Toward a more precise, clinically—informed pathophysiology of pathological laughing and crying

Neuroscience and Biobehavioral Reviews 37 (2013) 1893–1916

Contents lists available at ScienceDirect

Neuroscience and Biobehavioral Reviews journal homepage: www.elsevier.com/locate/neubiorev

Review

Toward a more precise, clinically—informed pathophysiology of pathological laughing and crying Edward C. Lauterbach a,∗ , Jeffrey L. Cummings b , Preetha Sharone Kuppuswamy c a b c

Departments of Psychiatry and Internal Medicine (Neurology), Mercer University School of Medicine, 655 First Street, Macon, GA 31201, USA Cleveland Clinic Lou Ruvo Center for Brain Health, 888 W. Bonneville, Las Vegas, NV 89106, USA Resident in Psychiatry, Department of Psychiatry and Psychology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA

a r t i c l e

i n f o

Article history: Received 6 August 2012 Received in revised form 1 March 2013 Accepted 11 March 2013 Keywords: Emotions Affective symptoms Pathophysiology Laughter Crying Pathological affect Pathological laughing or crying Forced laughter or crying Emotional incontinence Emotional lability Affective lability Pathological emotionality

a b s t r a c t Involuntary emotional expression disorder (IEED) includes the syndromes of pathological laughing and crying (PLC) and emotional lability (EL). Review of the lesion, epilepsy, and brain stimulation literature leads to an updated pathophysiology of IEED. A volitional system involving frontoparietal (primary motor, premotor, supplementary motor, posterior insular, dorsal anterior cingulate gyrus (ACG), primary sensory and related parietal) corticopontine projections inhibits an emotionally–controlled system involving frontotemporal (orbitofrontal, ventral ACG, anterior insular, inferior temporal, and parahippocampal) projections targeting the amygdala–hypothalamus–periaqueductal gray (PAG)–dorsal tegmentum (dTg) complex that regulates emotional displays. PAG activity is regulated by glutamatergic NMDA, muscarinic M1-3, GABA-A, dopamine D2, norepinephrine alpha-1,2, serotonin 5HT1a, 5HT1b/d, and sigma-1 receptors, with an acetylcholine/GABA balance mediating volitional inhibition of the PAG. Lesions of the volitional corticopontine projections (or of their feedback or processing circuits) can produce PLC. Direct activation of the emotional pathway can result in EL and the laughing or crying of gelastic and dacrystic epilepsy. A criterion-based nosology of PLC and EL subtypes is offered. © 2013 Elsevier Ltd. All rights reserved.

Contents 1. 2. 3.

4.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Volitional and emotional neural pathways in emotional expression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Neural structures implicated in the emotional pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Emotional expression neural correlates in animal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Emotional neural correlates in humans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The clinical literature of emotional expression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Lesions associated with IEED . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.1. Cortical structures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.2. Hypothalamus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.3. Subthalamic region . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.4. Internal capsule . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.5. Brainstem . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.6. Cerebellum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.7. Thalamus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.8. Basal ganglia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1894 1894 1895 1895 1895 1895 1896 1896 1904 1904 1904 1904 1905 1906 1906

∗ Corresponding author at: Center for Translational Studies in Neurodegenerative Disease, Mercer University School of Medicine, 331-4D College Street, Macon, GA 31201, USA. Tel.: +1 478 745 8531. E-mail addresses: [email protected] (E.C. Lauterbach), [email protected] (J.L. Cummings), [email protected] (P.S. Kuppuswamy). 0149-7634/$ – see front matter © 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.neubiorev.2013.03.002

1894

5.

6. 7. 8. 9.

E.C. Lauterbach et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 1893–1916

Organization of the emotional and volitional pathways and the PLC reflexes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Emotional pathway connectivity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Volitional pathway connectivity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Neurotransmitters associated with IEED . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Implications for IEED subtype pathophysiologies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Summary and conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Disclosures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction Syndromes of involuntary laughing and crying have long been recognized. Darwin is thought to have offered their first description in 1872 (Darwin, 1872). Oppenheim and Siemerling (1886) described exaggerated emotional behavior associated with lesions of tracts descending to the brainstem. Oppenheim first used the term pseudobulbar affect (PBA) to describe “spasmodic explosive bursts of laughter or weeping” and linked the condition to posterior frontal subcortical white matter, the internal capsule, and basal ganglia lesions (Oppenheim, 1911). PBA is classically associated with pseudobulbar palsy (Langworthy and Hesser, 1940) although some have used the term to encompass the syndromes of pathological laughing and crying (PLC) and emotional lability (EL) (Miller et al., 2011). Wilson first described PLC as uncontrollable emotional displays disproportionate to their evoking stimuli, dissociated from mood, and stereotyped in response (Wilson, 1924), and described a “voluntary” inhibitory system acting on brainstem centers that was first conceived of by Oppenheim (1911). Poeck subsequently proposed PLC diagnostic criteria, including evocation by non-specific stimuli, mood-independence, and involuntary nature, in contrast to EL, which was stimulus-appropriate, moodcongruent, variable (not stereotyped), and distractible, though not volitionally suppressible (Poeck, 1969). More recently, Cummings et al. (2006) detailed diagnostic criteria for involuntary emotional expression disorder (IEED), inclusive of PLC and EL subsyndromes. Parvizi et al. (2009) have provided a detailed history of the condition. Key features of PLC across the various nosologies (Wilson, 1924; Poeck, 1969; Cummings et al., 2006), then, include stereotyped episodes of involuntary laughing and/or crying that are inappropriate or disportionate to the inciting stimulus and occur independent of underlying mood. PLC may be distinguished from EL, which includes variable (non-stereotyped) episodes of involuntary laughing and/or crying that are consistent with, though disproportionate to, the stimulus and are congruent with mood. IEED occurs in a variety of neurological disorders (Schiffer and Pope, 2005; Wortzel et al., 2008; Parvizi et al., 2009), as listed in Table 1. More recently, PLC has been described in association with startle and immediately preceding the onset of akinetic mutism in 3 patients with Creutzfeldt-Jakob disease prion protein gene V180I mutations (Iwasaki, 2012). The epidemiology of IEED (Table 2) has been confounded by varying nomenclatures (Feinstein et al., 1997; Wortzel et al., 2008), including terms such as affective lability, emotionalism, emotional dyscontrol, emotional incontinence, EL, excessive emotionality, forced laughter or crying, inappropriate hilarity, pathological affect, pathologic emotionality, pathological emotionalism, pathological weeping, and pseudobulbar crying (Arciniegas et al., 2005; Cummings et al., 2006). We use the well-defined terms IEED, including PLC and EL, reserving PBA for cases attended by features of pseudobulbar palsy, as detailed above. A wide variety of treatments have been employed to treat these related conditions, including levodopa, antidepressants, glutamatergic agents, the dextromethorphan-quinidine combination approved by the US

1906 1906 1907 1907 1908 1910 1911 1911

Table 1 Distinguishing features of PLC and EL. PLC

EL

IEED feature Involuntary Uncontrollable Sudden Excessive Exaggerated expression Inappropriate response Consistent with mood Multiple episodes Change from baseline Significant distress Social/occupational dysfunction

Yes Yes Yes Yes Yes Yes Can be Yes Yes Usually Often

Yes Yes Often Often Yes Yes Usually Yes Often (if not congenital) Depends on insight Often

Distinguishing subtype features Stereotyped response Stimulus-inappropriate Mood-independent

Yes Yes Yes

No (variable) No No

Food and Drug Administration (FDA) for PBA, and other classes of drugs (Wortzel et al., 2008; Pioro, 2011). The purpose of this article is to provide a synopsis of the literature relevant to understanding PLC pathophysiology. In light of the phenomenological characteristics of PLC and EL, PLC would appear to involve the disinhibition, or release, of the affective relexes of laughing and crying whereas EL comprises a more complex dysmodulation of mood and its affective expression. PLC and EL likely have overlapping yet distinct pathophysiologies. We will consider the evidence for the emotional and volitional systems pertinent to IEED, the phenomena of emotional and volitional facial paresis (EFP and VFP), animal studies of neural structures implicated in emotional expression, the clinical literature of emotional expression, the connectivity (hodology) of involved structures, and neuropharmacological aspects of treatment. 2. Volitional and emotional neural pathways in emotional expression A variety of structures have been put forth as controlling emotional expression. The most compelling and time–tested concept is that of Wilson (1924), who championed the view of an emotionally-driven “involuntary” pathway that is inhibited by a consciously-driven “voluntary” pathway. Lesions in the volitional motor pathways would produce a disinhibition of emotional motor pathways, producing PLC. While the volitional pathway is Table 2 IEED prevalence in neurological diseases. Neurodegenerative disease Amyotrophic lateral sclerosis Alzheimer’s disease Multiple system atrophy–cerebellar type Parkinson’s disease Cerebrovascular disease Multiple sclerosis Traumatic brain injury

49% 18–74% 36% 4–6% 11–34% 10% 5–11%

E.C. Lauterbach et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 1893–1916

clinically evident in the lesions and motor signs associated with PLC, the emotional pathway is less obvious but can be discerned in the lesions associated with the phenomenon of emotional facial paresis (EFP). In contrast to the volitional facial paresis (VFP) that is observable in deficits on conventional clinical testing of cranial nerve VII, EFP is unmasked only by facial expression driven by emotion, such as when a patient is told a joke. The facial paresis of VFP is evident on the neurological exam but disappears when a patient is told a joke, whereas that of EFP is unapparent on the traditional neurological exam but becomes manifest when the patient is told a joke or challenged with other emotive stimuli. There are at least two separate controls on emotional expression, a volitional system with signs evident in VFP and an emotional system with signs evident in EFP. Lesion studies in EFP have revealed insular, opercular, mesial temporal, capsular (especially anterior limb), thalamic, subthalamic region, and midbrain–pontine tegmental loci in EFP (Wilson, 1924; Archer et al., 1981; Trosch et al., 1990; Hopf et al., 1992; Michel et al., 2008), consistent with a network of emotional motor pathways, whereas VFP is associated with motor cortical, pyramidal (corticospinal) tract, and ventral basis pontis lesions (Munschauer et al., 1991; Hopf et al., 1992). The phenomena of EFP and VFP provide evidence of distinct emotional and volitional pathways of emotional expression.

3. Neural structures implicated in the emotional pathway 3.1. Emotional expression neural correlates in animal studies Animal studies have necessarily focused on structures of the emotional pathway, rather than the volitional pathway. Monkeys exhibit laugh-like behavior similar to human laughter both in its social and situational context and functional anatomy (Meyer et al., 2007). Monkeys laugh while engaging in playful chases and being tickled (Matsusaka, 2004). Weinstein and Bender (1943) evoked laughter-like vocalizations in Macaca mulatta after stimulating sites in the diencephalon and brainstem. These studies indicate that emotional expressions related to laughing and crying are linked to sites in the anterior cingulate gyrus (ACG), amygdala, diencephalon, hypothalamus, midbrain, periaqueductal gray (PAG), brainstem tegmentum, pons, and medulla (Weinstein and Bender, 1943; Matsusaka, 2004; Meyer et al., 2007). The brainstem is particularly critical since decorticate animals express emotional behaviors and vocalizations normally, such as pleasure (including tail wagging) in dogs and purring in cats (Bekhterev, 1887; Schaltenbrand and Cobb, 1931; Bard, 1934), and stereotyped growling in both species (Goltz, 1892; Dusser De Barenne, 1920; Rothmann, 1923; Siegel et al., 2010). Across various species, the emotional motor system involves descending connections between the orbitofrontal (OBF) and anterior insular cortices, amygdala, and hypothalamus to the PAG, dorsal tegmentum, and brainstem nuclei such as the parabrachial, retroambiguous, and Kölliker-Fuse nuclei (Holstege, 1992; Nieuwenhuys, 1996; Nieuwenhuys et al., 1988). Lateral and dorsal caudal PAG projections to the nucleus retroambiguus in the caudal medulla are linked to vocalization, and motor efferents from this nucleus innervate the pharynx, soft palate, intercostals, abdominal muscles, and possibly the laryngeal muscles (Holstege, 1992) involved in laughing and crying. The Kölliker-Fuse nucleus pneumotaxic center lies ventral to the parabrachial nuclei and is thought to be involved in the respiratory components of laughing and crying (Nieuwenhuys, 1996). This system, and especially the PAG, is involved in mediating emotionally expressive behavior and vocalizations (Brown, 1915; Jürgens and Pratt, 1979; Holstege, 1992; Zhang et al., 1994; Nieuwenhuys, 1996; Esposito et al., 1999;

1895

Jürgens, 2002). Brown first produced laughter in chimpanzees while stimulating the PAG (Brown, 1915). While stimulation studies may not support precise localization, the PAG is involved in squirrel monkey emotional vocalizations (Jürgens and Pratt, 1979), and lesions of the midbrain-pontine PAG produce complete and irreversible mutism in humans (Esposito et al., 1999). 3.2. Emotional neural correlates in humans Emotion is processed in a variety of cortical areas that overlap with the structures implicated in EFP and animal studies of emotion. In humans, evidence from a number of studies of the perception, experience, recall, and expression of sadness and happiness reveal an emotional network involving the OBF, ACG, medial prefrontal cortex, left ventrolateral prefrontal cortex, anterior temporal pole, anterior and posterior temporal lobe, basal temporal cortex, parahippocampal gyrus (PHG), hippocampus, and amygdala in processing emotions of either valence (George et al., 1995; Lane et al., 1997; Schneider et al., 2000; Pelletier et al., 2003; Killgore and Yurgelun-Todd, 2004; Adolphs and Tranel, 2004; Surguladze et al., 2005; Habel et al., 2005). Sadness additionally involves the CG, anterior insula, mesial temporal cortex, transverse temporal gyrus, and superior temporal gyrus; happiness additionally involves mesial frontal cortex, dorsolateral prefrontal cortex, occipitotemporal (fusiform) gyrus (OTG), and inferior temporal gyrus (ITG). Although several of these investigations involved the perception of facial expression rather than evidence of a generation of emotional response (Killgore and Yurgelun-Todd, 2004; Adolphs and Tranel, 2004; Surguladze et al., 2005), the structures implicated in those studies (amygdala (Killgore and Yurgelun-Todd, 2004; Adolphs and Tranel, 2004), ACG (Killgore and Yurgelun-Todd, 2004), and OTG (Surguladze et al., 2005)) have also been identified in either induced mood or neurosurgical intra-operative emotional stimulation studies. Emotion processing structures are interconnected and organized into emotional processing networks. The ventral paralimbic network is thought to integrate social and motivational information to generate contextually relevant emotional expression whereas a dorsal paralimbic network provides conscious awareness and voluntary regulation of emotions (Wortzel et al., 2008). The ventral paralimbic network involves the ventral ACG, OBF, ventromedial frontal, and insular cortices and receives direct input from the limbic system (Wortzel et al., 2008). It is thought to process perceived emotions and automatically regulate the affective state (Phillips et al., 2003) that is then relayed through the emotional pathway of affective expression. The dorsal paralimbic network involves the dorsorostral ACG, paracingulate gyrus, dorsomedial prefrontal, dorsolateral prefrontal, and hippocampal cortices (Wortzel et al., 2008) and is thought to process emotions and execute responses that are then effortfully relayed (Phillips et al., 2003) through the volitional pathway regulating affective expression. External social context, internal motivation, conscious awareness, and volitional intent mediated through these emotional processing networks appear to regulate input to the emotional and volitional pathways that mediate emotional expression. 4. The clinical literature of emotional expression We reviewed the clinical literature of emotional expression disorders through February 28, 2013 in order to gain a more precise understanding of the structures involved in PLC circuitry. We used the following search strategy: ((affective symptoms[mh] OR “affective lability” OR “emotional dyscontrol” OR “pseudobulbar affect” OR “pathological affect” OR “pathological emotionality” OR “pathological emotionalism” OR “pathological laughing and crying”

1896

E.C. Lauterbach et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 1893–1916

OR “pathological weeping” OR “pseudobulbar crying” OR “emotional lability” OR “emotional incontinence” OR emotionalism OR “excessive emotionality” OR “forced laughter” OR “forced crying” OR “forced laughter or crying” OR “forced laughter and crying” OR “inappropriate hilarity” OR “involuntary emotional expression disorder” OR “IEED”) AND (laughter[mh] OR crying[mh] OR laugh*)) OR (pseudobulbar affect OR pathological laughing OR pathological crying), resulting in 655 citations. 4.1. Lesions associated with IEED Terminological confusion is apparent in the literature between IEED subtypes (PLC and EL), with some authors adhering to welldefined PLC whereas the majority incompletely specify the IEED subtype of interest. Thus, we use the term “IEED” when it is unclear which subtype (PLC or EL) is under consideration, reserving “PLC” and “EL” to instances where the IEED subtype studied is clearer (“possible” based on 1, “probable” based on 2, or “definite” based on 3 of 3 criteria, which include stereotyped presentation and relation to stimulus and mood). The overlapping and distinguishing features of PLC and EL are summarized in Table 1 above. IEED can result from solitary unilateral (Kim and Choi-Kwon, 2000; Poeck, 1969) cortical (Kim and Choi-Kwon, 2000) or subcortical (Kim and Choi-Kwon, 2000; Poeck, 1969) lesions. Associations with lesion laterality remain inconclusive. Sackheim et al. (1982) examined 119 cases from the literature that included PLC and EL, observing an association between crying with left hemisphere lesions and laughing with right hemispheric lesions. In contrast, right hemisphere lesions were associated with IEED of either valence in a single study of post-stroke patients (Choi-Kwon and Kim, 2002) and with emotionalism with tearfulness that was often controllable (McGrath, 2000). Other studies have observed no lateralized relationship in PLC, including the autopsy study of Poeck and Pilleri (1963), and the preponderance of evidence suggests that the valence (laughing vs. crying) of emotional expression relates neither strongly nor consistently to laterality. Similarly, the laughing seizures of gelastic epilepsy appear to be independent of lateralized constraints (Kovac et al., 2009). Female sex has been associated with IEED in general (Kim and Choi-Kwon, 2000), IEED crying (Sackheim et al., 1982), and emotionalism with tearfulness (McGrath, 2000). IEED has additionally been associated with ischemic stroke (as opposed to hemorrhagic), and severity of motor dysfunction (Kim and Choi-Kwon, 2000) as well as with sexual dysfunction (ChoiKwon and Kim, 2002). Neurodegenerative diseases frequently involve the degeneration of multiple systems, complicating attribution of PLC to a specific structure. Likewise, lesions such as strokes or tumors often involve several adjacent regions. Intra-operative brain stimulation and recording procedures allow more precise localization that controls for the recruitment of other structures. Thus, levels of precision are encountered in analyzing the various lesions of the PLC literature, and the findings in the ensuing literature review are organized from least to most precise for each anatomic structure. Additionally, a summary of study subjects, methodology, findings, and conclusiveness of anatomical findings is provided in Table 3. While grouped data from well-controlled studies (Andersen et al., 1994; Feinstein et al., 1999; Gallagher, 1989; Ghaffar et al., 2008; Haiman et al., 2008; Haiman et al., 2009; Kataoka et al., 1997; Kim and Choi-Kwon, 2000; Parvizi et al., 2007; Petracca et al., 2009; Poeck, 1969; Poeck and Pilleri, 1963; Siclari et al., 2011; Siddiqui et al., 2009; Strowd et al., 2010; Tateno et al., 2004; Zeilig et al., 1996) generally indicate statistically – likely anatomic correlates, these data are biased by predilections of certain diseases to more frequently affect certain sites (e.g., characteristically frequent loci for strokes and multiple sclerosis). Furthermore, certain diseases tend to be associated with multiple

lesions (e.g., multiple sclerosis, neurodegenerative disease, certain types of stroke), complicating anatomic attribution. For example, studies of excellent methodological quality can yield less conclusive anatomical conclusions due to ambiguous structural correlates (e.g., Feinstein et al., 1999) or the non-focal pathology of the neurological disease (e.g., Tateno et al., 2004). This suggests that the number of reports implicating a given structure across different diseases as well as the quality of the evidence base should both be considered. The former is evident in the text below while the latter can be seen in Table 3. Additionally, case reports of small solitary focal lesions and, especially, well-localized neurosurgical intraoperative stimulation can add more value than usual, especially in cases reporting loci that are infrequently associated with a given disease that may be missed by grouped data studies. 4.1.1. Cortical structures Although all subjects had multiple lesions, Davison and Kelman (1939) reviewed a series of 53 cases, 33 autopsied, with pathological affect and concluded that frontal, premotor, motor, sensory, temporal, and hippocampal cortices (as well as internal capsule, midbrain, pons, medulla, hypothalamus, thalamic nuclei, striatum, and pallidum, subcortical structures that are detailed below) were structures critical to emotional expression and feeling. Haiman and colleagues (2008) studied evoked potentials in multiple sclerosis (MS) patients with IEED, MS patients lacking IEED, and healthy ageand sex-matched controls (n = 11 in each group). IEED–associated differences in current density in response to subjectively significant emotional stimuli were observed at a number of sites, including the premotor cortex (PMC) and supplementary motor area (SMA) (Haiman et al., 2008). In a second study, Haiman et al. (2009) observed evoked response current density in 6 MS patients with IEED pre- and post-treatment with dextromethorphan–quinidine (DM-Q), relative to 6 untreated healthy controls. DM-Q had a normalizing effect on evoked potentials, and reduced current density in the ACG, primary motor cortex (M1), middle frontal gyrus, supramarginal gyrus, ITG, and right uncus while increasing current density in the CG and middle and inferior occipital gyri during subjectively significant stimuli (Haiman et al., 2009). Subjects in both studies were diagnosed with IEED using the Center for Neurological Study–Lability Scale (CNS-LS), which does not discriminate between PLC and EL subtypes. The CNS-LS is a 7-item self-administered scale developed for use in amyotrophic lateral sclerosis (Moore et al., 1997), also validated in MS (Smith et al., 2004), and used in IEED clinical trials (Brooks et al., 2004; Panitch et al., 2006; Pioro et al., 2010). The scale considers the relationship of episodes to stimuli as well as the ability to control the episode. The CNS-LS is useful for following clinical progress and treatment efficacy. 4.1.1.1. Orbitofrontal cortex. Evidence of involvement comes from studies of traumatic brain injury (TBI) and MS. In a study of 10 TBI patients with PLC and multiple lesions compared with 82 TBI patients lacking PLC, right ventral frontal lesions including the OBF area were over-represented in the PLC sample (odds ratio 5.13, 95% confidence interval (CI) 0.41–66.39) but did not reach statistical significance (p = 0.19) in this small PLC sample (Tateno et al., 2004). In a study of 14 MS patients with Poeck-defined PLC compared with 14 MS controls lacking PLC matched for demographics, disease course, and disability, PLC was associated with hyperintense lesions of the bilateral inferior frontal region involving the OBF area, as well as several other areas (Ghaffar et al., 2008). Campello Morer and Pérez Trullén (2007) reported a case of dacrystic seizures (DS) in the context of a ventral posterior frontal meningioma with ictal localization suggesting the OBF or right temporal lobe. Mendez et al. (1999) reported a patient with a 20 year history of IEED laughter that began after an anterior communicating

E.C. Lauterbach et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 1893–1916

1897

Table 3 Quality of clinical evidence base indicating anatomic correlates of IEED. Authors

Subjects

Methods

Findings

Comment

Achari and Colover (1976)

n = 2 with tumors and pathological laughter

A large epidermoid cyst and a presumed pontine glioma

Andersen et al. (1994)

n = 12 with multiple infarcts on MRI and IEED

Case report, ambiguous anatomical attribution inherent to large cyst and inoperable pontine glioma Selected for pathological crying severity, multiple lesions complicate anatomical attribution

Arif et al. (2005)

n = 1 with IEED laughing and crying, also provoked by swallowing

Case reports selected for laughter in the context of posterior fossa tumors Subjects selected for pathological crying severity, with location and volume determined by MRI Case report

Arroyo et al. (1993)

n = 1 with a mesiofrontal cavernous hemangioma and gelastic and dacrystic seizures n = 3 with TLE without gelastic or dacrystic components n = 1 with progressive PLC

Case reports, scalp and subdural electrode intraoperative EEG recording and stimulation

Assal et al. (2000)

n = 1 with infarction and fou rire prodromique

Case report

Bharathi and Lee (2006)

n = 1 infarct with pathological crying

Case report studied by CT and MRI

Campello Morer and Pérez Trullén (2007) Carel et al. (1997)

n = 1 with meningioma and dacrystic seizures

Case report studied by MRI and EEG

n = 1 with fou rire prodromique

Case report studied by MRI

Ceccaldi and Milandre (1994)

n = 1 infarct with fou rire prodromique

Case report with MRI study

Ceccaldi et al. (1994)

n = 3 infarcts with forced laughter

Case reports, selected for supratentorial infarction, studied by CT and EEG

Chassagnon et al. (2003)

n = 1 with gelastic seizures

Case report studied by intraoperative stereotactic EEG recordings

Chen et al. (2010)

n = 1 with post-infarct pathological laughing

Coria et al. (2000)

n = 1 with obstructive hydrocephalus leading to gelastic seizures with mirth n = 3 with midbrain infarcts and IEED laughter

Case report studied by CT, selected for showing response to quetiapine Case report studied by CT, MRI, and ictal EEG

Asfora et al. (1989)

Dabby et al. (2004)

Case report studied by CT, MRI, and angiography

Case reports selected for midbrain infarction studied by CT and, in one case, MRI

Davison and Kelman (1939)

n = 53 cases of IEED studied clinically

Retrospective review of cases with IEED with autopsy in 33

Dericioglu et al. (2005)

n = 1 with gelastic seizures with mirth

Case report, studied by EEG and MRI

IEED crying severity correlated with bilateral pontine infarcts and lesion proximity to the pons Bilateral pontine infarcts and left pontine compression were associated with progressive IEED with multiple brain stem signs Left ACG ictal focus associated with gelastic seizures and motor act of laughing without mirth; PHG and lateral OTG associated with laughter with mirth

Case report, pontine infarcts but also pontine compression complicate focal anatomic attribution Case reports selected for anatomic stimulation correlates, well localized

Pontine AVM and stroke were associated with PLC, remitting after radiotherapy of the AVM Pontine infarct associated with fou rire prodromique

Case report, may have involved caudal midbrain, complicating anatomic attribution Case report, large size of solitary lesion complicates anatomic attribution Case report, multiple structures and lesions involved complicate anatomical attribution

Right internal capsule anterior limb and external capsule infarct was associated with pathological crying bouts, but multiple old cerebral, cerebellar and brainstem infarcts evident on MRI Posterior frontal meningioma with ictal localization suggestive of OBF or right TL Left lenticular and caudate nucleus infarction also involving the insula Left internal capsule, posterolateral thalamus (pulvinar, lateral posterior, ventral posterior lateral nuclei), and posterior PHG infarction Left and right internal capsular – striatal and right internal capsule posterior limb lesions (without epileptiform activity) Epileptic zone limited to dorsal CG and contiguous anteroventral SMA with little or no spreading to adjacent structures, remitting after stereotactic radiofrequency lesion of the epileptic focus Paramedian pontine hemorrhagic infarct Right basolateral temporal cortical atrophy on MRI with right temporal and centro-temporal ictal focus on EEG Large bilateral midbrain and pons (n = 1) and small paramedian lower midbrain (n = 2; defined by MRI in one case) infarcts; premonitory laughter TIAs in 1 case Concluded frontal, premotor, motor, sensory, temporal, and hippocampal cortices, internal capsule, midbrain, pons, medulla, hypothalamus, thalamic nuclei, striatum, and pallidum were the critical structures Right ITG ictal focus with focal cortical dysplasia found on neurosurgical resection

Case report with ambiguous anatomical localization due to multiple structures involved Case report, multiple structures involved complicate anatomic attribution Case report, multiple structures involved complicate anatomic attribution

Selected case reports, multiple structures in 2 cases and absence of MRI studies complicate anatomic attribution Case report, well localized

Case report, selected for drug response, with ambiguous anatomic attribution inherent to CT Case report, diffuse TL loci complicate anatomical attribution

Case report, with ambiguous anatomic attribution inherent to CT

Retrospective study, consecutive cases, autopsy follow-up; all cases with multiple lesions, complicating anatomic attribution

Case report, ictal EEG unrevealing and cannot exclude other anatomic attribution since patient remained on anticonvulsants after surgery

1898

E.C. Lauterbach et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 1893–1916

Table 3 (Continued ) Authors

Subjects

Methods

Findings

Comment

de Seze et al. (2006)

n = 4 with MS and early presentation of IEED laughter

Case series, studied by MRI with gadolinium

Case reports, large midbrain lesion and multiple lesions complicate anatomic attribution

Dimova et al. (2009)

n = 1 with mutism, disturbed consciousness, disturbed sleep-wake cycle, bilateral corticospinal tract signs, and IEED laughter n = 1 with movement-induced IEED laughter

Case report studied by MRI

Midline midbrain (n = 1), and medullary – bulbopontine (n = 1) plaques; IEED laughter improved with steroids Cerebellitis was associated with IEED laughter and other signs

Doorenbos et al. (1993)

Dopper et al. (2011) Elyas et al. (2011)

n = 1 with progranulopathic corticobasal syndrome and emotional lability n = 1 with pontine abscess and PLC

Famularo et al. (2007)

n = 1 with pathological laughter and occasional gelastic syncope

Feinstein et al. (1999)

n = 24, including 11 with MS and Poeck-defined PLC and 13 MS controls lacking PLC with similar demographics, MS characteristics, IQ, and depression status n = 1 with intractable seizures without gelastic or dacrystic components

Fried et al. (1998)

Gallagher (1989)

n = 73 with ALS, selected for ALS onset before 45 years

Garg et al. (2000)

n = 1 with fou rire prodromique n = 28, including 14 with MS and Poeck-defined PLC and 14 matched MS controls without PLC; exclusion criteria involved psychiatric disorders, certain other diseases, and MS drugs n = 1 with fou rire prodromique n = 2 with Machado-Joseph disease and IEED crying from the same family

Ghaffar et al. (2008)

Gondim et al. (2001) Guimarães et al. (2008)

Haiman et al. (2008)

n = 33 subjects, including 11 with MS and IEED, 11 MS without IEED, and 11 matched healthy controls; IEED diagnosed with CNS-LS

Haiman et al. (2009)

n = 12 subjects, including 6 with MS and IEED and 6 matched healthy controls; IEED diagnosed with CNS-LS

Case report studied by MRI

Focal cerebellar hemorrhage

Case report studied by MRI, SPECT, and neuropsychological testing Case report studied by MRI with gadolinium enhancement Case report studied by CT, MRI with gadolinium enhancement, EEG, vascular ultrasonography, and head-up tilt test Controlled comparison of frontal release signs and neuropsychological assessment by Stroop, COWAT, and other tests including the Wisconsin Card Sort Test and PLACS Case report, intraoperative stimulation

Frontoparietal atrophy, temporal lobe degeneration, and striatal atrophy pathology present Lateral basis pontis abscess; PLC subsided after surgical drainage

Retrospective study of IEED prevalence among patients with motor corticospinal neuron degeneration Case report studied by CT and EEG Case-control study matching for demographics and disease variables, comparing atrophy and MS lesion distributions on 1.5 T MRI using logistic regression analysis

Cerebellar vermal ependymoma; both conditions resolved after tumor resection

Case report, but accompanying signs suggest brainstem compression, complicating anatomic attribution

Case report, question whether reflex IEED generalizes to usual IEED; patient at risk for brainstem compression, complicating anatomic attribution Case report, multiple structures involved that complicate anatomical attribution Case report, midbrain eye signs and proximity of cerebellar complicate anatomic attribution Case report, possible brainstem compression (syncope, tumor location) complicates anatomic attribution

PLC correlated with Stroop Word Color Test and COWAT performance suggesting ACG and left inferior frontal gyrus, respectively

Controlled study with rigorous diagnostic criteria, ambiguous anatomic localization inherent to multiple structural correlates of neuropsychological tests

Laughter with mirth and humorous perception was associated with stimulating the Pre-SMA, increased with increasing current strength 36 subjects had IEED (20 laughing and crying, 9 crying, 7 laughing); bulbar symptoms were present in nearly all with IEED Infarct of ventrolateral M1

Case report, well localized

Hyperintense lesions of the bilateral inferior frontal region (OBF area), PMC, SMA, M1, S1, and SMG and hypointense midbrain and pontine lesions reflecting neuronal loss

Case report with MRA and study and angiography Case reports, selected for IEED

Pontine ischemia, leading to pontine and cerebellar infarction 2 cases of Machado-Joseph disease had IEED crying

Relevant inclusion (CNS-LS score), exclusion criteria, group matching, with MS groups matched for disease variables; evoked potential analysis after subjectively significant emotional stimuli Similar inclusion and exclusion criteria and matching as in Haiman et al., 2008; comparisons of pre- and post-treatment (DM-Q) evoked potential analysis after subjectively significant emotional stimuli

Current density differences between groups at PMC, SMA, M1, and somatosensory cortices

Current density normalized with treatment; significant treatment differences within MS + IEED subjects in ACG/CG, M1, middle frontal gyrus, M1, post-central gyrus, SMG, ITG, OTG, uncus, middle occipital gyrus, inferior occipital gyrus

Relatively large sample size; selection for early onset cases may not generalize to typical onset ALS Case report, large infarct complicates anatomic attribution Controlled study, diagnostic criteria, well-matched groups, high inter-rater reliability on MRI analysis; the authors note limited sample size and MRI analysis technical limitations

Case report, multiple lesion sites complicate anatomic attribution Case reports, psychiatric disorder cannot be excluded, brainstem, cerebellar, and corticospinal signs complicate anatomical attribution Controlled study using CNS-LS diagnosis, small group sizes, group matching, with question whether stimulus–induced emotion is relevant to IEED; somewhat ambiguous localization inherent to dipole source localization Controlled study with small sample size, with same comments as for Haiman et al., 2008, as well as whether within-subject treatment differences reflect DM-Q effects unrelated to IEED pathophysiology

E.C. Lauterbach et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 1893–1916

1899

Table 3 (Continued ) Authors

Subjects

Methods

Findings

Comment

Hargrave et al. (2006)

n = 8 with pontine gliomas and pathological laughter and/or separation anxiety

Hu et al. (2011)

n = 1 with mirthless gelastic seizures n = 3 with gelastic seizures with or without mirth and selected for EEG localization n = 1 with cystic trigeminal schwannoma and IEED laughter

Some pontine gliomas extended into the midbrain or medulla; 4 cases improved with tumor regression Lateral and anterior aspect of inferior frontal gyrus focus; excision led to seizure remission Laughter without mirth associated with ACG, laughter with mirth associated with medial and medio-basal TL Anterolateral pons and probably many other structures compressed, with ventriculomegaly; IEED remitted after surgical excision 3 of 4 with laughing or crying episodes showed intrinsic hamartoma epileptiform activity; hamartoma stimulation reproduced gelastic and dacrystic seizures IEED exclusively evident in 4 basal infarcts sparing the lateral tegmentum (laughter in 3 and crying in 1)

Consecutive case series; variable tumor sizes and treatment response complicate anatomical attribution Case report, well localized

Iwasa et al. (2002)

Case series of all patients encountered over a 10 year period with pontine glioma and IEED Case report, MRI, video-EEG, MEG, and subdural electrode EEG Case series, studied by MRI and scalp EEG with dipole source localization

Jagetia et al. (2006)

Case report, studied by MRI, EEG, and angiography

Kahane et al. (2003)

n = 5 with hypothalamic hamartomas and intractable epilepsy, 3 with gelastic seizures

Case series studied by intraoperative stereotactic EEG recording and intraoperative stimulation

Kataoka et al. (1997)

n = 49 consecutive cases of acute paramedian pontine infarction including 27 with basal, 15 basal-tegmental, and 7 tegmental infarcts identified by MRI n = 148 with stroke (4 ACA, 10 MCA, 42 capsulolenticular, 3 midbrain, 24 pontine, 11 medullary, 9 cerebellar, 19 thalamic) and emotional incontinence (diagnosed by patient and relative concordance) and/or depression

Retrospective study analyzing clinical signs and MRI findings

Kim and Choi-Kwon (2000)

Komurasaki et al. (1989)

Kosaka et al. (2006)

n = 4 with IEED, including 4 with multiple strokes and 1 with olivopontocere-bellar atrophy n = 1 with cryptogenic pathological laughter

Kossorotoff et al. (2010)

n = 5 with posterior fossa infarcts

Kovac et al. (2009)

n = 1 with movement-induced reflex gelastic seizures n = 2 with dorsolateral subthalamic nucleus deep brain stimulation n = 2 with Fahr’s disease, including 1 with IEED laughter and crying n = 1 with pathological laughter

Krack et al. (2001)

Lam et al. (2007)

Lauterbach et al. (1994) Loiseau et al. (1971) Low et al. (2008)

Luciano et al. (1993)

n = 1 with frontocentral epilepsy with gelastic component n = 1 undergoing bilateral low intensity deep brain stimulation n = 7 with dacrystic seizures with or without inappropriate affect

Selected case series, ambiguous anatomical attribution inherent to EEG dipole source localization Case report, nature of large tumor complicates anatomic attribution

Case series, well localized

Anatomically-defined retrospective study with good anatomic localization, unequal group sizes, and IEED was not the objective of this study

Prospective study of consecutive cases after single unilateral stroke documented by MRI or CT, with multiple exclusion criteria; diagnosed by agreement on ≥ 2 occasions of “excessive or inappropriate” laughing or crying compared to pre-stroke baseline Case series selected for treatment of IEED with thyrotropin releasing hormone Case report, studied by MRI, SPECT, EEG, all normal, and by fMRI with neuropsycholog-ical evaluation Retrospective study of pediatric posterior fossa infarction with MRI localization Case report studied by MRI, EEG, fMRI, and DTI

4 ACA, 4 MCA, 19 capsulolenticular, 1 midbrain, 5 pontine (53% basis pontis, 0% dorsal pontine), 4 medullary, 2 focal cerebellar, 3 focal thalamic, and 19 lenticular nucleus strokes displayed emotional incontinence

Prospective study, consecutive cases, with exclusion criteria and reliable assessment; questionable IEED criteria; other causes of emotionality not excluded; CT imaging and multiple structural involvement (frontal, capsular, lenticular, cerebellar) complicate anatomical attribution

In a single patient, olivopontocere-bellar atrophy was associated with IEED laughter

Case series selected by treatment; diffuse olivopontocerebellar atrophy neuropathology complicates anatomic attribution Case report, well-controlled, well localized; question of whether reversal of pontine finding with SSRI is independent of its IEED treatment effect Retrospective study of all patients encountered over 2 year period, fair localization

Case reports, selected for IEED associated with deep brain stimulation Case reports, selected for Fahr’s disease, studied by CT Case report, studied by MRI

Stimulation with supratherapeutic parameters (150% higher) produced mirthful laughing IEED case had extensive frontal, caudate, and cerebellar calcifications Lesion of pulvinar and lateral thalamic nuclei

Case report

Gelastic seizures were associated with cyst in ACG

Case report, selected for pathological crying

Stimulation thought to be confined to the internal capsule posterior limb 6 had nondominant hemisphere ictal activity, maximal in the anteromesial TL in 5 and mesial FL in 1

Case series with video-EEG correlations

Abnormal pontine activation on fMRI not present in controls during neuropsychological evaluation, remitting with paroxetine 2 of 3 focal pontine and 0 of 2 cerebellar infarcts had IEED laughing and crying Right frontocentral epileptogenic focus

Case report, diffuse localization, question whether case generalizes to conventional IEED Case reports, ambiguous localization inherent to deep brain stimulation Case report, multiple structures involved complicate anatomic attribution Case report, multiple thalamic nuclei involved complicate anatomic attribution Case report, other structures may have been affected, complicating anatomic attribution Case report, tentative localization inherent to deep brain stimulation Case series, non-specific localization

1900

E.C. Lauterbach et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 1893–1916

Table 3 (Continued ) Authors

Subjects

Methods

Findings

Comment

Mariën et al. (2011)

n = 1 with disinhibition, psychosis, emotional lability and IEED laughing and crying after cerebellar surgery n = 1 with frontocentral epilepsy with gelastic component n = 1 with anterior communicating artery hemorrhage and chronic pathological laughter n = 1 recovering from locked-in syndrome due to a stroke n = 1 with mirthful gelastic seizures

Case report of patient undergoing cerebellar tumor resection, studied by MRI and SPECT

Recovery period possibly associated with emotional lability correlating with CG and inferolateral frontal hypoperfusion

Case report, cerebellar attribution complicated by diaschisic FL hypoperfusion and other factors such as medications

Case report, selected for lesion site, studied by EEG, MRI, and inter-ictal SPECT Case report, selected for laughter severity and chronicity, studied by CT and PET Case report studied by MRI and neuropsychological tests Case report with intraoperative subdural and depth electrode recordings Case report studied by skull films, pneumoencephalography, angiography, and EEG Case report, studied by MRI and CT angiography

Gelastic seizures were associated with ACG focal cortical dysplasia, with remission after resection Extensive bifrontal atrophy involving OBFC and ACG due to a shunt failure; improved with fluoxetine Midbrain-pontine stroke and PBA laughing and crying

Case report, anatomic attribution seemingly confirmed by post-surgical remission Case report, with multiple structures involved due to large lesion, complicating anatomic attribution Case report, but lesion complicates anatomical attribution

Basal TL rhythmic activity associated with smiling, laughter, and mirth, abated by right TL resection Cryptic etiology (possible neurosyphilis, vascular disease, and/or trauma) associated with dacrystic seizures Bilateral ventromedial pontine infarcts unresponsive to citalopram

Well-localized to basal temporal lobe but without more precise localization

Case report„ studied by MRI with gadolinium enhancement and lumbar puncture Case report

Enhancing bilateral midbrain basis pedunculi plaques; laughter remitted with steroids

McConachie and King (1997) Mendez et al. (1999)

New and Thomas (2005) Oehl et al. (2009)

Offen et al. (1976)

n = 1 with history of neurosyphilis and gelastic and dacrystic seizures

Oh et al. (2008)

n = 1 with stroke and pathological laughter

Okuda et al. (2005)

n = 1 with MS and pathological laughter (PBA) during second MS episode

Okun et al. (2004)

n = 1 undergoing deep brain stimulation inducing uncontrollable crying n = 1 with fou rire prodromique

Osseby et al. (1999)

Parvizi et al. (2001)

n = 1 with multiple infarcts and IEED with laughing and crying

Parvizi and Schiffer (2007)

n = 1 with ataxia and pathological crying without sadness

Parvizi et al. (2007)

n = 28 cases of multiple system atrophy, cerebellar type ascertained by MRI, including 1 autopsied case

Petracca et al. (2009)

n = 131 subjects with Parkinson’s disease (PD) from a single tertiary referral center clinic

Poeck and Pilleri (1963), Poeck (1969)

n = 30 cases of PLC verified at autopsy

Pustorino et al. (2007)

n = 1 with status gelasticus paradoxically developing when levetiracetam was added to oxcarbazepine and diazepam

Case report studied by CT and MRI Case report, selected for IEED and cerebro-ponto-cerebellar pathway lesions, studied by PLACS, MRI, and neuropsy-chological tests Case report selected for cerebellar features and pathological crying, studied by MRI Retrospective chart review for prevalence of IEED

Subjects assessed for frequency and correlates of IEED; blinded PD ascertainment by diagnostic criteria, exclusion of psychiatric disorders and MRI lesions, IEED diagnostic criteria, blinded PLACS ratings; cognitive and neuropsychiatric ratings Retrospective autopsy study selected for PLC clinical cases

Case report selected for its atypical features

Crying and increased gag and facial reflexes with subthalamic–thalamic stimulation Left lenticular nucleus, internal capsule, and insula infarction Infarcts in midbrain, pons, and cerebellum; IEED resolved with citalopram; memory impairments were evident on neuropsychological investigation Midline cerebellar cyst with progressive clinical signs and pathological crying; IEED improved with amitriptyline IEED in 10 cases (5 laughing, 5 laughing and crying); cerebellar, pontine, and medullary degeneration, dense olivary alpha-synuclein in autopsied laughter case 22 had IEED with crying (15.3% comorbid with depression), correlating only with severity of PD; no IEED laughter was observed

Unilateral lesions present in 10, solitary cortical lesions in 0, internal capsule anterior limb or genu involvement in 30, some also involving the caudate in 3, putamen in 4, globus pallidus in 2, thalamus in 1, claustrum, external, and extreme capsules in 4, and insular cortex in 3 Diplegic cerebral palsy and seizures, paradoxically developing status gelasticus when levetiracetam was added

Case report, anatomic attribution obscure

Case report, small lesions allow for anatomic attribution to the new right pons lesion Case report; gadolinium imaging and steroid response support anatomical attribution Case report, ambiguous localization inherent to deep brain stimulation Case report, large basal ganglia stroke complicates anatomic attribution Multiple lesions rostral ventral pons, cerebellar peduncle) involved complicate anatomic attribution; impaired memory may also indicate TL dysfunction or diashisis Case report, other structures including brainstem potentially involved, complicating anatomic attribution Retrospective chart review of cases selected for multiple system atrophy, cerebellar type, with multiple pathology complicating anatomic attribution Well-designed prospective assessment, gold standard PD and IEED diagnostic criteria and rating scales, relevant exclusion criteria; independence from depression and correlation with PD severity support an association of IEED with PD; multiple structures involved in PD complicate anatomic attribution Retrospective autopsy study, with multiple structures involved in many cases, complicating anatomic attribution

Case report, diplegic cerebral palsy may be independent of gelastic phenomena

E.C. Lauterbach et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 1893–1916

1901

Table 3 (Continued ) Authors

Subjects

Methods

Findings

Comment

Riggs et al. (1999)

n = 1 with progressive spastic quadriparesis

Case report

IEED developed in the context of the underlying disease

Ross and Rush (1981)

n = 4 with pathological affect from a series of 5 with depression in patients with brain lesions n = 2 with right frontal opercular lesions and pathological crying

Case reports of patients with pathological affect and depression from a depression case series Case reports selected for frontal opercular lesions and pathological crying, studied by CT

Right frontal opercular lesions together with depression were associated with pathological affect

Case report, IEED could be independent of motor system degeneration Case reports, possible additional pathology complicates anatomic attribution

Sacco et al. (2008)

n = 4 with locked-in syndrome and PLC

Case reports, selected for locked-in syndrome and PLC, studied by MRI in 3 cases and CT in 1

Large lesions involving most of the anterior ventral basal pons extending to close to the tegmentum were associated with PLC

Satow et al. (2003)

n = 1 with intractable complex partial seizures with a left mesial TL focus

Mirth dose-dependently progressed to laughter with increasing stimulation of the basal inferior temporal gyrus

Schmitt et al. (2006)

n = 2 with seizures with frontal cortical lesions undergoing frontal lobe stimulation

Case report studied by MRI, video-EEG, interictal PET, subdural and depth electrodes, and intraoperative stimulation and recording Case reports, selected for laughter and smiling induced by intraoperative electrical stimulation, studied by subdural grid electrodes

Sem-Jacobsen (1968)

n = 1 with laughter induced intraoperatively

Sethi and Rao (1976)

n = 1 of dacrystic, gelastic, and mixed (dacrystic and gelastic) seizures

Shahar et al. (2007)

n = 10 with pediatric gelastic epilepsy

Shin et al. (2006)

n = 1 with gelastic seizures

Siclari et al. (2011)

n = 67 with REM behavior disorder and polysomnography records

Siddiqui et al. (2009)

n = 719 of 860 consecutive patients with movement disorders meeting study inclusion criteria

Prospective study, subjects interviewed using a 4 item questionnaire to determine the prevalence of IEED in movement disorders and rated on Beck Depression Inventory I and mood scale

Sperli et al. (2006)

n = 1 with partial complex seizures without laughing or crying

Strowd et al. (2010)

n = 269 with movement disorders

Case report, studied by EEG, MRI, PET, and SPECT, depth electrodes, and intraoperative electrical stimulation Retrospective chart review of IEED prevalence in movement disorders; IEED diagnosed by CNS-LS ratings; also assessed on Beck Depression Inventory and quality of life scales

Ross and Stewart (1987)

Case report of intraoperative electrical stimulation Case report studied by EEG and angiography

Case series of all such cases incident in Israel over a 10 year period, studied by MRI and EEG Case report, selected for gelastic seizures with parietal lobe focus, studied by video-EEG, MRI, and ictal and interictal SPECT Retrospective review of consecutive cases studied for prevalence and correlates of laughing behavior during REM episodes

Right frontal opercular lesions together with depression were associated with pathological crying, with one case treated and rapidly resolving with doxepin

Laughter without mirth was induced by stimulation of the supplemental sensorimotor area in a 35 year old woman; laughter was induced by stimulation of the lateral premotor cortex in an 18 month old child Laughter induced by stimulation of OBF region and ACG, but not always reproducible Dacrystic seizures associated with circumscribed left temporal lobe (MTG, ITG, and near uncus) astrocytoma demonstrated on EEG, angiography, and surgically 4 of 10 had hypothalamic hamartomas

Deep parietal lobe white matter ictal focus, with ictal hyperperfusion of the parietal lobe and medial cerebellum 14 of 67 had laughing component to REM behavior disorder, including 10 with PD, 2 multiple system atrophy Parkinson type, 1 multiple system atrophy cerebellar type, and 1 dementia with Lewy bodies 2 of 64 with essential tremor, 2 of 74 with dystonia, and 18 of 387 with PD had IEED, associated with depression and antidepressant treatment

Mirthless laughter associated with right CG stimulation, ACG area correlated with motor act of laughing without mirth 4 of 35 with essential tremor, 0 of 13 with dystonia, and 12 of 168 with PD had IEED, associated with depression, lower emotional well-being, and antidepressant treatment

Case reports, one patient had additional frontal, temporal, and parietal opercular involvement, the other had additional anterior parietal opercular involvement, complicating anatomic attribution Case reports, with lesions in the typical pontine location for both conditions, however large lesions complicate anatomic attribution, and 3 patients had depression (potential confound) Case report, reliable localization

Case reports, selected for stimulation phenomena, well localized

Case report, unreliable effect, multiple loci, questions regarding laughter attribution to ACG Case report, multiple temporal lobe and other structures possibly involved inherent to astrocytomas, complicating anatomic attribution Case series of all consecutive cases from the population, well localized, but ictal foci varied between subjects Case report, well localized, laughter substrate may be remote from ictal focus

Multiple illnesses, disorder with cryptic anatomic attribution occurring in neurodegenerative diseases with neuropathology in multiple structures, complicating anatomical attribution Prospective study, large population with adequate group sizes, IEED defined as uncontrollable with absence of associated mirth or sadness producing a conservative estimate; associated depression and antidepressant treatment raise questions about the IEED diagnosis and etiology Case report, reliable localization

Retrospective study using an accepted diagnostic method; associated depression and antidepressant treatment raise questions about the IEED diagnosis and etiology; ambiguous anatomical attribution

1902

E.C. Lauterbach et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 1893–1916

Table 3 (Continued ) Authors

Subjects

Methods

Findings

Comment

Sugama et al. (1992)

n = 1 with frontal lobe gelastic seizures

Case report, studied by CT, MRI, and SPECT

Left opercular abnormalities on MRI and SPECT associated with gelastic seizures

Tateno et al. (2004)

n = 92 consecutive patients, including 10 with TBI and PLC and 82 with TBI without PLC

Blindly-assessed MRI-defined lesion sites between PLC and control groups; PLC diagnosed by diagnostic criteria

Increased frequency of left lateral frontal (OR 10.63, p=.03), right ventral frontal lesions including OBFC (OR 5.13, p N.S) associated with PLC

Tatum and Loddenkemper (2010) Tsutsumi et al. (2008)

n = 1 with left TLE with crying episodes

Case report, with EEG and MRI study

n = 1 with right frontal glioblastoma and pathological laughter

Case report, studied by MRI and fMRI with anatomical localization and follow-up after resection Case report, studied by MRI

Left TL ictal activity with mesial temporal sclerosis, remitted after left amygdalohippo-campectomy Tumor displaced CG and invaded PMC, with IEED resolving within 2 weeks of surgery

Case report, fairly reliable localization to FL, but FL affects on remote structures cannot be excluded Prospective study in consecutive well-characterized subjects, well-defined PLC diagnostic criteria and blinded MRI assessment; diffuse TBI lesions complicate anatomic attribution Case report, localization only to amygdalohippo-campal region

Uzunca et al. (2005)

n = 1 with stroke and fou rire prodromique

Wojtecki et al. (2007)

n = 1 undergoing deep brain stimulation

Case report with PET study

Wojtecki et al. (2011)

n = 1 undergoing deep brain stimulation

Case report

Zeilig et al. (1996)

n = 16 with TBI and IEED

Subjects from 301 consecutive TBI cases selected for IEED defined as excessive or exaggerated in response to minimal stimulus, diagnosed by agreement of two experienced clinicians, studied by blinded MRI or CT, and exclusion of mood disorders

Bilateral internal capsule genu infarct presenting with fou rire prodromique with residual sustained IEED, resolving within 1 week Stimulation induced stereotyped uncontrollable crying without sadness when taking PD medications, best associated with ventral subthalamic nucleus stimulation activating thalamus and cerebellum (although crying was not observed during PET) Mood-congruent mirthful laughter on left subthalamic nucleus stimulation; sadness and crying on stimulating right internal capsule Laughing and laughing and crying more frequent than crying; IEED correlated with hemiparesis, dysphagia, and dysarthria; 4 (25%) with IEED laughing or crying had MRI evidence of basal ganglia injury

Case report, but tumor and its edema were widespread and may have affected other structures, complicating anatomic attribution Case report, well delineated lesions that often involve adjacent structures, complicating anatomic attribution Case report, ambiguous anatomic attribution inherent to deep brain stimulation (all leads were associated with crying and with activation of thalamus and cerebellum on PET)

Case report, ambiguous anatomic attribution inherent to deep brain stimulation Retrospective study of well-defined subjects, blinded MRI rater, no control group; IEED stimulus criterion may under-ascertain cases; nature of TBI pathology and multiple motor signs complicate anatomical attribution

Quality of clinical data supporting anatomical correlates of IEED, summarizing subjects, methodology, findings, and conclusiveness of anatomical findings. Well-controlled grouped data (see “Comment” for those studies) indicate statistically most-likely anatomic correlates but are biased by predilections of certain diseases to more frequently affect certain sites (e.g., MS, stroke) or multiple sites (neurodegenerative disease, MS), complicating anatomic attribution. Thus, case reports of small solitary focal lesions, and, in particular, well-localized neurosurgical intraoperative stimulation, add more value than usual, especially in infrequently affected loci which may be missed by grouped data. This contraction in evidential quality value differential across methodologies suggests that the number of reports implicating a given structure (provided by the textual literature review) can be at least as informative as the quality of the evidence base provided in this table. Abbreviations: ACA anterior cerebral artery, ACG anterior cingulate gyrus, ALS amyotrophic lateral sclerosis, AVM arteriovenous malformation, CG cingulate gyrus, CNS-LS Center for Neurological Studies Lability Scale, COWAT Controlled Oral Word Association Test, DM-Q dextromethorphan–quinidine combination, DTI diffusion tensor imaging, EEG electroencephalogram, FL frontal lobe, fMRI functional magnetic resonance imaging, IEED involuntary emotional expression disorder, ITG inferior temporal gyrus, M1 primary motor cortex, MCA middle cerebral artery, MEG magnetoencephalography, MRA magnetic resonance angiogram, MRI magnetic resonance imaging, MS multiple sclerosis, MTG middle temporal gyrus, OBF orbitofrontal, OBFC orbitofrontal cortex, OTG occipitotemporal gyrus, PBA pseudobulbar affect, PET positron emission tomography, PD Parkinson’s disease, PHG parahippocampal gyrus, PLACS Pathological Laughter And Crying Scale, PLC pathological laughing and crying, PMC premotor cortex, S1 primary sensory cortex, SMA supplementary motor area, SMG supramarginal gyrus, SPECT single photon emission computed tomography, TBI traumatic brain injury, TL temporal lobe, TLE temporal lobe epilepsy.

artery hemorrhage, with subsequent extensive bifrontal and deep medial atrophy involving the OBF cortex and ACG. Furthermore, Sem-Jacobsen (1968) reported laughter evoked intra-operatively by electrical stimulation of the OBF region and ACG. Mirth was only variably present and probably related to underlying psychiatric conditions rather than the evoked behavior of laughter (Sem-Jacobsen, 1968, Arroyo et al., 1993). 4.1.1.2. Medial frontal cortex. Evidence for medial frontal cortical involvement is limited to TBI, MS, gelastic seizures (GS), and evidence of involvement of CG, ACG, PMC, and SMA. Medial frontal lesions associated with PLC in the Ghaffar et al. (2008) MS study were distributed across the PMC, SMA, and M1 cortical areas. Kovac

et al. (2009) reported movement–induced reflex GS in a 40-year-old man with a right frontocentral epileptogenic focus possibly related to medial frontal cortical dysplasia. Reviewing the GS literature, Oehl et al. (2009) concluded that the mesiofrontal cortex is involved in laughing motor activity but not mirth. Luciano et al. (1993) reported a patient with DS with maximal ictal activity present in the mesial frontal lobe. Finally, Kim and Choi-Kwon (2000) found emotional incontinence in all 4 patients with anterior cerebral artery territory frontal lobe infarcts. 4.1.1.3. Cingulate gyrus (CG). Haiman et al. (2009) found reduced current density over the CG after DM-Q treatment. Chassagnon et al. (2003) reported a patient with GS in whom the epileptogenic

E.C. Lauterbach et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 1893–1916

1903

zone was found to be limited to the dorsal CG and contiguous SMA. Tsutsumi et al. (2008) reported a right frontal glioblastoma in a 60 year-old woman that displaced the CG downward and was associated with IEED laughter that remitted after tumor resection. Sperli et al. (2006) found mirthless laughter after intra-operative stimulation of the right CG in a 21-year-old patient with intractable non-gelastic nocturnal partial complex seizures.

in the neuropsychological study of MS patients described under ACG. The COWAT itself has been associated with left inferior frontal gyrus activity in SPECT and fMRI studies (Feinstein et al., 1999). Hu and colleagues reported a unique case of mirthless GS localized to the anterior inferior frontal gyrus (Hu et al., 2011). Kim and ChoiKwon (2000) found emotional incontinence in 4 of 10 patients with middle cerebral artery territory frontal lobe infarcts.

4.1.1.4. Anterior cingulate gyrus (ACG). Haiman et al. (2009) found that DM-Q reduced current density in the left ACG and increased it in the right ACG. In MS, Feinstein and colleagues (1999) identified a correlation of Poeck-defined PLC with the Stroop Word Color Test (p = .05) in 11 MS patients relative to 13 MS controls lacking PLC; the Stroop test has been correlated with ACG functional activity. Arroyo et al. (1993) reported a 35 year-old woman with a mesial frontal cavernous hemangioma and a left ACG ictal focus associated with GS without mirth. ACG lesions have been frequently associated with GS across the literature, including a left cystic tumor, a left pleiomorphic xanthoastrocytoma, and right cortical dysplasia (Kovac et al., 2009). Similarly, GS has been associated with frontocentral epilepsy in ACG cortical dysplasia (McConachie and King, 1997) and a circumscribed CG cyst (Loiseau et al., 1971). The chronic pathological laughter (PL) case of Mendez et al. (1999) involved the ACG and OBF cortex. In intra-operative recordings, Talairach et al. (1973) observed upper and lower lip movements and, sometimes, increased respiration, mydriasis, or tachycardia without any affective component. In other intra-operative recordings, the ACG area correlates with the motor act of laughing but not mirth (Arroyo et al., 1993; Iwasa et al., 2002; Sperli et al., 2006). Sperli et al. reviewed the intra-operative electrical stimulation literature, finding only the case of Sem-Jacobsen (1968) involving laughter induced by ACG and OBF stimulation.

4.1.1.9. Operculum. Ross and Rush (1981) reported 4 patients with right frontal opercular lesions and pathological affect in association with depression. Ross and Stewart (1987) reported two additional patients including additional details of a previously reported pathological crying (PC) case, although the first case also involved other areas including other frontal and temporal structures and the parietal operculum, and the second case also involved the anterior parietal operculum. Sugama and colleagues (1992) reported a case of GS in a 9 year-old boy associated with MRI and SPECT abnormalities in the left operculum.

4.1.1.5. Premotor cortex (PMC). Haiman et al. (2008) found evoked potentials activated near the PMC in IEED. The glioblastoma linked to IEED laughter reported by Tsutsumi and colleagues (2008) invaded the PMC. Ghaffar et al. (2008) also found lesions in this area in patients with MS. Intraoperative stimulation of the superomedial PMC induced laughter in an 18 month-old child with tuberal cortical dysplasia (Schmitt et al., 2006). 4.1.1.6. Supplementary motor cortex (SMA). The Haiman et al. (2008) study revealed evoked potential activation in the vicinity of the SMA in IEED, and Ghaffar et al. (2008) found MS lesions in this same area. SMA lesions are a frequent cause of GS (Kovac et al., 2009). In the GS case reported by Chassagnon et al. (2003), the ictal zone was circumscribed to the anterior ventral SMA and underlying dorsal CG. Schmitt et al. (2006) reported a 35 year-old woman in whom intra-operative stimulation of the SMA induced laughter without mirth. 4.1.1.7. Pre-SMA. Fried et al. (1998) found laughter associated with mirth and humorous perception after stimulating the Pre-SMA, an area anterior to the SMA proper (Chassagnon et al., 2003). The PreSMA is involved in higher level programming, in contrast to the motor programming performed by the SMA, and the Pre-SMA may coordinate laughter with emotion and, therefore, integrate input from the basal temporal and other areas of mood-mediating cortex with motor programs for emotional expression. The Pre-SMA is also proximal to Brodmann area 9, which is involved in processing sadness and happiness (Lane et al., 1997). 4.1.1.8. Lateral frontal cortex. In the TBI study of Tateno et al. (2004), PLC correlated with left lateral frontal lesions (OR 10.63, 95% CI 1.39–18.35, p = .03). Feinstein et al. (1999) found a correlation of PLC with the Controlled Oral Word Association Test (COWAT; p = .03)

4.1.1.10. Insula. Gondim et al. (2001) reviewed the literature of fou rire prodromique (i.e. “prodromal crazy laughter,” or laughter at the onset of a progressive neurological lesion), finding an association with strokes involving the left insula and lenticulocapsular area (Carel et al., 1997; Osseby et al., 1999). 4.1.1.11. Primary motor cortex (M1). Haiman et al. found evoked potential activation over M1 in IEED (2008), with reduced evoked potential current density over M1 after DM-Q treatment (2009). Gallagher (1989) studied 73 patients with ALS onset before age 45 and found 36 cases of IEED, including 20 with laughing and crying (IEED-LC), 9 with crying (IEED-C), and 7 with laughing (IEED-L), with bulbar involvement in nearly all IEED-LC cases. Pustorino et al. (2007) reported a 5-year-old girl with diplegic cerebral palsy and seizures who paradoxically developed status gelasticus after the addition of levetiracetam to oxcarbazepine and diazepam. Riggs et al. (1999) described a 54 year-old man with progressive spastic quadriparesis and IEED. Zeilig et al. (1996) studied 16 patients with TBI and IEED, finding laughing and mixed-laughing-and-crying IEED-LC to be more frequent than crying IEED-C. In this study, IEED correlated with corticospinal tract (hemiparesis) and brainstem (dysphagia and dysarthria) signs, compatible with PBA. The corticospinal and corticobulbar signs may relate to lesions involving M1, subcortical white matter, internal capsule, or brainstem, but are most parsimoniously consistent with the latter site. As noted earlier, Ghaffar et al. (2008) found MS lesions in superomedial M1. In a case of fou rire prodromique, Garg et al. (2000) identified infarction of the ventrolateral aspect of M1. 4.1.1.12. Parietal Lobe. Haiman et al. found evoked potential activation over somatosensory areas in IEED (2008), latency changes over the post-central gyrus, and current density reductions over the supramarginal gyrus (SMG) after DM-Q treatment (2009). The MS study of Ghaffar et al. also revealed parietal lobe plaques spanning the inferior primary sensory cortex (S1) and SMG in PLC (Ghaffar et al., 2008). These parietal lobe areas happen to lie in the sensory cortical areas associated with facial expression, vocalization, and respiration (Plum and Leigh, 1981), and they correspond functionally to and communicate with the ventrolateral frontal cortical and M1 areas that have been identified above. Offen et al. (1976) reviewed the literature of DS and, of 5 cases, found one with syphilitic right parietotemporal cortical softening. Shin et al. (2006) reported a patient with GS with an ictal focus deep in the parietal lobe white matter. 4.1.1.13. Basal temporal cortex. Gondim et al. (2001) reviewed the fou rire prodromique literature, finding several reports of an

1904

E.C. Lauterbach et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 1893–1916

association with left temporal lobe ischemia. Haiman et al. (2009) found reduced current density in the left ITG and right uncus, and changes in fusiform gyrus (OTG) latencies, after DM-Q treatment. In contrast to the absence of mirth in most frontal lobe GS cases, a number of GS cases involving mirth have been reported, with foci in the basal temporal cortex (Coria et al., 2000), right ITG (Dericioglu et al., 2005), and basolateral temporal lobe (Oehl et al., 2009). DS have been associated with the temporal lobe (Sethi and Rao, 1976; Offen et al., 1976), especially the non-dominant temporal lobe (Sethi and Rao, 1976; Luciano et al., 1993), and the anterior mesial temporal region (Sethi and Rao, 1976; Luciano et al., 1993; Tatum and Loddenkemper, 2010). Several intra-operative recordings have documented mirth and laughter correlating with basal temporal cortical stimulation. Satow et al. (2003) found mirth that dosedependently evolved into laughter as the stimulus was increased over the basal inferior temporal cortex. Arroyo et al. (1993) found laughter with mirth upon stimulation of the PHG in one patient and the lateral OTG in 2 patients with non-GS temporal lobe epilepsy; humorous perception was also correlated with OTG stimulation in one of the patients. Similarly, Iwasa et al. (2002) reported laughter with mirth associated with EEG dipoles localized to the medio-basal temporal lobe, consistent with PHG or possibly OTG. 4.1.2. Hypothalamus Hypothalamic lesions are a frequent cause of GS, particularly hypothalamic hamartomas (Cascino et al., 1993), occurring in 4 of 10 cases of pediatric GS, the remaining 6 cases showing no localizing findings on MRI (Shahar et al., 2007). Kahane et al. (2003) studied 3 patients with GS and hypothalamic hamartoma, with 2 attributable to intrinsic epileptiform activity of the hamartoma itself evident on stereotactic electroencephalography. Parvizi et al. (2011) recently reviewed 100 cases of GS with hypothalamic hamartomas. Similarly, Sethi and Rao (1976) reviewed the literature of DS, finding the hypothalamus to be one of two major lesion sites. Direct stimulation of the floor of the third ventricle (Foerster and Gagel, 1933) and caudal hypothalamus (Bard, 1934) has produced laughter. In the Kahane et al. (2003) study, intraoperative stimulation of a hypothalamic hamartoma in a patient without GS or DS induced a pressure to laugh. 4.1.3. Subthalamic region There are several reports of IEED associated with subthalamic nucleus deep brain stimulation (DBS). Krack et al. (2001) reported laughing in 2 patients in the context of dorsolateral subthalamic nucleus DBS using high stimulus parameters. Okun et al. (2004) noted uncontrollable crying along with flat affect, psychomotor retardation, and increased gag and facial reflexes after DBS delivered through leads ranging from the medial subthalamic nucleus limbic territory to the thalamus in a single patient. Wojtecki et al. (2007) found brief, stereotyped, uncontrollable crying without sadness with DBS of the ventral subthalamic nucleus in a single patient, which was associated with activation of the thalamus on positron emission tomography. Although the subthalamic nucleus is targeted, current is capable of spreading to a wide variety of tracts and structures in its vicinity, including both the volitional (likely in the Okun et al. case) and emotional pathways implicated in IEED. Wojtecki et al. (2011) reported a 69-year-old man with PD who developed affective lability with mood congruent mirthful laughter associated with left-sided subthalamic nucleus DBS, attributed to connections of the subthalamic nucleus with the ACG, or by effects on proximal structures such as the median forebrain bundle or lateral hypothalamus (and, likely, hypothalamic connections with the basal temporal cortex linked to mirth). They also observed sadness and crying in the same patient, which they related to right-sided DBS affecting the internal capsule.

4.1.4. Internal capsule Kim and Choi-Kwon (2000) found emotional incontinence to be present in 45% of 42 stroke patients with capsulolenticular lesions (i.e., lesions involving the internal capsule plus globus pallidus). Overall, such lesions were the most frequent cause of emotional incontinence in their study. Gondim et al. (2001) reviewed the fou rire prodromique literature, finding an association with strokes involving the left internal capsule and thalamus (Ceccaldi and Milandre, 1994), left capsule and striatum (Ceccaldi et al., 1994), left capsule and putamen (Poeck, 1985), right capsule and lenticular nucleus (Burzio, 1900), and right capsule and striatum (Ceccaldi et al., 1994). A review of localizing lesions in GS revealed a right internal capsule focus in one case (Kovac et al., 2009). All three regions of the internal capsule, including the anterior limb (ALIC), genu, and posterior limb (PLIC) have been implicated as possible substrates. Bharathi and Lee (2006) reported a 67 year-old woman with PC after a stroke involving the right ALIC and external capsule. Poeck (Poeck and Pilleri, 1963; Poeck, 1969) found lesions of the ALIC to be associated with PLC in an autopsy study. ACG fibers course through the anterior and middle ALIC and ventrolateral PMC fibers occupy the posterior ALIC (Morecraft et al., 2001b). Uzunca et al. (2005) reported fou rire prodromique in association with bilateral genu lesions. Poeck (Poeck and Pilleri, 1963; Poeck, 1969) found the genu involved in all of 30 autopsied PLC cases. The genu also carries fibers from the ACG (Morecraft et al., 2001a,b) as well as the inferior precentral gyrus (the region of M1 involved in facial expression and vocalization) en route to the bulbar nuclei (Langworthy and Hesser, 1940), and genu lesions are associated with facial, palatopharyngeal, and vocal cord paresis (Bogousslavsky and Regli, 1990), structures that are used in laughing and crying. Finally, Ceccaldi et al. (1994) reported a patient with IEED-L and a lesion confined to the right PLIC, a region occupied primarily by efferents of M1 motor cortex (Morecraft et al., 2001b). Although the current used in targeted DBS can frequently diffuse to engage a number of surrounding structures and tracts, Low et al. (2008) have reported PC associated with DBS through an electrode implanted in the PLIC. In this case, using low intensity stimulus (130 Hz, 0.5 V), diffusion was thought not to exceed 2 mm and was likely confined to the PLIC. 4.1.5. Brainstem The TBI study of Zeilig et al. (1996) identified brainstem and corticospinal tract signs in association with IEED, including dysphagia, dysarthria, and hemiparesis, that are potentially compatible with brainstem midbrain, pontine, or medullary lesions associated with PBA. Achari and Colover (1976) reported PL related to extrinsic brainstem compression by a large supratentorial and infratentorial epidermoid cyst. The MS study of Ghaffar and colleagues (2008) found PLC to be associated with lesions distributed in the midbrain and pons. Whereas frontoparietal plaques were hyperintense on MRI and were consistent with acute inflammation, brainstem lesions were hypointense and indicative of actual neuronal loss (Ghaffar et al., 2008). Lesions of the midbrain–pontine PAG are associated with complete and irreversible mutism (Esposito et al., 1999). 4.1.5.1. Midbrain. Hargrave et al. (2006) reported cases of IEED-L associated with pontine gliomas, some of which extended into the midbrain. Ghaffar et al. (2008) found neuronal loss and midbrain plaques associated with PLC in MS. Offen et al. (1976) reviewed the literature of DS and, of 5 cases, found one with an interpeduncular glioma that also invaded the pons. New and Thomas (2005) observed PBA laughing and crying (PBA-LC) associated with the locked-in syndrome occurring in a midbrain-pontine stroke. Dabby et al. (2004) reported IEED-L in 3 patients, including one with a large bilateral infarct of the midbrain and pons, but also in two other

E.C. Lauterbach et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 1893–1916

patients with small strokes restricted to the left paramedian lower midbrain (one with possible PBA). IEED-LC (probable PBA type) has also been linked to confined midbrain lesions in MS, including a 16 year-old woman with PL reported by Okuda and colleagues (2005) in association with bilateral plaques in the basis pedunculi that carry the corticobulbar tracts. de Seze et al. (2006) reported 4 patients with MS and early presentation of IEED-L, including a 16-year-old man with an inaugural episode and a single symmetrical midline plaque circumscribed to the midbrain, with IEED-L improving with corticosteroid treatment. It is possible that the acute medial midbrain MS plaque in this case disrupted descending volitional pathway fibers or irritated more midline emotional pathway motor fibers mediating IEED, since IEED improved with corticosteroid treatment. Kim and Choi-Kwon (2000) found emotional incontinence to be present in 1 of 3 stroke patients with midbrain lesions. 4.1.5.2. Pons. In 3 cases of cryptogenic PL of unknown etiology, Kosaka et al. (2006) noted abnormal pontine activation on fMRI in the context of neuropsychological testing, remitting after treatment with paroxetine. In a review of 12 cases with multiple lesions on MRI, Andersen and colleagues (1994) observed that IEED-C severity correlated with lesion proximity to the pons. Pons-plus lesions have been identified in association with pathological emotional expression, including DS with a midbrainpontine tumor (Offen et al., 1976), IEED-L in pontine-midbrain MS (de Seze, 2006) and stroke (Dabby et al., 2004; New and Thomas, 2005), laughing and crying in pontine-medullary MS (de Seze et al., 2006), and fou rire prodromique in pontine-cerebellar stroke (Gondim et al., 2001). Jagetia et al. (2006) reported a cystic trigeminal schwannoma associated with IEED-L that compressed the anterolateral pons. They reviewed the literature and found 8 other cases of solid and cystic trigeminal schwannomas that also presented with IEED-L (Jagetia et al., 2006). Among lesions confined to the pons, Achari and Colover (1976) reported a patient with PL in the context of a pontine glioma. In a series of 9 children with pontine gliomas, Hargrave and colleagues (2006) found IEED-L in 8, and IEED-L improvement correlated with tumor regression after radiation therapy. Ghaffar et al. (2008) found pontine plaques associated with PLC in MS. Assal and colleagues (2000) reported a pontine stroke in association with fou rire prodromique in a child. In addition to their original case, Gondim et al. (2001) found several additional reports of pontine stroke associated with fou rire prodromique in their review of the literature. Asfora et al. (1989) found an arteriovenous malformation leading to a pontine stroke, with progressive PLC as the sole presenting sign. Sacco et al. (2008) reported 4 patients with locked-in syndrome and PLC with large lesions involving most of the anterior ventral basal pons extending dorsally to proximal to the tegmentum. They found that PLC produced significant patient discomfort, interfered with rehabilitation, and did not respond to pharmacologic treatment. Arif et al. (2005) encountered a 35 year-old man with IEED-LC (possible PBA), also provoked by swallowing liquids, associated with bilateral pontine infarcts. Oh and colleagues (2008) treated an 80 year-old woman with PL following bilateral pontine infarcts. Kossorotoff et al. (2010) reported 2 children who had IEED-LC after focal pontine infarcts. Chen et al. (2010) found PL after a paramedian pontine hemorrhagic stroke. Moreover, Kataoka et al. (1997) reviewed 49 cases of paramedial pontine infarction, finding IEED-L in 3 and IEED-C in 1 (all with possible PBA) that correlated with sparing of the lateral tegmentum after such strokes. Kim and Choi-Kwon (2000) found emotional incontinence to be present in 21% of 24 stroke patients with pontine lesions. They noted that pathological emotionality was linked exclusively to lesions of the basis pontis, occurring in 53% of 19 such cases, whereas it was not observed in lesions

1905

involving the dorsal pons (0% of 5 cases) (Kim and Choi-Kwon, 2000). Most recently, Elyas et al. (2011) reported a well-described case of PLC related to a pontine abscess in the lateral basis pontis. They further reviewed cases of focal pontine lesions associated with IEED and found the area of maximal lesion overlap to be localized to the anterior paramedian pontine nuclei. Thus, it appears that lesions of the anterior basal paramedian pons sparing the lateral tegmentum are highly associated with IEED and its PLC subtype. 4.1.5.3. Medulla. Hargrave et al. (2006) reported cases of IEEDL associated with pontine gliomas, some of which extended to involve the medulla. Of the 4 MS patients reported by de Seze et al. (2006), one patient had IEED-L and hiccups with bulbopontine junction and medullary lesions. Kim and Choi-Kwon (2000) found emotional incontinence to be present in 4 of 11 stroke patients with medullary lesions, found exclusively in medial lesions (in 4 of 4 cases) but not in lateral lesions (0 of 7 cases). 4.1.6. Cerebellum The cerebellum receives projections from the pons and is an integral member of the frontal and temporal cortico-pontocerebello-thalamo-cortical circuits. The cerebellum itself projects to the PAG as well as the cranial nerve nuclei of VII and X (Parvizi et al., 2001) and receives substantial serotoninergic projections from the raphe nuclei (Bishop and Ho, 1985). A problem in the IEED literature is that most cases reports of cerebellar pathology are complicated by either definite or probable pathology in additional structures, most often the brainstem. Guimarães et al. (2008) found IEED-C in two cases of Machado-Joseph disease, but a psychiatric disorder cannot be ruled out, and brainstem dysphagia and pyramidal corticospinal tract signs were also present. Komurasaki et al. (1989) noted a patient with IEED-L in the context of olivopontocerebellar atrophy (OPCA), a neurodegenerative disease that involves olivary, pontine, cerebellar, and medullary degeneration. Parvizi et al. (2007) reported IEED-LC and IEED-C in 10 of 27 cases of multiple system atrophy-cerebellar type (previously termed OPCA), another disease with extra-cerebellar pathology. Several cases had signs compatible with probable PBA. Essential tremor has been linked to cerebellar dentate nucleus degeneration (Nicoletti et al., 2010), Purkinje cell loss (Louis, 2010; Rajput et al., 2011), cerebellar axonal swelling (Louis et al., 2011), and GABA receptor upregulation (Boecker et al., 2010). Siddiqui et al. (2009) studied 65 patients with essential tremor and found IEED in 2 (3.1%). Confounds in this study included associations of IEED with depression and antidepressant treatment. Strowd et al. (2010) found IEED in 11.4% of 35 patients with essential tremor, but the same associations with depression, lower emotional well-being, and antidepressant treatment were again present. There have been a number of case reports of IEED in association with cerebellar lesions, however, these also are associated with either frank brainstem pathology or an inability to exclude coexisting brainstem compression. These cases include IEED-LC in the context of multiple infarcts involving the cerebellum, midbrain, and pons (Parvizi et al., 2001), PC with a midline cerebellar cyst (Parvizi and Schiffer, 2007), PL sometimes followed by syncope with a cerebellar tumor (Famularo et al., 2007), IEED-L in cerebellitis with mutism, brainstem signs (disturbed consciousness and sleep-wake cycle), and correlation with bilateral corticospinal tract signs (Dimova et al., 2009), IEED-LC with right cerebellar hemisphere and vermal infarction in association with bilateral brainstem lesions (Kossorotoff et al., 2010), and movement-induced reflex IEED-L with focal cerebellar hemorrhage (Doorenbos et al., 1993), notorious for its predisposition to compress the brainstem. Possible EL episodically developed along with a disinhibited personality change and psychotic features after resection of a cerebellar vermal tumor, also associated with bilateral CG and inferolateral frontal hypoperfusion (Mariën et al., 2011).

1906

E.C. Lauterbach et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 1893–1916

Finally, Kim and Choi-Kwon (2000) found emotional incontinence in 2 of 9 patients with focal cerebellar strokes. 4.1.7. Thalamus Weisenburg and Guilfoyle (1910) reported a case of IEED-C with a thalamic tumor. Gondim et al. (2001) reviewed the fou rire prodromique literature and, in addition to the capsulothalamic lesion cited above (internal capsule section), found a hemorrhagic stroke involving the bilateral thalamus (Andersen, 1936). Offen et al. (1976) reviewed the literature of DS and, of 5 cases, found one with encephalomalacia of the right thalamic medial nuclei. Kim and Choi-Kwon (2000) found emotional incontinence in 3 (16%) of 19 patients with focal thalamic strokes. Lauterbach and colleagues (1994) reported PL after a posterior thalamic stroke involving the pulvinar and lateral posterior nuclei. Fou rire prodromique has also been associated with posterior thalamic infarction (Fere, 1903; including the pulvinar, lateral posterior, and ventral posterior lateral nuclei although the internal capsule was also involved (Ceccaldi and Milandre, 1994)). The pulvinar and lateral posterior nuclei receive projections from the deep cerebellar nuclei (Künzle, 1998; Rodrigo-Angulo and Reinoso-Suarez, 1984), and the posterior thalamic nuclei project to frontal motor cortices (Kultas-Ilinsky et al., 2003; Baleydier and Mauguiere, 1980; Vogt et al., 1987) and affect frontal function (Crosson, 1999). The pulvinar and posterior thalamic nuclei also project to the basal temporal lobe (Siqueira and Franks, 1974; van Buren and Borke, 1972; van Buren et al., 1976). Consequently, the thalamus may mediate pontine influences on frontal emotional processing networks that are directed through pontocerebellar projections, as mentioned in the section on the pons. The thalamus further supports frontal and temporal corticoponto-cerebello-thalamo-cortical circuits that may be involved in both the volitional and emotional pathways associated with IEED. Moreover, it is also involved in afferent pathways to the parietal lobe to provide guiding feedback that informs the frontal and, possibly, temporal emotional cortices. Hassler and Reichert (1961) documented laughter with mirth, a feature associated with the basal temporal cortex, after intra-operative electrical stimulation of the thalamus. 4.1.8. Basal ganglia As is the case for the cerebellum, most basal ganglia cases are complicated by the involvement of other structures. The TBI study of Zeilig et al. (1996) found MRI evidence of basal ganglia injury in 4 of 16 subjects with IEED-L or IEED-C, but there was likely widespread traumatic pathology. There are several case reports of IEED in the context of subthalamic DBS (subthalamic nucleus section), however, diffusion of current precludes an interpretation of basal ganglia attribution. Lam and colleagues (2007) reported a 38 year-old man with IEED-LC, dysarthria, and choreoathetosis in Fahr’s disease involving symmetrical frontal lobe, caudate, and cerebellar dentate nucleus calcifications. The autopsy studies of Poeck (Poeck and Pilleri, 1963; Poeck, 1969) and Davison and Kelman (1939) discovered evidence of basal ganglia involvement in PLC, however each basal ganglia case also displayed involvement of the internal capsule or thalamus. Davison and Kelman also reported a single case of Wilson’s disease (Case 39) with IEED-L, but autopsy data were lacking in this systemic, multifocal disease that usually involves the basal ganglia. Kim and Choi-Kwon (2000) found emotional incontinence to be present in 45% of 42 stroke patients with lenticular lesions, but these patients also had capsular infarction. More recently, Dopper et al. (2011) reported IEED-C (termed “emotional lability”) in a case of progranulopathic corticobasal syndrome involving atrophy of the caudate and putamen, but frontoparietal atrophy and temporal lobe degeneration were also present. Several studies have investigated IEED in dystonia, a movement disorder that generally lacks structural pathology yet is

most clearly but not exclusively linked to putamenal dysfunction. Davison and Kelman found a single case of dystonia musculorum deformans (Case 38) associated with PC, although mental retardation was also present. Siddiqui et al. (2009) found IEED in 2 (2.7%) of 74 patients and Strowd et al. (2010) found IEED in 0 of 13 patients with primary dystonia. Intra-operative stimulation of the globus pallidus was noted to evoke laughter in a patient with torsion dystonia (Hassler and Reichert, 1961), attributed to pallidal influences on thalamic projections to the ACG. Three studies have examined the prevalence of IEED in Parkinson’s disease (PD), a neurodegenerative disease that involves degeneration primarily of the dopaminergic substantia nigra pars compacta, but also involves the serotoninergic raphe nucleus and noradrenergic locus coeruleus. Using IEED criteria, Petracca et al. (2009) found that IEED was present in 16.8% of 131 patients with PD (15.3% in depressed patients with PD) and correlated with PD severity. Siddiqui et al. (2009) studied 860 patients with movement disorders who were interviewed for IEED (defined as mood-incongruent uncontrollable crying or laughing) using a 4-item questionnaire and found IEED in 18 of 387 (4.7%) PD patients, but significant correlations with depression and antidepressant treatment raise questions as to whether depression led to false positive IEED diagnoses. Strowd et al. (2010) used the CNS-LS scale to determine the prevalence of IEED in a number of movement disorders including 168 patients with PD and found 12 cases (7.1%), however those with IEED had significantly elevated Beck Depression Inventory scores, lower PDQ-39 emotional well-being scores, and more antidepressant use, raising the same questions. Recently, Siclari et al. (2011) found laughing as a manifestation of rapid eye movement (REM) sleep behavior disorder (RBD) in10 patients with PD, 2 with MSA-P, and 1 each with MSA-C and dementia with Lewy bodies. These constituted 21% of their RBD patients with parkinsonism. They also found crying and other behaviors in some patients. 5. Organization of the emotional and volitional pathways and the PLC reflexes Emotional and volitional pathways of emotional expression arise from cortices regulated by emotional processing and the dorsal and ventral paralimbic networks. As evident from the clinical literature review, the emotional circuitry involves basal frontotemporal cortices that relay to the amygdala and hypothalamus, which in turn project to the dorsal brainstem (midbrain-pontine PAG, dorsal tegmentum (dTg), and related brainstem) that coordinates the motor patterns of reflex laughing and crying. This emotional pathway is regulated by the volitional pathway, driven by dorsal and lateral frontoparietal cortices that project through the internal capsule and midbrain basis pedunculi to the anteroventral basis pontis. Volitional pathway pontine projections then regulate the emotional pathway, primarily at the level of the PAG. 5.1. Emotional pathway connectivity The emotional pathway OBF, ACG, anterior insular, ITG, OTG, and PHG cortices project to the amygdala (Blumenfeld, 2002; Herzog and Van Hoesen, 1976; Pitkänen et al., 2000; Kemppainen et al., 2002; Höistad and Barbas, 2008) while OBF, ACG, opercular, insular, and PHG cortices simultaneously project to the hypothalamus (Nieuwenhuys, 1985; Nolte, 2002), PAG (Cavada et al., 2000; Floyd et al., 2001, Müller-Preuss and Jürgens, 1976; Irle and Markowitsch, 1982; Reep and Winans, 1982), and brainstem nuclei innervating the vocal cords (Van Daele and Cassell, 2009). In particular, the ACG

E.C. Lauterbach et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 1893–1916

emotional vocalization area has direct projections to the OBF cortex, amygdala, hypothalamus, and PAG (Müller-Preuss and Jürgens, 1976; Buchanan et al., 1994). The amygdala is a higher order modulator of the hypothalamus and has reciprocal connections with the hypothalamus through amygdalofugal, median forebrain bundle, and stria terminalis projections (Nolte, 2002). Additionally, the amygdala has reciprocal projections to the PAG, midbrain central gray, reticular formation, parabrachial nucleus, other brainstem nuclei, substantia nigra pars compacta, ventral tegmental area, locus coeruleus, and raphe nuclei (Price and Amaral, 1981; Usunoff et al., 2006; Blumenfeld, 2002). Thus, the amygdala not only influences the distal components of the emotional pathway, but also the major neurotransmitter nuclei that regulate this pathway. The hypothalamus receives projections from the operculum, medial temporal lobe, and PHG (Nieuwenhuys, 1985), and is reciprocally connected with the ACG, OBF, insula, and medial prefrontal cortex, as well as the amygdala, PAG, anterior thalamic nucleus, solitary and parabrachial nuclei, raphe nuclei, ventral tegmental area, and locus coeruleus (Nolte, 2002). The hypothalamus projects efferents to the PAG and brainstem nuclei (Berk and Finkelstein, 1982; Sims and Lorden, 1986). The PAG and dTg are the key targets of the emotional pathway. The PAG is considered the trigger of emotional expression, with impulses carried to the vocal pattern generator, the nucleus retroambiguous, and other nuclei involved in emotional expression (Holstege, 1992; Jürgens, 1994). Situated dorsally, adjacent to the cerebral aqueduct in the midbrain and rostral pons, the PAG receives inputs from the emotional pathway cortices, amygdala, and hypothalamus (Meller and Dennis, 1986), as well as from multiple thalamic nuclei (Grofová et al., 1978; Vasilenko and Eliseeva, 1980; Barbaresi and Conti, 1981), the caudal globus pallidus (Shammah-Lagnado et al., 1996), subthalamic nucleus (Smith et al., 1990), substantia nigra pars reticulata (Grofová et al., 1978; Beitz, 1982), ventral tegmental area (Beitz, 1982), locus coeruleus (Beitz, 1982), and raphe nuclei (Beitz, 1982). The PAG projects efferents to multiple structures through the dTG (Smith, 1975; Schuller et al., 1997), including the facial nucleus (Panneton and Martin, 1983), nucleus retroamibiguous (Holstege, 1992), and parabrachial nucleus (Mantyh, 1983; Tokita et al., 2009). Lesion studies in animals indicate that it is the ventral and ventrolateral aspects of the PAG that are relevant to emotional expression including vocalization (Meller and Dennis, 1986; Schuller et al., 1997). The PAG and dTg project fibers to the reticular formation and related nuclei involved in facial expression, vocalization, and respiration (e.g., cranial nerves VII, IX, X, XI, phrenic nerve, nucleus ambiguous, nucleus retroambiguous, Kolliker-Fuse, etc.). These brainstem areas and nuclei, the PAG, dTg, and their related structures, are the key targets of the emotional pathway and serve as substrate for the reflex behaviors of laughing and crying. The reflex nature of laughing and crying provides their stereotyped presentation in PLC. For example, in laughing, vocal cord and respiratory musculature contractions are coordinated and synchronized. Vocal cord adductors, the thyroarytenoid and lateral cricoarytenoid muscles, cycle synchronized reflex bursts of EMG activity at a rate of 4.9 Hz, whereas the abducting posterior cricoarytenoids are coordinated to fire at the same rate between contractions of (out of phase with) the other muscles (Luschei et al., 2006). Like other reflexes, PLC manifests as a stereotyped reproducible response to a stimulus (Luschei et al., 2006), is associated with other released brainstem reflexes (Langworthy and Hesser, 1940), is released by cortical damage or inhibition (Wild et al., 2003), and is modulated by sensory feedback such as swallowing, speaking, or even movement of a limb (Arif et al., 2005; Ceccaldi et al., 1994). The coordinated reflex nature of muscle contraction is achieved by brainstem nuclear connections with other

1907

brainstem nuclei (nucleus ambiguous, nucleus of the solitary tract, the Botzinger complex, oral and caudal pontine nuclei), reticular formation, PAG, hypothalamus, amygdala, and emotional and volitional motor cortices (Saper and Loewy, 1980), as is the case in the control of the thyroarytenoid muscle (Van Daele and Cassell, 2009). In summary, cortical networks regulate the emotional pathway, comprised of limbic components that project to dorsal brainstem structures coordinating stereotyped, patterned laughing and crying reflexes. The emotional pathway is controlled by the volitional pathway. 5.2. Volitional pathway connectivity The volitional pathway dorsal CG (dCG), PMC, SMA, M1, posterior insula, and S1 cortices project through the corona radiata, internal capsule, and midbrain basis pedunculi to the basis pontis and thence to motor nuclei relevant to emotional expression, with a return loop projecting back to the cortices via the cerebellum and thalamus. Specifically, the dCG (Brodal and Bjaalie, 1992), PMC (Leichnetz et al., 1984; Brodal and Bjaalie, 1992), SMA (Jürgens, 1984; Brodal and Bjaalie, 1992), M1 (Sharp and Ryan, 1984; Brodal and Bjaalie, 1992), S1 (Sharp and Ryan, 1984; Brodal and Bjaalie, 1992), and parietal cortices including areas 5 and 7 (Leichnetz et al., 1984; Brodal and Bjaalie, 1992; Baizer et al., 1993; Papoyan, 1997; Glickstein, 2003) project fibers to the basis pontis and pontine nuclei whereas the emotional pathway OBF (Leichnetz and Astruc, 1976; Schmahmann and Pandya, 1997), ACG (Leichnetz and Astruc, 1976; Schmahmann and Pandya, 1997), ventral prefrontal (Schmahmann and Pandya, 1997), dorsal medial prefrontal (Leichnetz and Astruc, 1976; Schmahmann and Pandya, 1997), anterior insula (Saper, 1982), and ITG (Baizer et al., 1993) do not. M1 and the lateral frontal cortex are modulated by the posterior granular and dysgranular insula (Yasui et al., 1991; Clascá et al., 2000; Cauda et al., 2011), SMA, and PMC, as well as by sensory feedback from S1 and SMG. This volitional pathway regulates the activity of the emotional pathway. The corticopontine volitional pathway is itself regulated by several feedback systems. First, volitional frontal cortices receive feedback from fronto-ponto-cerebello-thalamo-frontal circuits. Second, afferent feedback from the brainstem projects directly to the frontal and parietal cortices, with the parietal cortex projecting further feedback to frontal cortices. Third, emotion-related volitional cortices are modulated by basal ganglia and cerebellar processing circuits. These include basal ganglia cortico-striato-pallido-thalamo-cortical and cortico-striatopallido-subthalamo-pallido-thalamo-cortical loops (Lauterbach, 2003) and cerebellar cortico-ponto-cerebello-thalamo-cortical and cortico – zona incerta – inferior olive – cerebello – thalamo – cortical circuits (Lauterbach et al., 2010). Thus, the emotional pathway is consciously controlled through the corticopontine projections of the volitional pathway. Feedback is provided by corticocortical, sensory, pontocerebellothalamofrontal, and bulbocortical projections while modulation of cortical structures is in part achieved through basal ganglia and cerebellar processing. 6. Neurotransmitters associated with IEED A number of neurotransmitters have been implicated in PLC and EL; acetylcholine (Ach), dopamine (DA), norepinephrine (NE), serotonin (5HT), glutamate, sigma receptor systems, and GABA may adjust PAG-tegmental and bulbar motor nuclei gain (Holstege, 1992), consistent with both anatomy and the therapeutic effects of antimuscarinics, levodopa, tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), NMDA antagonists,

1908

E.C. Lauterbach et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 1893–1916

DM-Q, and possibly benzodiazepines. These neurotransmitters can act at many different sites along the emotional and volitional pathways that govern the laughing and crying reflexes, especially the brainstem PAG-dTg coordinating the laughing and crying reflexes. The PAG appears to be the final common pathway of emotional expression and has been conceptualized as a “trigger” for emotional expression (Holstege, 1992; Jürgens, 1994). Muscarinic transmission (Nakai et al., 1997) inhibits GABAergic neurons through M1, M2, and M3 muscarinic receptors in the PAG (Zubieta and Frey, 1993; Lau and Vaughan, 2008). Relatively high concentrations of catecholaminergic (Jones and Friedman, 1983; Flügge et al., 1992) and serotoninergic (Meoni et al., 1997) neuronal projections, 5HT transporters (Meoni et al., 1997), and DA D2 (Mansour et al., 1990), NE alpha-1 (Stone et al., 2004), alpha-2 (Flügge et al., 1992), 5HT1b/d (Vergé et al., 1986; Castro et al., 1997), NMDA (Monaghan and Cotman, 1985; Meoni et al., 1997), sigma-1 (Gundlach et al., 1986; Meoni et al., 1997), and benzodiazepine receptors (Rocha and Ondarza-Rovira, 1999) each have been documented in the PAG and brainstem dorsal tegmentum. Neurotransmitter-related observations link neurochemical systems to PLC and EL. Pyrethrin insecticide (cholinesterase inhibitor) exposure induced IEED-L in a 33 year-old man (Zellers et al., 1990). Cohn (1951) observed marked improvement in IEED in 9 patients with cerebrovascular accident (CVA) treated with the antimuscarinics atropine or scopolamine. Udaka and colleagues (1984) noted reduced CSF levels of the DA metabolite homovanillic acid in CVA patients with PLC relative to CVA controls. They reported remission or marked improvement in PLC in 25 mainly CVA (2 TBI) patients with 0.6–1.5 g/day levodopa under open-label conditions. They subsequently treated 8 of these CVA patients with amantadine100 mg/day, a weak DA presynaptic releaser and NMDA antagonist, noting improvement in 4, especially in IEED-C. Mariën et al. (2011) reported a case of possible EL after resection of a cerebellar tumor that responded to the D2 agonist ropinirole. Schindehütte and Trenkwalder (2007) reported that 2 of 4 PD patients treated with the atypical antipsychotic ziprasidone developed IEED-L, and the authors suggested that blockade of D2 receptors may induce IEED-L, at least in the context of diminished dopamine tone in PD patients. Thus, cholinergic agonists and D2 antagonists may precipitate IEED while antimuscarinics and D2 agonists display treatment efficacy. In contrast to the ziprasidone report, Chen et al. (2010) reported a patient with IEED-L rapidly remitting with the atypical antipsychotic quetiapine 25 mg/day, thought related to alpha-2 antagonism resulting in enhanced NE release. Møller and Andersen (2007) observed three patients with pontine lesions in whom IEED-L responded rapidly to reboxetine, a selective NE reuptake inhibiting antidepressant; these patients had been either unresponsive to or exacerbated by the SSRI citalopram. McCullagh and Feinstein (2000) and Oh et al. (2008) have reported additional cases of IEED-L resistant to SSRIs. McCullagh and Feinstein (2000) provided particularly well-documented PLC with PBA features in 3 cases of ALS, reporting conversion of PBA-C to PBA-L in one and poor or absent response of PBA-L in the other two, in contrast to remission of PBA-C. Brainstem 5HT transporters (Murai et al., 2003) and global 5HT1a binding potential (Møller et al., 2007) are reduced in IEED-C (presumably probable PC). SSRIs have shown efficacy in double-blind placebo controlled studies of IEED (Andersen et al., 1993; Burns et al., 1999; Choi-Kwon et al., 2006). Barbanti et al. (2008), however, reported a patient who developed IEED-L upon administration of the 5HT1b/d agonist sumatriptan, perhaps activating 5HT1b receptors on interneurons that inhibit the PAG. Projections from the cortex, amygdala, and hypothalamus to the PAG are glutamatergic (Jürgens, 1994). The glutamate release and DA, NE, and 5HT reuptake inhibitor lamotrigine has been reported to be effective in 5 cases of IEED-L and less effective for

IEED-C present in 2 of these cases (Ramasubbu, 2003; Chahine and Chemali, 2006). As noted above, Udaka et al. (1984) reported improvement in PC more than PL with the NMDA antagonist amantadine. DM-Q, an N-methyl-D-aspartate (NMDA) glutamate receptor antagonist and sigma-1 receptor agonist, is effective in treating IEED in double-blind placebo-controlled studies (Brooks et al., 2004; Panitch et al., 2006; Pioro et al., 2010). Sigma-1 agonists have multiple effects, including increasing the release of NE and 5HT (Bermack and Debonnel, 2005) and enhancing DA neurotransmission (Peeters et al., 2004). In addition to these sigma-1 effects, DM also inhibits NE and 5HT reuptake (Pubill et al., 1998) and has binding affinity at NE alpha-2, 5HT1b/d, and M1-3 receptors (Werling et al., 2007). The tricyclic amitriptyline and SSRI fluoxetine, each proven effective in IEED double-blind placebo controlled studies (Schiffer et al., 1985; Choi-Kwon et al., 2006), also inhibit 5HT reuptake, are sigma-1 agonists, and have binding affinities at alpha-2, 5HT1b/d, and M1-3 similar to DM (Werling et al., 2007). Similarly, the tricyclic nortriptyline inhibits both NE and 5HT reuptake and has been effective in a double-blind placebo controlled trial in post-stroke PLC (Robinson et al., 1993). Although data are scant for GABA agonists, the insecticide-induced IEED-L case described above was terminated by a single dose of intravenous diazepam (Zellers et al., 1990). Thus, glutamate transmission may be critical to emotional displays such as IEED and agents reducing glutamatergic transmission particularly at NMDA receptors, sigma agonists, and GABA agonists may constitute useful IEED treatments. The available observations suggest that IEED-L may be more sensitive to D2 and NE insufficiency whereas IEED-C may be more sensitive to 5HT and NMDA insufficiency. Thus, antagonists at muscarinic, alpha-2, glutamate, and NMDA receptors, and indirect agonists of DA, NE, and 5HT and direct agonists at sigma-1 and GABA-A receptors have been effective in treating IEED, whereas D2 antagonists and 5HT1b/d serotonin agonists have precipitated IEED-L, perhaps by acting directly at the PAG. In particular, muscarinic receptor–mediated inhibition of inhibitory GABA neurons acting on PAG glutamatergic neurons appears to disinhibit the PAG and induce IEED (Lau and Vaughan, 2008), likely constituting substrate for the therapeutic actions of muscarinic and NMDA antagonists and benzodiazepine GABA agonists. Additionally, inhibitory DA, NE, 5HT, and sigma systems further regulate dorsolateral PAG neurons involved in emotional expression and IEED (Grofová et al., 1978; Beitz, 1982; Jürgens, 1994; Gundlach et al., 1986; Meoni et al., 1997).

7. Implications for IEED subtype pathophysiologies The findings of this review are consistent with a modified Wilsonian model of emotional and volitional pathways as a substrate for PLC whereby release of reflex laughing or crying from volitional pathway constraint occurs in dissociation from mood. EL, with its non-stereotyped and mood-associated presentation, may be linked to disturbances of the emotional motor system cortex (ventral basal temporal lobe) or at a level above it (such as the emotion-processing paralimbic networks or cortical areas and structures that modulate them, including the cerebellum, basal ganglia, and thalamus). Olney et al. (2011) recently showed mood changes linked to frontal dysfunction in ALS patients with IEED while viewing emotional material, perhaps reflecting EL in the context of ALS frontal disturbances since selection criteria did not distinguish IEED subtypes. Tatum and Loddenkemper (2010) documented evidence of dual emotional and volitional pathways in an epilepsy patient with IEED crying. Nearly all reports of “PLC” associated with more focal lesions reported two features consistent with PLC (“probable PLC”), but these PLC features varied substantially between the reports, and

E.C. Lauterbach et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 1893–1916

1909

Fig. 1. Circuits involved in the pathophysiology of PBA. (a) Volitional Pathway. Volitional projections from PMC, SMA, CG, M1, and S1 project through the internal capsule and midbrain basis pedunculi to the basal pons where they synapse, and return feedback to the cortex through the cerebellum and thalamus to complete the circuit. Pontine information is relayed to brainstem nuclei involved in emotional expression. Somatosensory feedback from S1 and related parietal cortex including the supramarginal gyrus modulates volitional motor cortices, as do basal ganglia processing circuits. Not shown here, the Pre-SMA, posterior insula, and supramarginal gyrus are also components of this system. (b) Emotional Pathway. Emotional pathway projections from ventral ACG, OBF, anterior insula, ITG, OTG, and PHC regulate the amygdala, and the amygdala and hypothalamus activate the PAG, which, via the dTg, in turn activates the brainstem reflexes of laughing and crying. (c) Composite Pathways. The volitional pathway inhibits the emotional pathway at multiple levels, but most directly by cholinergic–GABAergic pontine regulation of the PAG glutamatergic neurons as described in the text. Together these observations provide a view of the complex anatomy and neurochemistry of the circuits mediating IEED and EL and offer a template for ongoing pathophysiologic and treatment related research. Abbreviations: ACG anterior cingulate gyrus, Amyg amygdala, CB cerebellum, CG cingulate gyrus, dTG dorsal tegmentum, Hyp hypothalamus, ITG inferior temporal gyrus, M1 primary motor cortex, NRA nucleus retroambiguus, OBF orbitofrontal cortex, OTG occipitotemporal (fusiform) gyrus, PAG periaqueductal gray, PHC parahippocampal gyrus, PMC premotor cortex, S1 primary sensory cortex, SMA supplementary motor area cortex. (Figures created by Cleveland Clinic Center for Medical Art and Photography.)

1910

E.C. Lauterbach et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 1893–1916

there were no cases that could be considered as either probable or definite EL. Given the lack of available clinical detail, inference of a precise PLC pathophysiology based on a literature review must remain tentative. The major sites targeted by the emotional basal frontotemporal cortical and volitional dorsal and inferolateral frontoparietal cortical pathways are, ultimately, the PAG and anterior ventral basal pontine nuclei/pontine gray, respectively. The OBF, ACG, anterior agranular insula, ITG, OTG, PHG, and related temporal cortices are the primary cortical drivers of the emotional pathway, and their key targets are the amygdala, hypothalamus, and PAG-dTg. As detailed above (see Section 5.1), the OBF, ACG, anterior insula, ITG, OTG, and PHG project to the amygdala while the OBF, ACG, anterior insula, PHG, and amygdala project to the hypothalamus. These same cortices, amygdala, and hypothalamus project to the PAG and brainstem nuclei that innervate the vocal cords. In contrast, volitional pathway cortical areas (the dCG, PMC, SMA, Pre-SMA, posterior insula, M1, lateral frontal, S1, and SMG) lack obvious primary connections to the amygdala, hypothalamus, or PAG. Thus, the primary cortical drivers of the emotional pathway are the OBF, ACG, anterior insula, ITG, OTG, PHG, and related temporal cortices. The PAG receives cortical, amygdalal, and hypothalamic glutamatergic projections, which are under tonic inhibitory GABAergic control, with additional modulatory controls exerted by cholinergic, dopaminergic, noradrenergic, and serotoninergic afferents (Grofová et al., 1978; Beitz, 1982; Jürgens, 1994). The PAG receives inputs from the substantia nigra pars reticulata (Grofová et al., 1978; Beitz, 1982), ventral tegmental area (Beitz, 1982), locus coeruleus (Beitz, 1982), and raphe nuclei (Beitz, 1982). In monkeys and other animals, emotional vocalization is primarily driven by glutamate and inhibited by GABA-A receptors, and is secondarily inhibited by acetylcholine, dopamine, norephinephrine, and serotonin (Jürgens, 1994). The dCG, PMC, SMA, Pre-SMA, posterior granular and dysgranular insula, M1, S1, and related parietal cortices are the primary cortical drivers of the volitional pathway. As detailed above (see Section 5.2), these cortices project through the corona radiata, internal capsule, and midbrain basis pedunculi to the basis pontis and thence to motor nuclei relevant to emotional expression, with a return loop projecting back to the cortices via the cerebellum and thalamus. Thus, the primary cortical drivers of the volitional pathway are the dCG, PMC, SMA, Pre-SMA, posterior insula, M1, S1, and related parietal cortices (Fig. 1). The basal ganglia modulate the activity of these cortical signals. Lesions of the volitional pathway disinhibit the emotional pathway. Volitional glutamatergic corticopontine projections (Thangnipon et al., 1983; Dinopoulos et al., 1991) activate inhibitory interneurons (Sasaki et al., 1970; Allen et al., 1977), synapsing on basis pontis GABAergic neuronal somata (Thangnipon et al., 1983; Border and Mihailoff, 1985; Mihailoff et al., 1988; Brodal and Bjaalie, 1992), consistent with documented GABAergic regulation of the PAG (Jürgens, 1994; Lonstein and De Vries, 2000; Morgan et al., 2003; Griffiths and Lovick, 2005; Xiao et al., 2008) and hypothalamus (Ford et al., 1995). Corticopontine fiber transection dramatically increases markers of pontine cholinergic transmission (Thangnipon et al., 1983) and M1-3 muscarinic receptor activation inhibits GABA transmission within the PAG (Lau and Vaughan, 2008), disinhibiting the PAG by cholinergic inhibition of the GABAergic inhibition on PAG glutamatergic excitatory fibers (Jürgens, 1994; Lau and Vaughan, 2008). In addition to this mechanism operant in diseases such as CVA, MS, and TBI, the PAG is also inhibited by DA, NE, and 5HT (Jürgens, 1994), neurotransmitters diminished in PD and other diseases associated with IEED. The OBF cortex drives DA, NE, and 5HT nuclei (Vázquez-Borsetti et al., 2009; Aston-Jones and Cohen, 2005), consistent with PLC arising in the context of OBF plaques in MS (Ghaffar et al., 2008).

A number of investigators have offered pathophysiological models of PLC. The above model is essentially a more detailed and precise elaboration of Wilson’s (1924) original PLC concept. Ross and Stewart (1987) proposed that right neocortical motor pathway lesions combined with left neocortical dysfunction associated with depression could produce IEED. This hypothesis is consistent with right and left unilateral frontal neocortical lesions associated with IEED. They also suggested that antidepressants treat IEED by acting on “nonvolitional” structures including the PAG, consistent with our model above. Also partially consistent with our model, Mendez et al. (1999) proposed a pathophysiology of PLC involving OBF, PHG, OTG, and amygdala indirect stimulation of the caudal hypothalamus. Herrmann and Brown (1967) proposed cerebellar mediation of inferior olivary feedback suppression of mesencephalo-pontine tegmental-based emotional expression. Parvizi et al. (2001) developed this concept further based on a patient with multiple pontomesencephalic/pontocerebellar projection lesions and nonstereotyped IEED-LC consistent with possible EL. Parvizi and colleagues suggested the cerebellum could potentially adjust laughter and crying behaviors according to specific social contexts and set the threshold for the laughing or crying response. Although cerebellar lesion attribution issues remain (see Section 4.1.6), the cerebellum as a substrate for IEED-EL remains an attractive hypothesis and would be consistent with the variable duration and intensity of emotional expression in EL. Cerebellar lesions could also disrupt feedback return for the PLC cortico-ponto-cerebellothalamo-cortical circuit. Based on evoked potentials in IEED, their response to DM-Q treatment, and analogous structural involvement in pain, Haiman et al. (2008) advanced a gate theory of PLC similar to the gate theory of pain. They suggested that PLC may arise from reduced voluntary (volitional) pathway activity related to lesions, increased involuntary (emotional) pathway activity engendered by stimulation, or deficient inhibitory pathways in the PAG or raphe magnus (Haiman et al., 2008). More recently, Miller et al. (2011) extended this concept, suggesting the cerebellum provides synaptic connections suitable for this gating functioning that can then influence sensorimotor cortical threshholds for emotional expression through cerebello-cortical projections, although similar cerebellar models of pain (Moulton et al., 2010) rely on brainstem (Fields, 2000) and PAG (Cerminara et al., 2009) gating. Most recently, Arias (2011) concluded that PMC, M1, and OBF inhibit the ACG and the mesencephalopontine laughter center, whereas the ACG, OTG, PHG, amygdala, and thalamus excite the hypothalamus, which in turn excites the mesencephalopontine laughter center (PAG), the latter also being both inhibited and excited by the cerebellum. Thus, aspects of previous models help validate our present model. In contrast to most previous models, the present model rests on a comprehensive, complementary synthesis of evidence across multiple domains, including animal, human, clinical disease, animal pharmacology, clinical IEED treatment studies, and hodological connectivity findings.

8. Summary and conclusions PLC is prevalent in a number of diseases although greater diagnostic clarity and consistency is needed to refine the epidemiological and clinical literature. Descriptions by Wilson (1924) and Poeck (1969) and the advent of the Cummings et al. criteria (2006) represent important advances in PLC nosology. Stereotyped episodes independent of underlying mood and stimulus valence are discriminating features of PLC in contrast to EL. Data from animal and clinical studies indicate a volitionally controlled system involving M1, PMC, SMA, and S1 corticopontine projections inhibits an emotionally controlled system involving ACG, OBF, ITG, OTG, PHG, and anterior insula projections to the

E.C. Lauterbach et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 1893–1916

1911

Table 4 Proposed IEED subtype criteria. PLC subtype At least 3 of the following are required for “Definite PLC,” 2 for “Probable PLC,” and 1 for “Possible PLC” 1. Stimuli are often inadequate in intensity or inappropriate in emotional valence to trigger a normal response of laughing or crying (e.g., sad stimuli can trigger laughing) 2. Laughing and/or crying often neither depends on, nor always corresponds to, the patient’s mood state immediately before the laughing and/or crying 3. The laughing and/or crying behavior is stereotyped in that it represents the same response each time (e.g., if laughter, laughter each time; if crying, crying each time) regardless of stimulus, AND exhibits AT LEAST ONE of the following stereotyped features: the laughing and/or crying behavior is usually of the same intensity (i.e., severity), duration, or frequency each time, regardless of stimulus. EL Subtype At least 3 of the following are required for “Definite EL,” 2 for “Probable EL,” and 1 for “Possible EL” 1. Stimuli may be inadequate in intensity but are appropriate in emotional valence to trigger the response of laughing or crying (i.e., sad stimuli trigger crying but not laughing, and pleasant or humorous stimuli trigger laughing but not crying) 2. Laughing and/or crying correspond to the patient’s mood state immediately before the laughing and/or crying (i.e., patients who were happy do not cry tears of sadness, and those who were sad do not laugh) unless valence-congruent stimulus is overwhelming 3. The laughing and/or crying behavior is not stereotyped (i.e., the emotional displays vary from episode to episode in their intensity, duration, or frequency of occurrence) Pseudobulbar Affect (PBA) Specifier Specify PLC or EL subtype (as indicated), with PBA features if present, which include: 1. Dysarthric bulbar speech 2. Dysphagia 3. Disinhibited facial and gag reflexes

amygdala-hypothalamic-PAG-dTg system. This latter emotional system directly controls the expression of PLC emotional displays through PAG-dTg connections to the reticular formation and brainstem nuclei, whereas the volitional system regulates the emotional system. These systems, particularly the emotional system, may be involved in EL as well, perhaps modulated by the cerebellum. Evidence suggests the involvement of glutamate, GABA, acetylcholine, dopamine, norepinephrine, and serotonin in the systems that mediate PLC. Receptors implicated in PLC include glutamatergic NMDA, GABA-A, muscarinic M1, M2, and M3, dopaminergic D2, adrenergic alpha-1 and alpha-2, serotoninergic 5HT1a and 5HT1b/d, and sigma-1. A variety of treatments have been used to treat PLC, including lamotrigine, amantadine, anticholinergics, levodopa, stimulants, noradrenergic antidepressants, TRH, SSRIs and serotoninergic antidepressants, and most recently DM-Q. DM-Q has been approved by the FDA for the treatment of PBA. Clinical evidence indicates that lesions anywhere along the volitional corticopontine projections, their feedback systems involving the cerebellum and thalamus, and, possibly, their off – line basal ganglia and cerebellar processing circuits can produce PLC, whereas activation of the emotional pathway can result in EL and the laughing or crying of GS and DS. A number of issues can influence the findings of this literature review. The search may not have been fully inclusive due to the search strategy, despite our testing multiple strategies to determine the most inclusive approach, since relevant articles may not have been indexed appropriately. The frequency of lesions in different structures is variable, potentially leading to rarely lesioned structures escaping detection. There are reporting biases in the literature in terms of what is reported and what is published. Structures have also been studied unevenly, especially across different diseases. Each of these considerations can influence the findings from the literature and has the potential to affect the conclusions. A major issue has been the variable definitions and techniques used to ascertain PLC. Looking forward, the Cummings diagnostic criteria will minimize false positive results and are superior to other forms of ascertainment, including rating scales and other methods, although the Pathological Laughter And Crying Scale (PLACS) and CNS-LS are quite useful for detecting improvement in clinical trials. The CNS-LS was discussed above, and the PLACS is an 18item interviewer-administered questionnaire validated in stroke (Robinson et al., 1993), Alzheimer’s disease (Starkstein et al., 1995), and TBI (Tateno et al., 2004). The scale considers the relationship of episodes to stimulus, mood, and the ability to control the episodes.

The PLACS is useful for following clinical progress and treatment efficacy. Until the Cummings criteria are uniformly applied to cases reported in the literature, and the distinction is made between PLC and EL subtypes, it will be difficult to further refine the pathophysiology of these disorders. To better distinguish PLC from EL, we offer the criteria in Table 4 that can be used once a diagnosis of IEED is made by Cummings et al. criteria. Systematic and consistent application of diagnostic criteria in reporting cases, with attention to diagnosing PLC and EL subtypes, will be important to advance our understanding of the epidemiology, semiology, pathophysiology, pharmacology, and treatment of these disorders. There is also the need to conduct validity and reliability studies of the proposed criteria. At present, it appears that Wilson’s original construct of PLC has withstood the test of time, albeit with some refinements, to be refined further by future data. Although the cerebellum as a principal modulator of these systems remains to be substantiated, it is heuristically appealing as a mechanism of EL. Our current understanding of PLC pathophysiology and treatment avails many opportunities for further investigation. 9. Disclosures Dr. Cummings and Dr. Lauterbach have served as consultants to Avanir Pharmaceuticals, the manufacturer of the only FDAapproved drug for PBA. References Achari, A.N., Colover, J., 1976. Posterior fossa tumors with pathological laughter. JAMA 235, 1469–1471. Adolphs, R., Tranel, D., 2004. Impaired judgments of sadness but not happiness following bilateral amygdala damage. Journal of Cognitive Neuroscience 16, 453–462. Allen, G.I., Oshima, T., Toyama, K., 1977. The mode of synaptic linkage in the cerebro-ponto-cerebellar pathway investigated with intracellular recording from pontine nuclei cells of the cat. Experimental Brain Research 29, 123–136. Andersen, C., 1936. Crise de rire spasmodique avant déc’es: Hémorragie thalamique double. Journal Belge de Neurologie et de Psychiatrie 36, 223–227. Andersen, G., Ingeman-Nielsen, M., Vestergaard, K., Riis, J.O., 1994. Pathoanatomic correlation between poststroke pathological crying and damage to brain areas involved in serotonergic neurotransmission. Stroke 25, 1050–1052. Andersen, G., Vestergaard, K., Riis, J.O., 1993. Citalopram for post-stroke pathological crying. Lancet 342, 837–839. Archer, C.R., Ilinsky, I.A., Goldfader, P.R., Smith Jr., K.R., 1981. Case report. Aphasia in thalamic stroke: CT stereotactic localization. Journal of Computer Assisted Tomography 5, 427–432. Arciniegas, D.B., Lauterbach, E.C., Anderson, K.E., Chow, T.W., Flashman, L.A., Hurley, R.A., Kaufer, D.I., McAllister, T.W., Reeve, A., Schiffer, R.B., Silver, J.M., 2005. The differential diagnosis of pseudobulbar affect (PBA). Distinguishing PBA among

1912

E.C. Lauterbach et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 1893–1916

disorders of mood and affect. Proceedings of a Roundtable Meeting. CNS. Spectr. 10, 1–14. Arias, M., 2011. Neurology of laughter and humour: pathological laughing and crying. Revista de Neurología 53, 415–421 [Article in Spanish]. Arif, H., Mohr, J.P., Elkind, M.S., 2005. Stimulus-induced pathologic laughter due to basilar artery dissection. Neurology 64, 2154–2155. Arroyo, S., Lesser, R.P., Gordon, B., Uematsu, S., Hart, J., Schwerdt, P., Andreasson, K., Fisher, R.S., 1993. Mirth, laughter and gelastic seizures. Brain 116, 757–780. Asfora, W.T., DeSalles, A.A., Masamitsu, A., Kjellberg, R.N., 1989. The syndrome of pathological laughter and crying a manifestation of pseudobulbar palsy? Journal of Neurology, Neurosurgery, and Psychiatry 52, 523–525. Assal, F., Valenza, N., Landis, T., Hornung, J.P., 2000. Clinicoanatomical correlates of a Fou rire prodromique in a pontine infarction. Journal of Neurology, Neurosurgery, and Psychiatry 69, 697–698. Aston-Jones, G., Cohen, J.D., 2005. Adaptive gain and the role of the locus coeruleus-norepinephrine system in optimal performance. Journal of Comparative Neurology 493, 99–110. Baizer, J.S., Desimone, R., Ungerleider, L.G., 1993. Comparison of subcortical connections of inferior temporal and posterior parietal cortex in monkeys. Visual Neuroscience 10, 59–72. Baleydier, C., Mauguiere, F., 1980. The duality of the cingulate gyrus in monkey. Neuroanatomical study and functional hypothesis. Brain 103, 525–554. Barbanti, P., Fabbrini, G., Berardelli, A., 2008. Acute pathological laughter induced by sumatriptan. Cephalalgia 28, 92–93. Barbaresi, P., Conti, F., 1981. Anatomic demonstration of axon collaterals of the periaqueductal gray formation and the ventrobasal thalamic nuclei of both sides. Bollettino della Società italiana di biologia sperimentale 57, 2377–2383. Bard, P., 1934. Emotion: the neuro-humoral basis of emotional reactions. In: Murchison, C. (Ed.), A Handbook of General Experimental Psychology. Clark University Press, Worcester, Massachusetts, pp. 264–311. Beitz, A.J., 1982. The organization of afferent projections to the midbrain periaqueductal gray of the rat. Neuroscience 7, 133–159. Bekhterev, V., 1887. Die Bedeutung der Seeigel auf Grund von experimentellen und pathologischen Daten. Virchows Archiv für pathologische Anatomie 110, 322–365. Berk, M.L., Finkelstein, J.A., 1982. Efferent connections of the lateral hypothalamic area of the rat: an autoradiographic investigation. Brain Research Bulletin 8, 511–526. Bermack, J.E., Debonnel, G., 2005. The role of sigma receptors in depression. Journal of Pharmacological Sciences 97, 317–336. Bharathi, V., Lee, F.S., 2006. Emotional incontinence—the other poststroke phenomenon. Medical Journal of Malaysia 61, 490–492. Bishop, G.A., Ho, R.H., 1985. The distribution and origin of serotonin immunoreactivity in the rat cerebellum. Brain Research 331, 195–207. Blumenfeld, H., 2002. Neuroanatomy Through Clinical Cases. Sinauer, Sunderland, Massachusetts. Boecker, H., Weindl, A., Brooks, D.J., Ceballos-Baumann, A.O., Liedtke, C., Miederer, M., Sprenger, T., Wagner, K.J., Miederer, I., 2010. GABAergic dysfunction in essential tremor: an 11C-flumazenil PET study. Journal of Nuclear Medicine 51, 1030–1035. Bogousslavsky, J., Regli, F., 1990. Capsular genu syndrome. Neurology 40, 1499–1502. Border, B.G., Mihailoff, G.A., 1985. GAD-immunoreactive neural elements in the basilar pontine nuclei and nucleus reticularis tegmenti pontis of the rat. I. Light microscopic studies. Experimental Brain Research 59, 600–614. Brodal, P., Bjaalie, J.G., 1992. Organization of the pontine nuclei. Neuroscience Research 13, 83–118. Brooks, B.R., Thisted, R.A., Appel, S.H., Bradley, W.G., Olney, R.K., Berg, J.E., Pope, L.E., Smith, R.A., AVP-923 ALS, 2004. Treatment of pseudobulbar affect in ALS with dextromethorphan/quinidine: a randomized trial. Neurology 63, 1364–1370. Brown, T.G., 1915. Note on the physiology of the basal ganglia and mid-brain of the anthropoid ape, especially in reference to the act of laughter. Journal of Physiology 49, 195. Buchanan, S.L., Thompson, R.H., Maxwell, B.L., Powell, D.A., 1994. Efferent connections of the medial prefrontal cortex in the rabbit. Experimental Brain Research 100, 469–483. Burns, A., Russell, E., Stratton-Powell, H., Tyrell, P., O’Neill, P., Baldwin, R., 1999. Sertraline in stroke-associated lability of mood. International Journal of Geriatric Psychiatry 14, 681–685. Burzio, F., 1900. Emiplegia con dolori ed accessi di riso spasmodico: da rammollimento del nucleo lenticolare. Analidi. Freniatria. e. Scienze. Affini. Freniat. Sciz. Affini 10, 140–148. Campello Morer, I., Pérez Trullén, J.M., 2007. Dacrystic epilepsy secondary to meningioma. Medicina Clinica (Barc) 129, 758. Carel, C., Albucher, J.F., Manelfe, C., Guiraud-Chaumeil, B., Chollet, F., 1997. Fou rire prodromique heralding a left internal carotid occlusion. Stroke 28, 2081–2083. Cascino, G.D., Andermann, F., Berkovic, S.F., Kuzniecky, R., Sharbrough, F.W., Keene, D.L., Bladin, P.F., Kelly, P.J., Olivier, A., Feindel, W., 1993. Gelastic seizures and hypothalamic hamartomas: evaluation of patients undergoing chronic intracranial EEG monitoring and outcome of surgical treatment. Neurology 43, 747–750. Castro, M.E., Pascual, J., Romón, T., Del Arco, C., Del Olmo, E., Pazos, A., 1997. Differential distribution of [3H] sumatriptan binding sites (5-HT1B, 5-HT1D and 5-HT1F receptors) in human brain: focus on brainstem and spinal cord. Neuropharmacology 36, 535–542.

Cauda, F., D’Agata, F., Sacco, K., Duca, S., Geminiani, G., Vercelli, A., 2011. Functional connectivity of the insula in the resting brain. Neuroimage 55, 8–23. ˜ T., Tejedor, J., Cruz-Rizzolo, R.J., Reinoso-Suárez, F., 2000. The Cavada, C., Company, anatomical connections of the macaque monkey orbitofrontal cortex. A review. Cerebral Cortex 10, 220–242. Ceccaldi, M., Milandre, L., 1994. A transient fit of laughter as the inaugural symptom of capsular-thalamic infarction. Neurology 44, 1762. Ceccaldi, M., Poncet, M., Milandre, L., Rouyer, C., 1994. Temporary forced laughter after unilateral strokes. European Neurology 34, 36–39. Cerminara, N.L., Koutsikou, S., Lumb, B.M., Apps, R., 2009. The periaqueductal grey modulates sensory input to the cerebellum: a role in coping behaviour? European Journal of Neuroscience 29, 2197–2206. Chahine, L.M., Chemali, Z., 2006. Du rire aux larmes: pathological laughing and crying in patients with traumatic brain injury and treatment with lamotrigine. Epilepsy Behaviour 8, 610–615. Chassagnon, S., Minotti, L., Kremer, S., Verceuil, L., Hoffmann, D., Benabid, A.L., Kahane, P., 2003. Restricted frontomesial epileptogenic focus generating dyskinetic behavior and laughter. Epilepsia 44, 859–863. Chen, Y.R., Huang, Y.P., Lin, S.J., Kuan, T.H., Lin, C.H., 2010. Effectiveness of quetiapine for poststroke pathological laughing: case report and review of the literature. Clinical Neuropharmacology 33, 319–322. Choi-Kwon, S., Han, S.W., Kwon, S.U., Kang, D.W., Choi, J.M., Kim, J.S., 2006. Fluoxetine treatment in poststroke depression, emotional incontinence, and anger proneness: a double-blind, placebo-controlled study. Stroke 37, 156–161. Choi-Kwon, S., Kim, J.S., 2002. Poststroke emotional incontinence and decreased sexual activity. Cerebrovascular Diseases 13, 31–37. Clascá, F., Llamas, A., Reinoso-Suárez, F., 2000. Cortical connections of the insular and adjacent parieto-temporal fields in the cat. Cerebral Cortex 10, 371–399. Cohn, R., 1951. Forced crying and laughing; treatment with atropine and atropinelike agents. AMA Archives of Neurology & Psychiatry 66, 738–743. Coria, F., Bahíllo Marcos, E., Moral Blanco, M., García Gutiérrez, P., Ortiz Sáenz de Santa María, R., 2000. Late-onset isolated gelastic epilepsy secondary to entrapment of the right temporal horn. Neurologia 15, 204–207. Crosson, B., 1999. Subcortical mechanisms in language: lexical-semantic mechanisms and the thalamus. Brain and Cognition 40, 414–438. Cummings, J.L., Arciniegas, D.B., Brooks, B.R., Herndon, R.M., Lauterbach, E.C., Pioro, E.P., Robinson, R.G., Scharre, D.W., Schiffer, R.B., Weintraub, D., 2006. Defining and diagnosing involuntary emotional expression disorder. CNS Spectrums 11, 1–7. Dabby, R., Watemberg, N., Lampl, Y., Eilam, A., Rapaport, A., Sadeh, M., 2004. Pathological laughter as a symptom of midbrain infarction. Behavioural Neurology 15, 73–76. Darwin, C., 1872. The Expression of the Emotions in Man and Animals. D Appelton and Company, New York and London. Davison, C., Kelman, H., 1939. Pathologic laughing and crying. Archives of Neurology & Psychiatry 42, 595–643. Dericioglu, N., Cataltepe, O., Tezel, G.G., Saygi, S., 2005. Gelastic seizures due to right temporal cortical dysplasia. Epileptic Disorders 7, 137–141. de Seze, J., Zephir, H., Hautecoeur, P., Mackowiak, A., Cabaret, M., Vermersch, P., 2006. Pathologic laughing and intractable hiccups canoccur early in multiple sclerosis. Neurology 67, 1684–1686. Dimova, P.S., Bojinova, V.S., Milanov, I.G., 2009. Transient mutism and pathologic laughter in the course of cerebellitis. Pediatric Neurology 41, 49–52. Dinopoulos, A., Dori, I., Parnavelas, J.G., 1991. Immunohistochemical localization of aspartate in corticofugal pathways. Neuroscience Letters 121, 25–28. Doorenbos, D.I., Haerer, A.F., Payment, M., Clifton, E.R., 1993. Stimulus-specific pathologic laughter: a case report with discrete unilateral localization. Neurology 43, 229–230. Dopper, E.G., Seelaar, H., Chiu, W.Z., De Koning, I., Van Minkelen, R., Baker, M.C., Rozemuller, A.J., Rademakers, R., Van Swieten, J.C., 2011. Symmetrical corticobasal syndrome caused by a novel C.314dup progranulin mutation. Journal of Molecular Neuroscience 45, 354–358. Dusser De Barenne, J.G., 1920. Recherches experimentales sur les functions du systeme nerveux central, faites en particulier sur deux chats don’t le neopallium avait ete enleve. Arch. Neer. Phys. del’Homme et des Animaux. IV, 31–123. Elyas, A.E., Bulters, D.O., Sparrow, O.C., 2011. Pathological laughter and crying in patients with pontine lesions. Journal of Neurosurgery: Pediatrics 8, 544–547. Esposito, A., Demeurisse, G., Alberti, B., Fabbro, F., 1999. Complete mutism after midbrain periaqueductal gray lesion. Neuroreport 10, 681–685. Famularo, G., Corsi, F.M., Minisola, G., De Simone, C., Nicotra, G.C., 2007. Cerebellar tumour presenting with pathological laughter and gelastic syncope. European Journal of Neurology 14, 940–943. Feinstein, A., Feinstein, K., Gray, T., O’Connor, P., 1997. Prevalence and neurobehavioral correlates of pathological laughing and crying in multiple sclerosis. Archives of Neurology 54, 1116–1121. Feinstein, A., O’Connor, P., Gray, T., Feinstein, K., 1999. Pathological laughing and crying in multiple sclerosis: a preliminary report suggesting a role for the prefrontal cortex. Multiple Sclerosis 5, 69–73. Fere, M.C., 1903. Le fou rire prodromique. Revista de Neurología 11, 353–358. Fields, H.L., 2000. Pain modulation: expectation, opioid analgesia and virtual pain. Progress in Brain Research 122, 245–253. Floyd, N.S., Price, J.L., Ferry, A.T., Keay, K.A., Bandler, R., 2001. Orbitomedial prefrontal cortical projections to hypothalamus in the rat. Journal of Comparative Neurology 432, 307–328.

E.C. Lauterbach et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 1893–1916 Flügge, G., Jöhren, O., Fuchs, E., 1992. [3H]Rauwolscine binding sites in the brains of male tree shrews are related to social status. Brain Research 597, 131–137. Foerster, O., Gagel, O., 1933. Ein fall von ependymcyste des in ventrikels. Ein beitrag zur frage der beziehungen psychischer storungen zum himstamm. Zeitschrift für die Gesamte Neurologie und Psychiatrie 149, 312–344. Ford, B., Holmes, C.J., Mainville, L., Jones, B.E., 1995. GABAergic neurons in the rat pontomesencephalic tegmentum: codistribution with cholinergic and other tegmental neurons projecting to the posterior lateral hypothalamus. Journal of Comparative Neurology 363, 177–196. Fried, I., Wilson, C.L., MacDonald, K.A., Behnke, E.J., 1998. Electric current stimulates laughter. Nature 391, 650. Gallagher, J.P., 1989. Pathologic laughter and crying in ALS: a search for their origin. Acta Neurologica Scandinavica 80, 114–117. Garg, R.K., Misra, S., Verma, R., 2000. Pathological laughter as heralding manifestation of left middle cerebral artery territory infarct: case report and review of literature. Neurology India 48, 388–390. George, M.S., Ketter, T.A., Parekh, P.I., Horwitz, B., Herscovitch, P., Post, R.M., 1995. Brain activity during transient sadness and happiness in healthy women. American Journal of Psychiatry 152, 341–351. Ghaffar, O., Chamelian, L., Feinstein, A., 2008. Neuroanatomy of pseudobulbar affect: a quantitative MRI study in multiple sclerosis. Journal of Neurology 255, 406–412. Glickstein, M., 2003. Subcortical projections of the parietal lobes. Advances in Neurology 93, 3–55. Goltz, P.F., 1892. The dog without cerebrum. Pfluger’s Archiv fur die gesamte Physilogie 51, 1–2. Gondim, F.A., Parks, B.J., Cruz-Flores, S., 2001. Fou rire prodromique as the presentation of pontine ischaemia secondary to vertebrobasilar stenosis. Journal of Neurology, Neurosurgery, and Psychiatry 71, 802–804. Griffiths, J.L., Lovick, T.A., 2005. GABAergic neurones in the rat periaqueductal grey matter express alpha4, beta1 and delta GABAA receptor subunits: plasticity of expression during the estrous cycle. Neuroscience 136, 457–466. Grofová, I., Ottersen, O.P., Rinvik, E., 1978. Mesencephalic and diencephalic afferents to the superior colliculus and periaqueductal gray substance demonstrated by retrograde axonal transport of horseradish peroxidase in the cat. Brain Research 146, 205–220. Guimarães, J., Bugalho, P., Coutinho, P., 2008. Pathological crying in patients with Machado-Joseph disease. Movement Disorders 23, 470–471. Gundlach, A.L., Largent, B.L., Snyder, S.H., 1986. Autoradiographic localization of sigma receptor binding sites in guinea pig and rat central nervous system with (+)3H-3-(3-Hydroxyphenyl)4V-(1-propyl)piperidine. Journal of Neuroscience 6, 1757–1770. Habel, U., Klein, M., Kellermann, T., Shah, N.J., Schneider, F., 2005. Same or different? Neural correlates of happy and sad mood in healthy males. Neuroimage 26, 206–214. Haiman, G., Pratt, H., Miller, A., 2008. Brain responses to verbal stimuli among multiple sclerosis patients with pseudobulbar affect. Journal of Neurology Science 271, 137–147. Haiman, G., Pratt, H., Miller, A., 2009. Effects of dextromethorphan/quinidine on auditory event-related potentials in multiple sclerosis patients with pseudobulbar affect. Journal of Clinical Psychopharmacology 29, 444–452. Hargrave, D.R., Mabbott, D.J., Bouffet, E., 2006. Pathological laughter and behavioural change in childhood pontine glioma. Journal of Neurooncology 77, 267–271. Hassler, R., Reichert, T., 1961. Wirkungen der Reizungen und Koagulationen in den Stammganglien bei stereotaktischen Hirnoperationen. Nervenarzt 32, 97–109. Herrmann Jr., C., Brown, J.W., 1967. Palatal myoclonus: a reappraisal. Journal of Neurology Science 5, 473–492. Herzog, A.G., Van Hoesen, G.W., 1976. Temporal neocortical afferent connections to the amygdala in the rhesus monkey. Brain Research 115, 57–69. Höistad, M., Barbas, H., 2008. Sequence of information processing for emotions through pathways linking temporal and insular cortices with the amygdala. Neuroimage 40, 1016–1033. Holstege, G., 1992. The emotional motor system. European Journal of Morphology 30, 67–79. Hopf, H.C., Müller-Forell, W., Hopf, N.J., 1992. Localization of emotional and volitional facial paresis. Neurology 42, 1918–1923. Hu, W.H., Zhang, K., Shao, X.Q., Li, D., Bai, Q., Qiao, H., Meng, F.G., Zhang, J.G., 2011. Surgical outcome of gelastic epilepsy of frontal lobe origin: a case report. Seizure 20, 352–356. Irle, E., Markowitsch, H.J., 1982. Connections of the hippocampal formation, mamillary bodies, anterior thalamus and cingulate cortex. A retrograde study using horseradish peroxidase in the cat. Experimental Brain Research 47, 79–94. Iwasa, H., Shibata, T., Mine, S., Koseki, K., Yasuda, K., Kasagi, Y., Okada, M., Yabe, H., Kaneko, S., Nakajima, Y., 2002. Different patterns of dipole source localization in gelastic seizure with or without a sense of mirth. Neuroscience Research 43, 23–29. Iwasaki, Y., 2012. Three cases of Creutzfeldt-Jakob disease with prion protein gene codon180 mutation presenting with pathological laughing and crying. Journal of Neurology Science May 31 [Epub ahead of print]. Jagetia, A., Pratap Kumar, N., Singh, D., Sinha, S., 2006. Pathological laughter in trigeminal schwannoma: case report and review of the literature. Neurosurgical Review 29, 348–352. Jones, B.E., Friedman, L., 1983. Atlas of catecholamine perikarya, varicosities and pathways in the brainstem of the cat. Journal of Comparative Neurology 215, 382–386.

1913

Jürgens, U., 1984. The efferent and afferent connections of the supplementary motor area. Brain Research 300, 63–81. Jürgens, U., 1994. The role of the periaqueductal grey in vocal behaviour. Behavioural Brain Research 62, 107–117. Jürgens, U., 2002. Neural pathways underlying vocal control. Neuroscience & Biobehavioral Reviews 26, 235–258. Jürgens, U., Pratt, R., 1979. Role of the periaqueductal grey in vocal expression of emotion. Brain Research 167, 367–378. Kahane, P., Ryvlin, P., Hoffmann, D., Minotti, L., Benabid, A.L., 2003. From hypothalamic hamartoma to cortex: what can be learnt from depth recordings and stimulation? Epileptic Disorders 5, 205–217. Kataoka, S., Hori, A., Shirakawa, T., Hirose, G., 1997. Paramedian pontine infarction. Stroke 28, 809–815. Kemppainen, S., Jolkkonen, E., Pitkänen, A., 2002. Projections from the posterior cortical nucleus of the amygdala to the hippocampal formation and parahippocampal region in rat. Hippocampus 12, 735–755. Killgore, W.D., Yurgelun-Todd, D.A., 2004. Activation of the amygdala and anterior cingulate during nonconscious processing of sad versus happy faces. Neuroimage 21, 1215–1223. Kim, J.S., Choi-Kwon, S., 2000. Poststroke depression and emotional incontinence: correlation with lesion location. Neurology 54, 1805–1810. Komurasaki, Y., Yokoyama, T., Ogura, J., Maeda, K., 1989. Treatment of pathologic emotionality with thyrotropin-releasing hormone. Japanese Journal of Psychiatry and Neurology 43, 665–668. Kosaka, H., Omata, N., Omori, M., Shimoyama, T., Murata, T., Kashikura, K., Takahashi, T., Murayama, J., Yonekura, Y., Wada, Y., 2006. Abnormal pontine activation in pathological laughing as shown by functional magnetic resonance imaging. Journal of Neurology, Neurosurgery, and Psychiatry 77, 1376–1380. Kossorotoff, M., Gonin-Flambois, C., Gitiaux, C., Quijano, S., Boddaert, N., BahiBuisson, N., Barnerias, C., Dulac, O., Brunelle, F., Desguerre, I., 2010. A cognitive and affective pattern in posterior fossa strokes in children: a case series. Developmental Medicine & Child Neurology 52, 626–631. Kovac, S., Deppe, M., Mohammadi, S., Schiffbauer, H., Schwindt, W., Möddel, G., Dogan, M., Evers, S., 2009. Gelastic seizures: A case of lateral frontal lobe epilepsy and review of the literature. Epilepsy & Behavior 15, 249–253. Krack, P., Kumar, R., Ardouin, C., Dowsey, P.L., McVicker, J.M., Benabid, A.L., Pollak, P., 2001. Mirthful laughter induced by subthalamic nucleus stimulation. Movement Disorders 16, 867–875. Kultas-Ilinsky, K., Sivan-Loukianova, E., Ilinsky, I.A., 2003. Reevaluation of the primary motor cortex connections with the thalamus in primates. Journal of Comparative Neurology 457, 133–158. Künzle, H., 1998. Thalamic territories innervated by cerebellar nuclear afferents in the hedgehog tenrec, Echinops telfairi. Journal of Comparative Neurology 402, 313–326. Lam, J.S., Fong, S.Y., Yiu, G.C., Wing, Y.K., 2007. Fahr’s disease: a differential diagnosis of frontal lobe syndrome. Hong Kong Medical Journal 13, 75–77. Lane, R.D., Reiman, E.M., Ahern, G.L., Schwartz, G.E., Davidson, R.J., 1997. Neuroanatomical correlates of happiness, sadness, and disgust. American Journal of Psychiatry 154, 926–933. Langworthy, O.R., Hesser, F.H., 1940. Syndrome of pseudobulbar palsy. Anatomic and physiologic analysis. Archives of Internal Medicine 65, 106–121. Lau, B.K., Vaughan, C.W., 2008. Muscarinic modulation of synaptic transmission via endocannabinoid signalling in the rat midbrain periaqueductal gray. Molecular Pharmacology 74, 1392–1398. Lauterbach, E.C., 2003. Mood disorders and the globus pallidus. In: Bédard, M.A., Agid, Y., Chouinard, S., Fahn, S., Korczyn, A., Lesperance, P. (Eds.), Mental and Behavioral Dysfunction in Movement Disorders. Humana Press, Totowa, New Jersey, pp. 305–320. Lauterbach, E.C., Harris, J.B., Bina, W.F., 2010. Mood and neurobehavioral correlates of cerebellar lesions. Cognitive and Behavioral Neurology 23, 63–73. Lauterbach, E.C., Price, S.T., Spears, T.E., Jackson, J.G., Kirsh, A.D., 1994. Serotonin responsive and nonresponsive diurnal depressive mood disorders and pathological affect in thalamic infarct associated with myoclonus and blepharospasm. Biological Psychiatry 5, 488–490. Leichnetz, G.R., Astruc, J., 1976. The efferent projections of the medial prefrontal cortex in the squirrel monkey (Saimiri sciureus). Brain Research 09, 455–472. Leichnetz, G.R., Smith, D.J., Spencer, R.F., 1984. Cortical projections to the paramedian tegmental and basilar pons in the monkey. Journal of Comparative Neurology 228, 388–408. Loiseau, P., Cohadon, F., Cohadon, S., 1971. Gelastic epilepsy. A review and report of five cases. Epilepsia 12, 313–323. Lonstein, J.S., De Vries, G.J., 2000. Maternal behaviour in lactating rats stimulates c-fos in glutamate decarboxylase-synthesizing neurons of the medial preoptic area, ventral bed nucleus of the stria terminalis, and ventrocaudal periaqueductal gray. Neuroscience 100, 557–568. Louis, E.D., 2010. Essential tremor: evolving clinicopathological concepts in an era of intensive post-mortem enquiry. Lancet Neurology 9, 613–622. Louis, E.D., Faust, P.L., Ma, K.J., Yu, M., Cortes, E., Vonsattel, J.P., 2011. Torpedoes in the cerebellar vermis in essential tremor cases vs. controls. Cerebellum 10, 812–819. Low, H.L., Sayer, F.T., Honey, C.R., 2008. Pathological crying caused by highfrequency stimulation in the region of the caudal internal capsule. Archives of Neurology 65, 264–266. Luciano, D., Devinsky, O., Perrine, K., 1993. Crying seizures. Neurology 43, 2113–2117.

1914

E.C. Lauterbach et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 1893–1916

Luschei, E.S., Ramig, L.O., Finnegan, E.M., Baker, K.K., Smith, M.E., 2006. Patterns of laryngeal electromyography and the activity of the respiratory system during spontaneous laughter. Journal of Neurophysiology 96, 442–450. Mansour, A., Meador-Woodruff, J.H., Bunzow, J.R., Civelli, O., Akil, H., Watson, S.J., 1990. Localization of dopamine D2 receptor mRNA and D1 and D2 receptor binding in the rat brain and pituitary: an in situ hybridization-receptor autoradiographic analysis. Journal of Neuroscience 70, 2587–2600. Mantyh, P.W., 1983. Connections of midbrain periaqueductal gray in the monkey. II. Descending efferent projections. Journal of Neurophysiology 49, 582–594. Mariën, P., De Smet, H.J., Wijgerde, E., Verhoeven, J., Crols, R., De Deyn, P.P., 2011. Posterior fossa syndrome in adults: A new case and comprehensive survey of the literature. Cortex. July 22 [Epub ahead of print]. Matsusaka, T., 2004. When does play panting occur during social play in wild chimpanzees? Primates 45, 221–229. McConachie, N.S., King, M.D., 1997. Gelastic seizures in a child with focal cortical dysplasia of the cingulate gyrus. Neuroradiology 39, 44–45. McCullagh, S., Feinstein, A., 2000. Treatment of pathological affect: variability of response for laughter and crying. Journal of Neuropsychiatry & Clinical Neurosciences 2, 100–102. McGrath, J., 2000. A study of emotionalism in patients undergoing rehabilitation following severe acquired brain injury. Behavioural Neurology 12, 201–207. Meller, S.T., Dennis, B.J., 1986. Afferent projections to the periaqueductal gray in rabbits. Neuroscience 19, 927–964. Mendez, M.F., Nakawatase, T.V., Brown, C.V., 1999. Involuntary laughter and inappropriate hilarity. Journal of Neuropsychiatry & Clinical Neurosciences 11, 253–258. Meoni, P., Tortella, F.C., Bowery, N.G., 1997. An autoradiographic study of dextromethorphan high-affinity binding sites in rat brain: sodium-dependency and colocalization with paroxetine. British Journal of Pharmacology 120, 1255–1262. How the brain Meyer, M., Baumann, S., Wildgruber, D., Alter, K., 2007. laughs. Comparative evidence from behavioral, electrophysiological and neuroimaging studies in human and monkey. Behavioural Brain Research 182, 245–260. Michel, L., Derkinderen, P., Laplaud, D., Daumas-Duport, B., Auffray-Calvier, E., Lebouvier, T., 2008. Emotional facial palsy following striato-capsular infarction. Journal of Neurology, Neurosurgery, and Psychiatry 79, 193–194. Mihailoff, G.A., Kosinski, R.J., Border, B.G., Lee, H.S., 1988. A review of recent observations concerning the synaptic organization of the basilar pontine nuclei. Journal of Electron Microscopy Technique 10, 229–246. Miller, A., Pratt, H., Schiffer, R.B., 2011. Pseudobulbar affect: the spectrum of clinical presentations, etiologies and treatment. Expert Review of Neurotherapeutics 11, 1077–1088. Møller, M., Andersen, G., 2007. Inhibition of selective noradrenergic reuptake as treatment of pathological laughter. Journal of Clinical Psychopharmacology 27, 108–110. Møller, M., Andersen, G., Gjedde, A., 2007. Serotonin 5HT1A receptor availability and pathological crying after stroke. Acta Neurologica Scandinavica 116, 83–90. Monaghan, D.T., Cotman, C.W., 1985. Distribution of N-methyl-D-aspartatesensitive L-[3H]glutamate-binding sites in rat brain. Journal of Neuroscience 5, 2909–2919. Moore, S.R., Gresham, L.S., Bromberg, M.B., Kasarkis, E.J., Smith, R.A., 1997. A self report measure of affective lability. Journal of Neurology, Neurosurgery, and Psychiatry 63, 89–93. Morecraft, R.J., Louie, J.L., Herrick, J.L., Stilwell-Morecraft, K.S., 2001a. Cortical innervation of the facial nucleus in the non-human primate: a new interpretation of the effects of stroke and related subtotal brain trauma on the muscles of facial expression. Brain 124, 176–208. Morecraft, R.J., Louie, J.L., Herrick, J.L., Stilwell-Morecraft, K.S., Gedney, M.T., Ottenbacher, J.L., 2001. Organization of face representation in the corona radiata and internal capsule of the non-human primate. Society for Neuroscience Abstracts, San Diego, California. 27, 825.7. Morgan, M.M., Clayton, C.C., Lane, D.A., 2003. Behavioral evidence linking opioidsensitive GABAergic neurons in the ventrolateral periaqueductal gray to morphine tolerance. Neuroscience 118, 227–232. Moulton, E.A., Schmahmann, J.D., Becerra, L., Borsook, D., 2010. The Cerebellum and Pain: Passive Integrator or Active Participator? Brain Research Reviews 65, 14–27. Müller-Preuss, P., Jürgens, U., 1976. Projections from the ‘cingular’ vocalization area in the squirrel monkey. Brain Research 103, 29–43. Munschauer, F.E., Mador, M.J., Ahuja, A., Jacobs, L., 1991. Selective paralysis of voluntary but not limbically influenced automatic respiration. Archives of Neurology 48, 1190–1192. Murai, T., Barthel, H., Berrouschot, J., Sorger, D., von Cramon, D.Y., Müller, U., 2003. Neuroimaging of serotonin transporters in post-stroke pathological crying. Psychiatry Research 123, 207–211. Nakai, M., Ogata, J., Fukui, K., Nakai, Y., Maeda, M., 1997. Basal forebrain and cerebral cortical muscarinic receptors mediate increase in cortical blood flow provoked by periaqueductal gray matter. Neuroscience 79, 571–579. New, P.W., Thomas, S.J., 2005. Cognitive impairments in the locked-in syndrome: a case report. Archives of Physical Medicine and Rehabilitation 86, 338–343. Nicoletti, G., Manners, D., Novellino, F., Condino, F., Malucelli, E., Barbiroli, B., Tonon, C., Arabia, G., Salsone, M., Giofre’, L., Testa, C., Lanza, P., Lodi, R., Quattrone, A., 2010. Diffusion tensor MRI changes in cerebellar structures of patients with familial essential tremor. Neurology 74, 988–994.

Nieuwenhuys, R., 1985. Chemoarchitecture of the Brain. Springer-Verlag, New York, pp. 114–176. Nieuwenhuys, R., 1996. The greater limbic system, the emotional motor system and the brain, in: Holstege, G., Bandler, R., Saper, C.B. (Eds.), The Emotional Motor System. Elsevier Science B.V., New York, pp. 551–580. (Progress in Brain Research 107, 551–580.). Nieuwenhuys, R., Veening, J.G., van Domburg, P., 1988–1989. Core and paracores; some new chemoarchitectural entities in the mammalian neuraxis. Acta Morphology Neerl. Scand. 26, 131–163. Nolte, J., 2002. The Human Brain: an Introduction To Its Functional Anatomy. Mosby. St. Louis. Oehl, B., Biethahn, S., Schulze-Bonhage, A., 2009. Mirthful gelastic seizures with ictal involvement of temporobasal regions. Epileptic Disorders 11, 82–86. Offen, M.L., Davidoff, R.A., Troost, B.T., Richey, E.T., 1976. Dacrystic epilepsy. Journal of Neurology, Neurosurgery, and Psychiatry 39, 829–834. Oh, K., Kim, H.J., Kim, B.J., Park, K.W., Lee, D.H., 2008. Pathological laughter as an unusual manifestation of acute stroke. European Neurology 59, 83–84. Okuda, D.T., Chyung, A.S., Chin, C.T., Waubant, E., 2005. Acute pathological laughter. Movement Disorders 20, 1389–1390. Okun, M.S., Raju, D.V., Walter, B.L., Juncos, J.L., DeLong, M.R., Heilman, K., McDonald, W.M., Vitek, J.L., 2004. Pseudobulbar crying induced by stimulation in the region of the subthalamic nucleus. Journal of Neurology, Neurosurgery, and Psychiatry 75, 921–923. Olney, N.T., Goodkind, M.S., Lomen-Hoerth, C., Whalen, P.K., Williamson, C.A., Holley, D.E., Verstaen, A., Brown, L.M., Miller, B.L., Kornak, J., Levenson, R.W., Rosen, H.J., 2011. Behaviour, physiology and experience of pathological laughing and crying in amyotrophic lateral sclerosis. Brain 134, 3458–3469. Oppenheim, H., 1911. Textbook of Nervous Diseases for Physicians and Students by Professor H. Oppenheim of Berlin. English translation by Alexander Bruce. T. N. Foulis Publisher, London, Edinburgh. Oppenheim, H., Siemerling, E., 1886. Mitteilungen uber Pseudobulbarparalyse und akute Bulbarparalyse. Berl. Klin. Woch., Berlin, pp. 46–49. Osseby, G., Manceau, E., Huet, F., 1999. Fou rire prodromique as the heralding symptom of lenticular infarction, caused by dissection of the internal carotid artery in a 12-year-old boy. European Journal of Paediatric Neurology 3, 133–136. Panitch, H.S., Thisted, R.A., Smith, R.A., Wynn, D.R., Wymer, J.P., Achiron, A., Vollmer, T.L., Mandler, R.N., Dietrich, D.W., Fletcher, M., Pope, L.E., Berg, J.E., Miller, A.; Psuedobulbar Affect in Multiple Sclerosis Study Group, 2006. Randomized, controlled trial of dextromethorphan/quinidine for pseudobulbar affect in multiple sclerosis. Annals of Neurology 59, 780–787. Panneton, W.M., Martin, G.F., 1983. Brainstem projections to the facial nucleus of the opossum. A study using axonal transport techniques. Brain Research 267, 19–33. Papoyan, E.V., 1997. Antidromal and synaptic activation of neurons of the associative parietal cortex of the cat brain elicited by spike activity from the intrinsic nuclei of the pons. Neuroscience and Behavioral Physiology 27, 695–701. Parvizi, J., Anderson, S.W., Martin, C.O., Damasio, H., Damasio, A.R., 2001. Pathological laughter and crying: a link to the cerebellum. Brain 124, 1708–1719. Parvizi, J., Coburn, K.L., Shillcutt, S.D., Coffey, C.E., Lauterbach, E.C., Mendez, F., 2009. Neuroanatomy of pathological laughing and crying: A report of the American Neuropsychiatric Association Committee On Research. Journal of Neuropsychiatry & Clinical Neurosciences 21, 75–87. Parvizi, J., Joseph, J., Press, D.Z., Schmahmann, J.D., 2007. Pathological laughter and crying in patients with multiple system atrophy-cerebellar type. Movement Disorders 22, 798–803. Parvizi, J., Le, S., Foster, B.L., Bourgeois, B., Riviello, J.J., Prenger, E., Saper, C., Kerrigan, J.F., 2011. Gelastic epilepsy and hypothalamic hamartomas: neuroanatomical analysis of brain lesions in 100 patients. Brain 134, 2960–2968. Parvizi, J., Schiffer, R., 2007. Exaggerated crying and tremor with a cerebellar cyst. Journal of Neuropsychiatry & Clinical Neurosciences 19, 187–190. Peeters, M., Romieu, P., Maurice, T., Su, T.P., Maloteaux, J.M., Hermans, E., 2004. Involvement of the sigma 1 receptor in the modulation of dopaminergic transmission by amantadine. European Journal of Neuroscience 19, 2212–2220. Pelletier, M., Bouthillier, A., Lévesque, J., Carrier, S., Breault, C., Paquette, V., Mensour, B., Leroux, J.M., Beaudoin, G., Bourgouin, P., Beauregard, M., 2003. Separate neural circuits for primary emotions? Brain activity during self-induced sadness and happiness in professional actors. Neuroreport 14, 1111–1116. Petracca, G.M., Jorge, R.E., Ación, L., Weintraub, D., Robinson, R.G., 2009. Frequency and correlates of involuntary emotional expression disorder in Parkinson’s disease. Journal of Neuropsychiatry & Clinical Neurosciences 21, 406–412. Phillips, M.L., Drevets, W.C., Rauch, S.L., Lane, R., 2003. Neurobiology of emotion perception: I. The neural basis of normal emotion perception. Biological Psychiatry 54, 504–514. Pioro, E.P., 2011. Current concepts in the pharmacotherapy of pseudobulbar affect. Drugs 71, 1193–1207. Pioro, E.P., Brooks, B.R., Cummings, J., Schiffer, R., Thisted, R.A., Wynn, D., Hepner, A., Kaye, R., Safety, Tolerability, and Efficacy Results Trial of AVP-923 in PBA Investigators, 2010. Dextromethorphan plus ultra low-dose quinidine reduces pseudobulbar affect. Annals of Neurology 68, 693–702. Pitkänen, A., Pikkarainen, M., Nurminen, N., Ylinen, A., 2000. Reciprocal connections between the amygdala and the hippocampal formation, perirhinal cortex, and postrhinal cortex in rat. A review. Annals of the New York Academy of Sciences 911, 369–391. Plum, F., Leigh, R.J., 1981. Abnormalities of central mechanisms, in: Hornbein, T.F. (Ed.), Regulation of Breathing, Part II. Marcel Dekker Inc., New York, pp. 1027–1032. (Lung Biology in Health and Disease, vol. 17).

E.C. Lauterbach et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 1893–1916 Poeck, K., 1969. Pathophysiology of emotional disorders associated with brain damage. Handbook of Clinical Neurology 3, 343–367. Poeck, K., 1985. Pathologic laughter and crying. In: Vinken, P.J., Bruyn, G.W., Klawans, H.L. (Eds.), Handbook of Clinical Neurology. Elsevier, Amsterdam, pp. 219–226. Poeck, K., Pilleri, G., 1963. Pathologishes lachen und weinen. Schweizer Archiv für Neurologie, Neurochirurgie und Psychiatrie 92, 323–370. Price, J.L., Amaral, D.G., 1981. An autoradiographic study of the projections of the central nucleus of the monkey amygdala. Journal of Neuroscience 1, 1242–1259. Pubill, D., Gasulla, D., Sureda, F.X., Camins, A., Pallàs, M., Escubedo, E., Camarasa, J., 1998. Characterization of [3H]nisoxetine binding in rat vas deferens membranes: modulation by sigma and PCP ligands. Life Science 62, 763–773. Pustorino, G., Spano, M., Sgro, D.L., Di Rosa, G., Tricomi, G., Bellantone, D., Tortorella, G., 2007. Status gelasticus associated with levetiracetam as add-on treatment. Epileptic Disorders 9, 186–189. Rajput, A.H., Robinson, C.A., Rajput, M.L., Rajput, A., 2011. Cerebellar Purkinje cell loss is not pathognomonic of essential tremor. Parkinsonism & Related Disorders 17, 16–21. Ramasubbu, R., 2003. Lamotrigine treatment for post-stroke pathological laughing and crying. Clinical Neuropharmacology 26, 233–235. Reep, R.L., Winans, S.S., 1982. Efferent connections of dorsal and ventral agranular insular cortex in the hamster, Mesocricetus auratus. Neuroscience 17, 2609–2635. Riggs, J.E., Schochet Jr., S.S., Hogg, J.P., 1999. Delayed diffuse upper motor neuron syndrome after compressive thoracic myelopathy. Military Medicine 164, 666–668. Robinson, R.G., Parikh, R.M., Lipsey, J.R., Starkstein, S.E., Price, T.R., 1993. Pathological laughing and crying following stroke: validation of a measurement scale and a double-blind treatment study. American Journal of Psychiatry 150, 286–293. Rocha, L., Ondarza-Rovira, R., 1999. Characterization of benzodiazepine receptor binding following kainic acid administration: an autoradiography study in rats. Neuroscience Letters 262, 211–214. Rodrigo-Angulo, M.L., Reinoso-Suarez, F., 1984. Cerebellar projections to the lateral posterior-pulvinar thalamic complex in the cat. Brain Research 322, 172–176. Ross, E.D., Rush, A.J., 1981. Diagnosis and neuroanatomical correlates of depression in brain-damaged patients. Implications for a neurology of depression. Archives of General Psychiatry 38, 1344–1354. Ross, E.D., Stewart, R.S., 1987. Pathological display of affect in patients with depression and right frontal brain damage. An alternative mechanism. Journal of Nervous & Mental Disease 175, 165–172. Rothmann, H., 1923. Zusammenfassender Bericht uber den Rothmannschen groshirnlosen Hund nach klinisher und anatomisher Untersuchung. Zeit Gesam Neurol Psychiatrie 87, 247–313. Sacco, S., Sará, M., Pistoia, F., Conson, M., Albertini, G., Carolei, A., 2008. Management of pathologic laughter and crying in patients with locked-in syndrome: a report of 4 cases. Archives of Physical Medicine and Rehabilitation 89, 775–778. Sackheim, H.A., Greenberg, M.S., Weiman, A.L., Gur, R.C., Hungerbuhler, J.P., Geschwind, N., 1982. Hemispheric asymmetry in the expression of positive and negative emotions. Neurologic evidence. Archives of Neurology 39, 210–218. Saper, C.B., 1982. Convergence of autonomic and limbic connections in the insular cortex of the rat. Journal of Comparative Neurology 210, 163–173. Saper, C.B., Loewy, A.D., 1980. Efferent connections of the parabrachial nucleus in the rat. Brain Research 197, 291–317. Sasaki, K., Kawaguchi, S., Shimono, T., Prelevic, S., 1970. Electrophysiological studies of the pontine nuclei. Brain Research 20, 425–438. Satow, T., Usui, K., Matsuhashi, M., Yamamoto, J., Begum, T., Shibasaki, H., Ikeda, A., Mikuni, N., Miyamoto, S., Hashimoto, N., 2003. Mirth and laughter arising from human temporal cortex. Journal of Neurology, Neurosurgery, and Psychiatry 74, 1004–1005. Schaltenbrand, G., Cobb, S., 1931. Clinical and anatomical studies on two cats without neocortex. Brain 53, 449–491. Schiffer, R.B., Herndon, R.M., Rudick, R.A., 1985. Treatment of pathologic laughing and weeping with amitriptyline. New England Journal of Medicine 312, 1480–1482. Schiffer, R., Pope, L.E., 2005. Review of pseudobulbar affect including a novel and potential therapy. Journal of Neuropsychiatry & Clinical Neurosciences 17, 447–454. Schindehütte, J., Trenkwalder, C., 2007. Treatment of drug-induced psychosis in Parkinson’s disease with ziprasidone can induce severe dose-dependent offperiods and pathological laughing. Clinical Neurology and Neurosurgery 109, 188–191. Schmahmann, J.D., Pandya, D.N., 1997. Anatomic organization of the basilar pontine projections from prefrontal cortices in rhesus monkey. Journal of Neuroscience 17, 438–458. Schmitt, J.J., Janszky, J., Woermann, F., Tuxhorn, I., Ebner, A., 2006. Laughter and the mesial and lateral premotor cortex. Epilepsy & Behavior 8, 773–775. Schneider, F., Habel, U., Kessler, C., Salloum, J.B., Posse, S., 2000. Gender differences in regional cerebral activity during sadness. Human Brain Mapping 9, 226–238. Schuller, G., Fischer, S., Schweizer, H., 1997. Significance of the paralemniscal tegmental area for audio-motor control in the moustached bat, Pteronotus p. parnellii: the afferent off efferent connections of the paralemniscal area. European Journal of Neuroscience 9, 342–355. Sem-Jacobsen, C.W., 1968. Depth-electrographic Stimulation of the Human Brain and Behavior. Charles C. Thomas, Springfield, Illinois, pp. 127–138.

1915

Sethi, P.K., Rao, T.S., 1976. Gelastic, quiritarian, and cursive epilepsy. A clinicopathological appraisal. Journal of Neurology, Neurosurgery, and Psychiatry 39, 823–828. Shahar, E., Kramer, U., Mahajnah, M., Lerman-Sagie, T., Goez, R., Gross, V., Kutai, M., Genizi, J., 2007. Pediatric-onset gelastic seizures: clinical data and outcome. Pediatric Neurology 37, 29–34. Shammah-Lagnado, S.J., Alheid, G.F., Heimer, L., 1996. Efferent connections of the caudal part of the globus pallidus in the rat. Journal of Comparative Neurology 376, 489–507. Sharp, F.R., Ryan, A.F., 1984. Regional (14 C) 2-deoxyglucose uptake during forelimb movements evoked by rat motor cortex stimulation: pons, cerebellum, medulla, spinal cord, muscle. Journal of Comparative Neurology 224, 286–306. Shin, H.Y., Hong, S.B., Joo, E.Y., Tae, W.S., Han, S.J., Cho, J.W., Seo, D.W., Kim, S.H., Lee, J.M., Kim, S.I., 2006. Gelastic seizures involving the right parietal lobe. Epileptic Disorders 8, 209–212. Siclari, F., Wienecke, M., Poryazova, R., Bassetti, C.L., Baumann, C.R., 2011. Laughing as a manifestation of rapid eye movement sleep behavior disorder. Parkinsonism & Related Disorders 17, 382–385. Siddiqui, M.S., Fernandez, H.H., Garvan, C.W., Kirsch-Darrow, L., Bowers, D., Rodriguez, R.L., Jacobson IV, C.E., Rosado, C., Vaidyanathan, S., Foote, K.D., Okun, M.S., 2009. Inappropriate crying and laughing in Parkinson disease and movement disorders. World Journal of Biological Psychiatry 10, 234–240. Siegel, A., Bhatt, S., Bhatt, R., Zalcman, S.S., 2010. Limbic, hypothalamic and periaqueductal gray circuitry and mechanisms controlling rage and vocalization in the cat. In: Brudzynski, S.M. (Ed.), Handbook of Mammalian Vocalization: An Integrative Neuroscience Approach. Elsevier B.V., Amsterdam, pp. 243–253. Sims, J.S., Lorden, J.F., 1986. Effect of paraventricular nucleus lesions on body weight, food intake and insulin levels. Behavioural Brain Research 22, 265–281. Siqueira, E.R., Franks, L.,;1; 1974. Anatomic connections of the pulvinar, in: Cooper, I.S., Rakic, P., Riklan, M. (Eds.), The Pulvinar-LP Complex. Charles C. Thomas, Springfield, Illinois, pp. 36–51. Smith, M.C., 1975. Histological findings after hemicerebellectomy in man: anterograde, retrograde and transneuronal degeneration. Brain Research 95, 423–442. Smith, R.A., Berg, J.E., Pope, L.E., Callahan, J.D., Wynn, D., Thisted, R.A., 2004. Validation of the CNS emotional lability scale for pseudobulbar affect (pathological laughing and crying) in multiple sclerosis patients. Multiple Sclerosis 10, 679–685. Smith, Y., Hazrati, L.N., Parent, A., 1990. Efferent projections of the subthalamic nucleus in the squirrel monkey as studied by the PHA-L anterograde tracing method. Journal of Comparative Neurology 294, 306–323. Sperli, F., Spinelli, L., Pollo, C., Seeck, M., 2006. Contralateral smile and laughter, but no mirth, induced by electrical stimulation of the cingulate cortex. Epilepsia 47, 440–443. Starkstein, S.E., Migliorelli, R., Tesón, A., Petracca, G., Chemerinsky, E., Manes, F., Leiguarda, R., 1995. Prevalence and clinical correlates of pathological affective display in Alzheimer’s disease. Journal of Neurology, Neurosurgery, and Psychiatry 59, 55–60. Stone, E.A., Lin, Y., Ahsan, R., Quartermain, D., 2004. Gross mapping of alpha1-adrenoceptors that regulate behavioral activation in the mouse brain. Behavioural Brain Research 152, 167–175. Strowd, R.E., Cartwright, M.S., Okun, M.S., Haq, I., Siddiqui, M.S., 2010. Pseudobulbar affect: prevalence and quality of life impact in movement disorders. Journal of Neurology 257, 1382–1387. Sugama, S., Ito, F., Eto, Y., Maekawa, K., 1992. A case of frontal lobe epilepsy presenting with gelastic seizures. No. To. Hattatsu 24, 475–479. Surguladze, S., Brammer, M.J., Keedwell, P., Giampietro, V., Young, A.W., Travis, M.J., Williams, S.C., Phillips, M.L., 2005. A differential pattern of neural response toward sad versus happy facial expressions in major depressive disorder. Biological Psychiatry 57, 201–209. Talairach, J., Bancaud, J., Geier, S., Bordas-Ferrer, M., Bonis, A., Szikla, G., Rusu, M., 1973. The cingulate gyrus and human behavior. Electroencephalography and Clinical Neurophysiology 34, 45–52. Tateno, A., Jorge, R.E., Robinson, R.G., 2004. Pathological laughing and crying following traumatic brain injury. Journal of Neuropsychiatry & Clinical Neurosciences 16, 426–434. Tatum, W.O., Loddenkemper, T., 2010. Crying with left temporal lobe seizures and Wada testing. Epilepsy & Behavior 18, 303–305. Thangnipon, W., Taxt, T., Brodal, P., Storm-Mathisen, J., 1983. The corticopontine projection: axotomy-induced loss of high affinity L-glutamate and D-aspartate uptake, but not of gamma-aminobutyrate uptake, glutamate decarboxylase or choline acetyltransferase, in the pontine nuclei. Neuroscience 8, 449–457. Tokita, K., Inoue, T., Boughter Jr., J.D., 2009. Afferent connections of the parabrachial nucleus in C57BL/6 J mice. Neuroscience 161, 475–488. Trosch, R.M., Sze, G., Brass, L.M., Waxman, S.G., 1990. Emotional facial paresis with striatocapsular infarction. Journal of the Neurological Sciences 98, 195–201. Tsutsumi, S., Yasumoto, Y., Ito, M., 2008. Pathological laughter caused by frontal glioblastoma: case report. Neurologia Medico-Chirurgica (Tokyo) 48, 307–310. Udaka, F., Yamao, S., Nagata, H., Nakamura, S., Kameyama, M., 1984. Pathologic laughing and crying treated with levodopa. Archives of Neurology 41, 1095–1096. Usunoff, K.G., Itzev, D.E., Rolfs, A., Schmitt, O., Wree, A., 2006. Brain stem afferent connections of the amygdala in the rat with special references to a projection

1916

E.C. Lauterbach et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 1893–1916

from the parabigeminal nucleus: a fluorescent retrograde tracing study. Anatomy and Embryology (Berlin) 211, 475–496. Uzunca, I., Utku, U., Asil, T., Celik, Y., 2005. Fou rire prodromique associated with simultaneous bilateral capsular genu infarction. Journal of Clinical Neuroscience 12, 174–175. Van Buren, J.M., Borke, R.C., 1972. Variations and Connections of the Human Thalamus. Springer, Berlin. Van Buren, J.M., Borke, R.C., Modesti, L.M., 1976. Sensory and nonsensory portions of the nucleus ventralis posterior thalami of chimpanzee and man. Journal of Neurosurgery 45, 37–48. Van Daele, D.J., Cassell, M.D., 2009. Multiple forebrain systems converge on motor neurons innervating the thyroarytenoid muscle. Neuroscience 162, 501–524. Vasilenko, G.F., Eliseeva, Z.V., 1980. Descending connections between the parafascicular complex of the thalamus and midbrain periaqueductal gray. Biulleten Eksperimentalnoi Biologii I Meditsiny 89, 105–107. Vázquez-Borsetti, P., Cortés, R., Artigas, F., 2009. Pyramidal neurons in rat prefrontal cortex projecting to ventral tegmental area and dorsal raphe nucleus express 5-HT2A receptors. Cerebral Cortex 19, 1678–1686. Vergé, D., Daval, G., Marcinkiewicz, M., Patey, A., El Mestikawy, S., Gozlan, H., Hamon, M., 1986. Quantitative autoradiography of multiple 5-HT1 receptor subtypes in the brain of control or 5,7-dihydroxytryptamine-treated rats. Journal of Neuroscience 6, 3474–3482. Vogt, B.A., Pandya, D.N., Rosene, D.L., 1987. Cingulate cortex of the rhesus monkey: I. Cytoarchitecture and thalamic afferents. Journal of Comparative Neurology 262, 256–270. Weinstein, E., Bender, M., 1943. Integrated facial patterns elicited by stimulation of the brain stem. Archives of Neurology & Psychiatry 50, 34–42. Weisenburg, T., Guilfoyle, W., 1910. Tumour destroying most of one optic thalamus and causing central pains, vasomotor and trophic disturbances, involuntary howling and deviation of the body to the opposite side. Review in Neurology and Psychiatry 8, 325. Werling, L.L., Keller, A., Frank, J.G., Nuwayhid, S.J., 2007. A comparison of the binding profiles of dextromethorphan, memantine, fluoxetine and amitriptyline:

treatment of involuntary emotional expression disorder. Experimental Neurology 207, 248–257. Wild, B., Rodden, F.A., Grodd, W., Ruch, W., 2003. Neural correlates of laughter and humour. Brain 126, 2121–2138. Wilson, S.A.K., 1924. Some problems in neurology. II: Pathological laughing and crying. Journal of Neurology and Psychopathology 4, 299–333. Wojtecki, L., Nickel, J., Timmermann, L., Maarouf, M., Südmeyer, M., Schneider, F., Seitz, R.J., Voges, J., Sturm, V., Schnitzler, A., 2007. Pathological crying induced by deep brain stimulation. Movement Disorders 22, 1314–1316. Wojtecki, L., Timmermann, L., Groiss, S.J., Elben, S., Reck, C., Südmeyer, M., Sturm, V., Schnitzler, A., 2011. Long-term time course of affective lability after subthalamic deep brain stimulation electrode implantation. Neurocase 17, 527–532. Wortzel, H.S., Oster, T.J., Anderson, C.A., Arciniegas, D.B., 2008. Pathological laughing and crying. Epidemiology, pathophysiology and treatment. CNS Drugs 22, 531–545. Xiao, C., Zhou, C., Atlas, G., Delphin, E., Ye, J.H., 2008. Labetalol facilitates GABAergic transmission to rat periaqueductal gray neurons via antagonizing beta1adrenergic receptors—a possible mechanism underlying labetalol-induced analgesia. Brain Research 1198, 34–43. Yasui, Y., Breder, C.D., Saper, C.B., Cechetto, D.F., 1991. Autonomic responses and efferent pathways from the insular cortex in the rat. Journal of Comparative Neurology 303, 355–374. Zeilig, G., Drubach, D.A., Katz-Zeilig, M., Karatinos, J., 1996. Pathological laughter and crying in patients with closed traumatic brain injury. Brain Injury 10, 591–597. Zellers, G.L., Frank, M., Dougherty, J., 1990. Pathological laughter. Annals of Emergency Medicine 19, 327–329. Zhang, S.P., Davis, P.J., Bandler, R., Carrive, P., 1994. Brain stem integration of vocalization: Role of the midbrain periaqueductal gray. Journal of Neurophysiology 72, 1337–1356. Zubieta, J.K., Frey, K.A., 1993. Autoradiographic mapping of M3 muscarinic receptors in the rat brain. Journal of Pharmacology and Experimental Therapeutics 264, 415–422.