Dopamine, fronto-striato-thalamic circuits and risk for psychosis

SCHRES-06941; No of Pages 10 Schizophrenia Research xxx (2016) xxx–xxx

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Dopamine, fronto-striato-thalamic circuits and risk for psychosis Orwa Dandash a,b,⁎, Christos Pantelis b,c, Alex Fornito a,b a b c

Brain & Mental Health Laboratory, Monash Institute of Cognitive and Clinical Neurosciences, School of Psychological Sciences, and Monash Biomedical Imaging, Monash University, Australia Melbourne Neuropsychiatry Centre, Department of Psychiatry, The University of Melbourne and Melbourne Health, Carlton South, VIC, Australia Centre for Neural Engineering (CfNE), Department of Electrical and Electronic Engineering, University of Melbourne, Carlton South, VIC, Australia

a r t i c l e

i n f o

Article history: Received 28 April 2016 Received in revised form 16 August 2016 Accepted 19 August 2016 Available online xxxx Keywords: Fronto-striato-thalamic Resting-state fMRI Dopamine GABA Glutamate

a b s t r a c t A series of parallel, integrated circuits link distinct regions of prefrontal cortex with specific nuclei of the striatum and thalamus. Dysfunction of these fronto-striato-thalamic systems is thought to play a major role in the pathogenesis of psychosis. In this review, we examine evidence from human and animal investigations that dysfunction of a specific dorsal fronto-striato-thalamic circuit, linking the dorsolateral prefrontal cortex, dorsal (associative) striatum, and mediodorsal nucleus of the thalamus, is apparent across different stages of psychosis, including prior to the onset of a first episode, suggesting that it represents a candidate risk biomarker. We consider how abnormalities at distinct points in the circuit may give rise to the pattern of findings seen in patient populations, and how these changes relate to disruptions in dopamine, glutamate and GABA signaling. © 2016 Elsevier B.V. All rights reserved.

1. Introduction Psychotic disorders such as schizophrenia are thought to arise from the dysfunction of distributed neural systems (Andreasen et al., 1998; Bullmore et al., 1997; Fornito et al., 2012; Friston, 1998; Stephan et al., 2009). In particular, pathology within a series of parallel, integrated circuits that link distinct regions of the frontal cortex with specific striatal and thalamic nuclei – the so-called fronto-striato-thalamic loops – are often implicated in pathophysiological models (Pantelis et al., 1992; Robbins, 1990) because their activity is heavily modulated by dopamine – the primary target of all currently available, therapeutically effective antipsychotic agents. In this review, we consider recent work suggesting that dysfunction of one specific circuit, linking the dorsolateral prefrontal cortex (DLPFC), dorsal (associative) striatum, and mediodorsal nucleus of the thalamus, plays a particularly prominent role in the onset of psychotic systems. We consider the possible circuit-level abnormalities that may explain this dysfunction, and examine the role of altered signaling in systems that regulate dopamine, glutamate and gamma-amino-butyric-acid (GABA). 1.1. A brief history of the dopamine hypothesis of psychosis The discovery of the first antipsychotic drug Chlorpromazine and its application in psychiatry in 1952 heralded a promising new era in the

⁎ Corresponding author at: Monash Biomedical Imaging, 1st Floor, 770 Blackburn Road, Clayton, VIC 3194, Australia. E-mail address: [email protected] (O. Dandash).

treatment of psychosis (Lopez-Munoz et al., 2005). The drug's mechanism of action was later uncovered by Carlsson & Linqvist who showed that chlorpromazine and haloperidol block monoamine receptors in the mouse brain (Carlsson and Lindqvist, 1963). This discovery was followed by observations that the dopamine agonist amphetamine induces psychotic symptoms in otherwise healthy individuals and rekindles psychotic symptoms in schizophrenia patients (Angrist and Gershon, 1970; Janowsky and Risch, 1979). These findings suggested that excess dopamine transmission plays an important role in the pathogenesis of psychosis, and led to the dopamine hypothesis of schizophrenia (Carlsson et al., 1972; Meltzer and Stahl, 1976; Snyder, 1976). The striatum, which comprises the caudate nucleus and putamen and which represents the major input structure to the basal ganglia, was thought to be a key site for this dopaminergic dysregulation due to the high density of dopamine afferents to this region. Accordingly, a tight correlation was found between the therapeutically effective doses of different antipsychotic agents and their occupancy of striatal dopamine receptors (Creese et al., 1976; Seeman and Lee, 1975), with one caveat being that the larger doses required for some of the drugs were often sufficient to induce extrapyramidal side effects. The dopamine hypothesis has continued to evolve since its inception (Davis et al., 1991; Howes and Kapur, 2009; Kapur and Mamo, 2003). According to one prominent variant, psychotic symptoms arise from increased dopamine transmission, or hyperdopaminergia, in the mesolimbic pathway, which primarily involves the ventral striatum and other limbic structures. The negative symptoms and cognitive impairments that often characterize schizophrenia are attributed to reduced dopamine signaling, or hypodopaminergia, in the mesocortical

http://dx.doi.org/10.1016/j.schres.2016.08.020 0920-9964/© 2016 Elsevier B.V. All rights reserved.

Please cite this article as: Dandash, O., et al., Dopamine, fronto-striato-thalamic circuits and risk for psychosis, Schizophr. Res. (2016), http:// dx.doi.org/10.1016/j.schres.2016.08.020

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dopamine system, which involves dorsolateral prefrontal cortex (DLPFC) and other cortical and extrastriatal subcortical areas (Davis et al., 1991; Slifstein et al., 2015; Weinberger, 1987; Weinstein et al., 2016). Evidence supporting a role for mesolimbic hyperdopaminergia in psychosis has come from in vivo microdialysis studies in freely-moving rats showing a preferential increase of extracellular dopamine in the ventral striatum following administration of dopamine agonists (Carboni et al., 1989; Robinson et al., 1988). Both post-mortem and in vivo positron emission tomography (PET) studies have reported evidence of increased density of dopamine receptors, particularly D2 receptors, in the striatum of treatment-naive and medicated schizophrenia patients (Howes et al., 2012; Lee and Seeman, 1980; Owen et al., 1978; Wong et al., 1986), although these increases may be partly driven by antipsychotic medication (for a discussion see (Howes et al., 2015)). Evidence supporting a role for mesocortical hypodopaminergia in negative symptoms and cognitive deficits has come from studies showing that schizophrenia patients perform poorly on cognitive tasks subserved by the DLPFC, and which are thought to depend on D1 receptor signaling (Barch and Ceaser, 2012; Goldman-Rakic, 1995; Sawaguchi and Goldman-Rakic, 1994). Patients with established schizophrenia often show reduced prefrontal glucose metabolism and task-related activation, and administration of dopamine agonists can reverse this effect (Daniel et al., 1989, 1991). PET studies of D1 receptor availability in prefrontal cortex have been inconsistent, with some reporting reduced receptor density while others have found increased density (Abi-Dargham, 2003; Abi-Dargham et al., 2002; Okubo et al., 1997). This inconsistency may be driven by a lack of binding specificity for some of the tracers used in this research (e.g., (Catafau et al., 2010)). 1.2. Fronto-striato-thalamic circuits and dopamine dysfunction in psychosis Where the focus of early models of dopamine dysfunction in psychosis was on diffusely projecting dopaminergic systems such as the mesolimbic and mesocortical pathways, recent work has attempted to more precisely delineate the specific neural circuits that mediate dopamine dysregulation. Particular attention has been paid to fronto-striatothalamic circuits, which topographically link discrete regions of the frontal cortex with specific subregions of the striatum pallidum, substantia nigra and thalamus (Fig. 1). The organization of these loops is highly conserved across mammalian species (Haber, 2003; Molnar,

2000; Parent and Hazrati, 1995a; Sherman and Guillery, 2006), and has been characterized through various anatomical tract-tracing (McFarland and Haber, 2000; Parent and Hazrati, 1995a), electrophysiological (Alexander and DeLong, 1985), clinical (Cummings, 1993), behavioural (Chudasama and Robbins, 2006), neurocognitive (Pantelis et al., 1999, 1997), and neuroimaging studies (Di Martino et al., 2008; Harrison et al., 2009; Zhang et al., 2010). The loops generally operate in a circuit-like fashion, such that information is relayed from the cortex through the basal ganglia, thalamus and then back to the same area of cortex (Alexander et al., 1986). The loops work as both independent “closed” circuits, in which each loop processes and relays certain types of information, and as an integrated and interdependent system, in which inputs from one loop can modify the output of other loops. Integration is made possible through neural projections that pass through restricted areas of the pallidum (Alexander et al., 1986). This organization supports the flexible modulation of internally generated and externally evoked behavioural responses to environmental cues (Haber, 2003). The fronto-striato-thalamic loops may be categorized into three broad classes along a rostroventral-to-dorsocaudal gradient. This gradient is most easily understood with respect to distinct subregions of the striatum (Draganski et al., 2008; Haber, 2003): a ventral ‘affective’ circuit links ventromedial PFC to the nucleus accumbens, which in turn projects to the mediodorsal (MD) and the ventral anterior (VA) nucleus of the thalamus; a dorsal ‘associative’ circuit links DLPFC to the dorsal striatum, which then also projects to the MD and VA nucleus of the thalamus; and a caudal ‘sensorimotor’ circuit links motor and sensory cortices to the tail of the caudate and putamen, which in turn project to the ventrolateral (VL) nucleus of the thalamus (Fig. 1). Recent studies using high-resolution positron emission tomography (PET) have localized dopaminergic dysfunction in patients with psychosis to specific subregions of the striatum, thus implying a preferential involvement of particular fronto-striato-thalamic circuits in disease pathophysiology. The majority of this work has measured uptake of 6[18F] fluoro-L-DOPA ([18F]-DOPA) to index presynaptic dopamine synthesis capacity in the striatum, as this marker has proven to be a robust and reliable probe of dopaminergic dysfunction in psychotic patients and at-risk populations (Fusar-Poli and Meyer-Lindenberg, 2013; Howes et al., 2012; Huttunen et al., 2008). Contrary to early views prioritizing hyperdopaminergia in the ventral striatum and the mesolimbic pathway as critical for the onset of psychosis, this work has shown that the most robust elevations of dopamine synthesis are found in the dorsal, associative division of the striatum. For example, one study

Fig. 1. Three major fronto-striato-thalamic loops. The left image shows the anatomical location of the main nuclei involved in each loop, as identified through functional connectivity analysis of resting-state fMRI data in 30 healthy individuals. Blue, red, and green clusters correspond to regions of prefrontal cortex and thalamus that show significant functional connectivity with seed regions placed in regions of the associative, limbic and sensorimotor divisions of the striatum, respectively. The diagrams to the right show the path of information flow through the circuits, as defined by Alexander et al. (1986). Information flows from the cortex to the striatum, then on to the pallidum and substantia nigra, and finally to the thalamus and back to the cortex. DLPFC: dorsolateral prefrontal cortex; ACC: anterior cingulate cortex; vmPFC: ventromedial prefrontal cortex; SNr: the reticular part of the substantia nigra. VA: ventral anterior thalamic nucleus; MD: mediodorsal thalamic nucleus; VL: ventral lateral thalamic nucleus. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Please cite this article as: Dandash, O., et al., Dopamine, fronto-striato-thalamic circuits and risk for psychosis, Schizophr. Res. (2016), http:// dx.doi.org/10.1016/j.schres.2016.08.020

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found significant [18F]-DOPA elevations in both patients with established schizophrenia and individuals with an at-risk mental state (ARMS) for psychosis compared to healthy controls (Howes et al., 2009). Moreover, the severity of prodromal symptoms in the ARMS group correlated with [18F]-DOPA levels in the dorsal but not ventral striatum. Later work showed that the [18F]-DOPA elevations in the ARMS group were specific to individuals who later developed psychosis (Howes et al., 2011b). Smaller elevations have been found in the sensorimotor division of the striatum of ARMS individuals, and these appear to increase longitudinally during the transition to psychosis (Egerton et al., 2013; Howes et al., 2011a). Increased [18F]-DOPA has also been found in the substantia nigra of patients with established schizophrenia, a result that is consistent with post-mortem evidence that patients show elevated nigral levels of tyrosine hydroxylase, the rate-limiting enzyme in the synthesis of dopamine (Howes et al., 2013). Collectively, these results form part of a growing body of evidence indicating that striatal dopamine synthesis and release are consistently elevated in patients, particularly those experiencing acute psychotic symptoms (Abi-Dargham et al., 2009; Fusar-Poli and Meyer-Lindenberg, 2013; Laruelle et al., 1999; Mizrahi et al., 2012; Pogarell et al., 2012), and suggest that striatal hyperdopaminergia may be primarily associated with abnormalities of presynaptic, rather than postsynaptic, function (Howes et al., 2012). Some studies have identified relatively smaller dopaminergic changes in the ventral striatum of patients (Kegeles et al., 2010), but reports have been less consistent than those for the dorsal subregion. Pathology in one component of a neural circuit seldom remains isolated; instead, it will spread to affect the functions of interconnected system elements (Fornito et al., 2015). Accordingly, elevated [18F]DOPA in the dorsal striatum of ARMS individuals correlates with altered prefrontal glucose metabolism (Meyer-Lindenberg et al., 2002) and prefrontal activation during the performance of executive function tasks (Fusar-Poli et al., 2010, 2011). In particular, there appears to be an inverse relationship between subcortical dopamine levels and measures of prefrontal activity. For example, prefrontal lesions in rats lead to increased striatal dopamine transmission (Pycock et al., 1980), dopamine agonism in prefrontal cortex can reduce dopamine signaling in the striatum (Scatton et al., 1982), and human imaging studies have found a strong negative correlation between striatal dopamine synthesis capacity and prefrontal glucose metabolism (Meyer-Lindenberg et al., 2002). However, an open question is whether striatal dopaminergic abnormalities are a cause or consequence of circuit-wide dysfunction in the associative fronto-striato-thalamic system. 2. Functional dysconnectivity of fronto-striato-thalamic circuitry Circuit-level dysfunction in psychosis can be directly probed with in vivo magnetic resonance imaging (MRI) of structural or functional connectivity. In particular, studies of functional connectivity in task-free, so-called resting-states (Fornito and Bullmore, 2010; Fox and Raichle, 2007), have proven to be very popular in psychosis because the data are relatively easy to acquire, the neural dynamics recorded under a ‘rest’ design are robust across individuals and time (Damoiseaux et al., 2006; Shehzad et al., 2009), they influence task-evoked activity and performance (Fox et al., 2006; Fox and Raichle, 2007), and they are under strong genetic control (Fornito and Bullmore, 2012; Fornito et al., 2011; Glahn et al., 2010). The absence of a task can also minimize the potential confounds associated with differences in task performance or motivation (although for limitations of resting-state designs, see (Fornito and Bullmore, 2010)). Studies in healthy individuals have shown that distinct corticostriato-thalamic networks can be readily mapped with resting-state functional connectivity analysis (Di Martino et al., 2008; Kim et al., 2013; Lenglet et al., 2012). For example, DLPFC and parietal association cortex show strong functional connectivity with dorsal caudate, whereas ventromedial PFC and parahippocampal gyrus show strong

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connectivity with the nucleus accumbens/ventral striatum (Di Martino et al., 2008). Other work focused on the thalamus has shown that fMRI signal fluctuations in the prefrontal cortex correlate with the mediodorsal and anterior thalamic nuclei, whereas activity in the motor cortex correlates with the ventrolateral thalamus (Zhang et al., 2008; Zhang et al., 2010). The same analyses also found that caudate activity correlates with prefrontal cortex while putamen activity correlates with motor areas (Zhang et al., 2008, 2010). The consistency between these fMRI findings and the known anatomy of these systems suggests that resting-state functional MRI offers a powerful means for delineating specific fronto-striato-thalamic systems, and for probing their dysfunction in clinical disorders. A number of resting-state functional MRI studies, using distinct methodologies, have suggested a prominent role for fronto-striato-thalamic dysconnectivity in people with psychosis. For example, one regionally unbiased, whole-brain analysis of pairwise functional connectivity between 116 brain regions found that the prefrontal cortex and striatum were among the regions showing the most significant reductions in functional connectivity with other areas (Liang et al., 2006). In a separate, more specific analysis, schizophrenia patients showed reduced functional connectivity between a seed region in the mediodorsal nucleus of the thalamus and the caudate and DLPFC (Welsh et al., 2010). Other authors using either the thalamus (Anticevic et al., 2014; Woodward et al., 2012) or DLPFC (Zhou et al., 2007) as a seed region have reported similar findings, suggesting that psychotic illness robustly affects functional connectivity within the dorsal fronto-striato-thalamic system. The repeated implication of dorsal circuit dysfunction across studies using different methods and sometimes non-specific seed regions points to a strong link between pathology of this system and psychosis. Dorsal system dysconnectivity is also associated with risk for psychosis. Seeding distinct subregions of the striatum, one study found that both patients with first episode psychosis and their unaffected relatives showed reduced functional connectivity in the dorsal system, with prominent reductions in connectivity between the dorsal caudate and DLPFC (Fornito et al., 2013). In patients, the magnitude of this connectivity reduction correlated with the severity of both positive and negative symptoms. A separate study in ARMS individuals later found evidence for a similar reduction of functional connectivity between the dorsal caudate and DLPFC, as well as reduced connectivity between the dorsal caudate and mediodorsal thalamus (Dandash et al., 2014). Once again, greater reduction in the functional connectivity of these regions was associated with more severe prodromal symptoms. In an independent study that seeded the thalamus, ARMS individuals who subsequently developed psychosis showed reduced functional connectivity with DLPFC (and dorsal caudate at a lower statistical threshold) compared to ARMS individuals who did not transition (Anticevic et al., 2015). The anatomical consistency of some of these results is shown in Fig. 2. Collectively, these findings suggest that dorsal fronto-striato-thalamic dysconnectivity is apparent before and after psychosis onset, correlates with the severity of prodromal, psychotic and negative symptoms, and is replicable across different samples and analysis methodologies. The consistency between the fMRI and PET findings points to an intimate relationship between dopaminergic dysfunction and dorsal circuit dysconnectivity. The implication of the dorsal system in the onset of psychotic symptoms challenges early variants of the dopamine hypothesis that assumed psychotic symptoms arose from hyperdopaminergia in the ventral striatum and the mesolimbic system. These new data suggest that dorsal circuit dysfunction may be sufficient to elicit positive symptoms, negative symptoms and cognitive impairments in patients. However, we note that one caveat is that some studies have either reported weak (Anticevic et al., 2014; Dandash et al., 2014) or no associations between fronto-striato-thalamic connectivity and symptom severity (Woodward and Heckers, 2016; Woodward et al., 2012). This inconsistency suggests that the association between

Please cite this article as: Dandash, O., et al., Dopamine, fronto-striato-thalamic circuits and risk for psychosis, Schizophr. Res. (2016), http:// dx.doi.org/10.1016/j.schres.2016.08.020

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Fig. 2. Regions of prefrontal cortex showing reduced functional connectivity with a seed region placed in the dorsal caudate in clinical and high-risk populations. The caudate seed is shown in the far left image. Red, magenta and yellow show prefrontal regions where functional connectivity was reduced, compared to healthy controls (CON), in patients with first episode psychosis (FEP), their unaffected first-degree relatives (REL), and ARMS individuals, respectively. Green shows regions were lower functional connectivity was correlated with more severe positive symptoms in the FEP group. The FEP and REL data was originally reported by Fornito et al. (2013). The ARMS data was reported by Dandash et al. (2014). The ARMS results are shown at a reduced threshold to that originally reported to highlight consistency with the other findings. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

circuit function and symptoms may depend on the method used to probe neural function or the measure used to measure clinical symptoms.

3. Mechanisms of fronto-striato-thalamic disruption in psychosis The complex interconnectivity of fronto-striato-thalamic circuitry makes it difficult to identify a single lesion that can cause the dopaminergic dysfunction and systems-level changes observed in clinical samples. The preceding discussion suggests that any mechanistic model must account for three key findings: (1) increased dopamine synthesis and release in the striatum; (2) a possible reduction of dopamine transmission in the prefrontal cortex; (3) and reduced functional connectivity between these two structures and thalamus. In the following section, we examine in more detail the neurochemical anatomy of fronto-striato-thalamic circuitry and consider sites of possible dysfunction, where pathology may result in the brain changes observed in patients.

3.1. The dual-route model of striatal hyperdopaminergia and frontal hypodopaminergia It has been suggested that increased dopamine signaling may represent a final common pathway that leads to psychosis onset, but that multiple different upstream causes may lead to this ultimate pathophysiological destination (Carlsson et al., 2001; Howes and Kapur, 2009; Seeman, 2011). One useful theory for understanding some of these upstream mechanisms is the ‘accelerator-brake’ or dual-route model of dopamine regulation proposed by Carlsson and colleagues (Carlsson et al., 1999; Carlsson and Carlsson, 1990). Based largely on microdialysis, tract-tracing and pharmacological studies in rats, the model identifies two routes through which the cortex can regulate the activity of dopaminergic cells in the midbrain. The first is a facilitatory pathway – the ‘accelerator’ – through which glutamatergic afferents from the PFC stimulate midbrain dopaminergic cells (Fig. 3A), thus augmenting dopamine transmission to the striatum through the mesolimbic and nigrostriatal systems (Karreman and Moghaddam, 1996; Swanson, 1982). The second route through which cortex regulates dopaminergic signaling is via

Fig. 3. A dual-route model of striatal hyperdopaminergia (A) and frontal hypodopaminergia (B). Arrows represent excitatory connections and blunt connections are inhibitory. Thin and thick lines represent potential paths of reduced and increased signaling, respectively. The cortex modulates midbrain dopamine neuron activity via direct excitatory projections to these neurons (accelerator pathway), or indirect projections onto midbrain GABAergic cells that inhibit their dopaminergic counterparts (brake pathway). (A) Increased signaling along the accelerator pathway can augment dopamine release in the striatum, and increase outflow to the thalamus and cortex. We show here a simplified representation of the net effect of the indirect striato-thalamic pathway, which is represented by the direct inhibitory projection of the striatal GABA neuron onto a thalamic glutamatergic neuron. In reality, this indirect pathway exerts a polysynaptic inhibitory influence over the thalamus via the pallidum and either the subthalamic nucleus or reticular nucleus of the thalamus. The indirect pathway is shown in more detail in Fig. 4A. The net excitatory effect of the direct striato-thalamic pathway is represented by the polysynaptic pathway through the pallidum. Increased cortical stimulation of striatal GABA cells in this pathway will upregulate the activity of thalamic neurons and augment thalamocortical signaling. This pathway is shown in more detail in Fig. 4B. (B) Increased signaling along the brake pathway can inhibit dopaminergic neurons projecting to the cortex, thus leading to prefrontal hypodopaminergia. Note that reduced signaling along the brake pathway may also explain striatal hyperdopaminergia, whereas reduced signaling along the accelerator pathway may explain frontal hypodopaminergia. Circuit anatomy has been simplified from the model presented by Carlsson et al. (1999).

Please cite this article as: Dandash, O., et al., Dopamine, fronto-striato-thalamic circuits and risk for psychosis, Schizophr. Res. (2016), http:// dx.doi.org/10.1016/j.schres.2016.08.020

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parallel projections to inhibitory GABAergic cells in the midbrain that, when activated, inhibit dopamine release – the so-called ‘brake’ pathway (Fig. 3A). According to this dual-route model, striatal hyperdopaminergia could arise from increased signaling along the accelerator pathway, reduced signaling along the brake pathway, or both, within the nigrostriatal or mesolimbic systems (Fig. 3A). Similarly, frontal hypodopaminergia may arise from either reduced activity of the accelerator pathway or increased activity of the brake pathway (or both) within the mesocortical system (Fig. 3B). It is as yet unclear which system is affected in schizophrenia and in which way, or whether distinct pathologies result in the same phenotype. However, the dual-route model does identify abnormalities of prefrontal signaling – specifically an increase or decrease of excitatory outflow to midbrain dopaminergic or GABAergic neurons– as a primary driver of dopaminergic dysregulation in psychosis. Increased prefrontal outflow may be the more likely candidate, given evidence of GABAergic deficits in the prefrontal cortex of schizophrenia patients (Lewis et al., 2005; Lisman et al., 2008), and reports of hyperperfusion in the prefrontal cortex, midbrain and striatum of ARMS individuals (Allen et al., 2016). The dual-route model suggests that the effects of this increased cortical outflow on midbrain neurons will be particularly pronounced on dopaminergic cells projecting to the nigrostriatal and/or mesolimbic systems (accelerator pathway), and GABAergic cells regulating the activity of dopamine neurons that project to the cortex (brake pathway; Fig. 3). In vivo assessment of whether the accelerator or brake pathway is differentially involved in psychosis is challenging. However techniques for modelling directed, circuit-level interactions with fMRI, such as dynamic causal modelling (Friston et al., 2003, 2014), may prove informative when combined with spectroscopic measures. For example, pathology of the accelerator pathway should be associated with reduced prefrontal drive to the midbrain, coupled with increased levels of midbrain GABA and altered striatal dopamine. Indeed, animal studies suggest that preferential inhibition of excitatory prefrontal input on VTA GABAergic cells (accelerator) reduces dopamine release in the medial associative striatum in freely moving rats (Karreman and Moghaddam, 1996). Conversely, inhibiting VTA GABAergic neurons (brake) increases dopamine release in the ventral (limbic) striatum/nucleus accumbens (Ikemoto et al., 1997). A key prediction of the dual-route model is that dopamine release in the striatum will enhance sensory information flow through the thalamo-cortical pathway (Figs. 1 & 3A). This can occur through indirect and direct pathways (Fig. 4). First, midbrain dopaminergic cells can

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inhibit striatal GABAergic cells, which indirectly influence thalamic activity via the lateral (external) pallidum and subthalamic nucleus (Fig. 4A). This indirect pathway inhibits thalamic neurons, so dopaminergic inhibition of this pathway will upregulate thalamic activity. Second, midbrain dopaminergic neurons can excite striatal GABAergic cells that modulate the thalamus via a direct pathway through the medial (internal) pallidum (Fig. 4B). This direct pathway excites thalamic neurons, so midbrain dopaminergic cells are positioned to augment signaling along this route. The indirect and direct pathways provide distinct routes through which enhanced dopamine signaling can upregulate thalamic and cortical activity, and through which increased striatal outflow can overload cortical processing and predispose patients to psychotic symptoms (Carlsson et al., 1999). Consistent with this view, resting-state functional connectivity studies of both patients with chronic schizophrenia and ARMS individuals have shown that reduced functional connectivity in the dorsal fronto-striato-thalamic circuit is correlated with increased functional connectivity between the thalamus and somatosensory cortex (Anticevic et al., 2014, 2015; Woodward et al., 2012). In other words, a breakdown in communication between DLPFC, dorsal caudate and thalamus is accompanied by enhanced communication between the thalamus and somatosensory cortex, consistent with poor filtering of sensory information. Unfortunately, the correlational nature of resting-state analyses does not allow us to infer whether reduced dorsal circuit signaling is a cause or consequence of increased functional connectivity in the somatosensory system. We have thus far considered evidence that excess afferent outflow from prefrontal cortex causes a dysregulation of subcortical dopamine, but it is also possible that abnormal bottom-up signaling drives cortical dysfunction. A further complication is that striatal outflow can be modulated by several feedback projections from the cortex, thalamus and subthalamic nucleus (STN; Fig. 4). Pathology affecting any of these pathways can exacerbate circuit-level dysfunction in psychosis. In the following sections, we consider how disruptions in some of these key pathways may cause or contribute to dopaminergic dysfunction in psychosis. 3.2. The frontostriatal pathway In addition to the direct and indirect effects that frontal activity can have on dopaminergic release from the midbrain (i.e., the accelerator and brake pathways), cortical neurons send glutamatergic projections to striatal GABA cells, offering a route through which the cortex can

Fig. 4. Schematic depiction of the mechanisms through which dopamine can either inhibit or enhance striato-thalamic output via indirect and direct pathways, respectively. (A) The indirect, inhibitory pathway, where striatal outflow modulates thalamic activity via the pallidum and subthalamic nucleus. Another indirect pathway (not shown here) can inhibit thalamic neurons via the lateral pallidum and reticular nucleus of the thalamus. (B) The direct, excitatory pathway that passes through the internal segment of the pallidum while bypassing the external segment (B). Increased dopaminergic signaling can increase thalamic activity via both pathways. Modified from Carlsson et al. (1999).

Please cite this article as: Dandash, O., et al., Dopamine, fronto-striato-thalamic circuits and risk for psychosis, Schizophr. Res. (2016), http:// dx.doi.org/10.1016/j.schres.2016.08.020

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directly regulate striatal outflow (Fig. 3A). Cortical stimulation of striatal GABAergic neurons, particularly those implicated in the direct striatothalamic pathway, can upregulate thalamic activity whereas cortical projections to striatal GABAergic cells implicated in the indirect pathway can downregulate thalamic activity (Carlsson et al., 1999) (Fig. 4B). Magnetic resonance spectroscopy (MRS) has revealed increased glutamate in the associative (dorsal) striatum of ARMS and FEP individuals (de la Fuente-Sandoval et al., 2011), which would be consistent with excess afferent input from the cortex. Increased glutamate in this cohort was later shown to persist until after the onset of psychosis and was normalized after treatment with the dopamine antagonist risperidone (de la Fuente-Sandoval et al., 2013). The direct cortical projections to the striatum create an asymmetry in fronto-striatal connectivity: prefrontal cortex sends direct projections to the striatum, whereas the striatum communicates indirectly with the cortex via the pallidum and thalamus (Figs. 1, 3A and 4). This pattern of connectivity suggests that findings of reduced functional connectivity between the cortex and striatum in patients and at-risk populations (Dandash et al., 2014; Fornito et al., 2013) may be driven by deficient top-down cortical modulation of striatal activity. However, reduced prefrontal regulation of striatal activity on its own cannot explain why striatal dopamine is increased. Reduced frontostriatal functional connectivity may thus reflect a secondary consequence of dysfunction elsewhere in the system. An important yet unresolved question concerns how variations in signaling along certain neurochemical pathways relates to systemslevel functional connectivity. For example, does increased glutamate transmission from prefrontal cortex to striatum increase or decrease the functional connectivity between these regions? This relationship is likely to be circuit-dependent and contingent on how variations in specific neurotransmitters affect inter-regional coupling. Further empirical work addressing the link between neurotransmitter levels and circuitlevel function is required. 3.3. The thalamostriatal pathway The centromedian and parafasicular nuclei of the thalamus can directly modulate striatal outflow via glutamatergic projections that activate striatal GABAergic cells (Brown et al., 2010; Nanda et al., 2009) (Sadikot et al., 1992). Indeed, stimulating these thalamic nuclei can activate inhibitory striatal GABAergic neurons and subsequently reduce striatal output, possibly via the indirect striatothalamic pathway (Fig. 4A) (Nanda et al., 2009). In this way, thalamostriatal projections can act as “circuit-breakers” to dampen the flow of sensory information through the system. Notably, reduced functional connectivity between the thalamus and striatum, which would be consistent with deficient thalamic inhibition of striatal outflow, has been observed in chronic schizophrenia and ARMS individuals (Anticevic et al., 2015; Dandash et al., 2014). This result suggests that thalamic regulation of striatal activity may be apparent from the earliest signs of illness. Thalamic feedback can also modulate striatal and frontal dopamine transmission. Electrophysiological studies in anaesthetized rats have shown that stimulation of the parafasicular thalamic nucleus reduces prefrontal dopamine concentrations while increasing dorsal striatum dopamine turn over (Kilpatrick and Phillipson, 1986). Accordingly, removal of thalamic input to the striatum by lesioning the parafascicular thalamic nucleus in rats leads to increased D2 receptor availability in the caudate nucleus (Kilpatrick et al., 1986). Thalamic dysfunction may thus represent a potential upstream cause of dopamine dysregulation in the striatum and cortex of patients with psychosis. 3.4. Subthalamic modulation of striatal activity The subthalamic nucleus (STN) is yet another regulator of striatal output (Parent and Hazrati, 1995b). The STN receives extensive cortical input, particularly from the prefrontal cortex, and projects to GABAergic

cells in the pallidum (Fig. 4A) and substantia nigra, while also connecting to the striatum (Nauta and Cole, 1978). This profile of connectivity positions the STN to modulate the flow of information from the striatum to thalamus. Deep-brain stimulation of the STN can induce psychotic symptoms in Parkinson's Disease (PD) patients who had no prior history of psychosis (Herzog et al., 2003; Widge et al., 2013; Zonana et al., 2011), and PD patients experiencing psychotic symptoms following treatment with dopamine agonists show reductions in these symptoms after the STN is stimulated (Umemura et al., 2011). Increased functional connectivity between the dorsal caudate and STN has also been associated with lower levels of psychotic symptoms experienced by healthy individuals administered an acute dose of the psychotomimetic agent ketamine (Dandash et al., 2015). Interventions that enhance STN regulation over striatal activity may thus represent a viable treatment target in psychosis. 3.5. Altered bottom-up signaling as a primary pathology While deficient top-down modulation of dopamine release or striatal outflow may lead to psychosis onset, it is also possible that excess bottom-up signaling of subcortical systems represents a primary pathology with downstream consequences for cortical activity. In one study, transgenic mice overexpressing the dopamine D2 receptor gene in the striatum showed increased striatal dopamine levels and schizophrenia-like cognitive deficits that are typically ascribed to prefrontal dysfunction (Drew et al., 2007; Kellendonk et al., 2006). D2 receptor expression in this model was most pronounced in the dorsal striatum, and was associated with reduced dopamine turnover in the PFC (Kellendonk et al., 2006). The inability to reverse the effects of early D2 overexpression by silencing the transgene at birth suggests that cognitive deficits in schizophrenia may have their origins in the prenatal development of the dopaminergic system (Murray et al., 1991; Weinberger, 1987). Interestingly, the transgenic mice also showed increased metabolic activity in the primary motor and somatosensory cortices. This result is consistent with the hypothesis that dorsal circuit dysfunction may result in excess information flow within somatosensory systems. It is also consistent with empirical findings in human ARMS individuals and established patients showing that reduced functional connectivity in the dorsal system correlates with increased functional connectivity in somatosensory systems (Anticevic et al., 2014, 2015; Woodward et al., 2012). Together, these findings indicate that early dysregulation of subcortical dopamine signaling can have secondary effects on other components of fronto-striato-thalamic circuits, and that these effects parallel the changes seen in clinical populations. 3.6. The hippocampus The hippocampus is a key region that regulates the activity of midbrain dopaminergic neurons. One influential preclinical model of schizophrenia, in which methylazoxymethanol acetate (MAM) is administered to pregnant dams on gestational day 17, is characterized by increased excitatory outflow from the ventral hippocampus to nucleus accumbens, which in turn diminishes pallidal inhibition of dopamine neurons in the ventral tegmental area (Lodge and Grace, 2007, 2011). The model reproduces many neural and behavioural features associated with schizophrenia (for reviews see (Lodge and Grace, 2011; Modinos et al., 2015)). The model is also consistent with evidence that human ARMS individuals show hyperperfusion of the hippocampus, in addition to the midbrain, striatum and prefrontal cortex (Allen et al., 2016; Schobel et al., 2013). At first glance, the focus of this model on the nucleus accumbens and mesolimbic pathway seems to contradict the human imaging evidence for dopaminergic dysfunction and functional dysconnectivity of the dorsal fronto-striato-thalamic circuit (Dandash et al., 2014; Fornito et al., 2013; Howes et al., 2011b). However, the MAM model elicits increased firing of dopaminergic neurons in the lateral aspect of the VTA, a region

Please cite this article as: Dandash, O., et al., Dopamine, fronto-striato-thalamic circuits and risk for psychosis, Schizophr. Res. (2016), http:// dx.doi.org/10.1016/j.schres.2016.08.020

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that projects to the associative striatum (Lodge and Grace, 2012). This finding thus suggests a plausible mechanism through which dysregulation of hippocampal activity could, via its effect on the nucleus accumbens, lead to elevated dopamine transmission in the dorsal frontostriato-thalamic circuit. Consistent with this model, patients with first episode psychosis showing reduced dorsal circuit functional connectivity also show increased functional connectivity between the ventral striatum and hippocampus (Fornito et al., 2013). The same changes have not been observed in first-degree relatives (Fornito et al., 2013) or ARMS individuals (Dandash et al., 2014), suggesting that altered connectivity between the ventral striatum and hippocampus is either only apparent in people who actually develop illness, or that it only arises after the onset of a first psychotic episode. The latter would be consistent with evidence of progressive brain structural changes in ventral prefrontal and medial temporal regions during the transition to psychosis (Pantelis et al., 2005), and may reflect a pathophysiological switch that triggers the transition from an at-risk state to frank illness.

4. Treatment implications In this article, we have focused on the role of dopamine signaling and fronto-striato-thalamic systems in the genesis of psychotic symptoms. The link between increased dopamine and psychosis is well-known and, more than 60 years after the discovery of the first antipsychotic, treatments for schizophrenia are still based on dopamine receptor blockade and modulation (Kapur and Mamo, 2003). However, the side effects of these drugs are often poorly tolerated and compliance is a problem (Manschreck and Boshes, 2007). The latest wave of imaging findings has enhanced our understanding of circuit-level dysfunction in psychotic disorders and identified the dorsal fronto-striato-thalamic system as a critical pathophysiological system. Viewing these findings through the lens of the dual-route model of cortical regulation over dopamine (Carlsson et al., 1997, 1999), we see that disruption of several different feedback and feedforward interactions could plausibly lead to the systems-level changes that are seen in psychotic patients. It will be important to determine which specific dysfunctions in this circuit are either necessary or sufficient to trigger psychosis onset, to understand whether distinct pathologies lead to different clinical phenotypes, and to characterize the treatment implications of these variations. Indeed, not all patients show elevated striatal dopamine, with recent evidence indicating that the increases are only apparent in treatment-responsive but not treatment-resistant patients (Demjaha et al., 2012). Other work suggests that glutamatergic signaling may be particularly dysfunctional in the latter patient group (Demjaha et al., 2014; Mouchlianitis et al., 2016). These findings support calls to split patients with psychotic illness into a subgroup characterized by striatal hyperdopaminergia and another subgroup with apparently normal subcortical dopamine function (Howes and Kapur, 2014). Although further work is required to characterize such subtypes, these data point to a biological rationale for the tailored treatment of distinct patient groups based on neurobiological data (Clementz et al., 2016). Beyond these broad designations, understanding the neural circuit abnormalities that underlie psychotic symptoms can facilitate the identification of more refined treatments. The discussion above suggests several plausible targets. For example, modulating STN regulation of striatal activity may be efficacious, given the evidence that deep-brain stimulation of the STN reduces psychotic symptoms in patients with Parkinson's disease (Umemura et al., 2011) and that increased functional connectivity between the dorsal caudate and STN correlates with fewer psychotic symptoms in healthy volunteers administered ketamine (Dandash et al., 2015). Deep brain stimulation of the ventral hippocampus has also been shown to normalize dopamine dysregulation and behavioural deficits in the MAM model of schizophrenia (Perez et al., 2013). However, surgical treatment of

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psychosis poses ethical challenges and requires further evidence to justify its application. In the shorter term, non-invasive brain stimulation techniques may prove useful in ameliorating circuit-level dysfunction. Prefrontal cortex is easily accessible with techniques such as transcranial magnetic stimulation (TMS), which has shown some clinical efficacy in the treatment of the negative and cognitive symptoms of schizophrenia (Cole et al., 2015), albeit with some inconsistent findings (Dougall et al., 2015). This inconsistency may partly reflect the lack of a principled method for determining a stimulation target. Functional connectivity is showing potential in this regard – several studies have shown that cortical stimulation with TMS exerts downstream effects on connected subcortical structures (Chou et al., 2015; Fox et al., 2012a,b), and that the clinical efficacy of TMS across a wide range of disorders is largely determined by whether the selected stimulation site is connected to subcortical areas implicated in the pathophysiology of that disease (Fox et al., 2014). Intervention protocols guided by a detailed knowledge of pathophysiological circuitry may enhance the therapeutic efficacy of non-invasive brain stimulation. In the case of psychosis, prefrontal regions that are strongly connected to the associative striatum represent prime candidates. Contributors Author contribution: where the authors were involved as first authors OD, AF, and CP had full access to the data in the studies mentioned in the review and take responsibility for the integrity of the data and the accuracy of the data analysis. Review concept and design: OD & AF. Data search, analysis, or interpretation of data: all. Drafting of the manuscript: OD. Critical revision of the manuscript for important intellectual content: all. Statistical analysis: OD & AF. Administrative, technical, or material support: all.

Role of the funding source CP was supported by a National Health and Medical Research Council (NHMRC) Senior Principal Research Fellowship (628386 & 1105825). AF was supported by NHMRC Project grants (3251213 and 3251250) and by the Australian Research Council (ID: FT130100589). Conflict of interest The authors declare no conflict of interest.

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