoms once stimulation had ceased. Posterior studies, such as the one performed by Fish and colleagues in 1979, strengthened the cerebellar involvement in fear-related behaviors as lesions directed at medial cerebellar nuclei impaired performance
in
an
active
avoidance
task.
A
similar
behavioral
task
in
which
ACCEPTED MANUSCRIPT
cerebellectomized
rats’ performance was assessed
confirmed the involvement as no
association was seen in cerebellum-removed rats (Dahhaoui et al., 1990). The role of the cerebellum could not be related to the execution of an active response, as cerebellectomy impaired performance in a passive avoidance task as well (Guillaumin et al., 1991). Some
PT
other early studies showed medial cerebellar lesions decreased fear responses when rats were presented with a predator (Supple et al., 1987), an effect also seen in a lever pressing
RI
paradigm (Steinmetz et al., 1993).
SC
Another fear-related measure in which the role of the cerebellum has been studied is conditioned bradycardia. In these experiments, an aversive footshock, which has the ability to
NU
lower heart rate, is applied to the experimental animal paired with a distinctive cue such as a
MA
tone or a light. After a number of cue-shock pairings, the animals are only presented with the cue, and the cue displays the ability to elicit the same heart rate response than the shock did.
ED
Cerebellar ablation proved to impair the acquisition of the conditioned heart response (Supple and Leaton, 1990a), and further studies demonstrated this effect can be attributed to the
EP T
cerebellar vermis both in rats and rabbits (Supple and Leaton, 1990b; Supple and Katz, 1993). A crucial role for the cerebellar cortex in these processes is inferred from studies using the
AC C
Lurcher mutant mice. These animals present a mutation which, in its heterozygous form, leads to the death of Purkinje cells. Mutants visited more frequently the open arms in the EPM (Lorivel and Hilber, 2006; Lorivel et al., 2010), and showed altered fear responses when presented with a predator (Lorivel et al., 2014). Not only Purkinje cells seem to be involved, as a fearful stimulus was also able to change the phenotype of ionotropic glutamate receptors in stellate cells (Liu et al., 2010). Transmission via Histamine-2 receptors could be modulating the cerebellar circuitry processing fear-related stimuli, as demonstrated in studies
ACCEPTED MANUSCRIPT
using microinjections of histamine and H2 receptor ligands in the medial cerebellum in an aversive conditioning paradigm (Gianlorenço et al., 2013; 2015). Additional evidence comes from the most used behavioral task for unraveling neural circuits of fear, the so-called fear conditioning paradigm. Pairing an originally neutral stimulus (a
PT
context or a tone) with a noxious one (a shock), enables the neutral stimulus to elicit fear responses in the animal. Sacchetti and coworkers, using an auditory fear conditioning
RI
paradigm, demonstrated the existence of AMPA-dependent fear learning-induced long-term
SC
potentiation (LTP) in parallel fiber-purkinje cell (PF-PC) synapses in cerebellar lobules V-VI capable to occlude electrically induced LTP (Sacchetti et al., 2004; Scelfo et al., 2008; Zhu et
NU
al., 2007). Additional studies revealed that functional integrity of lobules V-VI was necessary
MA
for consolidating fear memories (Sacchetti et al., 2002; 2007), and they also described that amygdalar lesions impaired fear learning-induced cerebellar plasticity (Zhu et al., 2011). compromising lobule VIII integrity produced the same effect than the
ED
Interestingly,
manipulation performed in lobules V-VI (Koutsikou et al., 2014), pointing to a general
EP T
involvement of the cerebellum in these behaviors. The role of the PF-PC synapse in fear processes has been stressed by a recent report in which mice lacking Cerebellin 1 selectively
AC C
in the cerebellum, a protein involved in the maintenance of the structure of this synapse, display an impaired acquisition of fear memories (Otsuka et al., 2016). Overall, these studies provide evidence for the cerebellum to be a part of the circuitry underlying fear-related behaviors that is comparable to other brain areas widely recognized as part of such circuitry (see LeDoux, 2000). Given that the involvement of brain areas in basic fear-related processes has been translated into alterations of such areas in anxiety patients (which are thought to be involved in the pathophysiology of these disorders), in the forthcoming section, we aim to demonstrate this relationship is also true for the cerebellum as
ACCEPTED MANUSCRIPT
we review neuroimaging reports of patients suffering from fear and anxiety-related disorders in which differential activation or connectivity of the cerebellum, relative to healthy controls, has been observed.
PT
5. The cerebellum and fear and anxiety-related disorders. The refinement of neuroimaging techniques during the first decade of the century has allowed
RI
mapping brain activity and connectivity with enhanced resolution and minimal invasiveness
SC
in human beings. When such techniques have been applied to the study of anxious patients, differential activation of the cerebellum is frequently found in many studies (Etkin et al.,
NU
2009; Talati et al., 2015), which will be discussed now. It is important to mention, however,
MA
that fear and anxiety-related disorders are a fairly heterogeneous group of conditions in which fearful/anxious symptomatology might be triggered by different stimuli and can also manifest
ED
in a variety of ways. These differences between disorders are summarized in Table 1. Within this group of conditions, the first study demonstrating changes in the cerebellum of
EP T
anxious patients was a PET study conducted in social anxiety disorder (SAD). SAD is characterized by avoiding interactions with unfamiliar people and experiencing interaction
AC C
episodes with extreme anxiety. In this first study, altered cerebellar activation was observed in a group of SAD patients that were anticipating they had to speak in public (Tillfors et al., 2002). Such changes demonstrated to be present also in baseline conditions when measured with single positron emission tomography (Warwick et al., 2008). Volumetric alterations within the cerebellum have also been described in SAD patients. An increase in cerebellar grey matter was reported in these patients (Talati et al., 2013), which was successfully rescued by different SSRIs (Talati et al., 2015; Cassimjee et al., 2010). In functional studies, enhanced cerebellar activity was found when SAD-afflicted individuals were presented with
ACCEPTED MANUSCRIPT
angry faces (Evans et al., 2008), when they faced a confrontational arithmetic task (Kilts et al., 2006) and after they were exposed to different social tasks (Nakao et al., 2011; Heeren et al., 2017). Connectivity changes between cerebellum and other parts of the anxiety circuitry in SAD patients might partially explain the different activation patterns, as these changes have
PT
been described in resting state and task-performing conditions for the connections linking amygdala (Liao et al., 2010), medial prefrontal cortex (Giménez et al., 2012; Yuan et al.,
RI
2016) and cingulate cortex (Doruyter et al., 2016) with the cerebellum. Interestingly,
SC
connectivity levels between mPFC and cerebellum predicted response to behavioral treatment (Yuan et al., 2016), thereby holding promise as a biomarker to refine therapy prescription and
NU
reducing the number of patients under ineffective treatments.
MA
Post-traumatic stress disorder (PTSD), a condition characterized by re-experiencing a traumatic episode of one’s life, also strengthens substantially the notion of the cerebellum
ED
being functionally involved in fear and anxiety-related disorders. PTSD patients showed an increase in cerebellar activity at resting conditions (Bing et al.,
EP T
2013). This finding cannot be related to trauma exposure per se, as differences in the cerebellum were still present when PTSD patients were compared with trauma-exposed,
AC C
PTSD-free individuals (Bonne et al., 2003). A subsequent study comparing trauma-exposed borderline personality disorder patients with and without PTSD revealed only the group suffering from PTSD displayed enhanced cerebellar activation (Driessen et al., 2004), pointing to increased cerebellar activity as a specific disease indicator, an assumption reinforced by a recent meta-analysis (Wang et al., 2016). These baseline activation patterns seem to be accompanied by a reduction in cerebellar volumes, as it was reported both in adult and pediatric patients afflicted from PTSD (Baldaçara et al., 2011; Carrion et al., 2009; De Bellis and Kuchibhatla, 2006). fMRI studies in which exposure to fearful faces or trauma-
ACCEPTED MANUSCRIPT
related images was performed provoked activation in the cerebellum (Ke et al., 2016; Crozier et al., 2014), and it was seen that a reduction in cerebellar activation after treatment correlated with symptom improvement (Ke et al., 2016). These activity patterns may be influenced by stronger connections of the cerebellum to effector areas, like the periaqueductal grey, found in
PT
PTSD patients (Thome et al., 2017).
RI
Another condition in which the cerebellum has popped out in several neuroimaging reports is
SC
specific phobia. These patients experience intense fear or anxiety when they face specific stimuli or situations, such as animals, flights or injections. In a PET study, both spider and
NU
snake phobics displayed cerebellar activation when viewing pictures of the respectively feared
MA
animals (Carlsson et al., 2004), a finding confirmed also by fMRI reports (Goossens et al., 2007; Ahs et al., 2009) which additionally demonstrated a correlation between the level of
ED
anxiety induced by viewing the stimuli and the activity in the cerebellum (Caseras et al., 2010). The cerebellar activation was seen even when neutral photos were conditioned to
EP T
photos depicting feared stimuli (Schweckendiek et al., 2011), and the activity patterns were accompanied by an increase in grey matter (Hilbert et al., 2015).
AC C
Studies on panic disorder patients, characterized by presenting recurrent panic attacks and intense worrying about suffering them in the future, show enhanced cerebellar activity in baseline conditions (Sakai et al., 2005) which was diminished by successful cognitivebehavioral therapy (Sakai et al., 2006), suggesting a role for the cerebellum in the neural circuitry
underlying
successful
behavioral
intervention.
Structural
abnormalities,
like
reductions in grey matter (Asami et al., 2009), and similar patterns for cerebellar white matter were found (Konishi et al., 2014). The structural abnormalities in the cerebellum seemed
ACCEPTED MANUSCRIPT
responsive to treatment interventions, as the grey matter reduction was rescued by antidepressant treatment (Lai and Hsu, 2011). Finally, there’s also evidence linking cerebellum with generalized anxiety disorder. Patients that deal with this condition suffer a long-lasting worry about a variety of situations leading to
PT
significant functional impairment. Enhanced connectivity between the cerebellum and the amygdala is the main finding regarding this disorder (Etkin et al., 2009), a finding reproduced
RI
in adolescents (Roy et al., 2013), which was shown to correlate with disease scores (Liu et al.,
SC
2015). Additionally, these patients demonstrated increased cerebellar metabolism when they were performing a verbal fluency task (Kalk et al., 2012).
NU
Taken together, these studies provide compelling evidence of cerebellar hyperactivity in
MA
different groups of anxiety disorders patients. Nonetheless, within the reviewed studies, explanations on the role of this activation are lacking or limited to mention the cerebellum
ED
seems to be involved in fear/emotion, but a specific role for this brain area has not been proposed yet. An attempt of providing such an explanation will be the goal of the forthcoming
EP T
section.
AC C
6. What is the role of the cerebellum? Overall, the collected evidence from both human and animal studies has confirmed that: 1) the cerebellum is heavily connected with a variety of areas considered part of the anxiety circuitry including those which provide the neurotransmitters involved in fear and anxiety, 2) manipulations on cerebellar integrity or functioning affect behavioral performance in fear and anxiety-related tasks in experimental animals and 3) patients suffering from anxiety disorders display enhanced cerebellar activity and connectivity with anxiety-related brain areas when
ACCEPTED MANUSCRIPT
compared
with
healthy
controls.
Nevertheless,
the
possibility
remains
that
several
methodological factors could account for the variability found between studies. In animal studies, some minor differences exist regarding the directionality of the effect of the cerebellar manipulation (Lorivel et al., 2010; Sacchetti et al., 2002). Loss-of-function can
produce
opposing
effects
in
fear-related
behavioral
paradigms.
PT
manipulations
Nonetheless, it is likely that such results are due to the use of markedly different behavioral
RI
tasks that rely on either unconditioned or conditioned fearful responses, that differ in the
clearly differentiated
SC
nature and intensity of the fear-inducing stimulus or that require the animals to perform a behavior. Such an assumption is supported by the convergent
NU
directionality of cerebellar manipulations within the same behavioral paradigm (Sacchetti et
MA
al., 2004; Koutsikou et al., 2014). In neuroimaging studies, variables such as the number of subjects, age, gender, years of diagnosis, presence of comorbid disorders and previous
ED
treatments are not equivalent in the majority of studies. Differences in the neuroimaging techniques used for monitoring activity, which include PET, SPECT and fMRI scans and
EP T
differences within the studies using the same technique (different tracers for PET scans, different intensities of magnetic fields in fMRI studies) could have also influenced the results.
AC C
Another concern that may arise due to the well-known involvement of the cerebellum in motor function is whether motor disturbances that might be present in patients suffering from fear and anxiety-related disorders are the cause of cerebellar activity seen in neuroimaging studies. Nevertheless, the available evidence indeed suggests a more central role of the cerebellum within these disorders rather than being a finding related to non-cardinal symptoms of these disorders. In fact, fear and anxiety-related behaviors are accompanied by motor alterations but these alterations may be present as increased or decreased motor activity depending, among other variables, on perceived threat intensity. Therefore, it seems likely
ACCEPTED MANUSCRIPT
that patients afflicted from fear and anxiety-related disorders can present motor alterations, but evidence regarding these features is mixed and doesn’t point univocally to the cerebellum as a possible substrate. Indeed, the presence of general motor impairments seems to be restricted to some, but not all, fear and anxiety-related conditions (Marchand et al., 2009;
PT
Hazlett et al., 1994; Brown and Boudewyns, 1996). Additionally, within the disorders that show a motor impairment, both enhanced and decreased activity has been described (Brown
RI
and Boudewyns, 1996; Malta et al., 2009), whereas in the neuroimaging studies with patients,
SC
cerebellar function is always increased when compared to controls (Carlsson et al., 2004; Evans et al., 2008; Ke et al., 2016). It is also remarkable that the increased cerebellar
NU
activation appears irrespective of whether the scan was performed with the patients in resting
MA
conditions (Warwick et al., 2008; Bing et al., 2013; Sakai et al., 2005) or while they were performing a task that had some motoric requirements (Kilts et al., 2006; Nakao et al., 2011;
ED
Ke et al., 2016). Moreover, available data suggest that variables which are not the disorder itself can show a more important effect in the observed motoric dysfunctions (Clark et al.,
EP T
1990), and the evidence for the neural basis of such impairments has not reported cerebellar involvement and indeed points to a major involvement of striatal areas (Marchand et al.,
AC C
2009). More importantly, the connectivity or activation patterns seen in the cerebellum of patients have been shown to predict treatment response, symptom improvement and anxiety self-reports in different studies (Yuan et al., 2016; Ke et al., 2016; Caseras et al., 2010), so the possibility that the role of the cerebellum goes beyond the motoric manifestations of fear and anxiety-related disorders needs to be strongly considered. In addition, evidence within the studies performed in both species is convergent. Different types of neuroimaging scans reveal enhanced cerebellar activation in most fear and anxietyrelated disorders (Carlsson et al., 2004; Evans et al., 2008; Ke et al., 2016), and in rodents
ACCEPTED MANUSCRIPT
acquisition of fear-related behaviors results in enhanced cerebellar function (Sacchetti et al., 2004) and loss-of-function manipulations such as lesions, pharmacological inactivation on gene deletions result in impaired fear-related behaviors (Sacchetti et al., 2002; Koutsikou et al., 2014; Otsuka et al., 2016). Interestingly, such a convergence seems to point to the
PT
necessity of cerebellar activity for the expression of exacerbated fear and anxiety-related behaviors towards stimuli or situations that normally do not suppose a remarkable threat.
RI
Looking into the functional role of the cerebellum in fear and anxiety-related disorders, a
SC
possible explanation for it, which will be consistent with recent definitions and theorizations on the anxiety and the etiology of the associated disorders as well as cerebellar functions,
NU
would be that the cerebellum is, at least, partly responsible for the anticipation/prediction
MA
processes that accompany pathological fear and anxiety-related conditions. The relationship between anxiety and anticipation becomes evident when anxiety definitions
ED
are consulted. Whether they were formulated decades ago or in the last few years, all of them define anxiety as a response oriented toward potential, upcoming threats (Borkovec, 1985;
EP T
Tovote et al., 2015), this is, the anxious response is produced because the subject anticipates there can be a harmful situation in the near future. The relevance of this anticipation processes
AC C
for the pathological anxiety conditions seems to be more evident when dysfunctions in these anticipatory processes, which lead to an aberrant prediction of future threats as more harmful than they really are, have been suggested to represent a crucial factor for the development and maintenance of such disorders (Grupe and Nitschke, 2013). Favoring this notion, such a heightened harmfulness prediction for upcoming threats has been demonstrated in patients afflicted from different pathological anxiety conditions (Andrews et al., 1994; Hazlett-Stevens and Borkovec, 2004; Grillon et al., 2008; Tillfors et al., 2002).
ACCEPTED MANUSCRIPT
On the other hand, the relationship between the cerebellum and prediction processes is also supported both at the theoretical and practical levels. From a theoretical standpoint, the cerebellum’s main function has been hypothesized to be to support generalized fast prediction processes (Courchesne and Allen, 1997; Moreno-Rius and Miquel, 2017). Such a predictive
PT
function is thought to be performed by “forward controllers” (Brown and Brüne, 2012; Wolpert et al., 1998). A forward controller can be defined as a brain circuit capable of
RI
recruiting forward models to produce such anticipatory responses. Forward models, in turn,
SC
are internal representations of specific environmental settings based on which the subject is able to estimate the consequences of his possible actions in such setting (Van der Meer and
NU
Redish, 2010). Importantly, the cerebellum is widely considered to act as a forward controller
MA
(Miall et al., 1993; Ito, 2008). This supposes that, via the use of internal memory and the processing of the environmental inputs, cerebellar systems are able to provide a virtual scenario based on which fast prediction of outcomes for a particular behavior are generated
ED
(D’Angelo and Casali, 2013), and this prediction will activate the preparation of the brain
EP T
networks that are required to trigger fear-related anticipatory behaviors. Accordingly, in the case of anxious patients, such a cerebellum-based predictive system is functioning in an
AC C
aberrant, hyperactive way. This leads to an overestimation of the environment-associated harms and to the appearance of anxiety symptoms, and, at a neural level, it is seen as enhanced cerebellar activation. Interestingly, such an enhanced cerebellar activation was prominently observed when they faced cues that can be able to trigger threat-like predictions, further stressing the role of the cerebellum in these processes (Tillfors et al., 2002; Crozier et al., 2014; Carlsson et al., 2004). This proposed working hypothesis of an aberrant cerebellumbased prediction process in pathological fear and anxiety is strongly reinforced by a metaanalytic work which demonstrates the cerebellum is involved in aversive learning-related
ACCEPTED MANUSCRIPT
prediction error in human subjects (Garrison et al., 2013), thereby providing strong evidence that the cerebellum is indeed involved in aversive stimuli-related prediction processes in human subjects. Interestingly, this prediction process that the author intends to relate to pathological fear and
PT
anxiety seems to be performed by the cerebellum even in other aspects within the emotional domain (Adamaszek et al., 2017). In fact, regarding emotional perception and recognition,
RI
especially negative emotions, a role for the cerebellum has been demonstrated in studies in
SC
patients afflicted from cerebellar lesions (Adamaszek et al., 2014; Lupo et al., 2015; Annoni et al., 2003), and has been related to a general predictive function of the cerebellum (Molinari
NU
et al., 2008).
MA
This hypothesis also nicely explains that, in fear-related associative paradigms, which basically consist in allowing an experimental animal to associate a neutral stimulus with an
ED
aversive one, and after repeated pairings the animal shows a physiological and behavioral anticipatory response related to the previous appearance of the aversive stimulus when the
EP T
conditioned stimulus is presented, cerebellar lesion or inactivation impairs the ability of the animals to display the classically conditioned anticipatory response (Sacchetti et al., 2002;
AC C
Koutsikou et al., 2014).
Additional evidence supporting a cerebellar role in anticipatory responses and therefore partially supporting the proposed hypothesis of cerebellar function in pathological fear and anxiety comes from the study of reward-related behaviors. Anticipation of psychostimulant administration in cocaine addicts resulted in enhanced cerebellar activation unrelated to the pharmacological effects of the drug (Volkow et al., 2003). Similarly, in a cocaine-conditioned preference paradigm,
animals that learned
to
anticipate
drug administration by the
presentation of a cocaine-paired stimulus displayed enhanced activation of cerebellar cortical
ACCEPTED MANUSCRIPT
excitatory neurons (granule cells) and restrictive metaplasticity mechanisms in the inhibitory interneurons controlling them (Carbo-Gas et al., 2014; 2017). The importance of granule cells in the predictive function of the cerebellum was confirmed by a recent report in which these cells were imaged while mice were performing a forelimb reward tasks, such cells were
PT
shown to encode reward anticipation in both paradigms tested (Wagner et al., 2017). Although the aforementioned studies provide support to the proposed predictive function of
RI
the cerebellum in fear and anxiety-related disorders, it could be that the cerebellum is also
SC
involved in other functions related to fear and anxiety that go beyond the proposed cerebellar predictive function. One of these functions related to fear and anxiety in which the cerebellum
NU
has been involved is the modulation of the autonomic nervous system. It is known that
MA
autonomic symptoms are part of the manifestations of fear and anxiety (Friedman, 2007; Alvares et al., 2016; Thome et al., 2017), and it is also known that the cerebellum is involved
ED
in the control of these responses (Emerson et al., 1961; Balaban and Porter, 1998; MuellerPfeiffer et al., 2014), so maybe cerebellar alterations could also be playing a role in autonomic
EP T
deregulations presents in patients afflicted from fear and anxiety-related disorders, although, as of today, studies relating autonomic symptoms and cerebellar function in patients are
AC C
lacking.
Another function related to fear and anxiety in which cerebellar involvement has been described is salience. Salience can be defined as the property that environmental stimuli or situations have that make them especially relevant when compared to other stimuli or situations within an environment (Uddin, 2015). Salience attribution is a crucial process in order to allow organisms to pursue beneficial goals or stimuli and avoid harmful ones (Borsook et al., 2013). Importantly, functional connectivity studies have helped to define the neural basis of salience attribution. A functional network termed “salience network”, which
ACCEPTED MANUSCRIPT
includes brain zones such as insula, anterior cingulate cortex and temporoparietal junction, has shown to respond to salient stimuli irrespective of the sensory modality of the stimuli (Downar et al., 2002). Notably, it has been described that the cerebellum is connected to these areas (Igelstrom et al., 2017; Habas et al., 2009; Shinn et al., 2015), and cerebellar activations
PT
in response to salient stimuli including threatening ones have been reported (Killgore et al., 2003; Moulton et al., 2011; Anderson et al., 2006). Therefore, it would be possible that, in
RI
studies in which threat-related cues are presented to fear and anxiety-related disorders’
SC
patients, its salience may explain differential cerebellar activations and connectivity patterns, but given that these changes are also seen in patients in resting conditions (Warwick et al.,
NU
2008; Bing et al., 2013; Sakai et al., 2005), it is likely that the involvement of the cerebellum
MA
in fear and anxiety cannot be explained only by its role in salience. Even though, the proposed predictive function of the cerebellum also seems to be compatible
ED
with one of the most influential theories of fear and anxiety (Gray, 1982; Gray and McNaughton, 2002; McNaughton and Corr, 2004). The basic feature of this theory can be
EP T
considered that a behavioral inhibition system, which neurobiological core is supposed to be the hippocampus and septal areas, referred by the authors of the theory as the
AC C
septohippocampal system, is responsible for controlling threat-related behaviors. The early finding that led to the authors to propose such a neural ground for threat-related behaviors was the fact that anxiolytic drugs impaired performance in hippocampus-dependent memory tasks (Timic et al., 2013). It is the author’s opinion that the cerebellum could be a fit within this theory. The proposal of the authors of the theory is that the septohippocampal system, briefly explained, is a comparator of the threat levels of the real, presented situation versus the expected one, and when there is a mismatch between the expected threat levels and the real situation, the activation of the behavioral inhibition system allows to increase arousal, the
ACCEPTED MANUSCRIPT
appearance of typical defensive behavior and the inhibition of any other sort of behavior (Gray and McNaughton, 2002). It’s been described in section 4 that lesioning or inactivating the cerebellum predominantly results in a reduction of threat-related anticipatory behaviors and in the reappearance of the non-threat-related behaviors that are inhibited in a threatening
PT
situation (Sacchetti et al., 2002; 2007; Koutsikou et al., 2014). Moreover, the cerebellum has shown to be anatomically and functionally connected with both the septum and hippocampus
RI
(Heath et al., 1978; Snider and Maiti, 1975; Swanson, 1977; Onuki et al., 2015; Yu and
SC
Krook-Magnusson, 2015). Given that it has been demonstrated that the cerebellum is able to provide forward models supporting predictions in other domains, and that its structural and
computational
studies
suggest
it
NU
homogeneity
most
likely
performs
a
single
MA
computational function (D’Angelo and Casali, 2013), the same function could be taking place regarding threat-like responses, and the provided model would be posteriorly compared with
ED
the actual situation by the septohippocampal formation. Taking into account from the aforementioned studies the involvement of the cerebellum in
EP T
aversive prediction processes, the role of prediction/anticipation in threat-related behaviors, the role of the cerebellum in fear-related behavioral paradigms and the findings of the
AC C
cerebellar hyperactivity seen in patients suffering from pathological fear and anxiety, the proposal of a cerebellum-based aberrant prediction process seems to be a parsimonious one which encompasses the previously mentioned findings, and could also be, at least, partially underlying the exacerbated fear and anxiety-related responses the patients afflicted from this conditions present. Nonetheless, this hypothesis is, as of today, not proven but partially supported by the aforementioned findings, which are consistent with such a proposal, but would need to be tested further as direct evidence for ascertaining whether cerebellar activity is reflecting the functioning of a prediction process based on the activity of a forward
ACCEPTED MANUSCRIPT
controller in patients suffering from fear and anxiety-related disorders is not available yet. To verify that cerebellar activity reflects the functioning of a forward model leading to predictions of upcoming harm in anxious patients, studies combining temporary modifications of cerebellar activity by transcranial magnetic stimulation together with threat cue exposure
PT
would be of interest. In a similar manner, presenting patients with ambiguously or mildly threatening cues, or cues that signal a probable but not sure threatening event, and then
RI
measuring their threat-like physiological responses and brain activation, could also shed some
SC
light on whether such a cerebellum-supported aberrant harm prediction is occurring in these patients. Given that the cerebellar predictive function is thought to occur at a subconscious
NU
level (Blakemore and Sirigu, 2003; Moreno-Rius and Miquel, 2017), presentation of
MA
threatening stimuli below the awareness threshold while monitoring cerebellar activity would also be useful to further verify this. In fact, in a recent report in which subliminal trauma-
ED
related cues were presented to PTSD patients, cerebellar activation was found (Rabellino et al., 2016). Also, in order to verify the neurochemical basis of the altered cerebellar function in
EP T
fear and anxiety-related disorders, magnetic resonance spectroscopy studies on the cerebellum of anxiety patients could be of use as well. In animal studies, the combination of fear-related
AC C
behavioral paradigms in which cues anticipate threatening events and modern techniques such as optogenetics would also help to clarify the role of specific cell subtypes and the circuit mechanisms mediating these behaviors within the cerebellum. In conclusion, fear and anxiety-related disorders are severely impairing conditions which may be
lacking
fully
effective
neurobiological basis.
treatments
because
of
incomplete
understanding
of its
The cerebellar activation found in anxious patients might involve the
use of threat memories to recruit forward models which lead to unconscious predictions of the faced situation as harmful. Information regarding this prediction would then be transmitted to
ACCEPTED MANUSCRIPT
other parts of the anxiety circuitry which would prepare the organism for performing the necessary actions to minimize possible harms. Characterizing this process would also be helpful in order to develop strategies to normalize aberrant threat predictions, which may lead to a new therapeutic option to reduce anxiety and treat its associated disorders.
PT
Conflict of Interest Statement: The author reports grants from Austrian Science Foundation (through University of Innsbruck), outside the submitted work.
RI
Acknowledgments: The author thanks Dr. Maria Carbo-Gas, Hussein Ghareh and Arnau
AC C
EP T
ED
MA
NU
SC
Ramos-Prats for their help through the writing process.
ACCEPTED MANUSCRIPT
References Adamaszek, M., D'Agata, F., Ferrucci, R., Habas, C., Keulen, S., Kirkby, K. C., Leggio, M., Mariën, P., Molinari, M., Moulton, E., Orsi, L., Van Overwalle, F., Papadelis, C., Priori, A., Sacchetti, B., Schutter, D. J., Styliadis, C., Verhoeven, J. 2017. Consensus Paper: Cerebellum
PT
and Emotion. Cerebellum. 16(2):552-576. Adamaszek, M., D'Agata, F., Kirkby, K. C., Trenner, M. U., Sehm, B., Steele, C. J.,
RI
Berneiser, J., Strecker, K. 2014. Impairment of emotional facial expression and prosody
SC
discrimination due to ischemic cerebellar lesions. Cerebellum. 13(3):338-45. Addis, D. R., Moloney, E. E., Tippett, L. J., Roberts, R., Hach, S. 2016. Characterizing cerebellar
NU
activity during autobiographical memory: ALE and functional connectivity investigations. Neuropsychologia, 90:80-93.
MA
Ahs, F., Pissiota, A., Michelgård, A., Frans, O., Furmark, T., Appel, L., Fredrikson, M. 2009. Disentangling the web of fear: amygdala reactivity and functional connectivity in spider and snake
ED
phobia. Psychiatry Res. 172(2):103-8.
EP T
Alvares, G. A., Quintana, D. S., Hickie, I. B., Guastella, A. J. 2016. Autonomic nervous system dysfunction in psychiatric disorders and the impact of psychotropic medications: a systematic review and meta-analysis. J. Psychiatry Neurosci. 41(2):89-104.
AC C
Alves, F. H., Gomes, F. V., Reis, D.G., Crestani, C. C., Corrêa, F. M., Guimarães, F. S., Resstel, L. B. 2013. Involvement of the insular cortex in the consolidation and expression of contextual fear conditioning. Eur. J. Neurosci. 38(2):2300-7. An, Y., Chen, C., Inoue, T., Nakagawa, S., Kitaichi, Y., Wang, C., Izumi, T., Kusumi, I. 2016. Mirtazapine exerts an anxiolytic-like effect through activation of the median raphe nucleus-dorsal hippocampal 5-HT pathway in contextual fear conditioning in rats. Prog. Neuropsychopharmacol. Biol. Psychiatry. 70:17-23.
ACCEPTED MANUSCRIPT
Anderson, C. M., Maas, L. C., Frederick, B. D., Bendor, J. T., Spencer, T. J., Livni, E., Lukas, S. E., Fischman, A. J., Madras, B. K., Renshaw, P. F., Kaufman, M. J. 2006. Cerebellar vermis involvement in cocaine-related behaviors. Neuropsychopharmacol. 31(6):1318-26. Andrews, G., Freed, S., Teesson, M. 1994. Proximity and anticipation of a negative outcome in
PT
phobias. Behav. Res. Ther. 32(6):643-5.
RI
Annoni, J. M., Ptak, R., Caldara-Schnetzer, A. S., Khateb, A., Pollermann, B. Z. 2003.
SC
Decoupling of autonomic and cognitive emotional reactions after cerebellar stroke. Ann. Neurol. 53(5):654-8.
NU
Asami, T., Yamasue, H., Hayano, F., Nakamura, M., Uehara, K., Otsuka, T., Roppongi, T., Nihashi, N., Inoue, T., Hirayasu, Y. 2009. Sexually dimorphic gray matter volume reduction in
MA
patients with panic disorder. Psychiatry Res.173(2):128-34. Balaban, C. D., Porter, J. D. 1998. Neuroanatomic substrates for vestibulo -autonomic
ED
interactions. J. Vestib. Res. 8(1):7-16.
EP T
Baldaçara, L., Jackowski, A. P., Schoedl, A., Pupo, M., Andreoli, S. B., Mello, M. F., Lacerda, A. L., Mari, J. J., Bressan, R. A. 2011. Reduced cerebellar left hemisphere and vermal volume in
AC C
adults with PTSD from a community sample. J. Psychiatr. Res. 45(12):1627-33. Ballenger, J. C., Burrows, G. D., DuPont, R. L. Jr., Lesser, I. M., Noyes, R. Jr., Pecknold. J. C., Rifkin, A., Swinson, R. P. 1988. Alprazolam in panic disorder and agoraphobia: results from a multicenter trial. I. Efficacy in short-term treatment. Arch. Gen. Psychiatry. 45(5):413-22. Barrera, T. L., Norton, P. J. 2009. Quality of life impairment in generalized anxiety disorder, social phobia and panic disorder. J. Anxiety Disord. 23(8):1086-90. Beliveau, V., Svarer, C., Frokjaer, V. G., Knudsen, G. M., Greve, D. N., Fisher, P. M. 2015. Functional connectivity of the dorsal and median raphe nuclei at rest. Neuroimage, 116:187-95.
ACCEPTED MANUSCRIPT
Bellebaum, C., Daum, I. 2007. Cerebellar involvement in executive control. Cerebellum 6, 184– 92. Berntson, G. G., Torello, M. W. 1982. The paleocerebellum and the integration of behavioral function. Physiol. Psychology, 10(1), 2-12.
PT
Bing, X., Ming-Guo, Q., Ye, Z., Jing-Na, Z., Min, L., Han, C., Yu, Z., Jia-Jia, Z., Jian, W., Wei, C., Han-Jian, D., Shao-Xiang, Z. 2013. Alterations in the cortical thickness and the amplitude of
RI
low-frequency fluctuation in patients with post-traumatic stress disorder. Brain Res. 1490:225-32.
the rat cerebellum. Brain Res. 331(2):195-207.
SC
Bishop, G. A., Ho, R. H. 1985. The distribution and origin of serotonin immunoreactivity in
NU
Blackwood, N., Simmons, A., Bentall, R., Murray, R., & Howard, R. 2004. The cerebellum and
MA
decision making under uncertainty. Cogn. Brain Res. 20(1), 46-53. Blakemore, S.J., Sirigu, A. 2003. Action prediction in the cerebellum and in the parietal lobe. Exp.
ED
Brain Res. 153, 239–45.
Bonne, O., Gilboa, A., Louzoun, Y., Brandes, D., Yona, I., Lester, H., Barkai, G., Freedman, N.,
EP T
Chisin, R., Shalev, A. Y. 2003. Resting regional cerebral perfusion in recent posttraumatic stress disorder. Biol. Psychiatry, 54(10):1077-86.
AC C
Borkovec, T. D. 1985. The role of cognitive and somatic cues in anxiety and anxiety disorders: Worry and relaxation-induced anxiety. In A. H. Tuma & J. D. Maser (Eds.), Anxiety and the anxiety disorders (pp. 463-478). Hillsdale, NJ: Lawrence Erlbaum Associates Borsook, D., Edwards, R., Elman, I., Becerra, L., Levine, J. 2013. Pain and analgesia: the value of salience circuits. Prog. Neurobiol. 104:93-105. Bostan, A.C., Dum, R.P., Strick, P.L. 2013. Cerebellar networks with the cerebral cortex and basal ganglia. Trends Cogn. Sci. 17, 241–54.
ACCEPTED MANUSCRIPT
Brodkin, J., Busse, C., Sukoff, S. J., Varney, M. A. 2002. Anxiolytic-like activity of the mGluR5 antagonist MPEP: a comparison with diazepam and buspirone. Pharmacol. Biochem. Behav. 73(2):359-66. Brown, T. M., Boudewyns, P. A. 1996. Periodic limb movements of sleep in combat veterans
PT
with posttraumatic stress disorder. J. Trauma Stress. 9(1):129-36. Brown, E.C., Brüne, M. 2012. The role of prediction in social neuroscience. Front. Hum.
RI
Neurosci. 6, 147.
SC
Calhoon, G. G., Tye, K. M. 2015. Resolving the neural circuits of anxiety. Nat. Neurosci. 18(10):1394-404.
NU
Carbo-Gas, M., Moreno-Rius, J., Guarque-Chabrera, J., Vazquez-Sanroman, D., Gil-Miravet, I.,
MA
Carulli, D., Hoebeek, F., De Zeeuw, C., Sanchis-Segura, C., Miquel M. 2017. Cerebellar perineuronal nets in cocaine-induced pavlovian memory: Site matters. Neuropharmacology.
ED
125:166-180.
Carbo-Gas, M., Vazquez-Sanroman, D., Aguirre-Manzo, L., Coria-Avila, G.A., Manzo, J.,
EP T
Sanchis-Segura, C., Miquel, M. 2014. Involving the cerebellum in cocaine-induced memory: pattern of cFos expression in mice trained to acquire conditioned preference for cocaine. Addict. Biol.19(1), 61–76.
AC C
Carlsson, K., Petersson, K. M., Lundqvist, D., Karlsson, A., Ingvar, M., Ohman, A. 2004. Fear and the amygdala: manipulation of awareness generates differential cerebral responses to phobic and fear-relevant (but nonfeared) stimuli. Emotion. 4(4):340-53. Carrion, V. G., Weems, C. F., Watson, C., Eliez, S., Menon, V., Reiss, A. L. 2009. Converging evidence for abnormalities of the prefrontal cortex and evaluation of midsagittal structures in pediatric posttraumatic stress disorder: an MRI study. Psychiatry Res. 172(3):226-34.
ACCEPTED MANUSCRIPT
Carnell, S., Benson, L., Pantazatos, S.P., Hirsch, J., Geliebter, A. 2014. Amodal brain activation and functional connectivity in response to high-energy-density food cues in obesity. Obesity 22, 2370–8. Casacalenda, N., Boulenger, J. P. 1998. Pharmacologic treatments effective in both generalized anxiety disorder and major depressive disorder: clinical and theoretical
PT
implications. Can. J. Psychiatry. 43(7):722-30.
RI
Caseras, X., Giampietro, V., Lamas, A., Brammer, M., Vilarroya, O., Carmona, S., Rovira, M.,
SC
Torrubia, R., Mataix-Cols, D. 2010. The functional neuroanatomy of blood-injection-injury phobia: a comparison with spider phobics and healthy controls. Psychol. Med. 40(1):125-34.
NU
Cassimjee, N., Fouche, J. P., Burnett, M., Lochner, C., Warwick, J., Dupont, P., Stein, D. J., Cloete, K. J., Carey, P. D. 2010. Changes in regional brain volumes in social anxiety disorder
MA
following 12 weeks of treatment with escitalopram. Metab. Brain Dis. 25(4):369-74. Cauda, F., Cavanna, A. E., D'agata, F., Sacco, K., Duca, S., Geminiani, G. C. 2011. Functional
ED
connectivity and coactivation of the nucleus accumbens: a combined functional connectivity and
EP T
structure-based meta-analysis. J. Cogn. Neurosci. 23(10), 2864-77. Caulfield, M. D., Zhu, D. C., McAuley, J. D., Servatius, R. J. 2016. Individual differences in resting-state functional connectivity with the executive network: support for a cerebellar role in
AC C
anxiety vulnerability. Brain Struct. Funct. 221(6):3081-93. Cha, J., Carlson, J. M., Dedora, D. J., Greenberg, T., Proudfit, G. H., Mujica-Parodi, L. R. 2014. Hyper-reactive human ventral tegmental area and aberrant mesocorticolimbic connectivity in overgeneralization of fear in generalized anxiety disorder. J. Neurosci. 34(17):5855-60. Clark, D. B., Taylor, C. B., Hayward, C., King, R., Margraf, J., Ehlers, A., Roth, W. T., Agras, W. S. 1990. Motor activity and tonic heart rate in panic disorder. Psychiatry Res. 32(1):45-53.
ACCEPTED MANUSCRIPT
Courchesne, E., Allen, G. 1997. Prediction and preparation, fundamental functions of the cerebellum. Learn. Mem. 4, 1–35. Crozier, J. C., Wang, L., Huettel, S. A., De Bellis, M. D. 2014. Neural correlates of cognitive and affective processing in maltreated youth with posttraumatic stress symptoms: does gender matter?
PT
Dev. Psychopathol. 26(2):491-513. Cservenka, A., Casimo, K., Fair, D. A., Nagel, B. J. 2014. Resting state functional connectivity of
RI
the nucleus accumbens in youth with a family history of alcoholism. Psychiatry Res:
SC
Neuroimaging, 221(3), 210-9.
D’Angelo, E., Casali, S. 2013. Seeking a unified framework for cerebellar function and
NU
dysfunction: from circuit operations to cognition. Front. Neural Circuits, 6:116.
MA
Dahhaoui, M., Caston, J., Auvray, N., Reber, A. 1990. Role of the cerebellum in an avoidance conditioning task in the rat. Physiol. Beh. 47(6):1175-80.
ED
Davis, M., Redmond, D. E. Jr., Baraban, J. M. 1979. Noradrenergic agonists and antagonists: effects on conditioned fear as measured by the potentiated startle paradigm.
EP T
Psychopharmacology (Berl).65(2):111-8. Davies, M. F., Tsui, J., Flannery, J. A., Li, X., DeLorey, T. M., Hoffman, B. B. 2004. Activation of alpha2 adrenergic receptors suppresses fear conditioning: expression of c-Fos
AC C
and phosphorylated CREB in mouse amygdala. Neuropsychopharmacol. 29(2):229-39. De Bellis, M. D., Kuchibhatla, M. 2006. Cerebellar volumes in pediatric maltreatment-related posttraumatic stress disorder. Biol. Psychiatry, 60(7):697-703. Dejean, C., Courtin, J., Rozeske, R. R., Bonnet, M. C., Dousset, V., Michelet, T., Herry, C. 2015. Neuronal Circuits for Fear Expression and Recovery: Recent Advances and Potential Therapeutic Strategies. Biol.Psychiatry. 78(5):298-306.
ACCEPTED MANUSCRIPT
Doruyter, A., Lochner, C., Jordaan, G. P., Stein, D. J., Dupont, P., Warwick, J.,M. 2016. Resting functional connectivity in social anxiety disorder and the effect of pharmacotherapy. Psychiatry Res. 251:34-44. Downar, J., Crawley, A. P., Mikulis, D. J., Davis, K. D. 2002. A cortical network sensitive to stimulus salience in a neutral behavioral context across multiple sensory modalities. J.
PT
Neurophysiol. 87(1):615-20.
RI
Driessen, M., Beblo, T., Mertens, M., Piefke, M., Rullkoetter, N., Silva-Saavedra, A., Reddemann,
SC
L., Rau, H., Markowitsch, H. J., Wulff, H., Lange, W., Woermann, F.G. 2004. Posttraumatic stress disorder and fMRI activation patterns of traumatic memory in patients with borderline personality
NU
disorder. Biol. Psychiatry, 55(6):603-11.
Emerson, J. D., Bruhn, J. M., Emerson, G. M., Foley, J. O. 1961. Autonomic response to
MA
chronic electrode stimulation of cerebellum. Am. J. Physiol. 201:697-9. Etkin, A., Prater, K. E., Schatzberg, A. F., Menon, V., Greicius, M. D. 2009. Disrupted amygdalar
ED
subregion functional connectivity and evidence of a compensatory network in generalized anxiety disorder. Arch.Gen. Psychiatry, 66(12), 1361-72.
EP T
Evans, K. C., Wright, C. I., Wedig, M. M., Gold, A. L., Pollack, M. H., Rauch, S. L. 2008. A functional MRI study of amygdala responses to angry schematic faces in social anxiety disorder.
AC C
Depress.Anxiety. 25(6):496-505.
Farley, S. J., Radley, J. J., Freeman, J. H. 2016. Amygdala Modulation of Cerebellar Learning. J. Neurosci. 36(7):2190-201. Felmingham, K. L., Falconer, E. M., Williams, L., Kemp, A. H., Allen, A., Peduto, A., Bryant, R. A. 2014. Reduced amygdala and ventral striatal activity to happy faces in PTSD is associated with emotional numbing. PLoS One. 9(9):e103653. Fish, B. S., Baisden, R. H., Woodruff, M. L. 1979. Cerebellar nuclear lesions in rats: subsequent avoidance behavior and ascending anatomical connections. Brain Res. 166(1):27-38.
ACCEPTED MANUSCRIPT
Fokos, S., Panagis, G. 2010. Effects of delta9-tetrahydrocannabinol on reward and anxiety in rats exposed to chronic unpredictable stress. J. Psychopharmacol. 24(5):767-77. Friedman, B. H. 2007. An autonomic flexibility-neurovisceral integration model of anxiety and cardiac vagal tone. Biol. Psychol. 74(2):185-99. Garrison, J., Erdeniz, B., Done, J. 2013. Prediction error in reinforcement learning: a
PT
meta-analysis of neuroimaging studies. Neurosci. Biobehav. Rev. 37(7):1297-310.
RI
Gianlorenço, A. C., Canto-de-Souza, A., Mattioli, R. 2013. Intra-cerebellar microinjection of histamine enhances memory consolidation of inhibitory avoidance learning in mice via H2
SC
receptors. Neurosci. Lett. 557:159-64.
NU
Gianlorenço, A. C., Riboldi, A. M., Silva-Marques, B., Mattioli, R. 2015. Cerebellar vermis H₂ receptors mediate fear memory consolidation in mice. Neurosci. Lett. 587:57-61.
MA
Giménez, M., Pujol, J., Ortiz, H., Soriano-Mas, C., López-Solà, M., Farré, M., Deus, J., MerloPich, E., Martín-Santos, R. 2012. Altered brain functional connectivity in relation to perception of scrutiny in social anxiety disorder. Psychiatry Res. 202(3):214-23.
ED
Goossens, L., Schruers, K., Peeters, R., Griez, E., Sunaert, S. 2007. Visual presentation of phobic
EP T
stimuli: amygdala activation via an extrageniculostriate pathway? Psychiatry Res.155(2):113-20. Graeff, F. G. 2004. Serotonin, the periaqueductal gray and panic. Neurosci. Biobehav. Rev. 28(3):239-59.
AC C
Gray, J. A. 1982. The Neuropsychology of anxiety: an enquiry into the functions of the septohippocampal system, 1st ed. Oxford: Oxford University Press Gray, J. A., McNaughton, N. 2003. The neuropsychology of anxiety: An enquiry into the function of the septo-hippocampal system, second edition. Oxford: Oxford University Press. Grillon, C., Lissek, S., Rabin, S., McDowell, D., Dvir, S., Pine, D. S. 2008. Increased anxiety during anticipation of unpredictable but not predictable aversive stimuli as a psychophysiologic marker of panic disorder. Am. J. Psychiatry, 165(7):898-904. Grupe, D. W., Nitschke, J. B. 2013. Uncertainty and anticipation in anxiety: an integrated neurobiological and psychological perspective. Nat. Rev. Neurosci. 14(7):488-501.
ACCEPTED MANUSCRIPT
Guillaumin, S., Dahhaoui, M., Caston, J. 1991. Cerebellum and memory: an experimental study in the rat using a passive avoidance conditioning test. Physiol. Beh. 49(3):507-11. Gunduz-Cinar, O., Flynn, S., Brockway, E., Kaugars, K., Baldi, R., Ramikie, T. S., Cinar, R., Kunos, G., Patel, S., Holmes, A. 2016. Fluoxetine Facilitates Fear Extinction Through Amygdala Endocannabinoids. Neuropsychopharmacol. 41(6):1598-609
PT
Habas, C., Kamdar, N., Nguyen, D., Prater, K., Beckmann, C. F., Menon, V., Greicius, M. D.
RI
2009. Distinct cerebellar contributions to intrinsic connectivity networks. J.Neurosci. 29(26),
SC
8586-94.
Harricharan, S., Rabellino, D., Frewen, P. A., Densmore, M., Théberge, J., McKinnon, M. C.,
NU
Schore, A. N., Lanius, R. A. 2016. fMRI functional connectivity of the periaqueductal gray in PTSD and its dissociative subtype. Brain Behav. (12):e00579.
MA
Hazlett, R. L., McLeod, D. R., Hoehn-Saric, R.. 1994. Muscle tension in generalized anxiety disorder: elevated muscle tonus or agitated movement? Psychophysiology. 31(2):189-95.
ED
Hazlett-Stevens, H., Borkovec, T. D. 2004. Interpretive cues and ambiguity in generalized anxiety
EP T
disorder. Behav. Res. Ther. 42(8):881-92.
Heath, R. G., Dempsey, C. W., Fontana, C. J., Myers, W. A. 1978 Cerebellar stimulation: effects on septal region, hippocampus, and amygdala of cats and rats. Biol. Psychiatry.
AC C
13(5):501-29.
Heeren, A., Dricot, L., Billieux, J., Philippot, P., Grynberg, D., de Timary, P., Maurage, P. 2017. Correlates of Social Exclusion in Social Anxiety Disorder: An fMRI study. Sci. Rep. 7(1):260. Herculano-Houzel, S. 2009. The human brain in numbers: a linearly scaled-up primate brain. Front. Hum. Neurosci. 3(November), article 31. Hilbert, K., Evens, R., Maslowski, N. I., Wittchen, H. U., Lueken, U. 2015. Neurostructural correlates of two subtypes of specific phobia: a voxel-based morphometry study. Psychiatry Res. 231(2):168-75.
ACCEPTED MANUSCRIPT
Hilbert, K., Lueken, U., Beesdo-Baum, K. 2014. Neural structures, functioning and connectivity in Generalized Anxiety Disorder and interaction with neuroendocrine systems: a systematic review. J. Affect. Disord. 158:114-26. Hofmann, S. G., Otto, M. W., Pollack, M. H., Smits, J. A. 2015. D-cycloserine augmentation
PT
of cognitive behavioral therapy for anxiety disorders: an update. Curr. Psychiatry Rep. 17(1):532.
RI
Igelström, K. M., Webb, T. W., Graziano, M. S. A. 2017. Functional Connectivity Between
SC
the Temporoparietal Cortex and Cerebellum in Autism Spectrum Disorder. Cereb. Cortex. 27(4):2617-2627.
NU
Igloi, K., Doeller, C.F., Paradis, A.-L., Benchenane, K., Berthoz, A., Burgess, N., Rondi-Reig, L. 2014. Interaction between hippocampus and cerebellum crus I in sequence-based but not place-
MA
based navigation. Cereb. Cortex 25(11):4146-54.
Ikai, Y., Takada, M., Shinonaga, Y., Mizuno, N. 1992. Dopaminergic and non-dopaminergic
ED
neurons in the ventral tegmental area of the rat project, respectively, to the cerebellar cortex and
EP T
deep cerebellar nuclei. Neuroscience 51(3), 719–28. Ito, M. 2008. Control of mental activities by internal models in the cerebellum. Nat. Rev. Neurosci. 9, 304–13.
AC C
Jatzko, A., Rothenhöfer, S., Schmitt, A., Gaser, C., Demirakca, T., Weber-Fahr, W., Wessa, M., Magnotta, V., Braus, D. F. 2006. Hippocampal volume in chronic posttraumatic stress disorder (PTSD): MRI study using two different evaluation methods. J. Affect. Disord. 94(1-3):121-6 Kalk, N. J., Melichar, J., Holmes, R. B., Taylor, L. G., Daglish, M. R., Hood, S., Edwards, T., Lennox-Smith, A., Lingford-Hughes, A. R., Nutt, D. J. 2012. Central noradrenergic responsiveness to a clonidine challenge in Generalized Anxiety Disorder: a Single Photon Emission Computed Tomography study. J. Psychopharmacol. 26(4):452-60.
ACCEPTED MANUSCRIPT
Kaufman, G. D., Mustari, M. J., Miselis, R. R., Perachio, A. A. 1996. Transneuronal pathways to the vestibulocerebellum. J. Comp. Neurol. 370(4):501-23 Ke, J., Zhang, L., Qi, R., Li, W., Hou, C., Zhong, Y., He, Z., Li, L., Lu, G. 2016. A longitudinal fMRI investigation in acute post-traumatic stress disorder (PTSD). Acta Radiol. 57(11):1387-
PT
1395. Kelly, R.M., Strick, P.L. 2003. Cerebellar loops with motor cortex and prefrontal cortex of a
RI
nonhuman primate. J. Neurosci. 23, 8432–44.
SC
Killgore, W. D., Young, A. D., Femia, L. A., Bogorodzki, P., Rogowska, J., Yurgelun-Todd, D. A. 2003. Cortical and limbic activation during viewing of high- versus low-calorie foods.
NU
Neuroimage, 19(4):1381-94.
MA
Kilts, C. D., Kelsey, J. E., Knight, B., Ely, T. D., Bowman, F. D., Gross, R. E., Selvig, A., Gordon, A., Newport, D. J., Nemeroff, C. B. 2006.The neural correlates of social anxiety disorder
ED
and response to pharmacotherapy. Neuropsychopharmacol. 31(10):2243-53. Kline, R. L., Zhang, S., Farr, O. M., Hu, S., Zaborszky, L., Samanez-Larkin, G. R., Li, C. S. R.
EP T
2016. The Effects of Methylphenidate on Resting-State Functional Connectivity of the Basal Nucleus of Meynert, Locus Coeruleus, and Ventral Tegmental Area in Healthy Adults. Front. Hum. Neurosci. 10:149.
AC C
Klumpp, H., Angstadt, M., Phan, K. L. 2012. Insula reactivity and connectivity to anterior cingulate cortex when processing threat in generalized social anxiety disorder. Biol. Psychol. 89(1):273-6.
Koehler, S., Ovadia-Caro, S., van der Meer, E., Villringer, A., Heinz, A., Romanczuk-Seiferth, N., Margulies, D. S. 2013. Increased functional connectivity between prefrontal cortex and reward system in pathological gambling. PLoS One, 8(12), e84565. Konishi, J., Asami, T., Hayano, F., Yoshimi, A., Hayasaka, S., Fukushima, H., Whitford, T. J., Inoue, T., Hirayasu, Y. 2014. Multiple white matter volume reductions in patients with panic
ACCEPTED MANUSCRIPT
disorder: relationships between orbitofrontal Gyrus volume and symptom severity and social dysfunction. PLoS One. 9(3):e92862. Koutsikou, S., Crook, J. J., Earl, E. V., Leith, J. L., Watson, T. C., Lumb, B. M., Apps, R. 2014. Neural substrates underlying fear-evoked freezing: the periaqueductal grey-cerebellar link. J.
PT
Physiol. 592(10):2197-213. Kwon, H. G., & Jang, S. H. 2014. Differences in neural connectivity between the substantia nigra
RI
and ventral tegmental area in the human brain. Front. Hum. Neurosci. 8, 41.
SC
Lai, C. H., Hsu, Y. Y. 2011. A subtle grey-matter increase in first-episode, drug-naive major
Neuropsychopharmacol.;14(2):225-35.
NU
depressive disorder with panic disorder after 6 weeks' duloxetine therapy. Int. J.
MA
LeDoux, J. E. 2000. Emotion circuits in the brain. Annu. Rev. Neurosci. 23:155-84. Leutgeb, V., Wabnegger, A., Leitner, M., Zussner, T., Scharmüller, W., Klug, D., Schienle, A.
Neurosci. Lett. 610, 160-164.
ED
2016. Altered cerebellar-amygdala connectivity in violent offenders: A resting-state fMRI study.
EP T
Liao, W., Qiu, C., Gentili, C., Walter, M., Pan, Z., Ding, J., Zhang, W., Gong, Q., Chen, H. 2010. Altered effective connectivity network of the amygdala in social anxiety disorder: a resting-state
AC C
FMRI study. PLoS One. 5(12):e15238. Liberzon, I., Martis, B. 2006. Neuroimaging studies of emotional responses in PTSD. Ann. N. Y. Acad. Sci. 1071:87-109.
Liu, Y., Formisano, L., Savtchouk, I., Takayasu, Y., Szabó, G., Zukin, R. S., Liu, S. J. 2010. A single fear-inducing stimulus induces a transcription-dependent switch in synaptic AMPAR phenotype. Nat. Neurosci. 13(2):223-31.
ACCEPTED MANUSCRIPT
Liu, W. J., Yin, D. Z., Cheng, W. H., Fan, M. X., You, M. N., Men, W. W., Zang, L. L., Shi, D. H., Zhang, F. 2015. Abnormal functional connectivity of the amygdala-based network in restingstate FMRI in adolescents with generalized anxiety disorder. Med. Sci. Monit. 21:459-67. Lorivel, T., Gras, M., Hilber, P. 2010. Effects of corticosterone synthesis inhibitor metyrapone on
PT
anxiety-related behaviors in Lurcher mutant mice. Physiol. Beh. 101(2):309-14. Lorivel, T., Hilber, P. 2006. Effects of chlordiazepoxide on the emotional reactivity and motor
RI
capacities in the cerebellar Lurcher mutant mice. Behav. Brain Res. 173(1):122-8.
SC
Lorivel, T., Roy, V., Hilber, P. 2014. Fear-related behaviors in Lurcher mutant mice exposed to a predator. Genes Brain Beh. 13(8):794-801.
NU
Lupo, M., Troisi, E., Chiricozzi, F. R., Clausi, S., Molinari, M., Leggio, M. 2015. Inability to
MA
Process Negative Emotions in Cerebellar Damage: a Functional Transcranial Doppler Sonographic Study. Cerebellum. 14(6):663-9.
ED
Malta, L. S., Wyka, K. E., Giosan, C., Jayasinghe, N., Difede, J. 2009 Numbing symptoms as predictors of unremitting posttraumatic stress disorder. J. Anxiety Disord. 23(2):223-9.
EP T
Marchand, W. R., Lee, J. N., Healy, L., Thatcher, J. W., Rashkin, E., Starr, J., Hsu, E. 2009. An fMRI motor activation paradigm demonstrates abnormalities of putamen activation in
AC C
females with panic disorder. J. Affect. Disord. 116(1-2):121-5. McNaughton, N., Corr, P. J. 2004. A two-dimensional neuropsychology of defense: fear/anxiety and defensive distance. Neurosci. Biobehav. Rev. 28(3):285-305. Melchitzky, D.S., Lewis, D.A. 2000. Tyrosine hydroxylase- and dopamine transporterimmunoreactive axons in the primate cerebellum dopamine innervation. Neuropsychopharmacol. 22(5), 466–72. Miall, R. C., Weir, D. J., Wolpert, D. M., Stein, J. F. 1993. Is the cerebellum a smith predictor? J Mot. Beh. 25(3):203-16.
ACCEPTED MANUSCRIPT
Molinari, M., Chiricozzi, F. R., Clausi, S., Tedesco, A. M., De Lisa, M., Leggio, M. G. 2008. Cerebellum and detection of sequences, from perception to cognition. Cerebellum. 7(4):6115. Moreno-Rius, J., Miquel, M. 2017. The cerebellum in drug craving. Drug Alcohol Depend.
PT
173:151-158. Moruzzi, G. 1947. Sham rage and localized autonomic responses elicited by cerebellar
RI
stimulation in the acute thalamic cat. Proc. XVII Internat. Congress Physiol. Oxford, 114-115.
SC
Moulton, E. A., Elman, I., Pendse, G., Schmahmann, J., Becerra, L., Borsook, D. 2011. Aversionrelated circuitry in the cerebellum: responses to noxious heat and unpleasant images. J. Neurosci.
NU
31(10), 3795-804.
MA
Mueller-Pfeiffer, C., Zeffiro, T., O'Gorman, R., Michels, L., Baumann, P., Wood, N., Spring, J., Rufer, M., Pitman, R. K., Orr, S. P. 2014. Cortical and cerebellar modulation of
ED
autonomic responses to loud sounds. Psychophysiology. 51(1):60-9. Nakao, T., Sanematsu, H., Yoshiura, T., Togao, O., Murayama, K., Tomita, M., Masuda, Y.,
EP T
Kanba, S. 2011. fMRI of patients with social anxiety disorder during a social situation task. Neurosci. Res. 69(1):67-72.
Norris, C., Loureiro, M., Kramar, C., Zunder, J., Renard, J., Rushlow, W., Laviolette, S. R. 2016.
AC C
Cannabidiol Modulates Fear Memory Formation Through Interactions with Serotonergic Transmission in the Mesolimbic System. Neuropsychopharmacol. 41(12):2839-2850. O'Reilly, J. X., Beckmann, C. F., Tomassini, V., Ramnani, N., & Johansen-Berg, H. 2010. Distinct and overlapping functional zones in the cerebellum defined by resting state functional connectivity. Cereb. Cortex, 20(4), 953-65. Oades, R. D., Halliday, G. M. 1987. Ventral tegmental (A10) system: neurobiology. 1. Anatomy and connectivity. Brain Res. 434(2):117-65.
ACCEPTED MANUSCRIPT
Olesen, J., Gustavsson, A., Svensson, M., Wittchen, H. U., Jönsson, B.; CDBE2010 study group; European Brain Council. 2012. The economic cost of brain disorders in Europe. Eur. J. Neurol. 19(1):155-62. Onuki, Y., Van Someren, E. J., De Zeeuw, C. I., Van der Werf, Y. D. 2015. Hippocampal–
PT
cerebellar interaction during spatio-temporal prediction. Cereb. Cortex 25(2), 313-21. Otsuka, S., Konno, K., Abe, M., Motohashi, J., Kohda, K., Sakimura, K., Watanabe, M., Yuzaki,
RI
M. 2016. Roles of Cbln1 in Non-Motor Functions of Mice. J. Neurosci. 36(46), 11801-11816.
SC
Perusini, J. N., Fanselow, M. S. 2015. Neurobehavioral perspectives on the distinction between fear and anxiety. Learn Mem. 22(9):417-25.
NU
Peters, J., Dieppa-Perea, L. M., Melendez, L. M., Quirk, G. J. 2010. Induction of fear extinction
MA
with hippocampal-infralimbic BDNF. Science. 328(5983):1288-90. Pignatelli, M., Umanah, G. K., Ribeiro, S. P., Chen, R., Karuppagounder, S. S., Yau, H. J., Eacker,
ED
S., Dawson, V. L., Dawson, T. M., Bonci, A. 2017. Synaptic Plasticity onto Dopamine Neurons Shapes Fear Learning. Neuron. 93(2):425-440.
EP T
Pyke, R. E., Greenberg, H. S. 1986. Norepinephrine challenges in panic patients. J. Clin. Psychopharmacol. 6(5):279-85.
AC C
Rabellino, D., Densmore, M., Frewen, P. A., Théberge, J., Lanius, R. A. 2016. The innate alarm circuit in post-traumatic stress disorder: Conscious and subconscious processing of fear- and trauma-related cues. Psychiatry Res. 248:142-50. Ravindran, L. N., Stein, M. B. 2010. The pharmacologic treatment of anxiety disorders: a review of progress. J. Clin. Psychiatry. 71(7):839-54. Rickels, K., Rynn, M. 2002. Pharmacotherapy of generalized anxiety disorder. J. Clin. Psychiatry. 63 Suppl 14:9-16.
ACCEPTED MANUSCRIPT
Roy, A. K., Fudge, J. L., Kelly, C., Perry, J. S., Daniele, T., Carlisi, C., Benson, B., Castellanos, F. X., Milham, M. P., Pine, D. S., Ernst, M. 2013. Intrinsic functional connectivity of amygdalabased networks in adolescent generalized anxiety disorder. J Am. Acad. Child Adolesc. Psychiatry; 52(3):290-299.
PT
Rubino, T., Sala, M., Viganò, D., Braida, D., Castiglioni, C., Limonta, V., Guidali, C., Realini, N., Parolaro, D. 2007. Cellular mechanisms underlying the anxiolytic effect of low
RI
doses of peripheral Delta9-tetrahydrocannabinol in rats. Neuropsychopharmacol. 32(9):2036-
SC
45.
Sacchetti, B., Scelfo, B., Tempia, F., Strata, P. 2004. Long-term synaptic changes induced in the
NU
cerebellar cortex by fear conditioning. Neuron 42(6), 973–82.
consolidation. PNAS, 99(12):8406-11.
MA
Sacchetti, B., Baldi, E., Lorenzini, C. A., Bucherelli, C. 2002. Cerebellar role in fear-conditioning
Sacchetti, B., Sacco, T., Strata, P. 2007. Reversible inactivation of amygdala and cerebellum but
ED
not perirhinal cortex impairs reactivated fear memories. Eur. J. Neurosci. 25(9):2875-84.
EP T
Sakai, Y., Kumano, H., Nishikawa, M., Sakano, Y., Kaiya, H., Imabayashi, E., Ohnishi, T., Matsuda, H., Yasuda, A., Sato, A., Diksic, M., Kuboki, T. 2005. Cerebral glucose metabolism associated with a fear network in panic disorder. Neuroreport; 16(9):927-31.
AC C
Sakai, Y., Kumano, H., Nishikawa, M., Sakano, Y., Kaiya, H., Imabayashi, E., Ohnishi, T., Matsuda, H., Yasuda, A., Sato, A., Diksic, M., Kuboki, T. 2006. Changes in cerebral glucose utilization in patients with panic disorder treated with cognitive-behavioral therapy. Neuroimage, 33(1):218-26. Sang, L., Qin, W., Liu, Y., Han, W., Zhang, Y., Jiang, T., Yu, C. 2012. Resting-state functional connectivity of the vermal and hemispheric subregions of the cerebellum with both the cerebral cortical networks and subcortical structures. Neuroimage, 61(4), 1213-25.
ACCEPTED MANUSCRIPT
Scelfo, B., Sacchetti, B., Strata, P. 2008. Learning-related long-term potentiation of inhibitory synapses in the cerebellar cortex. PNAS. 105(2):769-74. Schweckendiek, J., Klucken, T., Merz, C. J., Tabbert, K., Walter, B., Ambach, W., Vaitl, D., Stark, R. 2011. Weaving the (neuronal) web: fear learning in spider phobia. Neuroimage;
PT
54(1):681-8. Sethi, B. B., Trivedi, J. K., Kumar, P., Gulati, A., Agarwal, A. K., Sethi, N. 1986. Antianxiety
RI
effect of cannabis: involvement of central benzodiazepine receptors. Biol. Psychiatry. 21(1):3-
SC
10
Shinn, A. K., Baker, J. T., Lewandowski, K. E., Öngür, D., Cohen, B. M. 2015. Aberrant
NU
cerebellar connectivity in motor and association networks in schizophrenia. Front. Hum.
MA
Neurosci. 9:134.
Small, K. M., Nunes, E., Hughley, S., Addy, N. A. 2016. Ventral tegmental area muscarinic
ED
receptors modulate depression and anxiety-related behaviors in rats. Neurosci. Lett. 616:80-5. Smith, K. S., Engin, E., Meloni, E. G., Rudolph, U. 2012. Benzodiazepine-induced anxiolysis
EP T
and reduction of conditioned fear are mediated by distinct GABAA receptor subtypes in mice. Neuropharmacology. 63(2):250-8. Snider, R. S. 1950. Recent contributions to the anatomy and physiology of the cerebellum.
AC C
Arch. Neurol. Psychiatry; 64(2):196-219. Snider, R. S., Maiti, A. 1975. Septal afterdischarges and their modification by the cerebellum. Exp. Neurol. 49(2):529-39. Snider, R. S., Maiti, A. 1976. Cerebellar contributions to the Papez circuit. J. Neurosci. Res. 2(2):133-46. Spindelegger, C., Lanzenberger, R., Wadsak, W., Mien, L. K., Stein, P., Mitterhauser, M., Moser, U., Holik, A., Pezawas, L., Kletter, K., Kasper, S. 2009. Influence of escitalopram treatment on 5-
ACCEPTED MANUSCRIPT
HT 1A receptor binding in limbic regions in patients with anxiety disorders. Mol. Psychiatry. 14(11):1040-50. Steinmetz, J. E., Logue, S. F., Miller, D. P. 1993. Using signaled barpressing tasks to study the neural substrates of appetitive and aversive learning in rats: behavioral manipulations and
PT
cerebellar lesions. Behav. Neurosci. 107(6):941-54. Supple, W. F. Jr., Kapp, B. S. 1993. The anterior cerebellar vermis: essential involvement in
RI
classically conditioned bradycardia in the rabbit. J. Neurosci. 13(9):3705-11.
SC
Supple, W. F. Jr., Leaton, R. N. 1990a. Cerebellar vermis: essential for classically conditioned bradycardia in the rat. Brain Res. 509(1):17-23.
NU
Supple, W. F. Jr., Leaton, R. N. 1990b. Lesions of the cerebellar vermis and cerebellar
MA
hemispheres: effects on heart rate conditioning in rats . Behav. Neurosci. 104(6):934-47. Supple, W. F. Jr., Leaton, R. N., Fanselow, M. S. 1987. Effects of cerebellar vermal lesions on
ED
species-specific fear responses, neophobia, and taste-aversion learning in rats. Physiol.Beh. 39(5):579-86.
EP T
Swanson, L. W. 1977. The anatomical organization of septo-hippocampal projections. Ciba Found. Symp. (58):25-48.
AC C
Talati, A., Pantazatos, S. P., Hirsch, J., Schneier, F. 2015. A pilot study of gray matter volume changes associated with paroxetine treatment and response in social anxiety disorder. Psychiatry Res. 231(3):279-85.
Talati, A., Pantazatos, S. P., Schneier, F. R., Weissman, M. M., Hirsch, J. 2013. Gray matter abnormalities in social anxiety disorder: primary, replication, and specificity studies. Biol. Psychiatry. 73(1):75-84.
ACCEPTED MANUSCRIPT
Tanaka, S.C., Doya, K., Okada, G., Ueda, K., Okamoto, Y., Yamawaki, S. 2004. Prediction of immediate and future rewards differentially recruits cortico-basal ganglia loops. Nat. Neurosci. 7, 887–93. Taylor, J. M., Whalen, P. J. 2015. Neuroimaging and Anxiety: the Neural Substrates of
PT
Pathological and Non-pathological Anxiety. Curr. Psychiatry Rep. 17(6):49. Tillfors, M., Furmark, T., Marteinsdottir, I., Fredrikson, M. 2002. Cerebral blood flow during
RI
anticipation of public speaking in social phobia: a PET study. Biol. Psychiatry 52(11):1113-9.
SC
Timić, T., Joksimović, S., Milić, M., Divljaković, J., Batinić, B., Savić, M. M. 2013. Midazolam impairs acquisition and retrieval, but not consolidation of reference memory in
NU
the Morris water maze. Behav. Brain Res. 241:198-205.
MA
Tomasi, D., & Volkow, N. D. 2011. Association between functional connectivity hubs and brain networks. Cereb. Cortex, 21(9), 2003-13.
ED
Toth, I., Neumann, I. D., Slattery, D. A. 2012. Social fear conditioning: a novel and specific animal model to study social anxiety disorder. Neuropsychopharmacol. 37(6):1433-43.
16(6):317-31.
EP T
Tovote, P., Fadok, J. P., Lüthi, A. 2015. Neuronal circuits for fear and anxiety. Nat. Rev. Neurosci.
AC C
Uddin, L. Q. 2015. Salience processing and insular cortical function and dysfunction. Nat. Rev. Neurosci. 16(1):55-61. Van der Meer, M.A., Redish, A.D. 2010. Expectancies in decision making, reinforcement learning, and ventral striatum. Front. Neurosci. 4, 29–37. Volkow, N.D., Wang, G.-J., Ma, Y., Fowler, J.S., Zhu, W., Maynard, L., Swanson, J.M. 2003. Expectation enhances the regional brain metabolic and the reinforcing effects of stimulants in cocaine abusers. J. Neurosci. 23(36), 11461–8.
ACCEPTED MANUSCRIPT
Wagner, M. J., Kim, T. H., Savall, J., Schnitzer, M. J., Luo, L. 2017. Cerebellar granule cells encode the expectation of reward. Nature; 544(7648):96-100. Walker, D. L., Davis, M. 2002. The role of amygdala glutamate receptors in fear learning, fear-potentiated startle, and extinction. Pharmacol. Biochem. Behav. 71(3):379-92.
PT
Wang, T., Liu, J., Zhang, J., Zhan, W., Li, L., Wu, M., Huang, H., Zhu, H., Kemp, G. J., Gong, Q. 2016. Altered resting-state functional activity in posttraumatic stress disorder: A quantitative
RI
meta-analysis. Sci. Rep. 6:27131.
SC
Warwick, J. M., Carey, P., Jordaan, G. P., Dupont, P., Stein, D. J. 2008. Resting brain perfusion in social anxiety disorder: a voxel-wise whole brain comparison with healthy control subjects. Prog.
NU
Neuropsychopharmacol. Biol. Psychiatry. 32(5):1251-6.
MA
Watson, T. C., Becker, N., Apps, R., Jones, M. W. 2014. Back to front: cerebellar connections and interactions with the prefrontal cortex. Front. Syst. Neurosci. 8:4.
ED
Watson, T. C., Jones, M. W., Apps, R. 2009. Electrophysiological mapping of novel prefrontal - cerebellar pathways. Front. Integr. Neurosci. 3:18.
EP T
Watson, T. C., Cerminara, N. L., Lumb, B. M., Apps, R. 2016. Neural Correlates of Fear in the Periaqueductal Gray. J. Neurosci. 36(50):12707-12719.
AC C
Wolff, S. B., Gründemann, J., Tovote, P., Krabbe, S., Jacobson, G. A., Müller, C., Herry, C., Ehrlich, I., Friedrich, R. W., Letzkus, J. J., Lüthi, A. 2014. Amygdala interneuron subtypes control fear learning through disinhibition. Nature. 509(7501):453-8. Wolpert, D. M., Miall, R. C., Kawato, M. 1998. Internal models in the cerebellum. Trends Cogn. Sci. 2(9):338-47. Yonkers, K. A., Bruce, S. E., Dyck, I. R., Keller, M. B. 2003. Chronicity, relapse, and illnesscourse of panic disorder, social phobia, and generalized anxiety disorder: findings in men and women from 8 years of follow-up. Depress. Anxiety. 17(3):173-9.
ACCEPTED MANUSCRIPT
Yu, W., Krook-Magnuson, E. 2015. Cognitive Collaborations: Bidirectional Functional Connectivity Between the Cerebellum and the Hippocampus. Front. Syst. Neurosci. 9:177. Yu, X., Liu, L., Chen, W., Cao, Q., Zepf, F. D., Ji, G., ... Zang, Y. 2016. Integrity of Amygdala Subregion-Based Functional Networks and Emotional Lability in Drug-Naïve Boys With ADHD. J. Atten. Disord.
PT
Yuan, M., Zhu, H., Qiu, C., Meng, Y., Zhang, Y., Shang, J., Nie, X., Ren, Z., Gong, Q., Zhang,
RI
W., Lui, S. 2016. Group cognitive behavioral therapy modulates the resting-state functional
SC
connectivity of amygdala-related network in patients with generalized social anxiety disorder. BMC Psychiatry. 16:198.
NU
Zeng, L. L., Shen, H., Liu, L., Wang, L., Li, B., Fang, P., ... Hu, D. 2012. Identifying major depression using whole-brain functional connectivity: a multivariate pattern analysis. Brain
MA
135(5), 1498-1507.
Zhang, S. F., Chen, J. C., Zhang, J., Xu, J. G. 2017. miR-181a involves in the hippocampus-
ED
dependent memory formation via targeting PRKAA1. Sci. Rep. 7(1):8480. Zhu, L., Sacco, T., Strata, P., Sacchetti, B. 2011. Basolateral amygdala inactivation impairs
EP T
learning-induced long-term potentiation in the cerebellar cortex. PLoS One 6, e16673. Zhu, L., Scelfo, B., Hartell, N. A., Strata, P., Sacchetti, B. 2007. The effects of fear conditioning
AC C
on cerebellar LTP and LTD. Eur. J. Neurosci. 26(1):219-27.
ACCEPTED MANUSCRIPT
AC C
EP T
ED
MA
NU
SC
RI
PT
Highlights Fear and anxiety-related brain areas are connected with the cerebellum. Animal studies on fear and anxiety demonstrate cerebellar involvement. Fear and anxiety-related disorders’ patients show enhanced cerebellar function. A cerebellum-based predictive function is proposed to explain the observed results.
ACCEPTED MANUSCRIPT
Table 1: Fear and anxiety-related disorders and their associated symptomatology. Disorder Social Anxiety Disorder
Description Fear or intense anxiety in one or more social situations, in which the individual fears to behave in a way that will result in social rejection. As a result, social situations are avoided or endured with fear or extreme anxiety.
Specific Phobia
Fear or extreme anxiety when facing a particular stimulus or situation. As a result, such
PT
stimuli or situations are avoided or endured with fear or extreme anxiety.
Panic Disorder
Presence of recurrent, unexpected panic attacks. A panic attack can be defined as experiencing extreme fear or distress which peaks in few minutes, and during which physiological (heart
SC
losing control, derealization) may occur.
RI
rate changes, sweating, breathing difficulties…) or psychological symptoms (fear of dying, of
Generalized Anxiety
Long-lasting anxiety and worry about several events or activities. Anxiety and worry are
Disorder
associated with symptoms like restlessness, fatigability, lack of concentration, irritability, or
Post-traumatic Stress
Exposure to death or life threats which causes intrusive symptoms such as re-experiencing the
1
traumatic situation, nightmares related to it and psychological distress and heightened
MA
Disorder
NU
sleeping trouble.
physiological responses when a situation that resembles the t raumatic event is encountered.
Fear or extreme anxiety regarding situations in which escaping or receiving help in case of
ED
Agoraphobia
showing panic-like symptoms would be difficult, such as using public transport, being in the
EP T
middle of a crowd, or staying in open or closed spaces. As a result, such situations are avoided or endured with anxiety.
Separation Anxiety Disorder
Fear or excessive anxiety regarding separation of people for whom he/she feels attachment, reflected as excessive distress when experiencing or anticipating separation, worry about
AC C
losing the attachment figures, and nightmares on the possibility of losing them.
Substance-induced Anxiety
Presence of panic or anxiety symptoms time-locked to consumption or abstinence of a
Disorder
substance with the ability of causing them.
Selective M utism
Constant speaking failure in situations in which speaking is expected, which cannot be explained by lack of knowledge or lack of comfort related to the spoken language in the presented situation.
1: Post-traumatic Stress Disorder has been removed from the Anxiety Disorders chapter in DSM -5.
Josep Moreno-Rius PII: DOI: Reference:
S0278-5846(17)31056-4 doi:10.1016/j.pnpbp.2018.04.002 PNP 9379
To appear in:
Progress in Neuropsychopharmacology & Biological Psychiatry
Received date: Revised date: Accepted date:
31 December 2017 29 March 2018 4 April 2018
Please cite this article as: Josep Moreno-Rius , The cerebellum in fear and anxiety-related disorders. The address for the corresponding author was captured as affiliation for all authors. Please check if appropriate. Pnp(2018), doi:10.1016/j.pnpbp.2018.04.002
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
The cerebellum in fear and anxiety-related disorders Josep Moreno-Rius* Department of Pharmacology and Toxicology, University of Innsbruck, Innsbruck, Austria *Corresponding author:
PT
Department of Pharmacology and Toxicology, University of Innsbruck, Innrain 80-82, A-
AC C
EP T
ED
MA
NU
SC
RI
6020 Innsbruck, Austria. [email protected]
ACCEPTED MANUSCRIPT
ABSTRACT Fear and anxiety-related disorders are highly prevalent psychiatric conditions characterized by avoidant
and
fearful
reactions
towards
specific
stimuli
or
situations,
which
are
disproportionate given the real threat such stimuli entail.
PT
These conditions comprise the most common mental disorder group. There are a high proportion of patients who fail to achieve remission and the presence of high relapse rates
RI
indicate the therapeutic options available are far from being fully efficient. Despite an
SC
increased understanding the neural circuits underlying fear and anxiety-related behaviors in the last decades, a factor that could be partially contributing to the lack of adequate
NU
therapies may be an insufficient understanding of the core features of the disorders and
MA
their associated neurobiology.
Interestingly, the cerebellum shows connections with fear and anxiety-related brain areas and
ED
functional involvement in such processes, but explanations for its role in anxiety disorders are lacking.
EP T
Therefore, the aims of this review are to provide an overview of the neural circuitry of fear and anxiety and its connections to the cerebellum, and of the animal studies that directly
AC C
assess an involvement of the cerebellum in these processes. Then, the studies performed in patients suffering from anxiety disorders that explore the cerebellum will be discussed. Finally, we’ll propose a function for the cerebellum in these disorders, which could guide future experimental approaches to the topic and lead to a better understanding of the neurobiology of anxiety-related disorders, ultimately helping to develop more effective treatments for these conditions. Keywords: Anxiety; cerebellum; fear; prediction; anticipation.
ACCEPTED MANUSCRIPT
1. Introduction Fear and anxiety-related disorders comprise a group of conditions characterized by exaggerated emotional aversive responses to situations that don’t suppose a real threat. These
PT
disorders represent the most prevalent type of psychiatric illness (Ravindran and Stein, 2010), and their annual costs have been estimated to reach 75 billion € in 2010 (Olesen et al., 2012).
RI
In addition to the economic impact, it’s documented and recognized that patients suffering
SC
from these conditions also show a high degree of functional impairment and a decrease in life quality (Barrera and Norton, 2009). Moreover, a great number of patients fail to achieve
NU
remission, and, among the ones who do, relapse rates are very high (Yonkers et al., 2003).
MA
Although some differences exist (Tovote et al, 2015), the neural circuitries of fear and anxiety-related behavior show substantial overlap in several cortical and subcortical brain
ED
areas including limbic structures, such as amygdala or hippocampus (Liberzon and Martis, 2006), prefrontal cortical areas (Hilbert et al, 2014), midbrain structures as the periaqueductal
EP T
grey (Dejean et al., 2015) or raphe nuclei (Graeff, 2004), and other more recently identified contributors, such as dopaminergic areas (Small et al., 2016).
AC C
The literature and research on fear and anxiety has not paid much attention to the cerebellum. The cerebellum contains more neurons than the rest of the brain (Herculano-Houzel, 2009). Despite being traditionally associated to motor functions, an increasing number of recent findings have pointed to the possibility that functions unrelated to motor domains could require the cerebellum. Indeed, several studies now support the cerebellar implication in some of the brain functions involved in anxiety disorders, such as memory (Sacchetti et al., 2004) and prediction (Blakemore and Sirigu, 2003).
ACCEPTED MANUSCRIPT
Basic studies show the cerebellum to be connected with fear and anxiety-related areas, such as the amygdala (Farley et al., 2016), midbrain structures such as the periaqueductal grey (Koutsikou et al., 2014), the raphe nuclei (Kaufman et al., 1996), and the VTA (Oades and Halliday, 1987) and also prefrontal cortical areas (Kelly and Strick, 2003, Watson et al.,
PT
2014). Moreover, a number of studies performed in rodents assessing the contribution of the cerebellum to fear and anxiety-related behaviors also support the notion of the cerebellum
RI
being an important part of their underlying neural circuitries (Sacchetti et al., 2007; Otsuka et
SC
al., 2016).
As of today, multiple neuroimaging studies have reported differential activation, connectivity
NU
patterns and volumes in the cerebellum when anxiety patients are compared with healthy
MA
controls (Ke et al., 2016; Talati et al., 2015; Etkin et al., 2009; Konishi et al., 2014). Nevertheless, due to the traditional views of the cerebellum as a structure exclusively devoted
ED
to motor functions, there’s a lack of explanations on its role even in studies that report differential activity in patients and controls, so the functional significance of such cerebellar
EP T
activation in anxious patients remains unknown. Based on the aforementioned reasons, this work aims to review evidence about the
AC C
involvement of the cerebellum in the fear-related neural circuitry as well as in anxiety disorders, and to propose a hypothesis for its role. First, the neurocircuitry of anxiety-related conditions and its connections to the cerebellum is described. Afterwards, animal studies involving the cerebellum in fear and anxiety-related behaviors are discussed. Then, we review neuroimaging studies performed in anxious patients in which differential activation of the cerebellum was shown. Finally, a hypothesis to clarify the function cerebellar activation might play in pathological anxiety states is proposed. Hopefully, this work will help guiding future experimental approaches to the topic.
ACCEPTED MANUSCRIPT
2. Distinctions between fear and anxiety and relevance of animal models for the human disorders. Although a classical differentiation between fear and anxiety states that fear is a response
PT
directed towards external, definite or factual threatening stimuli, and anxiety is often defined
RI
as a response towards internal, vague and conflictual stimuli, this distinction has frequently been criticized and attempted to redefine because of providing little clarity both at the level of
SC
preclinical studies as well as in pathological human conditions (Gray, 1982; Perusini and
NU
Fanselow, 2015). For example, at the level of preclinical studies, it is well accepted that a paradigm such as cued fear conditioning reflects fear-like responses and the elevated plus
MA
maze (EPM) allows to measure anxiety-related behaviors. Nonetheless, according to the source of the potential threat, these two paradigms present an external allocation of the
ED
threatening stimuli. Further analyzing these two paradigms, now regarding how much of a factual threat is eliciting the threat-related behaviors, in the EPM, the threat-related behavior
EP T
reflected in avoiding open arms in which, if the animals perform a wrong movement while in there, may fall down from an important height, is considered as a nonfactual/conflictual
AC C
threat, whereas in the cued fear conditioning paradigm, in the session in which fear-like behavior uses to be assessed, such behavior is elicited by a cue which indeed, is, once training has finished, signals lack of threat and there is no possibility of harm to the animal, which again, does not seem to support a real usefulness of the previously mentioned definitions. In addition, later attempts of establishing such a differentiation, such as the one by Gray and McNaughton (2002), also proved to be unsuccessful. These authors defend that the proof that fear and anxiety are different entities is that fear-related behaviors are insensitive to anxiolytic drugs, but recent evidence contradicts this assumption (Gunduz-Cinar et al., 2016; Smith et
ACCEPTED MANUSCRIPT
al., 2012). Moreover, such a fear/anxiety distinction shows itself as confusing when the definitions and criteria for defining the disorders associated with these behavioral responses to threat are consulted. A clarifying example of this is provided by Perusini and Fanselow (2015). They report that even in the Diagnostic and Statistical Manual of Mental Disorders
PT
(DSM)’s chapter of anxiety disorders “the descriptions are unclear, inconsistent and often define one in terms of the other”. Specific phobia, classified within the anxiety disorders in
RI
the DSM is described as “a marked or persistent fear of clearly discernible and differentiated
SC
objects or situations” shows how unclear the fear/anxiety differentiation resembles even in diagnostic manuals. The fact that it is also stated in DSM’s definition of specific phobia that
NU
“exposure to the phobic stimuli immediately provokes an anxiety response” is also showing a
MA
discrepancy between the association of anxiety and non-discrete threats favored by the classical distinction. The very same picture emerges when the criteria for Social Anxiety Disorder are consulted, and other disorders classified within this chapter, a panic attack is
ED
defined as “feelings of intense fear or discomfort”.
In light of these discrepancies, the author
EP T
favors the consideration of fear and anxiety as different points within the continuum of threatrelated responses, rather than considering them two discrete entities. According to this view,
AC C
paradigms such as the EPM would allow to measure mild threat-related responses which can also be considered to reflect personality-like traits in experimental animals, whereas fear conditioning paradigms would be generating more vigorous threat-related responses. Within the range of human behaviors, exaggerated threat-like responses such as the ones observed in fear and anxiety-related disorders would be located in the upper extreme of the continuum, and proportional anxiety-related reactions such as enhanced anxious activation before a university exam could be located within the lower extreme of the continuum. Therefore, and in order to avoid
possible misunderstandings derived from conceptualizing fear and anxiety
ACCEPTED MANUSCRIPT
as categorically distinct, the author refers to these behaviors as “threat-related behaviors” or “fear and anxiety-related behaviors” and to the associated pathological conditions as “fear and anxiety-related disorders”. This conceptualization also enables to consider PTSD within this group as it might be the most paradigmatic disorder associated with threat-related behaviors.
PT
Another point that needs to be stressed in order to clarify the usefulness of fear and anxietyrelated animal models and the attempts of translating the animal findings to the human
RI
condition is to remark the common features the animal models and fear and anxiety-related
SC
disorders in humans. As mentioned before, it is the authors’ opinion that according to the intensity of the threat-related behaviors susceptible to appear and being measured in animal
NU
paradigms, the fear conditioning paradigm seems to be closer than other options to the
MA
pathological fear and anxiety-related conditions in human beings. Another feature that strengthens the consideration of fear conditioning paradigms as relevant for the discussed
ED
disorders is the fact that in both cases, threat-related behaviors are elicited by/developed towards stimuli or situations which, normally, are not threatening. And last but not least, it is
EP T
also worth to remark that the fear conditioning paradigm presents, in addition to the component of face validity that comes from the aforementioned similarity in developing
AC C
threat-like responses towards something that normally is not threatening, predictive validity in the sense that pharmacological treatments for fear and anxiety-related disorders are effective in reducing threat-related behaviors in fear conditioning paradigms and vice versa (GunduzCinar et al., 2016; Smith et al., 2012), and also construct validity, as demonstrated by involvement of common brain areas both in fear and anxiety-related disorders and in fear conditioning.
A brief description of these common areas affected in the human conditions
and animal paradigms, as well as their connections to the cerebellum, is presented in the following section.
ACCEPTED MANUSCRIPT
3. The circuitry of fear and anxiety and its connections to the cerebellum. Converging evidence coming from animal and clinical studies has increased our knowledge of the brain areas involved in fear and anxiety behaviors. We will succinctly describe the areas involved in fear and anxiety and their connections to the cerebellum, as excellent reviews on
PT
anxiety-related neural circuitry have been recently issued (Tovote et al., 2015; Taylor and Whalen, 2015; Calhoon and Tye, 2015).
RI
One of the core components of the anxiety circuitry is the amygdala. This limbic group of
SC
nuclei, a critical site for the aversive learning-associated plasticity, shows abnormal activation and connectivity patterns in anxious patients (Etkin et al., 2009; Wolff et al., 2014). The
NU
prefrontal cortex and its subdivisions, including the ventromedial part and the anterior
MA
cingulate cortex also seem to play different roles in fear-related behaviors and disorders (Carrion et al., 2009; Peters et al., 2010). Another cortical zone such as the insula, responsible interoception
and
multimodal sensory
processing,
presents
comparable evidence
ED
for
supporting its inclusion as part of this circuitry (Klumpp et al., 2012; Alves et al., 2013).
EP T
Similarly, the participation of the hippocampus in the circuitry of anxiety, a brain structure thought to be exclusively involved in spatial memory and navigation is now supported by
AC C
both clinical and preclinical evidence (Jatzko et al., 2006; Zhang et al., 2017). The periaqueductal gray, a midbrain structure responsible for returning neural signals related to aversive stimuli to the peripheral nervous system, also participates of fear and anxiety-related circuitries as indicated by patient and animal studies (Watson et al., 2016; Harricharan et al., 2016). An equivalent amount of findings also involves the raphe nuclei within these brain circuits. The main source of serotonergic neurons in the brain seems to be essential component of the structures mediating fear and anxiety-related responses (Spindelegger et al., 2009; An et al., 2016). The ventral tegmental area, the region in which the dopaminergic cell
ACCEPTED MANUSCRIPT
bodies are located, traditionally regarded as a reward processing and valuating area can also be considered as part of this circuitry in light of several lines of evidence (Pignatelli et al., 2017; Cha et al., 2014). The same could be applied to the striatum. Being classically involved in motivated behavior as well as in motor abilities, its connections and recent findings in
PT
animals and patients favor the inclusion of this structure in the anxiety circuitry (Norris et al., 2016; Felmingham et al., 2014). previously
mentioned
areas’
neuromodulators.
activity
is
strongly
modulated
by
several
This is of special relevance from a clinical
SC
neurotransmitters and
brain
RI
The
perspective, given that the available non-behavioral treatments of fear and anxiety-related
NU
disorders are essentially pharmacological compounds targeting those systems. Most of these
MA
treatments present a series of inconveniences such as being effective only in short-term reduction of symptoms, delayed onset of action and lack of targeting the cause of the anxiety-
ED
related symptoms among others. Nonetheless, the use of such chemicals has shed light on the neurotransmitter systems which are involved in fear and anxiety-related behaviors and
EP T
disorders within the aforementioned brain areas. One of the neurotransmitter systems involved is the GABAergic system. It is well known that drugs enhancing GABA
AC C
transmission are effective in reducing abnormal fear and anxiety-related behaviors in both experimental animals and humans (Ballenger et al., 1998; Rickels and Rynn, 2002; Toth et al., 2012). The serotonergic system also seems to be involved, as drugs enhancing serotonergic transmission are effective in relieving anxiety symptoms in patients (Cascalenda and Boulenger, 1998), and it is also the case for fear and anxiety-related paradigms in rodents (Toth et al., 2012; Gunduz-Cinar et al., 2016).
Similar evidence favors the involvement of
noradrenergic transmission. Norepinephrine itself or drugs enhancing norepinephrine function are able to induce panic attacks in humans (Pyke and Greenberg, 1986), and modulating the
ACCEPTED MANUSCRIPT
activity of the noradrenergic system affects fear and anxiety-related behaviors in rodents as well (Davies et al., 2004; Davis et al., 1979). Another neuromodulation system which is involved in anxiety is the endocannabinoid system. It is well known that the moderate doses of exogenous cannabinoids such as the ones present in marijuana produces anxiolytic effects
PT
in humans (Sethi et al., 1986), and this feature is paralleled by analogous effects in rodent models of fear and anxiety (Fokos and Panagis, 2010; Rubino et al., 2007). Glutamatergic
RI
neurotransmission may be similarly involved as well, as modulating it via pharmacological
SC
means alters fear and anxiety-related behaviors in rodents (Brodkin et al., 2002; Walker and Davis, 2002), and some of the compounds modulating this neurotransmitter system show
NU
promising effects in patients afflicted from fear and anxiety-related conditions (Hofmann et
MA
al., 2015).
Importantly, it is nowadays demonstrated that all the previously mentioned brain areas seem
ED
to be connected to the cerebellum. Animal studies proving the existence of connections between cerebellum and both cortical and subcortical areas involved in fear and anxiety, reciprocal connections
with
brain
areas
which
are the main source of
EP T
including
neurotransmitters involved these behaviors (Snider, 1950; Snider and Maiti, 1976; Kaufman
AC C
et al., 1996; Kelly and Strick, 2003; Berntson and Torello, 1982; Bishop and Ho, 1985; Watson et al., 2009; 2014; Farley et al., 2016) are reinforced by human neuroimaging studies that confirm these cerebrocerebellar relationships. In this regard, a functional relationship between cerebellum and different areas within the cortex, such as anterior cingulate cortex (Addis et al., 2016; Moulton et al., 2011; Sang et al., 2012; Zeng et al., 2012), insula (Addis et al., 2016; Habas et al., 2009; Moulton et al., 2011; Sang et al, 2012), and inferior frontal gyrus (Addis et al., 2016; Moulton et al., 2011; Tomasi and Volkow, 2011) has been shown. Other subcortical structures such as amygdala (Leutgeb et al., 2016; Sang et al., 2012; Zeng et al.,
ACCEPTED MANUSCRIPT
2012), hippocampus (Onuki et al., 2015; Sang et al., 2012; Zeng et al., 2012), raphe nuclei (Beliveau et al., 2015), ventral tegmental area (Carnell et al., 2014; Etkin et al., 2009; Kline et al, 2016; Kwon et al., 2014) and striatum (Cauda et al., 2011; Cservenka et al., 2014; Koehler et al., 2013) also seem to present a comparable relationship with the cerebellum.
PT
The aforementioned studies provide strong cross-species neuroanatomical evidence pointing to, although not proving, that the cerebellum may play a functional role in anxiety-related
RI
behaviors and disorders. Such a role has been demonstrated in experiments conducted in
SC
rodent models, which allow performing transient or permanent modifications of brain structure and function as well as studying the associated changes at molecular resolution. In
NU
the forthcoming section, we will discuss the studies that show this functional involvement for
MA
the cerebellum in paradigms aiming to measure fear and anxiety-related behaviors. 4. The cerebellum in fear and anxiety-related behaviors.
ED
When studying fear and anxiety-like behaviors in rodents, basic scientists make use of paradigms in which either a noxious stimulus is applied or a moderately aversive environment
EP T
that the animal can avoid is presented. As previously discussed, the latter type is thought to measure anxiety-like responses inferred from the avoidance of the aversive environment,
AC C
whereas the former are supposed to represent fear behaviors. The first study showing an involvement of the cerebellum in fear-related behaviors was the one conducted by Moruzzi in 1947. The author reported that sham rage elicited by cortical removal could
be temporarily blocked by cerebellar stimulation, but this cerebellar
manipulation led to increased rage-like symptoms once stimulation had ceased. Posterior studies, such as the one performed by Fish and colleagues in 1979, strengthened the cerebellar involvement in fear-related behaviors as lesions directed at medial cerebellar nuclei impaired performance
in
an
active
avoidance
task.
A
similar
behavioral
task
in
which
ACCEPTED MANUSCRIPT
cerebellectomized
rats’ performance was assessed
confirmed the involvement as no
association was seen in cerebellum-removed rats (Dahhaoui et al., 1990). The role of the cerebellum could not be related to the execution of an active response, as cerebellectomy impaired performance in a passive avoidance task as well (Guillaumin et al., 1991). Some
PT
other early studies showed medial cerebellar lesions decreased fear responses when rats were presented with a predator (Supple et al., 1987), an effect also seen in a lever pressing
RI
paradigm (Steinmetz et al., 1993).
SC
Another fear-related measure in which the role of the cerebellum has been studied is conditioned bradycardia. In these experiments, an aversive footshock, which has the ability to
NU
lower heart rate, is applied to the experimental animal paired with a distinctive cue such as a
MA
tone or a light. After a number of cue-shock pairings, the animals are only presented with the cue, and the cue displays the ability to elicit the same heart rate response than the shock did.
ED
Cerebellar ablation proved to impair the acquisition of the conditioned heart response (Supple and Leaton, 1990a), and further studies demonstrated this effect can be attributed to the
EP T
cerebellar vermis both in rats and rabbits (Supple and Leaton, 1990b; Supple and Katz, 1993). A crucial role for the cerebellar cortex in these processes is inferred from studies using the
AC C
Lurcher mutant mice. These animals present a mutation which, in its heterozygous form, leads to the death of Purkinje cells. Mutants visited more frequently the open arms in the EPM (Lorivel and Hilber, 2006; Lorivel et al., 2010), and showed altered fear responses when presented with a predator (Lorivel et al., 2014). Not only Purkinje cells seem to be involved, as a fearful stimulus was also able to change the phenotype of ionotropic glutamate receptors in stellate cells (Liu et al., 2010). Transmission via Histamine-2 receptors could be modulating the cerebellar circuitry processing fear-related stimuli, as demonstrated in studies
ACCEPTED MANUSCRIPT
using microinjections of histamine and H2 receptor ligands in the medial cerebellum in an aversive conditioning paradigm (Gianlorenço et al., 2013; 2015). Additional evidence comes from the most used behavioral task for unraveling neural circuits of fear, the so-called fear conditioning paradigm. Pairing an originally neutral stimulus (a
PT
context or a tone) with a noxious one (a shock), enables the neutral stimulus to elicit fear responses in the animal. Sacchetti and coworkers, using an auditory fear conditioning
RI
paradigm, demonstrated the existence of AMPA-dependent fear learning-induced long-term
SC
potentiation (LTP) in parallel fiber-purkinje cell (PF-PC) synapses in cerebellar lobules V-VI capable to occlude electrically induced LTP (Sacchetti et al., 2004; Scelfo et al., 2008; Zhu et
NU
al., 2007). Additional studies revealed that functional integrity of lobules V-VI was necessary
MA
for consolidating fear memories (Sacchetti et al., 2002; 2007), and they also described that amygdalar lesions impaired fear learning-induced cerebellar plasticity (Zhu et al., 2011). compromising lobule VIII integrity produced the same effect than the
ED
Interestingly,
manipulation performed in lobules V-VI (Koutsikou et al., 2014), pointing to a general
EP T
involvement of the cerebellum in these behaviors. The role of the PF-PC synapse in fear processes has been stressed by a recent report in which mice lacking Cerebellin 1 selectively
AC C
in the cerebellum, a protein involved in the maintenance of the structure of this synapse, display an impaired acquisition of fear memories (Otsuka et al., 2016). Overall, these studies provide evidence for the cerebellum to be a part of the circuitry underlying fear-related behaviors that is comparable to other brain areas widely recognized as part of such circuitry (see LeDoux, 2000). Given that the involvement of brain areas in basic fear-related processes has been translated into alterations of such areas in anxiety patients (which are thought to be involved in the pathophysiology of these disorders), in the forthcoming section, we aim to demonstrate this relationship is also true for the cerebellum as
ACCEPTED MANUSCRIPT
we review neuroimaging reports of patients suffering from fear and anxiety-related disorders in which differential activation or connectivity of the cerebellum, relative to healthy controls, has been observed.
PT
5. The cerebellum and fear and anxiety-related disorders. The refinement of neuroimaging techniques during the first decade of the century has allowed
RI
mapping brain activity and connectivity with enhanced resolution and minimal invasiveness
SC
in human beings. When such techniques have been applied to the study of anxious patients, differential activation of the cerebellum is frequently found in many studies (Etkin et al.,
NU
2009; Talati et al., 2015), which will be discussed now. It is important to mention, however,
MA
that fear and anxiety-related disorders are a fairly heterogeneous group of conditions in which fearful/anxious symptomatology might be triggered by different stimuli and can also manifest
ED
in a variety of ways. These differences between disorders are summarized in Table 1. Within this group of conditions, the first study demonstrating changes in the cerebellum of
EP T
anxious patients was a PET study conducted in social anxiety disorder (SAD). SAD is characterized by avoiding interactions with unfamiliar people and experiencing interaction
AC C
episodes with extreme anxiety. In this first study, altered cerebellar activation was observed in a group of SAD patients that were anticipating they had to speak in public (Tillfors et al., 2002). Such changes demonstrated to be present also in baseline conditions when measured with single positron emission tomography (Warwick et al., 2008). Volumetric alterations within the cerebellum have also been described in SAD patients. An increase in cerebellar grey matter was reported in these patients (Talati et al., 2013), which was successfully rescued by different SSRIs (Talati et al., 2015; Cassimjee et al., 2010). In functional studies, enhanced cerebellar activity was found when SAD-afflicted individuals were presented with
ACCEPTED MANUSCRIPT
angry faces (Evans et al., 2008), when they faced a confrontational arithmetic task (Kilts et al., 2006) and after they were exposed to different social tasks (Nakao et al., 2011; Heeren et al., 2017). Connectivity changes between cerebellum and other parts of the anxiety circuitry in SAD patients might partially explain the different activation patterns, as these changes have
PT
been described in resting state and task-performing conditions for the connections linking amygdala (Liao et al., 2010), medial prefrontal cortex (Giménez et al., 2012; Yuan et al.,
RI
2016) and cingulate cortex (Doruyter et al., 2016) with the cerebellum. Interestingly,
SC
connectivity levels between mPFC and cerebellum predicted response to behavioral treatment (Yuan et al., 2016), thereby holding promise as a biomarker to refine therapy prescription and
NU
reducing the number of patients under ineffective treatments.
MA
Post-traumatic stress disorder (PTSD), a condition characterized by re-experiencing a traumatic episode of one’s life, also strengthens substantially the notion of the cerebellum
ED
being functionally involved in fear and anxiety-related disorders. PTSD patients showed an increase in cerebellar activity at resting conditions (Bing et al.,
EP T
2013). This finding cannot be related to trauma exposure per se, as differences in the cerebellum were still present when PTSD patients were compared with trauma-exposed,
AC C
PTSD-free individuals (Bonne et al., 2003). A subsequent study comparing trauma-exposed borderline personality disorder patients with and without PTSD revealed only the group suffering from PTSD displayed enhanced cerebellar activation (Driessen et al., 2004), pointing to increased cerebellar activity as a specific disease indicator, an assumption reinforced by a recent meta-analysis (Wang et al., 2016). These baseline activation patterns seem to be accompanied by a reduction in cerebellar volumes, as it was reported both in adult and pediatric patients afflicted from PTSD (Baldaçara et al., 2011; Carrion et al., 2009; De Bellis and Kuchibhatla, 2006). fMRI studies in which exposure to fearful faces or trauma-
ACCEPTED MANUSCRIPT
related images was performed provoked activation in the cerebellum (Ke et al., 2016; Crozier et al., 2014), and it was seen that a reduction in cerebellar activation after treatment correlated with symptom improvement (Ke et al., 2016). These activity patterns may be influenced by stronger connections of the cerebellum to effector areas, like the periaqueductal grey, found in
PT
PTSD patients (Thome et al., 2017).
RI
Another condition in which the cerebellum has popped out in several neuroimaging reports is
SC
specific phobia. These patients experience intense fear or anxiety when they face specific stimuli or situations, such as animals, flights or injections. In a PET study, both spider and
NU
snake phobics displayed cerebellar activation when viewing pictures of the respectively feared
MA
animals (Carlsson et al., 2004), a finding confirmed also by fMRI reports (Goossens et al., 2007; Ahs et al., 2009) which additionally demonstrated a correlation between the level of
ED
anxiety induced by viewing the stimuli and the activity in the cerebellum (Caseras et al., 2010). The cerebellar activation was seen even when neutral photos were conditioned to
EP T
photos depicting feared stimuli (Schweckendiek et al., 2011), and the activity patterns were accompanied by an increase in grey matter (Hilbert et al., 2015).
AC C
Studies on panic disorder patients, characterized by presenting recurrent panic attacks and intense worrying about suffering them in the future, show enhanced cerebellar activity in baseline conditions (Sakai et al., 2005) which was diminished by successful cognitivebehavioral therapy (Sakai et al., 2006), suggesting a role for the cerebellum in the neural circuitry
underlying
successful
behavioral
intervention.
Structural
abnormalities,
like
reductions in grey matter (Asami et al., 2009), and similar patterns for cerebellar white matter were found (Konishi et al., 2014). The structural abnormalities in the cerebellum seemed
ACCEPTED MANUSCRIPT
responsive to treatment interventions, as the grey matter reduction was rescued by antidepressant treatment (Lai and Hsu, 2011). Finally, there’s also evidence linking cerebellum with generalized anxiety disorder. Patients that deal with this condition suffer a long-lasting worry about a variety of situations leading to
PT
significant functional impairment. Enhanced connectivity between the cerebellum and the amygdala is the main finding regarding this disorder (Etkin et al., 2009), a finding reproduced
RI
in adolescents (Roy et al., 2013), which was shown to correlate with disease scores (Liu et al.,
SC
2015). Additionally, these patients demonstrated increased cerebellar metabolism when they were performing a verbal fluency task (Kalk et al., 2012).
NU
Taken together, these studies provide compelling evidence of cerebellar hyperactivity in
MA
different groups of anxiety disorders patients. Nonetheless, within the reviewed studies, explanations on the role of this activation are lacking or limited to mention the cerebellum
ED
seems to be involved in fear/emotion, but a specific role for this brain area has not been proposed yet. An attempt of providing such an explanation will be the goal of the forthcoming
EP T
section.
AC C
6. What is the role of the cerebellum? Overall, the collected evidence from both human and animal studies has confirmed that: 1) the cerebellum is heavily connected with a variety of areas considered part of the anxiety circuitry including those which provide the neurotransmitters involved in fear and anxiety, 2) manipulations on cerebellar integrity or functioning affect behavioral performance in fear and anxiety-related tasks in experimental animals and 3) patients suffering from anxiety disorders display enhanced cerebellar activity and connectivity with anxiety-related brain areas when
ACCEPTED MANUSCRIPT
compared
with
healthy
controls.
Nevertheless,
the
possibility
remains
that
several
methodological factors could account for the variability found between studies. In animal studies, some minor differences exist regarding the directionality of the effect of the cerebellar manipulation (Lorivel et al., 2010; Sacchetti et al., 2002). Loss-of-function can
produce
opposing
effects
in
fear-related
behavioral
paradigms.
PT
manipulations
Nonetheless, it is likely that such results are due to the use of markedly different behavioral
RI
tasks that rely on either unconditioned or conditioned fearful responses, that differ in the
clearly differentiated
SC
nature and intensity of the fear-inducing stimulus or that require the animals to perform a behavior. Such an assumption is supported by the convergent
NU
directionality of cerebellar manipulations within the same behavioral paradigm (Sacchetti et
MA
al., 2004; Koutsikou et al., 2014). In neuroimaging studies, variables such as the number of subjects, age, gender, years of diagnosis, presence of comorbid disorders and previous
ED
treatments are not equivalent in the majority of studies. Differences in the neuroimaging techniques used for monitoring activity, which include PET, SPECT and fMRI scans and
EP T
differences within the studies using the same technique (different tracers for PET scans, different intensities of magnetic fields in fMRI studies) could have also influenced the results.
AC C
Another concern that may arise due to the well-known involvement of the cerebellum in motor function is whether motor disturbances that might be present in patients suffering from fear and anxiety-related disorders are the cause of cerebellar activity seen in neuroimaging studies. Nevertheless, the available evidence indeed suggests a more central role of the cerebellum within these disorders rather than being a finding related to non-cardinal symptoms of these disorders. In fact, fear and anxiety-related behaviors are accompanied by motor alterations but these alterations may be present as increased or decreased motor activity depending, among other variables, on perceived threat intensity. Therefore, it seems likely
ACCEPTED MANUSCRIPT
that patients afflicted from fear and anxiety-related disorders can present motor alterations, but evidence regarding these features is mixed and doesn’t point univocally to the cerebellum as a possible substrate. Indeed, the presence of general motor impairments seems to be restricted to some, but not all, fear and anxiety-related conditions (Marchand et al., 2009;
PT
Hazlett et al., 1994; Brown and Boudewyns, 1996). Additionally, within the disorders that show a motor impairment, both enhanced and decreased activity has been described (Brown
RI
and Boudewyns, 1996; Malta et al., 2009), whereas in the neuroimaging studies with patients,
SC
cerebellar function is always increased when compared to controls (Carlsson et al., 2004; Evans et al., 2008; Ke et al., 2016). It is also remarkable that the increased cerebellar
NU
activation appears irrespective of whether the scan was performed with the patients in resting
MA
conditions (Warwick et al., 2008; Bing et al., 2013; Sakai et al., 2005) or while they were performing a task that had some motoric requirements (Kilts et al., 2006; Nakao et al., 2011;
ED
Ke et al., 2016). Moreover, available data suggest that variables which are not the disorder itself can show a more important effect in the observed motoric dysfunctions (Clark et al.,
EP T
1990), and the evidence for the neural basis of such impairments has not reported cerebellar involvement and indeed points to a major involvement of striatal areas (Marchand et al.,
AC C
2009). More importantly, the connectivity or activation patterns seen in the cerebellum of patients have been shown to predict treatment response, symptom improvement and anxiety self-reports in different studies (Yuan et al., 2016; Ke et al., 2016; Caseras et al., 2010), so the possibility that the role of the cerebellum goes beyond the motoric manifestations of fear and anxiety-related disorders needs to be strongly considered. In addition, evidence within the studies performed in both species is convergent. Different types of neuroimaging scans reveal enhanced cerebellar activation in most fear and anxietyrelated disorders (Carlsson et al., 2004; Evans et al., 2008; Ke et al., 2016), and in rodents
ACCEPTED MANUSCRIPT
acquisition of fear-related behaviors results in enhanced cerebellar function (Sacchetti et al., 2004) and loss-of-function manipulations such as lesions, pharmacological inactivation on gene deletions result in impaired fear-related behaviors (Sacchetti et al., 2002; Koutsikou et al., 2014; Otsuka et al., 2016). Interestingly, such a convergence seems to point to the
PT
necessity of cerebellar activity for the expression of exacerbated fear and anxiety-related behaviors towards stimuli or situations that normally do not suppose a remarkable threat.
RI
Looking into the functional role of the cerebellum in fear and anxiety-related disorders, a
SC
possible explanation for it, which will be consistent with recent definitions and theorizations on the anxiety and the etiology of the associated disorders as well as cerebellar functions,
NU
would be that the cerebellum is, at least, partly responsible for the anticipation/prediction
MA
processes that accompany pathological fear and anxiety-related conditions. The relationship between anxiety and anticipation becomes evident when anxiety definitions
ED
are consulted. Whether they were formulated decades ago or in the last few years, all of them define anxiety as a response oriented toward potential, upcoming threats (Borkovec, 1985;
EP T
Tovote et al., 2015), this is, the anxious response is produced because the subject anticipates there can be a harmful situation in the near future. The relevance of this anticipation processes
AC C
for the pathological anxiety conditions seems to be more evident when dysfunctions in these anticipatory processes, which lead to an aberrant prediction of future threats as more harmful than they really are, have been suggested to represent a crucial factor for the development and maintenance of such disorders (Grupe and Nitschke, 2013). Favoring this notion, such a heightened harmfulness prediction for upcoming threats has been demonstrated in patients afflicted from different pathological anxiety conditions (Andrews et al., 1994; Hazlett-Stevens and Borkovec, 2004; Grillon et al., 2008; Tillfors et al., 2002).
ACCEPTED MANUSCRIPT
On the other hand, the relationship between the cerebellum and prediction processes is also supported both at the theoretical and practical levels. From a theoretical standpoint, the cerebellum’s main function has been hypothesized to be to support generalized fast prediction processes (Courchesne and Allen, 1997; Moreno-Rius and Miquel, 2017). Such a predictive
PT
function is thought to be performed by “forward controllers” (Brown and Brüne, 2012; Wolpert et al., 1998). A forward controller can be defined as a brain circuit capable of
RI
recruiting forward models to produce such anticipatory responses. Forward models, in turn,
SC
are internal representations of specific environmental settings based on which the subject is able to estimate the consequences of his possible actions in such setting (Van der Meer and
NU
Redish, 2010). Importantly, the cerebellum is widely considered to act as a forward controller
MA
(Miall et al., 1993; Ito, 2008). This supposes that, via the use of internal memory and the processing of the environmental inputs, cerebellar systems are able to provide a virtual scenario based on which fast prediction of outcomes for a particular behavior are generated
ED
(D’Angelo and Casali, 2013), and this prediction will activate the preparation of the brain
EP T
networks that are required to trigger fear-related anticipatory behaviors. Accordingly, in the case of anxious patients, such a cerebellum-based predictive system is functioning in an
AC C
aberrant, hyperactive way. This leads to an overestimation of the environment-associated harms and to the appearance of anxiety symptoms, and, at a neural level, it is seen as enhanced cerebellar activation. Interestingly, such an enhanced cerebellar activation was prominently observed when they faced cues that can be able to trigger threat-like predictions, further stressing the role of the cerebellum in these processes (Tillfors et al., 2002; Crozier et al., 2014; Carlsson et al., 2004). This proposed working hypothesis of an aberrant cerebellumbased prediction process in pathological fear and anxiety is strongly reinforced by a metaanalytic work which demonstrates the cerebellum is involved in aversive learning-related
ACCEPTED MANUSCRIPT
prediction error in human subjects (Garrison et al., 2013), thereby providing strong evidence that the cerebellum is indeed involved in aversive stimuli-related prediction processes in human subjects. Interestingly, this prediction process that the author intends to relate to pathological fear and
PT
anxiety seems to be performed by the cerebellum even in other aspects within the emotional domain (Adamaszek et al., 2017). In fact, regarding emotional perception and recognition,
RI
especially negative emotions, a role for the cerebellum has been demonstrated in studies in
SC
patients afflicted from cerebellar lesions (Adamaszek et al., 2014; Lupo et al., 2015; Annoni et al., 2003), and has been related to a general predictive function of the cerebellum (Molinari
NU
et al., 2008).
MA
This hypothesis also nicely explains that, in fear-related associative paradigms, which basically consist in allowing an experimental animal to associate a neutral stimulus with an
ED
aversive one, and after repeated pairings the animal shows a physiological and behavioral anticipatory response related to the previous appearance of the aversive stimulus when the
EP T
conditioned stimulus is presented, cerebellar lesion or inactivation impairs the ability of the animals to display the classically conditioned anticipatory response (Sacchetti et al., 2002;
AC C
Koutsikou et al., 2014).
Additional evidence supporting a cerebellar role in anticipatory responses and therefore partially supporting the proposed hypothesis of cerebellar function in pathological fear and anxiety comes from the study of reward-related behaviors. Anticipation of psychostimulant administration in cocaine addicts resulted in enhanced cerebellar activation unrelated to the pharmacological effects of the drug (Volkow et al., 2003). Similarly, in a cocaine-conditioned preference paradigm,
animals that learned
to
anticipate
drug administration by the
presentation of a cocaine-paired stimulus displayed enhanced activation of cerebellar cortical
ACCEPTED MANUSCRIPT
excitatory neurons (granule cells) and restrictive metaplasticity mechanisms in the inhibitory interneurons controlling them (Carbo-Gas et al., 2014; 2017). The importance of granule cells in the predictive function of the cerebellum was confirmed by a recent report in which these cells were imaged while mice were performing a forelimb reward tasks, such cells were
PT
shown to encode reward anticipation in both paradigms tested (Wagner et al., 2017). Although the aforementioned studies provide support to the proposed predictive function of
RI
the cerebellum in fear and anxiety-related disorders, it could be that the cerebellum is also
SC
involved in other functions related to fear and anxiety that go beyond the proposed cerebellar predictive function. One of these functions related to fear and anxiety in which the cerebellum
NU
has been involved is the modulation of the autonomic nervous system. It is known that
MA
autonomic symptoms are part of the manifestations of fear and anxiety (Friedman, 2007; Alvares et al., 2016; Thome et al., 2017), and it is also known that the cerebellum is involved
ED
in the control of these responses (Emerson et al., 1961; Balaban and Porter, 1998; MuellerPfeiffer et al., 2014), so maybe cerebellar alterations could also be playing a role in autonomic
EP T
deregulations presents in patients afflicted from fear and anxiety-related disorders, although, as of today, studies relating autonomic symptoms and cerebellar function in patients are
AC C
lacking.
Another function related to fear and anxiety in which cerebellar involvement has been described is salience. Salience can be defined as the property that environmental stimuli or situations have that make them especially relevant when compared to other stimuli or situations within an environment (Uddin, 2015). Salience attribution is a crucial process in order to allow organisms to pursue beneficial goals or stimuli and avoid harmful ones (Borsook et al., 2013). Importantly, functional connectivity studies have helped to define the neural basis of salience attribution. A functional network termed “salience network”, which
ACCEPTED MANUSCRIPT
includes brain zones such as insula, anterior cingulate cortex and temporoparietal junction, has shown to respond to salient stimuli irrespective of the sensory modality of the stimuli (Downar et al., 2002). Notably, it has been described that the cerebellum is connected to these areas (Igelstrom et al., 2017; Habas et al., 2009; Shinn et al., 2015), and cerebellar activations
PT
in response to salient stimuli including threatening ones have been reported (Killgore et al., 2003; Moulton et al., 2011; Anderson et al., 2006). Therefore, it would be possible that, in
RI
studies in which threat-related cues are presented to fear and anxiety-related disorders’
SC
patients, its salience may explain differential cerebellar activations and connectivity patterns, but given that these changes are also seen in patients in resting conditions (Warwick et al.,
NU
2008; Bing et al., 2013; Sakai et al., 2005), it is likely that the involvement of the cerebellum
MA
in fear and anxiety cannot be explained only by its role in salience. Even though, the proposed predictive function of the cerebellum also seems to be compatible
ED
with one of the most influential theories of fear and anxiety (Gray, 1982; Gray and McNaughton, 2002; McNaughton and Corr, 2004). The basic feature of this theory can be
EP T
considered that a behavioral inhibition system, which neurobiological core is supposed to be the hippocampus and septal areas, referred by the authors of the theory as the
AC C
septohippocampal system, is responsible for controlling threat-related behaviors. The early finding that led to the authors to propose such a neural ground for threat-related behaviors was the fact that anxiolytic drugs impaired performance in hippocampus-dependent memory tasks (Timic et al., 2013). It is the author’s opinion that the cerebellum could be a fit within this theory. The proposal of the authors of the theory is that the septohippocampal system, briefly explained, is a comparator of the threat levels of the real, presented situation versus the expected one, and when there is a mismatch between the expected threat levels and the real situation, the activation of the behavioral inhibition system allows to increase arousal, the
ACCEPTED MANUSCRIPT
appearance of typical defensive behavior and the inhibition of any other sort of behavior (Gray and McNaughton, 2002). It’s been described in section 4 that lesioning or inactivating the cerebellum predominantly results in a reduction of threat-related anticipatory behaviors and in the reappearance of the non-threat-related behaviors that are inhibited in a threatening
PT
situation (Sacchetti et al., 2002; 2007; Koutsikou et al., 2014). Moreover, the cerebellum has shown to be anatomically and functionally connected with both the septum and hippocampus
RI
(Heath et al., 1978; Snider and Maiti, 1975; Swanson, 1977; Onuki et al., 2015; Yu and
SC
Krook-Magnusson, 2015). Given that it has been demonstrated that the cerebellum is able to provide forward models supporting predictions in other domains, and that its structural and
computational
studies
suggest
it
NU
homogeneity
most
likely
performs
a
single
MA
computational function (D’Angelo and Casali, 2013), the same function could be taking place regarding threat-like responses, and the provided model would be posteriorly compared with
ED
the actual situation by the septohippocampal formation. Taking into account from the aforementioned studies the involvement of the cerebellum in
EP T
aversive prediction processes, the role of prediction/anticipation in threat-related behaviors, the role of the cerebellum in fear-related behavioral paradigms and the findings of the
AC C
cerebellar hyperactivity seen in patients suffering from pathological fear and anxiety, the proposal of a cerebellum-based aberrant prediction process seems to be a parsimonious one which encompasses the previously mentioned findings, and could also be, at least, partially underlying the exacerbated fear and anxiety-related responses the patients afflicted from this conditions present. Nonetheless, this hypothesis is, as of today, not proven but partially supported by the aforementioned findings, which are consistent with such a proposal, but would need to be tested further as direct evidence for ascertaining whether cerebellar activity is reflecting the functioning of a prediction process based on the activity of a forward
ACCEPTED MANUSCRIPT
controller in patients suffering from fear and anxiety-related disorders is not available yet. To verify that cerebellar activity reflects the functioning of a forward model leading to predictions of upcoming harm in anxious patients, studies combining temporary modifications of cerebellar activity by transcranial magnetic stimulation together with threat cue exposure
PT
would be of interest. In a similar manner, presenting patients with ambiguously or mildly threatening cues, or cues that signal a probable but not sure threatening event, and then
RI
measuring their threat-like physiological responses and brain activation, could also shed some
SC
light on whether such a cerebellum-supported aberrant harm prediction is occurring in these patients. Given that the cerebellar predictive function is thought to occur at a subconscious
NU
level (Blakemore and Sirigu, 2003; Moreno-Rius and Miquel, 2017), presentation of
MA
threatening stimuli below the awareness threshold while monitoring cerebellar activity would also be useful to further verify this. In fact, in a recent report in which subliminal trauma-
ED
related cues were presented to PTSD patients, cerebellar activation was found (Rabellino et al., 2016). Also, in order to verify the neurochemical basis of the altered cerebellar function in
EP T
fear and anxiety-related disorders, magnetic resonance spectroscopy studies on the cerebellum of anxiety patients could be of use as well. In animal studies, the combination of fear-related
AC C
behavioral paradigms in which cues anticipate threatening events and modern techniques such as optogenetics would also help to clarify the role of specific cell subtypes and the circuit mechanisms mediating these behaviors within the cerebellum. In conclusion, fear and anxiety-related disorders are severely impairing conditions which may be
lacking
fully
effective
neurobiological basis.
treatments
because
of
incomplete
understanding
of its
The cerebellar activation found in anxious patients might involve the
use of threat memories to recruit forward models which lead to unconscious predictions of the faced situation as harmful. Information regarding this prediction would then be transmitted to
ACCEPTED MANUSCRIPT
other parts of the anxiety circuitry which would prepare the organism for performing the necessary actions to minimize possible harms. Characterizing this process would also be helpful in order to develop strategies to normalize aberrant threat predictions, which may lead to a new therapeutic option to reduce anxiety and treat its associated disorders.
PT
Conflict of Interest Statement: The author reports grants from Austrian Science Foundation (through University of Innsbruck), outside the submitted work.
RI
Acknowledgments: The author thanks Dr. Maria Carbo-Gas, Hussein Ghareh and Arnau
AC C
EP T
ED
MA
NU
SC
Ramos-Prats for their help through the writing process.
ACCEPTED MANUSCRIPT
References Adamaszek, M., D'Agata, F., Ferrucci, R., Habas, C., Keulen, S., Kirkby, K. C., Leggio, M., Mariën, P., Molinari, M., Moulton, E., Orsi, L., Van Overwalle, F., Papadelis, C., Priori, A., Sacchetti, B., Schutter, D. J., Styliadis, C., Verhoeven, J. 2017. Consensus Paper: Cerebellum
PT
and Emotion. Cerebellum. 16(2):552-576. Adamaszek, M., D'Agata, F., Kirkby, K. C., Trenner, M. U., Sehm, B., Steele, C. J.,
RI
Berneiser, J., Strecker, K. 2014. Impairment of emotional facial expression and prosody
SC
discrimination due to ischemic cerebellar lesions. Cerebellum. 13(3):338-45. Addis, D. R., Moloney, E. E., Tippett, L. J., Roberts, R., Hach, S. 2016. Characterizing cerebellar
NU
activity during autobiographical memory: ALE and functional connectivity investigations. Neuropsychologia, 90:80-93.
MA
Ahs, F., Pissiota, A., Michelgård, A., Frans, O., Furmark, T., Appel, L., Fredrikson, M. 2009. Disentangling the web of fear: amygdala reactivity and functional connectivity in spider and snake
ED
phobia. Psychiatry Res. 172(2):103-8.
EP T
Alvares, G. A., Quintana, D. S., Hickie, I. B., Guastella, A. J. 2016. Autonomic nervous system dysfunction in psychiatric disorders and the impact of psychotropic medications: a systematic review and meta-analysis. J. Psychiatry Neurosci. 41(2):89-104.
AC C
Alves, F. H., Gomes, F. V., Reis, D.G., Crestani, C. C., Corrêa, F. M., Guimarães, F. S., Resstel, L. B. 2013. Involvement of the insular cortex in the consolidation and expression of contextual fear conditioning. Eur. J. Neurosci. 38(2):2300-7. An, Y., Chen, C., Inoue, T., Nakagawa, S., Kitaichi, Y., Wang, C., Izumi, T., Kusumi, I. 2016. Mirtazapine exerts an anxiolytic-like effect through activation of the median raphe nucleus-dorsal hippocampal 5-HT pathway in contextual fear conditioning in rats. Prog. Neuropsychopharmacol. Biol. Psychiatry. 70:17-23.
ACCEPTED MANUSCRIPT
Anderson, C. M., Maas, L. C., Frederick, B. D., Bendor, J. T., Spencer, T. J., Livni, E., Lukas, S. E., Fischman, A. J., Madras, B. K., Renshaw, P. F., Kaufman, M. J. 2006. Cerebellar vermis involvement in cocaine-related behaviors. Neuropsychopharmacol. 31(6):1318-26. Andrews, G., Freed, S., Teesson, M. 1994. Proximity and anticipation of a negative outcome in
PT
phobias. Behav. Res. Ther. 32(6):643-5.
RI
Annoni, J. M., Ptak, R., Caldara-Schnetzer, A. S., Khateb, A., Pollermann, B. Z. 2003.
SC
Decoupling of autonomic and cognitive emotional reactions after cerebellar stroke. Ann. Neurol. 53(5):654-8.
NU
Asami, T., Yamasue, H., Hayano, F., Nakamura, M., Uehara, K., Otsuka, T., Roppongi, T., Nihashi, N., Inoue, T., Hirayasu, Y. 2009. Sexually dimorphic gray matter volume reduction in
MA
patients with panic disorder. Psychiatry Res.173(2):128-34. Balaban, C. D., Porter, J. D. 1998. Neuroanatomic substrates for vestibulo -autonomic
ED
interactions. J. Vestib. Res. 8(1):7-16.
EP T
Baldaçara, L., Jackowski, A. P., Schoedl, A., Pupo, M., Andreoli, S. B., Mello, M. F., Lacerda, A. L., Mari, J. J., Bressan, R. A. 2011. Reduced cerebellar left hemisphere and vermal volume in
AC C
adults with PTSD from a community sample. J. Psychiatr. Res. 45(12):1627-33. Ballenger, J. C., Burrows, G. D., DuPont, R. L. Jr., Lesser, I. M., Noyes, R. Jr., Pecknold. J. C., Rifkin, A., Swinson, R. P. 1988. Alprazolam in panic disorder and agoraphobia: results from a multicenter trial. I. Efficacy in short-term treatment. Arch. Gen. Psychiatry. 45(5):413-22. Barrera, T. L., Norton, P. J. 2009. Quality of life impairment in generalized anxiety disorder, social phobia and panic disorder. J. Anxiety Disord. 23(8):1086-90. Beliveau, V., Svarer, C., Frokjaer, V. G., Knudsen, G. M., Greve, D. N., Fisher, P. M. 2015. Functional connectivity of the dorsal and median raphe nuclei at rest. Neuroimage, 116:187-95.
ACCEPTED MANUSCRIPT
Bellebaum, C., Daum, I. 2007. Cerebellar involvement in executive control. Cerebellum 6, 184– 92. Berntson, G. G., Torello, M. W. 1982. The paleocerebellum and the integration of behavioral function. Physiol. Psychology, 10(1), 2-12.
PT
Bing, X., Ming-Guo, Q., Ye, Z., Jing-Na, Z., Min, L., Han, C., Yu, Z., Jia-Jia, Z., Jian, W., Wei, C., Han-Jian, D., Shao-Xiang, Z. 2013. Alterations in the cortical thickness and the amplitude of
RI
low-frequency fluctuation in patients with post-traumatic stress disorder. Brain Res. 1490:225-32.
the rat cerebellum. Brain Res. 331(2):195-207.
SC
Bishop, G. A., Ho, R. H. 1985. The distribution and origin of serotonin immunoreactivity in
NU
Blackwood, N., Simmons, A., Bentall, R., Murray, R., & Howard, R. 2004. The cerebellum and
MA
decision making under uncertainty. Cogn. Brain Res. 20(1), 46-53. Blakemore, S.J., Sirigu, A. 2003. Action prediction in the cerebellum and in the parietal lobe. Exp.
ED
Brain Res. 153, 239–45.
Bonne, O., Gilboa, A., Louzoun, Y., Brandes, D., Yona, I., Lester, H., Barkai, G., Freedman, N.,
EP T
Chisin, R., Shalev, A. Y. 2003. Resting regional cerebral perfusion in recent posttraumatic stress disorder. Biol. Psychiatry, 54(10):1077-86.
AC C
Borkovec, T. D. 1985. The role of cognitive and somatic cues in anxiety and anxiety disorders: Worry and relaxation-induced anxiety. In A. H. Tuma & J. D. Maser (Eds.), Anxiety and the anxiety disorders (pp. 463-478). Hillsdale, NJ: Lawrence Erlbaum Associates Borsook, D., Edwards, R., Elman, I., Becerra, L., Levine, J. 2013. Pain and analgesia: the value of salience circuits. Prog. Neurobiol. 104:93-105. Bostan, A.C., Dum, R.P., Strick, P.L. 2013. Cerebellar networks with the cerebral cortex and basal ganglia. Trends Cogn. Sci. 17, 241–54.
ACCEPTED MANUSCRIPT
Brodkin, J., Busse, C., Sukoff, S. J., Varney, M. A. 2002. Anxiolytic-like activity of the mGluR5 antagonist MPEP: a comparison with diazepam and buspirone. Pharmacol. Biochem. Behav. 73(2):359-66. Brown, T. M., Boudewyns, P. A. 1996. Periodic limb movements of sleep in combat veterans
PT
with posttraumatic stress disorder. J. Trauma Stress. 9(1):129-36. Brown, E.C., Brüne, M. 2012. The role of prediction in social neuroscience. Front. Hum.
RI
Neurosci. 6, 147.
SC
Calhoon, G. G., Tye, K. M. 2015. Resolving the neural circuits of anxiety. Nat. Neurosci. 18(10):1394-404.
NU
Carbo-Gas, M., Moreno-Rius, J., Guarque-Chabrera, J., Vazquez-Sanroman, D., Gil-Miravet, I.,
MA
Carulli, D., Hoebeek, F., De Zeeuw, C., Sanchis-Segura, C., Miquel M. 2017. Cerebellar perineuronal nets in cocaine-induced pavlovian memory: Site matters. Neuropharmacology.
ED
125:166-180.
Carbo-Gas, M., Vazquez-Sanroman, D., Aguirre-Manzo, L., Coria-Avila, G.A., Manzo, J.,
EP T
Sanchis-Segura, C., Miquel, M. 2014. Involving the cerebellum in cocaine-induced memory: pattern of cFos expression in mice trained to acquire conditioned preference for cocaine. Addict. Biol.19(1), 61–76.
AC C
Carlsson, K., Petersson, K. M., Lundqvist, D., Karlsson, A., Ingvar, M., Ohman, A. 2004. Fear and the amygdala: manipulation of awareness generates differential cerebral responses to phobic and fear-relevant (but nonfeared) stimuli. Emotion. 4(4):340-53. Carrion, V. G., Weems, C. F., Watson, C., Eliez, S., Menon, V., Reiss, A. L. 2009. Converging evidence for abnormalities of the prefrontal cortex and evaluation of midsagittal structures in pediatric posttraumatic stress disorder: an MRI study. Psychiatry Res. 172(3):226-34.
ACCEPTED MANUSCRIPT
Carnell, S., Benson, L., Pantazatos, S.P., Hirsch, J., Geliebter, A. 2014. Amodal brain activation and functional connectivity in response to high-energy-density food cues in obesity. Obesity 22, 2370–8. Casacalenda, N., Boulenger, J. P. 1998. Pharmacologic treatments effective in both generalized anxiety disorder and major depressive disorder: clinical and theoretical
PT
implications. Can. J. Psychiatry. 43(7):722-30.
RI
Caseras, X., Giampietro, V., Lamas, A., Brammer, M., Vilarroya, O., Carmona, S., Rovira, M.,
SC
Torrubia, R., Mataix-Cols, D. 2010. The functional neuroanatomy of blood-injection-injury phobia: a comparison with spider phobics and healthy controls. Psychol. Med. 40(1):125-34.
NU
Cassimjee, N., Fouche, J. P., Burnett, M., Lochner, C., Warwick, J., Dupont, P., Stein, D. J., Cloete, K. J., Carey, P. D. 2010. Changes in regional brain volumes in social anxiety disorder
MA
following 12 weeks of treatment with escitalopram. Metab. Brain Dis. 25(4):369-74. Cauda, F., Cavanna, A. E., D'agata, F., Sacco, K., Duca, S., Geminiani, G. C. 2011. Functional
ED
connectivity and coactivation of the nucleus accumbens: a combined functional connectivity and
EP T
structure-based meta-analysis. J. Cogn. Neurosci. 23(10), 2864-77. Caulfield, M. D., Zhu, D. C., McAuley, J. D., Servatius, R. J. 2016. Individual differences in resting-state functional connectivity with the executive network: support for a cerebellar role in
AC C
anxiety vulnerability. Brain Struct. Funct. 221(6):3081-93. Cha, J., Carlson, J. M., Dedora, D. J., Greenberg, T., Proudfit, G. H., Mujica-Parodi, L. R. 2014. Hyper-reactive human ventral tegmental area and aberrant mesocorticolimbic connectivity in overgeneralization of fear in generalized anxiety disorder. J. Neurosci. 34(17):5855-60. Clark, D. B., Taylor, C. B., Hayward, C., King, R., Margraf, J., Ehlers, A., Roth, W. T., Agras, W. S. 1990. Motor activity and tonic heart rate in panic disorder. Psychiatry Res. 32(1):45-53.
ACCEPTED MANUSCRIPT
Courchesne, E., Allen, G. 1997. Prediction and preparation, fundamental functions of the cerebellum. Learn. Mem. 4, 1–35. Crozier, J. C., Wang, L., Huettel, S. A., De Bellis, M. D. 2014. Neural correlates of cognitive and affective processing in maltreated youth with posttraumatic stress symptoms: does gender matter?
PT
Dev. Psychopathol. 26(2):491-513. Cservenka, A., Casimo, K., Fair, D. A., Nagel, B. J. 2014. Resting state functional connectivity of
RI
the nucleus accumbens in youth with a family history of alcoholism. Psychiatry Res:
SC
Neuroimaging, 221(3), 210-9.
D’Angelo, E., Casali, S. 2013. Seeking a unified framework for cerebellar function and
NU
dysfunction: from circuit operations to cognition. Front. Neural Circuits, 6:116.
MA
Dahhaoui, M., Caston, J., Auvray, N., Reber, A. 1990. Role of the cerebellum in an avoidance conditioning task in the rat. Physiol. Beh. 47(6):1175-80.
ED
Davis, M., Redmond, D. E. Jr., Baraban, J. M. 1979. Noradrenergic agonists and antagonists: effects on conditioned fear as measured by the potentiated startle paradigm.
EP T
Psychopharmacology (Berl).65(2):111-8. Davies, M. F., Tsui, J., Flannery, J. A., Li, X., DeLorey, T. M., Hoffman, B. B. 2004. Activation of alpha2 adrenergic receptors suppresses fear conditioning: expression of c-Fos
AC C
and phosphorylated CREB in mouse amygdala. Neuropsychopharmacol. 29(2):229-39. De Bellis, M. D., Kuchibhatla, M. 2006. Cerebellar volumes in pediatric maltreatment-related posttraumatic stress disorder. Biol. Psychiatry, 60(7):697-703. Dejean, C., Courtin, J., Rozeske, R. R., Bonnet, M. C., Dousset, V., Michelet, T., Herry, C. 2015. Neuronal Circuits for Fear Expression and Recovery: Recent Advances and Potential Therapeutic Strategies. Biol.Psychiatry. 78(5):298-306.
ACCEPTED MANUSCRIPT
Doruyter, A., Lochner, C., Jordaan, G. P., Stein, D. J., Dupont, P., Warwick, J.,M. 2016. Resting functional connectivity in social anxiety disorder and the effect of pharmacotherapy. Psychiatry Res. 251:34-44. Downar, J., Crawley, A. P., Mikulis, D. J., Davis, K. D. 2002. A cortical network sensitive to stimulus salience in a neutral behavioral context across multiple sensory modalities. J.
PT
Neurophysiol. 87(1):615-20.
RI
Driessen, M., Beblo, T., Mertens, M., Piefke, M., Rullkoetter, N., Silva-Saavedra, A., Reddemann,
SC
L., Rau, H., Markowitsch, H. J., Wulff, H., Lange, W., Woermann, F.G. 2004. Posttraumatic stress disorder and fMRI activation patterns of traumatic memory in patients with borderline personality
NU
disorder. Biol. Psychiatry, 55(6):603-11.
Emerson, J. D., Bruhn, J. M., Emerson, G. M., Foley, J. O. 1961. Autonomic response to
MA
chronic electrode stimulation of cerebellum. Am. J. Physiol. 201:697-9. Etkin, A., Prater, K. E., Schatzberg, A. F., Menon, V., Greicius, M. D. 2009. Disrupted amygdalar
ED
subregion functional connectivity and evidence of a compensatory network in generalized anxiety disorder. Arch.Gen. Psychiatry, 66(12), 1361-72.
EP T
Evans, K. C., Wright, C. I., Wedig, M. M., Gold, A. L., Pollack, M. H., Rauch, S. L. 2008. A functional MRI study of amygdala responses to angry schematic faces in social anxiety disorder.
AC C
Depress.Anxiety. 25(6):496-505.
Farley, S. J., Radley, J. J., Freeman, J. H. 2016. Amygdala Modulation of Cerebellar Learning. J. Neurosci. 36(7):2190-201. Felmingham, K. L., Falconer, E. M., Williams, L., Kemp, A. H., Allen, A., Peduto, A., Bryant, R. A. 2014. Reduced amygdala and ventral striatal activity to happy faces in PTSD is associated with emotional numbing. PLoS One. 9(9):e103653. Fish, B. S., Baisden, R. H., Woodruff, M. L. 1979. Cerebellar nuclear lesions in rats: subsequent avoidance behavior and ascending anatomical connections. Brain Res. 166(1):27-38.
ACCEPTED MANUSCRIPT
Fokos, S., Panagis, G. 2010. Effects of delta9-tetrahydrocannabinol on reward and anxiety in rats exposed to chronic unpredictable stress. J. Psychopharmacol. 24(5):767-77. Friedman, B. H. 2007. An autonomic flexibility-neurovisceral integration model of anxiety and cardiac vagal tone. Biol. Psychol. 74(2):185-99. Garrison, J., Erdeniz, B., Done, J. 2013. Prediction error in reinforcement learning: a
PT
meta-analysis of neuroimaging studies. Neurosci. Biobehav. Rev. 37(7):1297-310.
RI
Gianlorenço, A. C., Canto-de-Souza, A., Mattioli, R. 2013. Intra-cerebellar microinjection of histamine enhances memory consolidation of inhibitory avoidance learning in mice via H2
SC
receptors. Neurosci. Lett. 557:159-64.
NU
Gianlorenço, A. C., Riboldi, A. M., Silva-Marques, B., Mattioli, R. 2015. Cerebellar vermis H₂ receptors mediate fear memory consolidation in mice. Neurosci. Lett. 587:57-61.
MA
Giménez, M., Pujol, J., Ortiz, H., Soriano-Mas, C., López-Solà, M., Farré, M., Deus, J., MerloPich, E., Martín-Santos, R. 2012. Altered brain functional connectivity in relation to perception of scrutiny in social anxiety disorder. Psychiatry Res. 202(3):214-23.
ED
Goossens, L., Schruers, K., Peeters, R., Griez, E., Sunaert, S. 2007. Visual presentation of phobic
EP T
stimuli: amygdala activation via an extrageniculostriate pathway? Psychiatry Res.155(2):113-20. Graeff, F. G. 2004. Serotonin, the periaqueductal gray and panic. Neurosci. Biobehav. Rev. 28(3):239-59.
AC C
Gray, J. A. 1982. The Neuropsychology of anxiety: an enquiry into the functions of the septohippocampal system, 1st ed. Oxford: Oxford University Press Gray, J. A., McNaughton, N. 2003. The neuropsychology of anxiety: An enquiry into the function of the septo-hippocampal system, second edition. Oxford: Oxford University Press. Grillon, C., Lissek, S., Rabin, S., McDowell, D., Dvir, S., Pine, D. S. 2008. Increased anxiety during anticipation of unpredictable but not predictable aversive stimuli as a psychophysiologic marker of panic disorder. Am. J. Psychiatry, 165(7):898-904. Grupe, D. W., Nitschke, J. B. 2013. Uncertainty and anticipation in anxiety: an integrated neurobiological and psychological perspective. Nat. Rev. Neurosci. 14(7):488-501.
ACCEPTED MANUSCRIPT
Guillaumin, S., Dahhaoui, M., Caston, J. 1991. Cerebellum and memory: an experimental study in the rat using a passive avoidance conditioning test. Physiol. Beh. 49(3):507-11. Gunduz-Cinar, O., Flynn, S., Brockway, E., Kaugars, K., Baldi, R., Ramikie, T. S., Cinar, R., Kunos, G., Patel, S., Holmes, A. 2016. Fluoxetine Facilitates Fear Extinction Through Amygdala Endocannabinoids. Neuropsychopharmacol. 41(6):1598-609
PT
Habas, C., Kamdar, N., Nguyen, D., Prater, K., Beckmann, C. F., Menon, V., Greicius, M. D.
RI
2009. Distinct cerebellar contributions to intrinsic connectivity networks. J.Neurosci. 29(26),
SC
8586-94.
Harricharan, S., Rabellino, D., Frewen, P. A., Densmore, M., Théberge, J., McKinnon, M. C.,
NU
Schore, A. N., Lanius, R. A. 2016. fMRI functional connectivity of the periaqueductal gray in PTSD and its dissociative subtype. Brain Behav. (12):e00579.
MA
Hazlett, R. L., McLeod, D. R., Hoehn-Saric, R.. 1994. Muscle tension in generalized anxiety disorder: elevated muscle tonus or agitated movement? Psychophysiology. 31(2):189-95.
ED
Hazlett-Stevens, H., Borkovec, T. D. 2004. Interpretive cues and ambiguity in generalized anxiety
EP T
disorder. Behav. Res. Ther. 42(8):881-92.
Heath, R. G., Dempsey, C. W., Fontana, C. J., Myers, W. A. 1978 Cerebellar stimulation: effects on septal region, hippocampus, and amygdala of cats and rats. Biol. Psychiatry.
AC C
13(5):501-29.
Heeren, A., Dricot, L., Billieux, J., Philippot, P., Grynberg, D., de Timary, P., Maurage, P. 2017. Correlates of Social Exclusion in Social Anxiety Disorder: An fMRI study. Sci. Rep. 7(1):260. Herculano-Houzel, S. 2009. The human brain in numbers: a linearly scaled-up primate brain. Front. Hum. Neurosci. 3(November), article 31. Hilbert, K., Evens, R., Maslowski, N. I., Wittchen, H. U., Lueken, U. 2015. Neurostructural correlates of two subtypes of specific phobia: a voxel-based morphometry study. Psychiatry Res. 231(2):168-75.
ACCEPTED MANUSCRIPT
Hilbert, K., Lueken, U., Beesdo-Baum, K. 2014. Neural structures, functioning and connectivity in Generalized Anxiety Disorder and interaction with neuroendocrine systems: a systematic review. J. Affect. Disord. 158:114-26. Hofmann, S. G., Otto, M. W., Pollack, M. H., Smits, J. A. 2015. D-cycloserine augmentation
PT
of cognitive behavioral therapy for anxiety disorders: an update. Curr. Psychiatry Rep. 17(1):532.
RI
Igelström, K. M., Webb, T. W., Graziano, M. S. A. 2017. Functional Connectivity Between
SC
the Temporoparietal Cortex and Cerebellum in Autism Spectrum Disorder. Cereb. Cortex. 27(4):2617-2627.
NU
Igloi, K., Doeller, C.F., Paradis, A.-L., Benchenane, K., Berthoz, A., Burgess, N., Rondi-Reig, L. 2014. Interaction between hippocampus and cerebellum crus I in sequence-based but not place-
MA
based navigation. Cereb. Cortex 25(11):4146-54.
Ikai, Y., Takada, M., Shinonaga, Y., Mizuno, N. 1992. Dopaminergic and non-dopaminergic
ED
neurons in the ventral tegmental area of the rat project, respectively, to the cerebellar cortex and
EP T
deep cerebellar nuclei. Neuroscience 51(3), 719–28. Ito, M. 2008. Control of mental activities by internal models in the cerebellum. Nat. Rev. Neurosci. 9, 304–13.
AC C
Jatzko, A., Rothenhöfer, S., Schmitt, A., Gaser, C., Demirakca, T., Weber-Fahr, W., Wessa, M., Magnotta, V., Braus, D. F. 2006. Hippocampal volume in chronic posttraumatic stress disorder (PTSD): MRI study using two different evaluation methods. J. Affect. Disord. 94(1-3):121-6 Kalk, N. J., Melichar, J., Holmes, R. B., Taylor, L. G., Daglish, M. R., Hood, S., Edwards, T., Lennox-Smith, A., Lingford-Hughes, A. R., Nutt, D. J. 2012. Central noradrenergic responsiveness to a clonidine challenge in Generalized Anxiety Disorder: a Single Photon Emission Computed Tomography study. J. Psychopharmacol. 26(4):452-60.
ACCEPTED MANUSCRIPT
Kaufman, G. D., Mustari, M. J., Miselis, R. R., Perachio, A. A. 1996. Transneuronal pathways to the vestibulocerebellum. J. Comp. Neurol. 370(4):501-23 Ke, J., Zhang, L., Qi, R., Li, W., Hou, C., Zhong, Y., He, Z., Li, L., Lu, G. 2016. A longitudinal fMRI investigation in acute post-traumatic stress disorder (PTSD). Acta Radiol. 57(11):1387-
PT
1395. Kelly, R.M., Strick, P.L. 2003. Cerebellar loops with motor cortex and prefrontal cortex of a
RI
nonhuman primate. J. Neurosci. 23, 8432–44.
SC
Killgore, W. D., Young, A. D., Femia, L. A., Bogorodzki, P., Rogowska, J., Yurgelun-Todd, D. A. 2003. Cortical and limbic activation during viewing of high- versus low-calorie foods.
NU
Neuroimage, 19(4):1381-94.
MA
Kilts, C. D., Kelsey, J. E., Knight, B., Ely, T. D., Bowman, F. D., Gross, R. E., Selvig, A., Gordon, A., Newport, D. J., Nemeroff, C. B. 2006.The neural correlates of social anxiety disorder
ED
and response to pharmacotherapy. Neuropsychopharmacol. 31(10):2243-53. Kline, R. L., Zhang, S., Farr, O. M., Hu, S., Zaborszky, L., Samanez-Larkin, G. R., Li, C. S. R.
EP T
2016. The Effects of Methylphenidate on Resting-State Functional Connectivity of the Basal Nucleus of Meynert, Locus Coeruleus, and Ventral Tegmental Area in Healthy Adults. Front. Hum. Neurosci. 10:149.
AC C
Klumpp, H., Angstadt, M., Phan, K. L. 2012. Insula reactivity and connectivity to anterior cingulate cortex when processing threat in generalized social anxiety disorder. Biol. Psychol. 89(1):273-6.
Koehler, S., Ovadia-Caro, S., van der Meer, E., Villringer, A., Heinz, A., Romanczuk-Seiferth, N., Margulies, D. S. 2013. Increased functional connectivity between prefrontal cortex and reward system in pathological gambling. PLoS One, 8(12), e84565. Konishi, J., Asami, T., Hayano, F., Yoshimi, A., Hayasaka, S., Fukushima, H., Whitford, T. J., Inoue, T., Hirayasu, Y. 2014. Multiple white matter volume reductions in patients with panic
ACCEPTED MANUSCRIPT
disorder: relationships between orbitofrontal Gyrus volume and symptom severity and social dysfunction. PLoS One. 9(3):e92862. Koutsikou, S., Crook, J. J., Earl, E. V., Leith, J. L., Watson, T. C., Lumb, B. M., Apps, R. 2014. Neural substrates underlying fear-evoked freezing: the periaqueductal grey-cerebellar link. J.
PT
Physiol. 592(10):2197-213. Kwon, H. G., & Jang, S. H. 2014. Differences in neural connectivity between the substantia nigra
RI
and ventral tegmental area in the human brain. Front. Hum. Neurosci. 8, 41.
SC
Lai, C. H., Hsu, Y. Y. 2011. A subtle grey-matter increase in first-episode, drug-naive major
Neuropsychopharmacol.;14(2):225-35.
NU
depressive disorder with panic disorder after 6 weeks' duloxetine therapy. Int. J.
MA
LeDoux, J. E. 2000. Emotion circuits in the brain. Annu. Rev. Neurosci. 23:155-84. Leutgeb, V., Wabnegger, A., Leitner, M., Zussner, T., Scharmüller, W., Klug, D., Schienle, A.
Neurosci. Lett. 610, 160-164.
ED
2016. Altered cerebellar-amygdala connectivity in violent offenders: A resting-state fMRI study.
EP T
Liao, W., Qiu, C., Gentili, C., Walter, M., Pan, Z., Ding, J., Zhang, W., Gong, Q., Chen, H. 2010. Altered effective connectivity network of the amygdala in social anxiety disorder: a resting-state
AC C
FMRI study. PLoS One. 5(12):e15238. Liberzon, I., Martis, B. 2006. Neuroimaging studies of emotional responses in PTSD. Ann. N. Y. Acad. Sci. 1071:87-109.
Liu, Y., Formisano, L., Savtchouk, I., Takayasu, Y., Szabó, G., Zukin, R. S., Liu, S. J. 2010. A single fear-inducing stimulus induces a transcription-dependent switch in synaptic AMPAR phenotype. Nat. Neurosci. 13(2):223-31.
ACCEPTED MANUSCRIPT
Liu, W. J., Yin, D. Z., Cheng, W. H., Fan, M. X., You, M. N., Men, W. W., Zang, L. L., Shi, D. H., Zhang, F. 2015. Abnormal functional connectivity of the amygdala-based network in restingstate FMRI in adolescents with generalized anxiety disorder. Med. Sci. Monit. 21:459-67. Lorivel, T., Gras, M., Hilber, P. 2010. Effects of corticosterone synthesis inhibitor metyrapone on
PT
anxiety-related behaviors in Lurcher mutant mice. Physiol. Beh. 101(2):309-14. Lorivel, T., Hilber, P. 2006. Effects of chlordiazepoxide on the emotional reactivity and motor
RI
capacities in the cerebellar Lurcher mutant mice. Behav. Brain Res. 173(1):122-8.
SC
Lorivel, T., Roy, V., Hilber, P. 2014. Fear-related behaviors in Lurcher mutant mice exposed to a predator. Genes Brain Beh. 13(8):794-801.
NU
Lupo, M., Troisi, E., Chiricozzi, F. R., Clausi, S., Molinari, M., Leggio, M. 2015. Inability to
MA
Process Negative Emotions in Cerebellar Damage: a Functional Transcranial Doppler Sonographic Study. Cerebellum. 14(6):663-9.
ED
Malta, L. S., Wyka, K. E., Giosan, C., Jayasinghe, N., Difede, J. 2009 Numbing symptoms as predictors of unremitting posttraumatic stress disorder. J. Anxiety Disord. 23(2):223-9.
EP T
Marchand, W. R., Lee, J. N., Healy, L., Thatcher, J. W., Rashkin, E., Starr, J., Hsu, E. 2009. An fMRI motor activation paradigm demonstrates abnormalities of putamen activation in
AC C
females with panic disorder. J. Affect. Disord. 116(1-2):121-5. McNaughton, N., Corr, P. J. 2004. A two-dimensional neuropsychology of defense: fear/anxiety and defensive distance. Neurosci. Biobehav. Rev. 28(3):285-305. Melchitzky, D.S., Lewis, D.A. 2000. Tyrosine hydroxylase- and dopamine transporterimmunoreactive axons in the primate cerebellum dopamine innervation. Neuropsychopharmacol. 22(5), 466–72. Miall, R. C., Weir, D. J., Wolpert, D. M., Stein, J. F. 1993. Is the cerebellum a smith predictor? J Mot. Beh. 25(3):203-16.
ACCEPTED MANUSCRIPT
Molinari, M., Chiricozzi, F. R., Clausi, S., Tedesco, A. M., De Lisa, M., Leggio, M. G. 2008. Cerebellum and detection of sequences, from perception to cognition. Cerebellum. 7(4):6115. Moreno-Rius, J., Miquel, M. 2017. The cerebellum in drug craving. Drug Alcohol Depend.
PT
173:151-158. Moruzzi, G. 1947. Sham rage and localized autonomic responses elicited by cerebellar
RI
stimulation in the acute thalamic cat. Proc. XVII Internat. Congress Physiol. Oxford, 114-115.
SC
Moulton, E. A., Elman, I., Pendse, G., Schmahmann, J., Becerra, L., Borsook, D. 2011. Aversionrelated circuitry in the cerebellum: responses to noxious heat and unpleasant images. J. Neurosci.
NU
31(10), 3795-804.
MA
Mueller-Pfeiffer, C., Zeffiro, T., O'Gorman, R., Michels, L., Baumann, P., Wood, N., Spring, J., Rufer, M., Pitman, R. K., Orr, S. P. 2014. Cortical and cerebellar modulation of
ED
autonomic responses to loud sounds. Psychophysiology. 51(1):60-9. Nakao, T., Sanematsu, H., Yoshiura, T., Togao, O., Murayama, K., Tomita, M., Masuda, Y.,
EP T
Kanba, S. 2011. fMRI of patients with social anxiety disorder during a social situation task. Neurosci. Res. 69(1):67-72.
Norris, C., Loureiro, M., Kramar, C., Zunder, J., Renard, J., Rushlow, W., Laviolette, S. R. 2016.
AC C
Cannabidiol Modulates Fear Memory Formation Through Interactions with Serotonergic Transmission in the Mesolimbic System. Neuropsychopharmacol. 41(12):2839-2850. O'Reilly, J. X., Beckmann, C. F., Tomassini, V., Ramnani, N., & Johansen-Berg, H. 2010. Distinct and overlapping functional zones in the cerebellum defined by resting state functional connectivity. Cereb. Cortex, 20(4), 953-65. Oades, R. D., Halliday, G. M. 1987. Ventral tegmental (A10) system: neurobiology. 1. Anatomy and connectivity. Brain Res. 434(2):117-65.
ACCEPTED MANUSCRIPT
Olesen, J., Gustavsson, A., Svensson, M., Wittchen, H. U., Jönsson, B.; CDBE2010 study group; European Brain Council. 2012. The economic cost of brain disorders in Europe. Eur. J. Neurol. 19(1):155-62. Onuki, Y., Van Someren, E. J., De Zeeuw, C. I., Van der Werf, Y. D. 2015. Hippocampal–
PT
cerebellar interaction during spatio-temporal prediction. Cereb. Cortex 25(2), 313-21. Otsuka, S., Konno, K., Abe, M., Motohashi, J., Kohda, K., Sakimura, K., Watanabe, M., Yuzaki,
RI
M. 2016. Roles of Cbln1 in Non-Motor Functions of Mice. J. Neurosci. 36(46), 11801-11816.
SC
Perusini, J. N., Fanselow, M. S. 2015. Neurobehavioral perspectives on the distinction between fear and anxiety. Learn Mem. 22(9):417-25.
NU
Peters, J., Dieppa-Perea, L. M., Melendez, L. M., Quirk, G. J. 2010. Induction of fear extinction
MA
with hippocampal-infralimbic BDNF. Science. 328(5983):1288-90. Pignatelli, M., Umanah, G. K., Ribeiro, S. P., Chen, R., Karuppagounder, S. S., Yau, H. J., Eacker,
ED
S., Dawson, V. L., Dawson, T. M., Bonci, A. 2017. Synaptic Plasticity onto Dopamine Neurons Shapes Fear Learning. Neuron. 93(2):425-440.
EP T
Pyke, R. E., Greenberg, H. S. 1986. Norepinephrine challenges in panic patients. J. Clin. Psychopharmacol. 6(5):279-85.
AC C
Rabellino, D., Densmore, M., Frewen, P. A., Théberge, J., Lanius, R. A. 2016. The innate alarm circuit in post-traumatic stress disorder: Conscious and subconscious processing of fear- and trauma-related cues. Psychiatry Res. 248:142-50. Ravindran, L. N., Stein, M. B. 2010. The pharmacologic treatment of anxiety disorders: a review of progress. J. Clin. Psychiatry. 71(7):839-54. Rickels, K., Rynn, M. 2002. Pharmacotherapy of generalized anxiety disorder. J. Clin. Psychiatry. 63 Suppl 14:9-16.
ACCEPTED MANUSCRIPT
Roy, A. K., Fudge, J. L., Kelly, C., Perry, J. S., Daniele, T., Carlisi, C., Benson, B., Castellanos, F. X., Milham, M. P., Pine, D. S., Ernst, M. 2013. Intrinsic functional connectivity of amygdalabased networks in adolescent generalized anxiety disorder. J Am. Acad. Child Adolesc. Psychiatry; 52(3):290-299.
PT
Rubino, T., Sala, M., Viganò, D., Braida, D., Castiglioni, C., Limonta, V., Guidali, C., Realini, N., Parolaro, D. 2007. Cellular mechanisms underlying the anxiolytic effect of low
RI
doses of peripheral Delta9-tetrahydrocannabinol in rats. Neuropsychopharmacol. 32(9):2036-
SC
45.
Sacchetti, B., Scelfo, B., Tempia, F., Strata, P. 2004. Long-term synaptic changes induced in the
NU
cerebellar cortex by fear conditioning. Neuron 42(6), 973–82.
consolidation. PNAS, 99(12):8406-11.
MA
Sacchetti, B., Baldi, E., Lorenzini, C. A., Bucherelli, C. 2002. Cerebellar role in fear-conditioning
Sacchetti, B., Sacco, T., Strata, P. 2007. Reversible inactivation of amygdala and cerebellum but
ED
not perirhinal cortex impairs reactivated fear memories. Eur. J. Neurosci. 25(9):2875-84.
EP T
Sakai, Y., Kumano, H., Nishikawa, M., Sakano, Y., Kaiya, H., Imabayashi, E., Ohnishi, T., Matsuda, H., Yasuda, A., Sato, A., Diksic, M., Kuboki, T. 2005. Cerebral glucose metabolism associated with a fear network in panic disorder. Neuroreport; 16(9):927-31.
AC C
Sakai, Y., Kumano, H., Nishikawa, M., Sakano, Y., Kaiya, H., Imabayashi, E., Ohnishi, T., Matsuda, H., Yasuda, A., Sato, A., Diksic, M., Kuboki, T. 2006. Changes in cerebral glucose utilization in patients with panic disorder treated with cognitive-behavioral therapy. Neuroimage, 33(1):218-26. Sang, L., Qin, W., Liu, Y., Han, W., Zhang, Y., Jiang, T., Yu, C. 2012. Resting-state functional connectivity of the vermal and hemispheric subregions of the cerebellum with both the cerebral cortical networks and subcortical structures. Neuroimage, 61(4), 1213-25.
ACCEPTED MANUSCRIPT
Scelfo, B., Sacchetti, B., Strata, P. 2008. Learning-related long-term potentiation of inhibitory synapses in the cerebellar cortex. PNAS. 105(2):769-74. Schweckendiek, J., Klucken, T., Merz, C. J., Tabbert, K., Walter, B., Ambach, W., Vaitl, D., Stark, R. 2011. Weaving the (neuronal) web: fear learning in spider phobia. Neuroimage;
PT
54(1):681-8. Sethi, B. B., Trivedi, J. K., Kumar, P., Gulati, A., Agarwal, A. K., Sethi, N. 1986. Antianxiety
RI
effect of cannabis: involvement of central benzodiazepine receptors. Biol. Psychiatry. 21(1):3-
SC
10
Shinn, A. K., Baker, J. T., Lewandowski, K. E., Öngür, D., Cohen, B. M. 2015. Aberrant
NU
cerebellar connectivity in motor and association networks in schizophrenia. Front. Hum.
MA
Neurosci. 9:134.
Small, K. M., Nunes, E., Hughley, S., Addy, N. A. 2016. Ventral tegmental area muscarinic
ED
receptors modulate depression and anxiety-related behaviors in rats. Neurosci. Lett. 616:80-5. Smith, K. S., Engin, E., Meloni, E. G., Rudolph, U. 2012. Benzodiazepine-induced anxiolysis
EP T
and reduction of conditioned fear are mediated by distinct GABAA receptor subtypes in mice. Neuropharmacology. 63(2):250-8. Snider, R. S. 1950. Recent contributions to the anatomy and physiology of the cerebellum.
AC C
Arch. Neurol. Psychiatry; 64(2):196-219. Snider, R. S., Maiti, A. 1975. Septal afterdischarges and their modification by the cerebellum. Exp. Neurol. 49(2):529-39. Snider, R. S., Maiti, A. 1976. Cerebellar contributions to the Papez circuit. J. Neurosci. Res. 2(2):133-46. Spindelegger, C., Lanzenberger, R., Wadsak, W., Mien, L. K., Stein, P., Mitterhauser, M., Moser, U., Holik, A., Pezawas, L., Kletter, K., Kasper, S. 2009. Influence of escitalopram treatment on 5-
ACCEPTED MANUSCRIPT
HT 1A receptor binding in limbic regions in patients with anxiety disorders. Mol. Psychiatry. 14(11):1040-50. Steinmetz, J. E., Logue, S. F., Miller, D. P. 1993. Using signaled barpressing tasks to study the neural substrates of appetitive and aversive learning in rats: behavioral manipulations and
PT
cerebellar lesions. Behav. Neurosci. 107(6):941-54. Supple, W. F. Jr., Kapp, B. S. 1993. The anterior cerebellar vermis: essential involvement in
RI
classically conditioned bradycardia in the rabbit. J. Neurosci. 13(9):3705-11.
SC
Supple, W. F. Jr., Leaton, R. N. 1990a. Cerebellar vermis: essential for classically conditioned bradycardia in the rat. Brain Res. 509(1):17-23.
NU
Supple, W. F. Jr., Leaton, R. N. 1990b. Lesions of the cerebellar vermis and cerebellar
MA
hemispheres: effects on heart rate conditioning in rats . Behav. Neurosci. 104(6):934-47. Supple, W. F. Jr., Leaton, R. N., Fanselow, M. S. 1987. Effects of cerebellar vermal lesions on
ED
species-specific fear responses, neophobia, and taste-aversion learning in rats. Physiol.Beh. 39(5):579-86.
EP T
Swanson, L. W. 1977. The anatomical organization of septo-hippocampal projections. Ciba Found. Symp. (58):25-48.
AC C
Talati, A., Pantazatos, S. P., Hirsch, J., Schneier, F. 2015. A pilot study of gray matter volume changes associated with paroxetine treatment and response in social anxiety disorder. Psychiatry Res. 231(3):279-85.
Talati, A., Pantazatos, S. P., Schneier, F. R., Weissman, M. M., Hirsch, J. 2013. Gray matter abnormalities in social anxiety disorder: primary, replication, and specificity studies. Biol. Psychiatry. 73(1):75-84.
ACCEPTED MANUSCRIPT
Tanaka, S.C., Doya, K., Okada, G., Ueda, K., Okamoto, Y., Yamawaki, S. 2004. Prediction of immediate and future rewards differentially recruits cortico-basal ganglia loops. Nat. Neurosci. 7, 887–93. Taylor, J. M., Whalen, P. J. 2015. Neuroimaging and Anxiety: the Neural Substrates of
PT
Pathological and Non-pathological Anxiety. Curr. Psychiatry Rep. 17(6):49. Tillfors, M., Furmark, T., Marteinsdottir, I., Fredrikson, M. 2002. Cerebral blood flow during
RI
anticipation of public speaking in social phobia: a PET study. Biol. Psychiatry 52(11):1113-9.
SC
Timić, T., Joksimović, S., Milić, M., Divljaković, J., Batinić, B., Savić, M. M. 2013. Midazolam impairs acquisition and retrieval, but not consolidation of reference memory in
NU
the Morris water maze. Behav. Brain Res. 241:198-205.
MA
Tomasi, D., & Volkow, N. D. 2011. Association between functional connectivity hubs and brain networks. Cereb. Cortex, 21(9), 2003-13.
ED
Toth, I., Neumann, I. D., Slattery, D. A. 2012. Social fear conditioning: a novel and specific animal model to study social anxiety disorder. Neuropsychopharmacol. 37(6):1433-43.
16(6):317-31.
EP T
Tovote, P., Fadok, J. P., Lüthi, A. 2015. Neuronal circuits for fear and anxiety. Nat. Rev. Neurosci.
AC C
Uddin, L. Q. 2015. Salience processing and insular cortical function and dysfunction. Nat. Rev. Neurosci. 16(1):55-61. Van der Meer, M.A., Redish, A.D. 2010. Expectancies in decision making, reinforcement learning, and ventral striatum. Front. Neurosci. 4, 29–37. Volkow, N.D., Wang, G.-J., Ma, Y., Fowler, J.S., Zhu, W., Maynard, L., Swanson, J.M. 2003. Expectation enhances the regional brain metabolic and the reinforcing effects of stimulants in cocaine abusers. J. Neurosci. 23(36), 11461–8.
ACCEPTED MANUSCRIPT
Wagner, M. J., Kim, T. H., Savall, J., Schnitzer, M. J., Luo, L. 2017. Cerebellar granule cells encode the expectation of reward. Nature; 544(7648):96-100. Walker, D. L., Davis, M. 2002. The role of amygdala glutamate receptors in fear learning, fear-potentiated startle, and extinction. Pharmacol. Biochem. Behav. 71(3):379-92.
PT
Wang, T., Liu, J., Zhang, J., Zhan, W., Li, L., Wu, M., Huang, H., Zhu, H., Kemp, G. J., Gong, Q. 2016. Altered resting-state functional activity in posttraumatic stress disorder: A quantitative
RI
meta-analysis. Sci. Rep. 6:27131.
SC
Warwick, J. M., Carey, P., Jordaan, G. P., Dupont, P., Stein, D. J. 2008. Resting brain perfusion in social anxiety disorder: a voxel-wise whole brain comparison with healthy control subjects. Prog.
NU
Neuropsychopharmacol. Biol. Psychiatry. 32(5):1251-6.
MA
Watson, T. C., Becker, N., Apps, R., Jones, M. W. 2014. Back to front: cerebellar connections and interactions with the prefrontal cortex. Front. Syst. Neurosci. 8:4.
ED
Watson, T. C., Jones, M. W., Apps, R. 2009. Electrophysiological mapping of novel prefrontal - cerebellar pathways. Front. Integr. Neurosci. 3:18.
EP T
Watson, T. C., Cerminara, N. L., Lumb, B. M., Apps, R. 2016. Neural Correlates of Fear in the Periaqueductal Gray. J. Neurosci. 36(50):12707-12719.
AC C
Wolff, S. B., Gründemann, J., Tovote, P., Krabbe, S., Jacobson, G. A., Müller, C., Herry, C., Ehrlich, I., Friedrich, R. W., Letzkus, J. J., Lüthi, A. 2014. Amygdala interneuron subtypes control fear learning through disinhibition. Nature. 509(7501):453-8. Wolpert, D. M., Miall, R. C., Kawato, M. 1998. Internal models in the cerebellum. Trends Cogn. Sci. 2(9):338-47. Yonkers, K. A., Bruce, S. E., Dyck, I. R., Keller, M. B. 2003. Chronicity, relapse, and illnesscourse of panic disorder, social phobia, and generalized anxiety disorder: findings in men and women from 8 years of follow-up. Depress. Anxiety. 17(3):173-9.
ACCEPTED MANUSCRIPT
Yu, W., Krook-Magnuson, E. 2015. Cognitive Collaborations: Bidirectional Functional Connectivity Between the Cerebellum and the Hippocampus. Front. Syst. Neurosci. 9:177. Yu, X., Liu, L., Chen, W., Cao, Q., Zepf, F. D., Ji, G., ... Zang, Y. 2016. Integrity of Amygdala Subregion-Based Functional Networks and Emotional Lability in Drug-Naïve Boys With ADHD. J. Atten. Disord.
PT
Yuan, M., Zhu, H., Qiu, C., Meng, Y., Zhang, Y., Shang, J., Nie, X., Ren, Z., Gong, Q., Zhang,
RI
W., Lui, S. 2016. Group cognitive behavioral therapy modulates the resting-state functional
SC
connectivity of amygdala-related network in patients with generalized social anxiety disorder. BMC Psychiatry. 16:198.
NU
Zeng, L. L., Shen, H., Liu, L., Wang, L., Li, B., Fang, P., ... Hu, D. 2012. Identifying major depression using whole-brain functional connectivity: a multivariate pattern analysis. Brain
MA
135(5), 1498-1507.
Zhang, S. F., Chen, J. C., Zhang, J., Xu, J. G. 2017. miR-181a involves in the hippocampus-
ED
dependent memory formation via targeting PRKAA1. Sci. Rep. 7(1):8480. Zhu, L., Sacco, T., Strata, P., Sacchetti, B. 2011. Basolateral amygdala inactivation impairs
EP T
learning-induced long-term potentiation in the cerebellar cortex. PLoS One 6, e16673. Zhu, L., Scelfo, B., Hartell, N. A., Strata, P., Sacchetti, B. 2007. The effects of fear conditioning
AC C
on cerebellar LTP and LTD. Eur. J. Neurosci. 26(1):219-27.
ACCEPTED MANUSCRIPT
AC C
EP T
ED
MA
NU
SC
RI
PT
Highlights Fear and anxiety-related brain areas are connected with the cerebellum. Animal studies on fear and anxiety demonstrate cerebellar involvement. Fear and anxiety-related disorders’ patients show enhanced cerebellar function. A cerebellum-based predictive function is proposed to explain the observed results.
ACCEPTED MANUSCRIPT
Table 1: Fear and anxiety-related disorders and their associated symptomatology. Disorder Social Anxiety Disorder
Description Fear or intense anxiety in one or more social situations, in which the individual fears to behave in a way that will result in social rejection. As a result, social situations are avoided or endured with fear or extreme anxiety.
Specific Phobia
Fear or extreme anxiety when facing a particular stimulus or situation. As a result, such
PT
stimuli or situations are avoided or endured with fear or extreme anxiety.
Panic Disorder
Presence of recurrent, unexpected panic attacks. A panic attack can be defined as experiencing extreme fear or distress which peaks in few minutes, and during which physiological (heart
SC
losing control, derealization) may occur.
RI
rate changes, sweating, breathing difficulties…) or psychological symptoms (fear of dying, of
Generalized Anxiety
Long-lasting anxiety and worry about several events or activities. Anxiety and worry are
Disorder
associated with symptoms like restlessness, fatigability, lack of concentration, irritability, or
Post-traumatic Stress
Exposure to death or life threats which causes intrusive symptoms such as re-experiencing the
1
traumatic situation, nightmares related to it and psychological distress and heightened
MA
Disorder
NU
sleeping trouble.
physiological responses when a situation that resembles the t raumatic event is encountered.
Fear or extreme anxiety regarding situations in which escaping or receiving help in case of
ED
Agoraphobia
showing panic-like symptoms would be difficult, such as using public transport, being in the
EP T
middle of a crowd, or staying in open or closed spaces. As a result, such situations are avoided or endured with anxiety.
Separation Anxiety Disorder
Fear or excessive anxiety regarding separation of people for whom he/she feels attachment, reflected as excessive distress when experiencing or anticipating separation, worry about
AC C
losing the attachment figures, and nightmares on the possibility of losing them.
Substance-induced Anxiety
Presence of panic or anxiety symptoms time-locked to consumption or abstinence of a
Disorder
substance with the ability of causing them.
Selective M utism
Constant speaking failure in situations in which speaking is expected, which cannot be explained by lack of knowledge or lack of comfort related to the spoken language in the presented situation.
1: Post-traumatic Stress Disorder has been removed from the Anxiety Disorders chapter in DSM -5.