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Circuit-based approaches to understanding corticostriatothalamic dysfunction across the psychosis continuum

  • Kristina Sabaroedin
    Correspondence
    Corresponding author: Kristina Sabaroedin, , University of Calgary, 3300 Hospital Drive NW, Calgary, AB, T2N 4N1, Canada
    Affiliations
    Departments of Radiology and Paediatrics, Hotchkiss Brain Institute and Alberta Children’s Hospital Research Institute, University of Calgary, Calgary, AB, Canada
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  • Jeggan Tiego
    Affiliations
    Turner Institute for Brain and Mental Health, School of Psychological Sciences and Monash Biomedical Imaging, Monash University, Clayton, VIC, Australia
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  • Alex Fornito
    Affiliations
    Turner Institute for Brain and Mental Health, School of Psychological Sciences and Monash Biomedical Imaging, Monash University, Clayton, VIC, Australia
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Open AccessPublished:August 07, 2022DOI:https://doi.org/10.1016/j.biopsych.2022.07.017

      Abstract

      Dopamine is known to play a role in the pathogenesis of psychotic symptoms, but the mechanisms driving dopaminergic dysfunction in psychosis remain unclear. Considerable attention has focused on the role of corticostriatothalamic (CST) circuits, given that they regulate, and are modulated by, the activity of dopaminergic cells in the midbrain. Preclinical studies have proposed multiple models of CST dysfunction in psychosis, each prioritizing different brain regions and pathophysiological mechanisms. A particular challenge is that CST circuits have undergone considerable evolutionary modification from the rodent to primate and human brains, complicating comparisons across species. Here, we consider preclinical models of CST dysfunction in psychosis and evaluate the degree to which they are supported by evidence from human resting-state fMRI studies conducted across the psychosis continuum, ranging from subclinical schizotypy to established schizophrenia. In partial support of some preclinical models, human studies indicate that dorsal CST and hippocampal-striatal functional dysconnectivity are apparent across the psychosis spectrum and may represent a vulnerability marker for psychosis. In contrast, midbrain dysfunction may emerge when symptoms warrant clinical assistance and may thus be a trigger for illness onset. The major difference between clinical and preclinical findings is the strong involvement of the dorsal CST in the former, consistent with an increasing prominence of this circuitry in the primate brain. We close by underscoring the need for high-resolution characterization of phenotypic heterogeneity in psychosis to develop a refined understanding of how dysfunction of specific circuit elements gives rise to distinct symptom profiles.

      Keywords

      The symptoms of psychosis are proposed to lie on a continuum of severity (
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      Models of schizotypy: the importance of conceptual clarity.
      ), with the subclinical expression of schizotypal traits and transient psychosis-like experiences at one end (
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      Evidence for instrument and family-specific variation of subclinical psychosis dimensions in the general population.
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      Genetics, cognition, and neurobiology of schizotypal personality: a review of the overlap with schizophrenia.
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      Prevalence of Psychotic Disorder and Community Level of Psychotic Symptoms.
      ) and clinically diagnosed psychotic disorders such as schizophrenia at the other. Interposed between these extremes lie various levels of symptom expression that include prodromal or at-risk mental states (ARMS) (
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      ) and first-episode psychosis (FEP), which is commonly operationalized as the period of first treatment contact following symptom onset (
      • Breitborde N.J.K.
      • Srihari V.H.
      • Woods S.W.
      Review of the operational definition for first-episode psychosis.
      ). Each incremental level of severity across the continuum is associated with an increased risk of developing a more severe form of illness (
      • Upthegrove R.
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      ).
      Since seminal discoveries over half a century ago that dopamine antagonists are effective in treating psychotic symptoms (
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      ,
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      ), extensive evidence has supported a central role for dopamine, and the corticostriatothalamic (CST) systems that regulate its release, in the pathogenesis of psychosis (
      • Carlsson A.
      • Waters N.
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      Neurotransmitter interactions in schizophrenia-therapeutic implications.
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      • Kapur S.
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      ,
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      • McGuire P.
      • Borgwardt S.
      Mapping prodromal psychosis: A critical review of neuroimaging studies.
      ). Different models of CST and dopamine dysregulation in psychosis have been proposed. Many of these models are based on preclinical studies and vary in the degree to which different circuit elements are emphasized as primary sites of dysfunction. In parallel, advances in circuit mapping techniques with non-invasive neuroimaging have progressed our understanding of CST disruptions in patients at different illness stages. Here, we review this work in relation to existing preclinical models of CST dysfunction, with the aim of identifying continuities and discontinuities between these models and the human literature. We focus principally on classical models of the dorsal and ventral CST circuits (
      • Carlsson A.
      • Waters N.
      • Carlsson M.
      Neurotransmitter interactions in schizophrenia-therapeutic implications.
      ,
      • Grace A.A.
      Dysregulation of the dopamine system in the pathophysiology of schizophrenia and depression.
      ,
      • Weinberger D.R.
      Implications of Normal Brain Development for the Pathogenesis of Schizophrenia.
      ,
      • Modinos G.
      • Allen P.
      • Grace A.A.
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      Translating the MAM model of psychosis to humans.
      ,
      • Maia T.V.
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      ,
      • Lipska B.K.
      • Weinberger D.R.
      A neurodevelopmental model of schizophrenia: Neonatal disconnection of the hippocampus.
      ) due to their central role in dopamine regulation and extensive characterizations of these circuits by past work, which have been central to pathophysiological models of psychosis. Other systems also likely play an important role in symptom expression (e.g., Andreasen & Pierson, 2008; Horga & Abi-Dargham, 2019; Schmack et al., 2021) but they have not been subjected to the same degree of translational investigation. We also focus on findings from human resting-state fMRI, which has become the most popular method for studying CST dysconnectivity in psychosis. We examine findings across different stages of the psychosis continuum to understand how CST dysfunction might evolve across different illness stages. We close by emphasizing the need for high-resolution phenotyping of the psychosis spectrum to better understand the individual clinical and neurobiological heterogeneity that characterizes symptom expression along the continuum. We begin with a brief description of CST circuit anatomy and function.

      Corticostriatothalamic circuitry and dopamine function

      CST circuitry is classically divided into five parallel, integrated circuits that topographically link the striatum with the prefrontal cortex (PFC) along a rostroventral-to-dorsocaudal gradient, which each circuit subserving a specific set of functions (
      • Alexander G.E.
      • DeLong M.R.
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      Parallel organization of functionally segregated circuits linking basal ganglia and cortex.
      ,
      • Marquand A.F.
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      Functional corticostriatal connection topographies predict goal-directed behaviour in humans.
      ,
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      ,
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      Evidence for segregated and integrative connectivity patterns in the human basal ganglia.
      ,
      • Haber S.N.
      The primate basal ganglia: Parallel and integrative networks.
      ). These prefrontal systems are accompanied by additional CST circuits connecting to early and associative sensory cortices, and the cerebellum (
      • Foster N.N.
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      ).
      Two CST circuits that are frequently implicated in psychosis are the ventral ‘limbic’ and dorsal ‘associative’ circuits. The ventral circuit links the ventral region of the striatum, including the nucleus accumbens, with PFC regions subserving emotion function and regulation, such as the ventromedial PFC (VMPFC) and orbitofrontal cortex (OFC) (
      • Alexander G.E.
      • DeLong M.R.
      • Strick P.L.
      Parallel organization of functionally segregated circuits linking basal ganglia and cortex.
      ,
      • Haber S.N.
      Corticostriatal circuitry.
      ,
      • Haber S.N.
      The primate basal ganglia: Parallel and integrative networks.
      ). The ventral striatum also has extensive connections to the hippocampus and amygdala (
      • Haber S.N.
      • Fudge J.L.
      The interface between dopamine neurons and the amygdala: Implications for schizophrenia.
      ,
      • Grace A.A.
      Dysregulation of the dopamine system in the pathophysiology of schizophrenia and depression.
      ,
      • Lodge D.J.
      • Grace A.A.
      The hippocampus modulates dopamine neuron responsivity by regulating the intensity of phasic neuron activation.
      ,
      • Harrison O.K.
      • Guell X.
      • Klein-flügge M.C.
      • Barry R.L.
      Structural and resting state functional connectivity beyond the cortex.
      ,
      • Kahn I.
      • Shohamy D.
      Intrinsic connectivity between the hippocampus, nucleus accumbens, and ventral tegmental area in humans.
      ,
      • Chang C.H.
      • Grace A.A.
      Amygdala-ventral pallidum pathway decreases dopamine activity after chronic mild stress in rats.
      ). The dorsal circuit links the dorsolateral PFC (DLPFC) with the dorsal caudate and putamen, and plays a role in information integration and associative learning (
      • Alexander G.E.
      • DeLong M.R.
      • Strick P.L.
      Parallel organization of functionally segregated circuits linking basal ganglia and cortex.
      ,
      • Haber S.N.
      The primate basal ganglia: Parallel and integrative networks.
      ,
      • Balleine B.W.
      • Delgado M.R.
      • Hikosaka O.
      The role of the dorsal striatum in reward and decision-making.
      ,
      • Graybiel A.M.
      The basal ganglia and chunking of action repertoires.
      ). Interposed between the dorsal and ventral systems is the anterior cingulate cortex (ACC) circuit, which links reward and affective valuation with executive cognition, and projections from this cortical area terminate at the intersection of the ventral and dorsal striatum (
      • Haber S.N.
      Corticostriatal circuitry.
      ,
      • Shenhav A.
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      • Botvinick M.M.
      Dorsal anterior cingulate cortex and the value of control.
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      • Bush G.
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      ,
      • Bush G.
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      Dorsal anterior cingulate cortex: A role in reward-based decision making.
      ). Each striatal sub-region then projects back to the cortex via the pallidum and thalamus, forming a series of closed corticostriatal feedback loops (
      • Haber S.N.
      • McFarland N.R.
      The place of the thalamus in frontal cortical-basal ganglia circuits.
      ,
      • Sherman S.M.
      Thalamus plays a central role in ongoing cortical functioning.
      ).
      Dopamine neurons in the midbrain project diffusely throughout the striatum and cortex via the mesolimbic, nigrostriatal, and mesocortical pathways, respectively (
      • Haber S.N.
      • Fudge J.L.
      • McFarland N.R.
      Striatonigrostriatal pathways in primates form an ascending spiral from the shell to the dorsolateral striatum.
      ,
      • Hurd Y.L.
      • Hall H.
      Chapter IX Human forebrain dopamine systems: Characterization of the normal brain and in relation to psychiatric disorders.
      ,
      • Thierry A.M.
      • Tassin J.P.
      • Blanc G.
      • Glowinski J.
      Selective activation of the mesocortical DA system by stress.
      ). At baseline, or during normal contexts, dopamine neurons exhibit tonic, spontaneous firing driven by membrane currents of dopamine neurons that are regulated by inhibitory projections from the striatum (
      • Grace A.A.
      • Bunney B.S.
      The control of firing pattern in nigral dopamine neurons: single spike firing.
      ,
      • Grace A.A.
      • Bunney B.S.
      Opposing effects of striatonigral feedback pathways on midbrain dopamine cell activity.
      ). Classical views of dopamine function posit that in salient contexts, such as the presentation of an unexpected reward, dopamine neurons switch to phasic activity, characterised by transient, high amplitude, burst firing, which is integral to reinforcement learning (
      • Floresco S.B.
      • West A.R.
      • Ash B.
      • Moorel H.
      • Grace A.A.
      Afferent modulation of dopamine neuron firing differentially regulates tonic and phasic dopamine transmission.
      ,
      • Grace A.A.
      Phasic versus tonic dopamine release and the modulation of dopamine system responsivity: A hypothesis for the etiology of schizophrenia.
      ). In addition to this form of prediction error signalling, dopamine neurons also play essential roles in the maintenance of internal states, value computation, action selection, and motivation, with each behavior associated with the firing of specific, spatially clustered neurons within the midbrain and striatum (
      • Cox J.
      • Witten I.B.
      Striatal circuits for reward learning and decision-making.
      ,
      • Engelhard B.
      • Finkelstein J.
      • Cox J.
      • Fleming W.
      • Jang H.J.
      • Ornelas S.
      • et al.
      Specialized coding of sensory, motor and cognitive variables in VTA dopamine neurons.
      ,
      • Schultz W.
      • Apicella P.
      • Ljungberg T.
      Responses of monkey dopamine neurons to reward and conditioned stimuli during successive steps of learning a delayed response task.
      ). Only tonically active neurons can switch to phasic firing; as such, cortical and medial temporal areas can govern the responsivity of the dopamine system through the striatum (
      • Grace A.A.
      Phasic versus tonic dopamine release and the modulation of dopamine system responsivity: A hypothesis for the etiology of schizophrenia.
      ) and through direct projections to the midbrain. The latter control midbrain activity via two opposing mechanisms: one that increases the likelihood of dopamine release through direct glutamatergic input to dopaminergic neurons (
      • Karreman M.
      • Moghaddam B.
      The prefrontal cortex regulates the basal release of dopamine in the limbic striatum: An effect mediated by ventral tegmental area.
      ) and another that inhibits dopaminergic cells via glutamatergic synapses onto γ-aminobutyric acid (GABA) cells in the midbrain (
      • Carlsson A.
      • Waters N.
      • Carlsson M.
      Neurotransmitter interactions in schizophrenia-therapeutic implications.
      ). These two mechanisms respectively act like an accelerator and brake on dopamine neurons, ensuring the appropriate regulation of dopamine release (
      • Carlsson A.
      • Waters N.
      • Carlsson M.
      Neurotransmitter interactions in schizophrenia-therapeutic implications.
      ,
      • Dandash O.
      • Pantelis C.
      • Fornito A.
      Dopamine, fronto-striato-thalamic circuits and risk for psychosis.
      ).
      The striatum is positioned between the cortex and the midbrain and is therefore regulated by glutamatergic cortical and thalamic projections in addition to dopaminergic afferents from the midbrain (
      • Surmeier D.J.
      • Ding J.
      • Day M.
      • Wang Z.
      • Shen W.
      D1 and D2 dopamine-receptor modulation of striatal glutamatergic signaling in striatal medium spiny neurons.
      ,
      • Nicola S.M.
      • James Surmeier D.
      • Malenka R.C.
      Dopaminergic modulation of neuronal excitability in the striatum and nucleus accumbens.
      ). The ventral striatum also receives inputs from the hippocampus and the amygdala, and these regions, in turn, regulate pallidal inhibition of midbrain neurons (
      • Lodge D.J.
      • Grace A.A.
      Hippocampal dysregulation of dopamine system function and the pathophysiology of schizophrenia.
      ,
      • Lodge D.J.
      • Grace A.A.
      Aberrant hippocampal activity underlies the dopamine dysregulation in an animal model of schizophrenia.
      ). Midbrain dopaminergic afferents control information flow from the striatum to the thalamus by modulating the activity of striatal GABAergic medium spiny neurons, which constitute approximately 95% of neurons in the striatum (
      • Carlsson A.
      • Waters N.
      • Carlsson M.
      Neurotransmitter interactions in schizophrenia-therapeutic implications.
      ,
      • Surmeier D.J.
      • Ding J.
      • Day M.
      • Wang Z.
      • Shen W.
      D1 and D2 dopamine-receptor modulation of striatal glutamatergic signaling in striatal medium spiny neurons.
      ,
      • Kemp J.M.
      • Powell T.P.S.
      The structure of the caudate nucleus of the cat: light and electron microscopy.
      ). These ascending striatothalamic pathways are classified into the D1-receptor-mediated direct pathway and D2-receptor-mediated indirect pathway; the former relays signals from the striatum to the internal segment of the pallidum before terminating in the thalamus, while striatal outputs of the latter inhibit the internal pallidum indirectly via the external segment of the pallidum and subthalamic nucleus, suppressing information transmission to the thalamus (
      • Gerfen C.R.
      • Surmeier D.J.
      Modulation of Striatal Projection Systems by Dopamine.
      ,
      • Keeler J.F.
      • Pretsell D.O.
      • Robbins T.W.
      Functional implications of dopamine D1 vs. D2 receptors: A “prepare and select” model of the striatal direct vs. indirect pathways.
      ). The balance of activity in direct and indirect pathways is modulated by dopamine and is thought to subserve learning, action selection, and value computation (
      • Maia T.V.
      • Frank M.J.
      An Integrative Perspective on the Role of Dopamine in Schizophrenia.
      ,
      • Cox J.
      • Witten I.B.
      Striatal circuits for reward learning and decision-making.
      ). An overview of key aspects of dorsal and ventral CST connectivity is presented in Figure 1.
      Figure thumbnail gr1
      Figure 1An overview of the dorsal and ventral CST connections identified by tract-tracing and neuroimaging studies. The blue to pink colouring represents a gradient of function that spans cognitive (blue) and emotional (pink) function. Circles at the ends of a line represent bi-directional connectivity. A single circle represents a directed connection. Note that this anatomical model is largely derived from tract-tracing studies in rodents and primates and the underlying circuit in humans may vary somewhat. OFC: orbitofrontal cortex; MPFC: medial prefrontal cortex; ACC: anterior cingulate cortex; DLPFC: dorsolateral prefrontal cortex; Thal: thalamus; Pulv: pulvinar; MG: medial geniculate body; LG: lateral geniculate body; MD: mediodorsal nucleus; LP: lateral posterior nucleus; VP: ventral posterior nucleus; LD: lateral dorsal nucleus; VL: ventral lateral nucleus; VA: ventral anterior nucleus; Ant: anterior thalamus; Hipp: hippocampus; Sub: subiculum; CA1, CA2, CA3, CA4: cornu ammonis hippocampal subfields; DG: dentate gyrus; Amyg: amygdala; CeN: central amygdala; CoN: cortical nuclei Lat: lateral amygdala; Bas: basal amygdala: Aux Bas: auxiliary basal; Stri: striatum; Pu: putamen; Cd: caudate; Dors: dorsal; Vent: ventral; NAcc: nucleus accumbens; Pall: pallidum; GPe: globus pallidus external; GPi: globus pallidus internal; STN: subthalamic nucleus; VTA: ventral tegmental area; SN: substantia nigra.

      Preclinical models of CST dysfunction

      CST circuitry influences, and is influenced by, dopamine release. Dopamine dysregulation is therefore intimately linked to CST dysfunction in psychosis (
      • Carlsson A.
      • Waters N.
      • Carlsson M.
      Neurotransmitter interactions in schizophrenia-therapeutic implications.
      ,
      • Fusar-Poli P.
      • Howes O.D.
      • Allen P.
      • Broome M.
      • Valli I.
      • Asselin M.
      Abnormal frontostriatal interactions in people with prodromal signs of psychosis: a multimodal imaging study.
      ,
      • Allen P.
      • Luigjes J.
      • Howes O.D.
      • Egerton A.
      • Hirao K.
      • Valli I.
      • et al.
      Transition to psychosis associated with prefrontal and subcortical dysfunction in ultra high-risk individuals.
      ). Leading preclinical models of psychosis, based on a detailed delineation of the circuit mechanisms regulating dopamine release and their impact on psychosis-like behaviors in animals, have highlighted a role for deficient cortical-subcortical control, either from the cortex or medial temporal areas, particularly the hippocampus, over midbrain dopaminergic cells (
      • Weinberger D.R.
      Implications of Normal Brain Development for the Pathogenesis of Schizophrenia.
      ,
      • Lodge D.J.
      • Grace A.A.
      Hippocampal dysregulation of dopamine system function and the pathophysiology of schizophrenia.
      ). In fact, these proposed mechanisms are not mutually exclusive but are likely to interact as part of an extended network. For instance, PFC dysfunction is thought to be central to the pathophysiology of psychosis because this area reaches full maturity during the period of peak risk for psychosis onset (
      • Weinberger D.R.
      Implications of Normal Brain Development for the Pathogenesis of Schizophrenia.
      ), PFC dysfunction is prominent in patients with psychosis (
      • Fusar-Poli P.
      • Perez J.
      • Broome M.
      • Borgwardt S.
      • Placentino A.
      • Caverzasi E.
      • et al.
      Neurofunctional correlates of vulnerability to psychosis : A systematic review and meta-analysis.
      ), and lesions of the DLPFC impair working memory performance in adolescent monkeys compared to younger groups (
      • Goldman P.S.
      • Alexander G.E.
      Maturation of prefrontal cortex in the monkey revealed by local reversible cryogenic depression.
      ). Medial prefrontal lesions in rats lead to diminished PFC dopamine, increased dopamine concentration and uptake in the nucleus accumbens and the striatum, up-regulation of post-synaptic dopamine receptors in the VTA, and hyperactivity, suggesting a disinhibition of dopamine release in the striatum (
      • Weinberger D.R.
      Implications of Normal Brain Development for the Pathogenesis of Schizophrenia.
      ,
      • Bertolino A.
      • Knable M.B.
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      • Callicott J.H.
      • Kolachana B.
      • Mattay V.S.
      • et al.
      The relationship between dorsolateral prefrontal N-acetylaspartate measures and striatal dopamine activity in schizophrenia.
      ,
      • Pycock C.J.
      • Kerwin R.W.
      • Carter C.J.
      Effect of lesion of cortical dopamine terminals on subcortical dopamine receptors in rats.
      ). This abnormally elevated dopaminergic activity in the striatum is thought to imbue innocuous stimuli with inappropriate salience, triggering psychosis onset (
      • Schmack K.
      • Bosc M.
      • Ott T.
      • Sturgill J.F.
      • Kepecs A.
      Striatal dopamine mediates hallucination-like perception in mice.
      ,
      • Cassidy C.M.
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      • Daw N.D.
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      A perceptual inference mechanism for hallucinations linked to striatal dopamine.
      ,
      • Corlett P.R.
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      ). Notably, neonatal excitotoxic lesions of the ventral hippocampus in rats also elicit PFC-related working memory deficits and compromise the integrity of PFC neurons once the rats reach adolescence (
      • Lipska B.K.
      • Aultman J.M.
      • Verma A.
      • Weinberger D.R.
      • Moghaddam B.
      Neonatal damage of the ventral hippocampus impairs working memory in the rat.
      ,
      • Bertolino A.
      • Roffman J.L.
      • Lipska B.K.
      • Van Gelderen P.
      • Olson A.
      • Weinberger D.R.
      Reduced N-acetylaspartate in prefrontal cortex of adult rats with neonatal hippocampal damage.
      ).
      Together, these findings suggest that an early medial temporal lesion may disrupt subsequent maturation of the PFC, which in turn dysregulates subcortical dopamine transmission (
      • Weinberger D.R.
      Implications of Normal Brain Development for the Pathogenesis of Schizophrenia.
      ,
      • Knable M.B.
      • Weinberger D.R.
      Dopamine, the prefrontal cortex and schizophrenia.
      ). However, other factors can trigger PFC dysfunction. Psychosocial stress and early life adversity, known risk factors for psychosis (
      • Mccutcheon R.A.
      • Bloomfield M.
      • Dahoun T.
      • Mehta M.
      • Howes O.D.
      Chronic psychosocial stressors are associated with alterations in salience processing and corticostriatal connectivity.
      ,
      • Howes O.D.
      • McCutcheon R.
      • Owen M.J.
      • Murray R.M.
      The Role of Genes, Stress, and Dopamine in the Development of Schizophrenia.
      ), can compromise PFC function, increase dopamine release, and increase dopamine metabolite levels in genetically high-risk individuals (
      • Kasanova Z.
      • Hernaus D.
      • Vaessen T.
      • Van Amelsvoort T.
      • Winz O.
      • Heinzel A.
      • et al.
      Early-life stress affects stress-related prefrontal dopamine activity in healthy adults, but not in individuals with psychotic disorder.
      ,
      • McEwen B.S.
      • Morrison J.H.
      The Brain on Stress: Vulnerability and Plasticity of the Prefrontal Cortex over the Life Course.
      ,
      • Brunelin J.
      • d’Amato T.
      • van Os J.
      • Cochet A.
      • Suaud-Chagny M.F.
      • Saoud M.
      Effects of acute metabolic stress on the dopaminergic and pituitary-adrenal axis activity in patients with schizophrenia, their unaffected siblings and controls.
      ). Convergent evidence from preclinical models and human post-mortem findings indicates that hypofunction of N-methyl-D-aspartate (NMDA) receptors on cortical GABA neurons, which is thought to disinhibit cortical pyramidal cells, augments the activity of glutamatergic projections to the midbrain and ultimately disinhibits dopamine activity (
      • Lisman J.E.
      • Coyle J.T.
      • Green R.W.
      • Javitt D.C.
      • Benes F.M.
      • Heckers S.
      • Grace A.A.
      Circuit-based framework for understanding neurotransmitter and risk gene interactions in schizophrenia.
      ,
      • Lewis D.A.
      • Hashimoto T.
      • Volk D.W.
      Cortical inhibitory neurons and schizophrenia.
      ). Pharmacological studies in rodents demonstrate that administration of either ketamine or phencyclidine (PCP), both of which act on NMDA receptors, produce schizophrenia-like behaviors in rodents such as sensorimotor gating disruptions, cognitive deficits, and social impairments (
      • Egerton A.
      • Reid L.
      • McKerchar C.E.
      • Morris B.J.
      • Pratt J.A.
      Impairment in perceptual attentional set-shifting following PCP administration: A rodent model of set-shifting deficits in schizophrenia.
      ,
      • Morris B.J.
      • Cochran S.M.
      • Pratt J.A.
      PCP: From pharmacology to modelling schizophrenia.
      ,
      • Cordon I.
      • Nicolás M.J.
      • Arrieta S.
      • Lopetegui E.
      • López-Azcárate J.
      • Alegre M.
      • et al.
      Coupling in the cortico-basal ganglia circuit is aberrant in the ketamine model of schizophrenia.
      ,
      • Hauser M.J.
      • Isbrandt D.
      • Roeper J.
      Disturbances of novel object exploration and recognition in a chronic ketamine mouse model of schizophrenia.
      ). Acute administration of PCP can trigger dopamine release in the nucleus accumbens and medial PFC in rats (
      • Adams B.
      • Moghaddam B.
      Corticolimbic dopamine neurotransmission is temporally dissociated from the cognitive and locomotor effects of phencyclidine.
      ,
      • Yonezawa Y.
      • Kuroki T.
      • Kawahara T.
      • Tashiro N.
      • Uchimura H.
      Involvement of γ-aminobutyric acid neurotransmission in phencyclidine-induced dopamine release in the medial prefrontal cortex.
      ), whereas chronic administration in monkeys induces poor response inhibition and reduced dopamine signalling in the DLPFC (
      • Jentsch J.D.
      • Redmond D.E.
      • Elsworth J.D.
      • Taylor J.R.
      • Youngren K.D.
      • Roth R.H.
      Enduring cognitive deficits and cortical dopamine dysfunction in monkeys after long-term administration of phencyclidine.
      ).
      Medial temporal and subcortical structures can also directly trigger dysregulation of midbrain neurons. The hippocampus and the amygdala exert opposing effects on the VTA; specifically, the VTA is inhibited by the amygdala and disinhibited by the ventral hippocampus (
      • Patton M.H.
      • Bizup B.T.
      • Grace A.A.
      The infralimbic cortex bidirectionally modulates mesolimbic dopamine neuron activity via distinct neural pathways.
      ). Hyperactivity of the hippocampus leads to augmented dopaminergic cell activity in the midbrain (
      • Lisman J.E.
      • Coyle J.T.
      • Green R.W.
      • Javitt D.C.
      • Benes F.M.
      • Heckers S.
      • Grace A.A.
      Circuit-based framework for understanding neurotransmitter and risk gene interactions in schizophrenia.
      ,
      • Boley A.M.
      • Perez S.M.
      • Lodge D.J.
      A fundamental role for hippocampal parvalbumin in the dopamine hyperfunction associated with schizophrenia.
      ) and ventral hippocampal lesions sustained after birth (
      • Lipska B.K.
      • Jaskiw G.E.
      • Weinberger D.R.
      Postpubertal emergence of hyperresponsiveness to stress and to amphetamine after neonatal excitotoxic hippocampal damage: A potential animal model of schizophrenia.
      ) lead to behavior consistent with schizophrenia symptoms in adolescence, including impaired social interaction (
      • Sams-Dodd F.
      • Lipska B.K.
      • Weinberger D.R.
      Neonatal lesions in the rat ventral hippocampus result in hyperlocomotion and deficits in social behaviour in adulthood.
      ) and spatial learning (
      • Chambers R.A.
      • Moore J.
      • McEvoy J.P.
      • Levin E.D.
      Cognitive effects of neonatal hippocampal lesions in a rat model of schizophrenia.
      ), along with symptoms of dopamine hyperactivity such as impaired sensorimotor gating (
      • Lipska B.K.
      • Weinberger D.R.
      • Swerdlow N.R.
      • Geyer M.A.
      • Braff D.L.
      • Jaskiw G.E.
      Neonatal excitotoxic hippocampal damage in rats causes post-pubertal changes in prepulse inhibition of startle and its disruption by apomorphine.
      ) and enhanced sensitivity to dopamine agonism (
      • Lipska B.K.
      • Weinberger D.R.
      Delayed effects of neonatal hippocampal damage on haloperidol-induced catalepsy and apomorphine-induced stereotypic behaviors in the rat.
      ,
      • Beninger R.J.
      • Tuerke K.J.
      • Forsyth J.K.
      • Giles A.
      • Xue L.
      • Boegman R.J.
      • Jhamandas K.
      Neonatal ventral hippocampal lesions in male and female rats: Effects on water maze, locomotor activity, plus-maze and prefrontal cortical GABA and glutamate release in adulthood.
      ). One prominent developmental model, in which pregnant rats are treated with the neurotoxin methylazoxymethanol (MAM), leads to hyperactivity of the ventral subiculum in the hippocampus of offspring during adolescence, which releases inhibitory control of the striatum over the midbrain and elicits psychosis-like behaviors such as augmented amphetamine-induced locomotion (
      • Lodge D.J.
      • Grace A.A.
      Hippocampal dysregulation of dopamine system function and the pathophysiology of schizophrenia.
      ,
      • Lodge D.J.
      • Grace A.A.
      Aberrant hippocampal activity underlies the dopamine dysregulation in an animal model of schizophrenia.
      ). Hippocampal hyperactivity in this model is proposed to arise from the loss of parvalbumin-containing GABA-ergic interneurons in the hippocampus as well alterations in glutamate metabolism (
      • Grace A.A.
      Dysregulation of the dopamine system in the pathophysiology of schizophrenia and depression.
      ,
      • Kraguljac N.V.
      • White D.M.
      • Reid M.A.
      • Lahti A.C.
      Increased hippocampal glutamate and volumetric deficits in unmedicated patients with schizophrenia.
      ,
      • Stone J.M.
      • Howes O.D.
      • Egerton A.
      • Kambeitz J.
      • Allen P.
      • Lythgoe D.J.
      • et al.
      Altered relationship between hippocampal glutamate levels and striatal dopamine function in subjects at ultra high risk of psychosis.
      ,
      • Lodge D.J.
      • Behrens M.M.
      • Grace A.A.
      A loss of parvalbumin-containing interneurons is associated with diminished oscillatory activity in an animal model of schizophrenia.
      ). Hyperactivity of the hippocampus also interferes with the segregated activity of discrete hippocampal subfields, which is thought to give rise to positive and disorganized dimensions of psychosis symptomatology (
      • Olypher A.V.
      • Klement D.
      • Fenton A.A.
      Cognitive disorganization in hippocampus: A physiological model of the disorganization in psychosis.
      ). Activity of midline thalamic neurons can also trigger firing of dopaminergic cells in the VTA indirectly through their effect on the ventral subiculum of the hippocampus (
      • Zimmerman E.C.
      • Grace A.A.
      The nucleus reuniens of the midline thalamus gates prefrontal-hippocampal modulation of ventral tegmental area dopamine neuron activity.
      ). Dysregulation of dopamine can affect striatothalamic signalling along both direct and indirect pathways. An imbalance of these striatothalamic pathways is thought to compromise striatal filtering of extraneous stimuli and elicit psychotic symptoms (
      • Carlsson A.
      • Waters N.
      • Carlsson M.
      Neurotransmitter interactions in schizophrenia-therapeutic implications.
      ,
      • Maia T.V.
      • Frank M.J.
      An Integrative Perspective on the Role of Dopamine in Schizophrenia.
      ,
      • Carlsson M.
      • Carlsson A.
      Interactions between glutamatergic and monoaminergic systems within the basal ganglia-implications for schizophrenia and Parkinson’s disease.
      ).
      Together, preclinical models suggest that dopamine dysregulation can arise from deficient cortical or medial temporal regulation of midbrain neuronal activity, but whether cortical or hippocampal deficits are primary remains unclear. It is well-known that early hippocampal lesions can lead to prefrontal deficits that only emerge in adolescence (
      • Beninger R.J.
      • Tuerke K.J.
      • Forsyth J.K.
      • Giles A.
      • Xue L.
      • Boegman R.J.
      • Jhamandas K.
      Neonatal ventral hippocampal lesions in male and female rats: Effects on water maze, locomotor activity, plus-maze and prefrontal cortical GABA and glutamate release in adulthood.
      ,
      • Lipska B.K.
      Using animal models to test a neurodevelopmental hypothesis of schizophrenia.
      ). Administration of PCP in the ventral hippocampus increases spontaneous discharge of PFC neurons whereas administration of NMDA antagonists in the PFC has not produced similar effects (
      • Jodo E.
      • Suzuki Y.
      • Katayama T.
      • Hoshino H.-Y.
      • Takeuchi S.
      • Niwa S.-I.
      • Kayama Y.
      Activation of medial prefrontal cortex by phencyclidine is mediated via a hippocampo-prefrontal pathway.
      ), suggesting that the hippocampus may be a primary site. However, the finding that the gene coding for the DRD2 receptor, which is strongly expressed in the striatum, contains a genome-wide risk variant for schizophrenia, challenges the idea that deficient regulation from medial temporal or higher cortical areas is a primary pathophysiological mechanism (
      • Ripke S.
      • Neale B.M.
      • Corvin A.
      • Walters J.T.R.
      • Farh K.H.
      • Holmans P.A.
      • et al.
      Biological insights from 108 schizophrenia-associated genetic loci.
      ). In mice, overexpression of D2 receptors in the striatum increases cortical D1 receptor sensitivity (potentially due to reduced PFC dopamine) and induces working memory deficits (
      • Kellendonk C.
      • Simpson E.H.
      • Polan H.J.
      • Malleret G.
      • Vronskaya S.
      • Winiger V.
      • et al.
      Transient and selective overexpression of dopamine D2 receptors in the striatum causes persistent abnormalities in prefrontal cortex functioning.
      ,
      • Abi-Dargham A.
      • Moore H.
      Prefrontal DA transmission at D1 receptors and the pathology of schizophrenia.
      ). Such findings suggest that subcortical deficits may also play a primary role in symptom onset.

      Evidence of CST dysconnectivity in human neuroimaging studies

      One caveat of preclinical rodent models is that homologies with primates, particularly within CST circuitry, are often limited, which hampers our ability to extrapolate these models to humans (
      • Balsters J.H.
      • Zerbi V.
      • Sallet J.
      • Wenderoth N.
      • Mars R.B.
      Primate homologs of mouse cortico-striatal circuits.
      ). For instance, tract-tracing in non-human primates indicates that midbrain afferents primarily come from the striatum, with prefrontal neurons only sparsely projecting to either the VTA and substantia nigra (
      • Frankle W.G.
      • Laruelle M.
      • Haber S.N.
      Prefrontal cortical projections to the midbrain in primates: Evidence for a sparse connection.
      ,
      • Haber S.N.
      • Knutson B.
      The reward circuit: linking primate anatomy and human imaging.
      ), suggesting that direct cortical control over dopamine release may not be as pervasive as in rodents. Preclinical models place a considerable emphasis on the ventral CST circuit, and hippocampal regulation of the midbrain through the nucleus accumbens in particular (
      • Lodge D.J.
      • Grace A.A.
      The hippocampus modulates dopamine neuron responsivity by regulating the intensity of phasic neuron activation.
      ). In rodents, dopaminergic afferents to the ventral striatum originate in the VTA but they emanate from the dorsal tier of the substantia nigra in primates (
      • Joel D.
      • Weiner I.
      The connections of the dopaminergic system with the striatum in rats and primates: An analysis with respect to the functional and compartmental organization of the striatum.
      ). Moreover, the ventral striatum and VTA are proportionally smaller in primates compared to rodents, and dorsal areas of the caudate and putamen that support executive functioning, social processing and language, have not been found in rodents (
      • Joel D.
      • Weiner I.
      The connections of the dopaminergic system with the striatum in rats and primates: An analysis with respect to the functional and compartmental organization of the striatum.
      ,

      Balsters JH, Zerbi V, Wenderoth N, Mars RB, Hospital JR (2019): Primate homologs of mouse cortico- striatal circuits. 44.

      ,
      • Pauli W.M.
      • O’Reilly R.C.
      • Yarkoni T.
      • Wager T.D.
      Regional specialization within the human striatum for diverse psychological functions.
      ). Accordingly, the dorsal striatum of primates receives more prominent dopaminergic innervation than the ventral striatum, suggesting that the effects of dopaminergic dysregulation may be more pronounced in the dorsal CST of primates (
      • Haber S.N.
      • Fudge J.L.
      • McFarland N.R.
      Striatonigrostriatal pathways in primates form an ascending spiral from the shell to the dorsolateral striatum.
      ). Indeed, molecular imaging in humans indicates that dopamine is released at different levels within specific functional subdivisions of the striatum (
      • Martinez D.
      • Slifstein M.
      • Broft A.
      • Mawlawi O.
      • Chatterjee R.
      • Hwang D.
      • et al.
      Imaging Human Mesolimbic Dopamine Transmission With Positron Emission Tomography. Part II: Amphetamine-Induced Dopamine Release in the Functional Subdivisions of the Striatum.
      ). Moreover, some features of CST circuitry appear unique to humans. For instance, caudate regions receiving afferents from lateral PFC subserve higher order functions unique to human behavior, such as language and complex social cognition, and humans show more extensive connectivity of the limbic CST with frontal and temporal cortices (
      • Balsters J.H.
      • Zerbi V.
      • Sallet J.
      • Wenderoth N.
      • Mars R.B.
      Primate homologs of mouse cortico-striatal circuits.
      ,
      • Folloni D.
      • Sallet J.
      • Khrapitchev A.A.
      • Sibson N.
      • Verhagen L.
      • Mars R.B.
      Dichotomous organization of amygdala/temporal-prefrontal bundles in both humans and monkeys.
      ).
      In line with more prominent dopaminergic innervation of the dorsal striatum in humans, positron emission tomography (PET) studies have found evidence for prominent dopamine dysfunction in the dorsal striatum of both clinically high-risk and antipsychotic-naïve schizophrenia patients, measured through either dopamine depletion or stress-induced dopamine release paradigms (
      • Kegeles L.S.
      • Abi-Dargham A.
      • Frankle W.G.
      • Gil R.
      • Cooper T.B.
      • Slifstein M.
      • et al.
      Increased synaptic dopamine function in associative regions of the striatum in schizophrenia.
      ,
      • Mizrahi R.
      • Addington J.
      • Rusjan P.M.
      • Suridjan I.
      • Ng A.
      • Boileau I.
      • et al.
      Increased stress-induced dopamine release in psychosis.
      ). Such findings challenge the mesolimbic, ventral CST focus of preclinical models and suggest that the dorsal CST may play a more prominent role in disease pathophysiology. Of particular note, positron emission tomography (PET) studies using the tracer L-3,4-Dihydroxy-6-[18F]fluorophenylalanine (18F-DOPA) have consistently reported increased dopamine synthesis capacity in the dorsal striatum of ARMS and other high-risk individuals, particularly those who later transition to psychosis (
      • Kegeles L.S.
      • Abi-Dargham A.
      • Frankle W.G.
      • Gil R.
      • Cooper T.B.
      • Slifstein M.
      • et al.
      Increased synaptic dopamine function in associative regions of the striatum in schizophrenia.
      ,
      • Howes O.D.
      • Bose S.K.
      • Turkheimer F.
      • Valli I.
      • Egerton A.
      • Valmaggia L.R.
      • et al.
      Dopamine Synthesis Capacity Before Onset of Psychosis: A Prospective [18F]-DOPA PET Imaging Study.
      ,
      • Howes O.D.
      • Montgomery A.J.
      • Asselin M.C.
      • Murray R.M.
      • Valli I.
      • Tabraham P.
      • et al.
      Elevated striatal dopamine function linked to prodromal signs of schizophenia.
      ,
      • McCutcheon R.A.
      • Merritt K.
      • Howes O.D.
      Dopamine and glutamate in individuals at high risk for psychosis: a meta‐analysis of in vivo imaging findings and their variability compared to controls.
      ,
      • Egerton A.
      • Howes O.D.
      • Houle S.
      • McKenzie K.
      • Valmaggia L.R.
      • Bagby M.R.
      • et al.
      Elevated striatal dopamine function in immigrants and their children: a risk mechanism for psychosis.
      ). Increased 18F-DOPA in the ventral striatum has been reported (
      • McGowan S.
      • Lawrence A.D.
      • Sales T.
      • Quested D.
      • Grasby P.
      Presynaptic Dopaminergic Dysfunction in Schizophrenia.
      ), but the findings have been less consistent (
      • McCutcheon R.
      • Beck K.
      • Jauhar S.
      • Howes O.D.
      Defining the locus of dopaminergic dysfunction in schizophrenia: A meta-analysis and test of the mesolimbic hypothesis.
      ).
      These PET findings align with fMRI studies, particularly those examining patterns of coupled spontaneous fluctuations of the blood-oxygenation-level dependent (BOLD) signal––so-called resting-state functional connectivity (FC) (
      • Fornito A.
      • Bullmore E.T.
      What can spontaneous fluctuations of the blood oxygenation-level-dependent signal tell us about psychiatric disorders?.
      ,
      • Biswal B.B.
      • Yetkin
      • Zerin F.
      • Haughton V.M.
      • Hyde J.S.
      Functional connectivity in the motor cortex of restinf human brain using echo-planar MRI.
      ,
      • Fox M.D.
      • Raichle M.E.
      Spontaneous fluctuations in brain activity observed with functional magnetic resonance imaging.
      ). A summary of FC findings reported in the literature at different stages of the psychosis continuum is provided in Figure 2 (see also Tables S1-4). Although direct comparison across these various studies and illness stages is complicated by numerous factors (see Supplementary Information), the Figure offers a heuristic summary of general trends reported in the literature. We discuss four particularly noteworthy trends in the following.
      Figure thumbnail gr2
      Figure 2A summary of dorsal and ventral CST dysconnectivity across the psychosis continuum. Affected connections were identified in studies investigating resting-state functional connectivity of corticostriatal circuits, which were found using a PubMed search using keywords that include either ‘psychosis’, ‘schizophrenia’, ‘schizotypy’, ‘psychosis-like experiences’ and ‘functional connectivity,’ and one of each of the listed brain regions within the dorsal and ventral CST systems, yielding a total of 74 studies (see Supplementary Information for further details of the studies and selection process). The top row depicts FC differences identified in non-clinical samples with subthreshold, schizotypal traits and/or psychosis-like experiences and at-risk groups that include ARMS individuals and first-degree relatives of patients. The bottom row maps connections identified as different in first-episode psychosis and established schizophrenia cohort. Blue lines depict connections within the dorsal circuit whereas pink lines are connections within the ventral circuit. Dotted lines depict reduced FC, whereas solid lines depict increased FC. We draw an edge if at least one study has found a difference in FC between the corresponding pair of regions; as such, the figure does not encode quantitative information about the robustness of a given result across the literature (see Supplementary Information for a more detailed discussion of this issue). The polarity of the FC difference (i.e., increased or decreased in patients) in this figure is determined by the effect reported in the majority of studies finding a difference at that particular connection. Note that the anatomical precision of fMRI studies is often lower than that used to describe CST anatomy (e.g., ) due to resolution limits of the technique (∼2-3 mm3) and preprocessing strategies employed (e.g., spatial smoothing). OFC: orbitofrontal cortex; MPFC: medial prefrontal cortex; ACC: anterior cingulate cortex; VLPFC: ventrolateral prefrontal cortex; DLPFC: dorsolateral prefrontal cortex; Thal: thalamus; Hipp: hippocampus; Amyg: amygdala; Stri: striatum; Pu: putamen; Cd: caudate; Dors: dorsal; Vent: ventral; NAcc: nucleus accumbens; VTA: ventral tegmental area; SN: substantia nigra.
      One robust trend in the fMRI literature is that reduced FC of the dorsal CST circuit is found across the psychosis continuum (Figure 3), consistent with preclinical models supporting a primary role for PFC dysregulation of subcortical areas. Multiple studies have reported reduced FC between the dorsal striatum and ACC and DLPFC in non-clinical individuals with psychosis-like experiences, as well as ARMS individuals, healthy first-degree relatives of schizophrenia patients, affective and non-affective first-episode psychosis cohorts, and chronic schizophrenia patients (
      • Sabaroedin K.
      • Tiego J.
      • Parkes L.
      • Sforazzini F.
      • Finlay A.
      • Johnson B.
      • et al.
      Functional connectivity of corticostriatal circuitry and psychosis-like experiences in the general community.
      ,
      • Pani S.M.
      • Sabaroedin K.
      • Tiego J.
      • Bellgrove M.A.
      • Fornito A.
      A multivariate analysis of the association between corticostriatal functional connectivity and psychosis-like experiences in the general community.
      ,
      • Waltmann M.
      • O’Daly O.
      • Egerton A.
      • McMullen K.
      • Kumari V.
      • Barker G.J.
      • et al.
      Multi-echo fMRI, resting-state connectivity, and high psychometric schizotypy.
      ,
      • Wang L ling
      • Sun X.
      • Chiu C De
      • Leung P.W.L.
      • Chan R.C.K.
      • So S.H.W.
      Altered cortico-striatal functional connectivity in people with high levels of schizotypy: A longitudinal resting-state study.
      ,
      • Fornito A.
      • Harrison B.J.
      • Goodby E.
      • Dean A.
      • Ooi C.
      • Nathan P.J.
      • et al.
      Functional dysconnectivity of corticostriatal circuitry as a risk phenotype for psychosis.
      ,
      • Oh S.
      • Kim M.
      • Kim T.
      • Lee T.Y.
      • Kwon J.S.
      Resting-state functional connectivity of the striatum predicts improvement in negative symptoms and general functioning in patients with first-episode psychosis: A 1-year naturalistic follow-up study.
      ,
      • Peters H.
      • Riedl V.
      • Manoliu A.
      • Scherr M.
      • Schwerthoffer D.
      • Zimmer C.
      • et al.
      Changes in extra-striatal functional connectivity in patients with schizophrenia in a psychotic episode.
      ,
      • Zhou Y.
      • Liang M.
      • Jiang T.
      • Tian L.
      • Liu Y.
      • Liu Z.
      • et al.
      Functional dysconnectivity of the dorsolateral prefrontal cortex in first-episode schizophrenia using resting-state fMRI.
      ,
      • Li P.
      • Jing R.X.
      • Zhao R.J.
      • Shi L.
      • Sun H.Q.
      • Ding Z.
      • et al.
      Association between functional and structural connectivity of the corticostriatal network in people with schizophrenia and unaffected first-degree relatives.
      ,
      • Viher P.V.
      • Docx L.
      • Van Hecke W.
      • Parizel P.M.
      • Sabbe B.
      • Federspiel A.
      • et al.
      Aberrant fronto-striatal connectivity and fine motor function in schizophrenia.
      ,
      • Chechko N.
      • Cieslik E.C.
      • Müller V.I.
      • Nickl-Jockschat T.
      • Derntl B.
      • Kogler L.
      • et al.
      Differential resting-state connectivity patterns of the right anterior and posterior dorsolateral prefrontal cortices (DLPFC) in Schizophrenia.
      ,
      • Dandash O.
      • Fornito A.
      • Lee J.
      • Keefe R.S.E.
      • Chee M.W.L.
      • Adcock R.A.
      • et al.
      Altered striatal functional connectivity in subjects with an at-risk mental state for psychosis.
      ). Reduced FC between the thalamus (mapped by seeding either the whole thalamus or dorsomedial, ventral, or anterior regions) and various striatal and prefrontal regions has also been consistently found in clinically significant stages of illness, from the ARMS to established schizophrenia (
      • Dandash O.
      • Fornito A.
      • Lee J.
      • Keefe R.S.E.
      • Chee M.W.L.
      • Adcock R.A.
      • et al.
      Altered striatal functional connectivity in subjects with an at-risk mental state for psychosis.
      ,
      • Martino M.
      • Magioncalda P.
      • Yu H.
      • Li X.
      • Wang Q.
      • Meng Y.
      • et al.
      Abnormal resting-state connectivity in a substantia nigra-related striato-thalamo-cortical network in a large sample of first-episode drug-naïve patients with schizophrenia.
      ,
      • Anticevic A.
      • Cole M.W.
      • Repovs G.
      • Murray J.D.
      • Brumbaugh M.S.
      • Winkler A.M.
      • et al.
      Characterizing thalamo-cortical disturbances in schizophrenia and bipolar illness.
      ,
      • Anticevic A.
      • Yang G.
      • Savic A.
      • Murray J.D.
      • Cole M.W.
      • Repovs G.
      • et al.
      Mediodorsal and visual thalamic connectivity differ in schizophrenia and bipolar disorder with and without psychosis history.
      ,
      • Wang Y.
      • Yan C.
      • Yin D.Z.
      • Fan M.X.
      • Cheung E.F.C.
      • Pantelis C.
      • Chan R.C.K.
      Neurobiological changes of schizotypy: Evidence from both volume-based morphometric analysis and resting-state functional connectivity.
      ,
      • Woodward N.D.
      • Karbasforoushan H.
      • Heckers S.
      Thalamocortical dysconnectivity in schizophrenia.
      ,
      • Woodward N.D.
      • Heckers S.
      Mapping thalamocortical functional connectivity in chronic and early stages of psychotic disorders.
      ,
      • Zhou Y.
      • Liang M.
      • Jiang T.
      • Tian L.
      • Liu Y.
      • Liu Z.
      • et al.
      Functional dysconnectivity of the dorsolateral prefrontal cortex in first-episode schizophrenia using resting-state fMRI.
      ).
      Figure thumbnail gr3
      Figure 3Consistency of results obtained in studies of dorsal CST functional connectivity across the psychosis spectrum, using seed-based analysis of the dorsal caudate. The coronal slice on the left shows the location of the dorsal caudate (DC) seed region used in these studies. The cortical surface map on the right depicts the area of dorsolateral prefrontal cortex where seed-related functional connectivity correlates with subthreshold psychosis traits in healthy people from a community sample (
      • Pani S.M.
      • Sabaroedin K.
      • Tiego J.
      • Bellgrove M.A.
      • Fornito A.
      A multivariate analysis of the association between corticostriatal functional connectivity and psychosis-like experiences in the general community.
      ), together with prefrontal areas implicated in work conducted in patients with non-affective first-episode psychosis and their healthy first-degree relatives (
      • Fornito A.
      • Harrison B.J.
      • Goodby E.
      • Dean A.
      • Ooi C.
      • Nathan P.J.
      • et al.
      Functional dysconnectivity of corticostriatal circuitry as a risk phenotype for psychosis.
      ), ARMS individuals (
      • Dandash O.
      • Fornito A.
      • Lee J.
      • Keefe R.S.E.
      • Chee M.W.L.
      • Adcock R.A.
      • et al.
      Altered striatal functional connectivity in subjects with an at-risk mental state for psychosis.
      ), and first-episode mania patients with psychosis (
      • Dandash O.
      • Yücel M.
      • Daglas R.
      • Pantelis C.
      • McGorry P.
      • Berk M.
      • Fornito A.
      Differential effect of quetiapine and lithium on functional connectivity of the striatum in first episode mania.
      ). The map of positive symptoms denotes regions associated with positive symptom severity in first-episode psychosis patients (
      • Fornito A.
      • Harrison B.J.
      • Goodby E.
      • Dean A.
      • Ooi C.
      • Nathan P.J.
      • et al.
      Functional dysconnectivity of corticostriatal circuitry as a risk phenotype for psychosis.
      ). Figure reproduced from Pani et al. (2021), with permission.
      A second trend in Figure 2 is that lower FC between the hippocampus, when either seeding the whole structure or just the anterior hippocampus, and striatum has also been reported across all stages, with the ventral striatum being involved consistently when symptom severity triggers help-seeking behavior (i.e., from ARMS individuals to chronic patients) (
      • Waltmann M.
      • O’Daly O.
      • Egerton A.
      • McMullen K.
      • Kumari V.
      • Barker G.J.
      • et al.
      Multi-echo fMRI, resting-state connectivity, and high psychometric schizotypy.
      ,
      • Edmiston E.K.
      • Song Y.
      • Chang M.
      • Yin Z.
      • Zhou Q.
      • Zhou Y.
      • et al.
      Hippocampal Resting State Functional Connectivity in Patients With Schizophrenia and Unaffected Family Members.
      ,
      • Gregory D.F.
      • Rothrock J.M.
      • Jalbrzikowski M.
      • Foran W.
      • Montez D.F.
      • Luna B.
      • Murty V.P.
      Increased functional coupling between VTA and hippocampus during rest in first-episode psychosis.
      ,
      • Kozhuharova P.
      • Saviola F.
      • Diaconescu A.
      • Allen P.
      High schizotypy traits are associated with reduced hippocampal resting state functional connectivity.
      ,
      • Sarpal D.K.
      • Robinson D.G.
      • Lencz T.
      • Argyelan M.
      • Ikuta T.
      • Karlsgodt K.
      • et al.
      Antipsychotic treatment and functional connectivity of the striatum in first-episode schizophrenia.
      ,
      • Hadley J.A.
      • Nenert R.
      • Kraguljac N.V.
      • Bolding M.S.
      • White D.M.
      • Skidmore F.M.
      • et al.
      Ventral tegmental area/midbrain functional connectivity and response to antipsychotic medication in schizophrenia.
      ,
      • Gradin V.B.
      • Waiter G.
      • O’Connor A.
      • Romaniuk L.
      • Stickle C.
      • Matthews K.
      • et al.
      Salience network-midbrain dysconnectivity and blunted reward signals in schizophrenia.
      ). A third trend in Figure 2 is that dysconnectivity of the midbrain has been reported only in at-risk and clinical cohorts, with little involvement in subclinical psychosis (
      • Martino M.
      • Magioncalda P.
      • Yu H.
      • Li X.
      • Wang Q.
      • Meng Y.
      • et al.
      Abnormal resting-state connectivity in a substantia nigra-related striato-thalamo-cortical network in a large sample of first-episode drug-naïve patients with schizophrenia.
      ,
      • Gregory D.F.
      • Rothrock J.M.
      • Jalbrzikowski M.
      • Foran W.
      • Montez D.F.
      • Luna B.
      • Murty V.P.
      Increased functional coupling between VTA and hippocampus during rest in first-episode psychosis.
      ,
      • Hadley J.A.
      • Nenert R.
      • Kraguljac N.V.
      • Bolding M.S.
      • White D.M.
      • Skidmore F.M.
      • et al.
      Ventral tegmental area/midbrain functional connectivity and response to antipsychotic medication in schizophrenia.
      ,
      • Gradin V.B.
      • Waiter G.
      • O’Connor A.
      • Romaniuk L.
      • Stickle C.
      • Matthews K.
      • et al.
      Salience network-midbrain dysconnectivity and blunted reward signals in schizophrenia.
      ,
      • White T.P.
      • Wigton R.
      • Joyce D.W.
      • Collier T.
      • Fornito A.
      • Shergill S.S.
      Dysfunctional Striatal Systems in Treatment-Resistant Schizophrenia.
      ,
      • Giordano G.M.
      • Stanziano M.
      • Papa M.
      • Mucci A.
      • Prinster A.
      • Soricelli A.
      • Galderisi S.
      Functional connectivity of the ventral tegmental area and avolition in subjects with schizophrenia: a resting state functional MRI study.
      ,
      • Gangadin S.S.
      • Cahn W.
      • Scheewe T.W.
      • Hulshoff Pol H.E.
      • Bossong M.G.
      Reduced resting state functional connectivity in the hippocampus-midbrain-striatum network of schizophrenia patients.
      ,
      • Anticevic A.
      • Tang Y.
      • Cho Y.T.
      • Repovs G.
      • Cole M.W.
      • Savic A.
      • et al.
      Amygdala connectivity differs among chronic, early course, and individuals at risk for developing schizophrenia.
      ). This trend suggests that midbrain dysfunction may be a trait marker of genetic risk and/or clinically significant symptoms. Accordingly, PET studies have not found evidence for elevated striatal 18F-DOPA in healthy people with subthreshold psychosis symptoms or in ARMS individuals that do not transition to psychosis (
      • McCutcheon R.A.
      • Merritt K.
      • Howes O.D.
      Dopamine and glutamate in individuals at high risk for psychosis: a meta‐analysis of in vivo imaging findings and their variability compared to controls.
      ,
      • Howes O.D.
      • Shotbolt P.
      • Bloomfield M.
      • Daalman K.
      • Demjaha A.
      • Diederen K.M.J.
      • et al.
      Dopaminergic function in the psychosis spectrum: An [18F]-DOPA imaging study in healthy individuals with auditory hallucinations.
      ,
      • Howes O.D.
      • Bose S.
      • Turkheimer F.
      • Valli I.
      • Egerton A.
      • Stahl D.
      • et al.
      Progressive increase in striatal dopamine synthesis capacity as patients develop psychosis: a PET study.
      ). Thus, the fMRI and PET findings converge to indicate that dysregulation of midbrain dopaminergic afferents to the striatum is closely linked to the emergence of clinically significant symptoms. Critically however, elevated dopamine in the dorsal striatum has not been identified in patients that do not respond to antipsychotic treatment and healthy people with hallucinations, suggesting that treatment-resistant patients and schizotypal personalities may represent pathophysiologically distinct subtypes within the psychosis continuum (
      • Jauhar S.
      • Veronese M.
      • Nour M.M.
      • Rogdaki M.
      • Hathway P.
      • Turkheimer F.E.
      • et al.
      Determinants of treatment response in first-episode psychosis: an 18F-DOPA PET study.
      ,
      • Howes O.D.
      • Kapur S.
      A neurobiological hypothesis for the classification of schizophrenia: Type a (hyperdopaminergic) and type b (normodopaminergic).
      ,
      • Howes O.D.
      • Shotbolt P.
      • Bloomfield M.
      • Daalman K.
      • Demjaha A.
      • Diederen K.M.J.
      • et al.
      Dopaminergic function in the psychosis spectrum: An [18F]-DOPA imaging study in healthy individuals with auditory hallucinations.
      ).
      Taken together, these findings indicate that lower dorsal CST and hippocampal-striatal FC may represent a trait-like vulnerability marker for psychosis. In line with this view, delusional ideation is thought to arise from aberrant dopamine signaling in the dorsal striatum, which influences striatothalamic gating mechanisms (
      • Maia T.V.
      • Frank M.J.
      An Integrative Perspective on the Role of Dopamine in Schizophrenia.
      ,
      • Carlsson M.
      • Carlsson A.
      Interactions between glutamatergic and monoaminergic systems within the basal ganglia-implications for schizophrenia and Parkinson’s disease.
      ) and the prefrontal and striatal functions that subserve associative and executive functions (
      • McCutcheon R.A.
      • Abi-Dargham A.
      • Howes O.D.
      Schizophrenia, Dopamine and the Striatum: From Biology to Symptoms.
      ,
      • Corlett P.R.
      • Taylor J.R.
      • Wang X.J.
      • Fletcher P.C.
      • Krystal J.H.
      Toward a neurobiology of delusions.
      ). Indeed, the dorsal striatum plays a critical role in action valuation and habit formation, offering a plausible mechanism through which certain trains of thought may be consolidated into rigid and persistent beliefs (
      • Pauli W.M.
      • O’Reilly R.C.
      • Yarkoni T.
      • Wager T.D.
      Regional specialization within the human striatum for diverse psychological functions.
      ,
      • McCutcheon R.A.
      • Abi-Dargham A.
      • Howes O.D.
      Schizophrenia, Dopamine and the Striatum: From Biology to Symptoms.
      ,
      • Malvaez M.
      • Wassum K.M.
      Regulation of habit formation in the dorsal striatum.
      ,
      • Yin H.H.
      • Knowlton B.J.
      • Balleine B.W.
      Lesions of dorsolateral striatum preserve outcome expectancy but disrupt habit formation in instrumental learning.
      ). Reduced coupling between the hippocampus and striatum may reflect diminished regulation of the former region over the latter, as predicted by preclinical models (
      • Lodge D.J.
      • Grace A.A.
      Hippocampal dysregulation of dopamine system function and the pathophysiology of schizophrenia.
      ,
      • Lodge D.J.
      • Grace A.A.
      Aberrant hippocampal activity underlies the dopamine dysregulation in an animal model of schizophrenia.
      ), and may sensitize striatal neurons to dopaminergic transmission. Symptoms may only reach clinical severity once there is a dysregulation of dopaminergic transmission from midbrain to striatum, which can be detected with fMRI as altered FC between these regions.
      A fourth trend evident in Figure 2 is that reduced FC in CST circuitry is a common finding across all illness stages, with the reductions being particularly widespread in schizophrenia (
      • Peters H.
      • Riedl V.
      • Manoliu A.
      • Scherr M.
      • Schwerthoffer D.
      • Zimmer C.
      • et al.
      Changes in extra-striatal functional connectivity in patients with schizophrenia in a psychotic episode.
      ,
      • Anticevic A.
      • Cole M.W.
      • Repovs G.
      • Murray J.D.
      • Brumbaugh M.S.
      • Winkler A.M.
      • et al.
      Characterizing thalamo-cortical disturbances in schizophrenia and bipolar illness.
      ,
      • Woodward N.D.
      • Karbasforoushan H.
      • Heckers S.
      Thalamocortical dysconnectivity in schizophrenia.
      ,
      • Fryer S.L.
      • Ferri J.M.
      • Roach B.J.
      • Loewy R.L.
      • Stuart B.K.
      • Anticevic A.
      • et al.
      Thalamic dysconnectivity in the psychosis risk syndrome and early illness schizophrenia.
      ). There is some evidence for increased FC within the ventral circuitry across clinically significant stages of illness (i.e., at-risk, first-episode and established schizophrenia) and while the specific circuit elements affected vary across stages, the amygdala is consistently involved in these increases (
      • Liu H.
      • Tang Y.
      • Womer F.
      • Fan G.
      • Lu T.
      • Driesen N.
      • et al.
      Differentiating patterns of amygdala-frontal functional connectivity in schizophrenia and bipolar disorder.
      ,
      • Tian L.
      • Meng C.
      • Yan H.
      • Zhao Q.
      • Liu Q.
      • Yan J.
      • et al.
      Convergent evidence from multimodal imaging reveals amygdala abnormalities in schizophrenic patients and their first-degree relatives.
      ,
      • Kim W.S.
      • Shen G.
      • Liu C.
      • Kang N.I.
      • Lee K.H.
      • Sui J.
      • Chung Y.C.
      Altered amygdala-based functional connectivity in individuals with attenuated psychosis syndrome and first-episode schizophrenia.
      ,
      • Jalbrzikowski M.
      • Murty V.P.
      • Tervo-Clemmens B.
      • Foran W.
      • Luna B.
      Age-associated deviations of amygdala functional connectivity in youths with psychosis spectrum disorders: Relevance to psychotic symptoms.
      ). This evidence of selective FC increases coupled with widespread FC reductions aligns with prior reports that consistent FC increases within specific neural systems, such as between sensorimotor corticothalamic circuits (
      • Anticevic A.
      • Cole M.W.
      • Repovs G.
      • Murray J.D.
      • Brumbaugh M.S.
      • Winkler A.M.
      • et al.
      Characterizing thalamo-cortical disturbances in schizophrenia and bipolar illness.
      ,
      • Woodward N.D.
      • Heckers S.
      Mapping thalamocortical functional connectivity in chronic and early stages of psychotic disorders.
      ,
      • Avram M.
      • Brandl F.
      • Bäuml J.
      • Sorg C.
      Cortico-thalamic hypo- and hyperconnectivity extend consistently to basal ganglia in schizophrenia.
      ), may occur against a backdrop of globally reduced FC in patients (
      • Fornito A.
      • Zalesky A.
      • Pantelis C.
      • Bullmore E.T.
      Schizophrenia, neuroimaging and connectomics.
      ). Clinical differences of the patient cohorts studied in different investigations are also likely to play a role. For instance, the dominant trend for widespread reductions of FC in patients with established illness may either reflect the natural progression of the illness or the effects of prolonged exposure to medication, which can be difficult to disentangle (
      • Chopra S.
      • Francey S.M.
      • O’Donoghue B.
      • Sabaroedin K.
      • Arnatkeviciute A.
      • Cropley V.
      • et al.
      Functional Connectivity in Antipsychotic-Treated and Antipsychotic-Naive Patients With First-Episode Psychosis and Low Risk of Self-harm or Aggression.
      ,
      • Chopra S.
      • Fornito A.
      • Francey S.M.
      • O’Donoghue B.
      • Cropley V.
      • Nelson B.
      • et al.
      Differentiating the effect of antipsychotic medication and illness on brain volume reductions in first-episode psychosis: A Longitudinal, Randomised, Triple-blind, Placebo-controlled MRI Study.
      ,
      • Navari S.
      • Dazzan P.
      Do antipsychotic drugs affect brain structure? A systematic and critical review of MRI findings.
      ).
      Preclinical work indicates that persistent elevations of midbrain activity, arising from chronic stress or drug administration, are dampened by regulatory feedback from the amygdala (
      • Chang C.H.
      • Grace A.A.
      Amygdala-ventral pallidum pathway decreases dopamine activity after chronic mild stress in rats.
      ,
      • Belujon P.
      • Jakobowski N.L.
      • Dollish H.K.
      • Grace A.A.
      Withdrawal from Acute Amphetamine Induces an Amygdala-Driven Attenuation of Dopamine Neuron Activity: Reversal by Ketamine.
      ). One might therefore expect that amygdala dysconnectivity should emerge later in the illness, as a response to ongoing dopamine dysfunction. Patients with established schizophrenia do show widespread amygdala dysconnectivity (
      • Anticevic A.
      • Tang Y.
      • Cho Y.T.
      • Repovs G.
      • Cole M.W.
      • Savic A.
      • et al.
      Amygdala connectivity differs among chronic, early course, and individuals at risk for developing schizophrenia.
      ,
      • Jalbrzikowski M.
      • Murty V.P.
      • Tervo-Clemmens B.
      • Foran W.
      • Luna B.
      Age-associated deviations of amygdala functional connectivity in youths with psychosis spectrum disorders: Relevance to psychotic symptoms.
      ), while amygdala-related FC changes in FEP appear to be more circumscribed (Figure 2). Cortico-amygdala dysconnectivity has been implicated in both schizotypy and at-risk individuals, with the latter also showing prominent dysconnectivity between amygdala and subcortical areas, including the midbrain (Figure 2A-B). The amygdala is involved in fear, paranoia, and emotion regulation (
      • Corlett P.R.
      • Taylor J.R.
      • Wang X.J.
      • Fletcher P.C.
      • Krystal J.H.
      Toward a neurobiology of delusions.
      ), and shows aberrant reactivity to threat and adverse environments in cohorts that are at an increased risk of psychosis (
      • McCutcheon R.
      • Bloomfield M.A.P.
      • Dahoun T.
      • Quinlan M.
      • Terbeck S.
      • Mehta M.
      • Howes O.
      Amygdala reactivity in ethnic minorities and its relationship to the social environment: an fMRI study.
      ), suggesting that this region may influence psychosis liability.
      A particular limitation of FC studies is that they cannot identify primary sites of pathology or disentangle the relative influence of cortical-subcortical vs subcortical-cortical signals. This is because FC is often quantified as a correlation between fMRI signals recorded in two or more regions; therefore, it cannot resolve the directionality of influences between areas and is susceptible to differences in regional to signal-to-noise ratio (
      • Friston K.J.
      Functional and Effective Connectivity: A Review.
      ). Thus, while the consistent identification of disrupted dorsal CST and hippocampal-striatal FC across the psychosis continuum aligns with preclinical models emphasizing cortical and hippocampal control over dopamine signalling (
      • Lipska B.K.
      • Weinberger D.R.
      A neurodevelopmental model of schizophrenia: Neonatal disconnection of the hippocampus.
      ,
      • Lodge D.J.
      • Grace A.A.
      Hippocampal dysregulation of dopamine system function and the pathophysiology of schizophrenia.
      ,
      • Lodge D.J.
      • Grace A.A.
      Aberrant hippocampal activity underlies the dopamine dysregulation in an animal model of schizophrenia.
      ,
      • Goldman P.S.
      • Alexander G.E.
      Maturation of prefrontal cortex in the monkey revealed by local reversible cryogenic depression.
      ,
      • Bertolino A.
      • Knable M.B.
      • Saunders R.C.
      • Callicott J.H.
      • Kolachana B.
      • Mattay V.S.
      • et al.
      The relationship between dorsolateral prefrontal N-acetylaspartate measures and striatal dopamine activity in schizophrenia.
      ,
      • Pycock C.J.
      • Kerwin R.W.
      • Carter C.J.
      Effect of lesion of cortical dopamine terminals on subcortical dopamine receptors in rats.
      ,
      • Beninger R.J.
      • Tuerke K.J.
      • Forsyth J.K.
      • Giles A.
      • Xue L.
      • Boegman R.J.
      • Jhamandas K.
      Neonatal ventral hippocampal lesions in male and female rats: Effects on water maze, locomotor activity, plus-maze and prefrontal cortical GABA and glutamate release in adulthood.
      ,
      • Lipska B.K.
      Using animal models to test a neurodevelopmental hypothesis of schizophrenia.
      ), the fMRI findings do not allow us to determine whether cortical or hippocampal abnormalities are primary. Indeed, it is possible that hippocampal dysregulation is linked to a diminished influence from cortex, given that reduced FC between the medial PFC and the hippocampus has been reported only in people with clinically diagnosable illness (i.e., FEP and schizophrenia patients); in this sense, disrupted cortico-hippocampal communication may be a trigger for clinically significant symptom expression by altering hippocampal regulation over dopamine transmission (
      • Li P.
      • Jing R.X.
      • Zhao R.J.
      • Shi L.
      • Sun H.Q.
      • Ding Z.
      • et al.
      Association between functional and structural connectivity of the corticostriatal network in people with schizophrenia and unaffected first-degree relatives.
      ,
      • Zhang B.
      • Lin P.
      • Wang X.
      • Öngür D.
      • Ji X.
      • Situ W.
      • et al.
      Altered Functional Connectivity of Striatum Based on the Integrated Connectivity Model in First-Episode Schizophrenia.
      ,
      • Karcher N.R.
      • Rogers B.P.
      • Woodward N.D.
      Functional Connectivity of the Striatum in Schizophrenia and Psychotic Bipolar Disorder.
      ,
      • Tu P.C.
      • Hsieh J.C.
      • Li C.T.
      • Bai Y.M.
      • Su T.P.
      Cortico-striatal disconnection within the cingulo-opercular network in schizophrenia revealed by intrinsic functional connectivity analysis: A resting fMRI study.
      ,
      • Lin P.
      • Wang X.
      • Zhang B.
      • Kirkpatrick B.
      • Öngür D.
      • Levitt J.J.
      • et al.
      Functional dysconnectivity of the limbic loop of frontostriatal circuits in first-episode, treatment-naive schizophrenia.
      ). It is also important to note that, due to the small size of the midbrain, whole-brain fMRI studies have limited sensitivity for mapping effects in this region unless they specifically try to investigate the area. The extant literature may therefore under-estimate the involvement of this region.
      Dynamic causal modelling (DCM) has emerged as a popular approach for quantifying causal interactions between neuronal populations, known as effective connectivity, with fMRI (
      • Friston K.J.
      Functional and Effective Connectivity: A Review.
      ,
      • Friston K.J.
      • Harrison L.
      • Penny W.
      Dynamic causal modelling.
      ). One recent DCM study of dorsal and ventral CST circuitry compared effective connectivity in antipsychotic-naïve FEP and schizophrenia patients with matched controls (
      • Sabaroedin K.
      • Razi A.
      • Chopra S.
      • Tran N.
      • Pozaruk A.
      • Chen Z.
      • et al.
      Frontostriatothalamic effective connectivity and dopaminergic function in the psychosis continuum.
      ). Both groups showed a relative disinhibition of the midbrain. Aberrant influences from midbrain to the ventral striatum and hippocampus were also identified in FEP patients with schizophrenia, whereas bidirectional effective connectivity between the midbrain and dorsal striatum was disrupted in patients with established schizophrenia. Both FEP and schizophrenia patients showed a stronger inhibitory influence of thalamus on ventral striatum. Positive symptom severity was also prominently associated with midbrain connectivity in both FEP and schizophrenia patients. These findings suggest a prominent role for midbrain dysfunction in clinically significant illness and do not provide strong evidence for early disruptions of cortical-subcortical control over midbrain activity, as suggested by preclinical models. However, these effects may be state-dependent, as DCM studies of task-evoked activity in ARMS individuals have identified an increased influence of the ventral striatum on the midbrain during rewarding stimuli (
      • Winton-Brown T.T.
      • Schmidt A.
      • Roiser J.P.
      • Howes O.D.
      • Egerton A.
      • Fusar-Poli P.
      • et al.
      Altered activation and connectivity in a hippocampal-basal ganglia-midbrain circuit during salience processing in subjects at ultra high risk for psychosis.
      ) and an increased influence of the hippocampus on the striatum during novel stimuli (
      • Modinos G.
      • Allen P.
      • Zugman A.
      • Dima D.
      • Azis M.
      • Samson C.
      • et al.
      Neural Circuitry of Novelty Salience Processing in Psychosis Risk: Association with Clinical Outcome.
      ). Together, these DCM findings suggest that spontaneous activity in psychosis is characterized by aberrant tonic firing of dopaminergic neurons, perhaps resulting from an intrinsic dysfunction of the midbrain that interacts with altered cortical-subcortical regulation of medial temporal structures to result in dysregulated phasic, stimulus-evoked dopamine release.

      Conclusions and future directions

      In summary, preclinical models have emphasized a primary role for aberrant cortical or medial temporal regulation over midbrain dopamine neuron activity, leading to elevated dopamine release and disrupted striatothalamic signaling, particularly within the ventral CST (
      • Weinberger D.R.
      Implications of Normal Brain Development for the Pathogenesis of Schizophrenia.
      ,
      • Lipska B.K.
      • Weinberger D.R.
      A neurodevelopmental model of schizophrenia: Neonatal disconnection of the hippocampus.
      ,
      • Lodge D.J.
      • Grace A.A.
      Hippocampal dysregulation of dopamine system function and the pathophysiology of schizophrenia.
      ,
      • Lodge D.J.
      • Grace A.A.
      Aberrant hippocampal activity underlies the dopamine dysregulation in an animal model of schizophrenia.
      ,
      • Goldman P.S.
      • Alexander G.E.
      Maturation of prefrontal cortex in the monkey revealed by local reversible cryogenic depression.
      ,
      • Patton M.H.
      • Bizup B.T.
      • Grace A.A.
      The infralimbic cortex bidirectionally modulates mesolimbic dopamine neuron activity via distinct neural pathways.
      ). Human neuroimaging studies are partially consistent with these models, suggesting that disrupted corticostriatal and hippocampal-striatal FC are apparent across the psychosis spectrum and may thus represent a vulnerability marker for psychosis, with midbrain dysfunction emerging when symptoms require some level of clinical attention. However, both ventral and dorsal CST dysconnectivity is found across the continuum, with elevated markers of dopamine function being more robustly identified in the latter system (
      • Kegeles L.S.
      • Abi-Dargham A.
      • Frankle W.G.
      • Gil R.
      • Cooper T.B.
      • Slifstein M.
      • et al.
      Increased synaptic dopamine function in associative regions of the striatum in schizophrenia.
      ,
      • Howes O.D.
      • Bose S.K.
      • Turkheimer F.
      • Valli I.
      • Egerton A.
      • Valmaggia L.R.
      • et al.
      Dopamine Synthesis Capacity Before Onset of Psychosis: A Prospective [18F]-DOPA PET Imaging Study.
      ,
      • Howes O.D.
      • Montgomery A.J.
      • Asselin M.C.
      • Murray R.M.
      • Valli I.
      • Tabraham P.
      • et al.
      Elevated striatal dopamine function linked to prodromal signs of schizophenia.
      ,
      • McCutcheon R.A.
      • Merritt K.
      • Howes O.D.
      Dopamine and glutamate in individuals at high risk for psychosis: a meta‐analysis of in vivo imaging findings and their variability compared to controls.
      ,
      • Egerton A.
      • Howes O.D.
      • Houle S.
      • McKenzie K.
      • Valmaggia L.R.
      • Bagby M.R.
      • et al.
      Elevated striatal dopamine function in immigrants and their children: a risk mechanism for psychosis.
      ), consistent with the increasing prominence of dorsal circuitry in the primate brain (
      • Joel D.
      • Weiner I.
      The connections of the dopaminergic system with the striatum in rats and primates: An analysis with respect to the functional and compartmental organization of the striatum.
      ,

      Balsters JH, Zerbi V, Wenderoth N, Mars RB, Hospital JR (2019): Primate homologs of mouse cortico- striatal circuits. 44.

      ,
      • Pauli W.M.
      • O’Reilly R.C.
      • Yarkoni T.
      • Wager T.D.
      Regional specialization within the human striatum for diverse psychological functions.
      ). These findings therefore suggest that dysfunction of distinct elements of the ventral and dorsal systems may emerge contemporaneously and may influence different aspects of psychosis, with the ventral system driving aberrant salience signaling and the dorsal system contributing to the development of persistent thought patterns (
      • Kapur S.
      Psychosis as a state of aberrant salience: a framework linking biology, phenomenology, and pharmacology in schizophrenia.
      ,
      • Maia T.V.
      • Frank M.J.
      An Integrative Perspective on the Role of Dopamine in Schizophrenia.
      ,
      • McCutcheon R.A.
      • Abi-Dargham A.
      • Howes O.D.
      Schizophrenia, Dopamine and the Striatum: From Biology to Symptoms.
      ,
      • Corlett P.R.
      • Taylor J.R.
      • Wang X.J.
      • Fletcher P.C.
      • Krystal J.H.
      Toward a neurobiology of delusions.
      ,
      • Malvaez M.
      • Wassum K.M.
      Regulation of habit formation in the dorsal striatum.
      ,
      • Feeney E.
      • Groman S.M.
      • Taylor J.R.
      • Corlett P.R.
      Explaining Delusions: Reducing uncertainty through basic and computational neuroscience.
      ). Preliminary work modeling effective connectivity also suggests that spontaneous neural dynamics may be driven by intrinsic midbrain deficits apparent from the outset of illness (

      Sabaroedin K, Razi A, Chopra S, Tran N, Pozaruk A, Chen Z, et al. (2021): Effective Connectivity and Dopaminergic Function of Fronto-Striato-Thalamic Circuitry in First-Episode Psychosis, Established Schizophrenia, and Healthy Controls. medRxiv.

      ), whereas stimulus-evoked dynamics may be more robustly associated with diminished cortical control over the midbrain (
      • Winton-Brown T.T.
      • Schmidt A.
      • Roiser J.P.
      • Howes O.D.
      • Egerton A.
      • Fusar-Poli P.
      • et al.
      Altered activation and connectivity in a hippocampal-basal ganglia-midbrain circuit during salience processing in subjects at ultra high risk for psychosis.
      ,
      • Modinos G.
      • Allen P.
      • Zugman A.
      • Dima D.
      • Azis M.
      • Samson C.
      • et al.
      Neural Circuitry of Novelty Salience Processing in Psychosis Risk: Association with Clinical Outcome.
      ), highlighting the importance of understanding both tonic and phasic dopamine release in models of psychosis (
      • Maia T.V.
      • Frank M.J.
      An Integrative Perspective on the Role of Dopamine in Schizophrenia.
      ).
      One critical consideration is that the precise relationship between dopamine levels and inter-regional functional or effective connectivity is unclear. While several studies have examined how pharmacological manipulation of dopamine levels influences regional activity and functional connectivity (
      • Conio B.
      • Martino M.
      • Magioncalda P.
      • Escelsior A.
      • Inglese M.
      • Amore M.
      • Northoff G.
      Opposite effects of dopamine and serotonin on resting-state networks: review and implications for psychiatric disorders.
      ,
      • Cole D.M.
      • Beckmann C.F.
      • Oei N.Y.L.
      • Both S.
      • van Gerven J.M.A.
      • Rombouts S.A.R.B.
      Differential and distributed effects of dopamine neuromodulations on resting-state network connectivity.
      ), links with psychosis are complicated because the manipulations themselves may not accurately mimic the underlying dopamine disruption in psychosis. The link between dopamine and fMRI signals is complex and the influence of dopamine on brain function may not be sufficiently captured by FC analyses (
      • Conio B.
      • Martino M.
      • Magioncalda P.
      • Escelsior A.
      • Inglese M.
      • Amore M.
      • Northoff G.
      Opposite effects of dopamine and serotonin on resting-state networks: review and implications for psychiatric disorders.
      ,
      • Cole D.M.
      • Beckmann C.F.
      • Oei N.Y.L.
      • Both S.
      • van Gerven J.M.A.
      • Rombouts S.A.R.B.
      Differential and distributed effects of dopamine neuromodulations on resting-state network connectivity.
      ). Thus, while mapping CST dysconnectivity across different stages of psychosis can help to identify candidate causes or consequences of DA dysregulation, the precise relation between DA function and FC is yet to be established.
      Another consideration is that comparisons of findings across different studies, cohorts, and illness stages should not be over-interpreted. Differences between studies may be driven by variations in statistical power, the clinical characteristics and medication exposure of patients, data processing strategies, analytic methods, and publication bias. Such influences underscore a need for the recruitment of large, longitudinally-followed samples. We propose that future research should focus on high-resolution characterization of the psychosis phenotype, across all levels of the continuum. Within clinical groups, there is evidence to suggest that positive, negative, and disorganized symptoms can be further differentiated into multiple subdimensions (
      • Corlett P.R.
      • Taylor J.R.
      • Wang X.J.
      • Fletcher P.C.
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      ,
      • Strauss G.P.
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      • Ahmed A.O.
      • Barchard K.A.
      • Granholm E.
      • Kirkpatrick B.
      • et al.
      The Latent Structure of Negative Symptoms in Schizophrenia.
      ). These distinctions are rarely addressed in fMRI research, which mostly focuses on associations with symptom scales that aggregate across diverse domains, such as total symptom scores. Differentiating between the various sub-domains of these symptom dimensions may reveal distinct neurobiological correlates, and detailed work is now beginning to characterize the putative computational processes and neural circuitry involved in specific symptom domains such as delusions (
      • Corlett P.R.
      • Taylor J.R.
      • Wang X.J.
      • Fletcher P.C.
      • Krystal J.H.
      Toward a neurobiology of delusions.
      ), hallucinations (
      • Cassidy C.M.
      • Balsam P.D.
      • Weinstein J.J.
      • Rosengard R.J.
      • Slifstein M.
      • Daw N.D.
      • et al.
      A perceptual inference mechanism for hallucinations linked to striatal dopamine.
      ), and particular negative symptoms (
      • Maia T.V.
      • Frank M.J.
      An Integrative Perspective on the Role of Dopamine in Schizophrenia.
      ,
      • Jeganathan J.
      • Breakspear M.
      An active inference perspective on the negative symptoms of schizophrenia.
      ).
      The same approach could be extended to subclinical aspects of the psychosis continuum, given that they are phenotypically continuous with clinical psychosis (
      • Kotov R.
      • Jonas K.G.
      • Carpenter W.T.
      • Dretsch M.N.
      • Eaton N.R.
      • Forbes M.K.
      • et al.
      Validity and utility of Hierarchical Taxonomy of Psychopathology (HiTOP): I. Psychosis superspectrum.
      ,
      • Tiego J.
      • Lochner C.
      • Ioannidis K.
      • Brand M.
      • Stein D.J.
      • Yücel M.
      • et al.
      Measurement of the problematic usage of the Internet unidimensional quasitrait continuum with item response theory.
      ). Indeed, evidence for genetic and environmental aetiological continuity between subclinical and clinical psychosis suggests that a unified model of subclinical and clinical symptom expression may prove useful (
      • Ettinger U.
      • Meyhöfer I.
      • Steffens M.
      • Wagner M.
      • Koutsouleris N.
      Genetics, cognition, and neurobiology of schizotypal personality: a review of the overlap with schizophrenia.
      ). Our review above offers some insight into neurobiological continuities across several levels of the psychosis spectrum with respect to CST and dopamine dysfunction, but a more systematic investigation may provide further clues regarding the risk mechanisms of psychotic illness. Such an approach will benefit strongly from a psychometrically rigorous investigation of the latent architecture of psychosis to develop a hierarchical model that specifies how specific symptoms covary with each other, and which specific hierarchical levels correlate most strongly with biological measures. Recent work has shown that such an approach can substantially improve associations between schizotypy-related constructs and polygenic risk for schizophrenia (

      Tiego J, Thompson K, Arnatkeviciute A, Hawi Z, Finlay A, Sabaroedin K, et al. (2021): Dissecting schizotypy and its association with cognition and polygenic risk for schizophrenia in a non-clinical sample. Manuscript Retrieved from osf.io/t7gj9. https://doi.org/10.20710/dojo.11.4_383

      ). We anticipate that such high-resolution phenotyping will also yield more detailed insights into the neurobiological correlates of psychosis risk and help to delineate the transdiagnostic influence of CST function, given its involvement in other psychiatric disorders (
      • Shepherd G.M.G.
      Corticostriatal connectivity and its role in disease.
      ). Other circuits, such as those involving auditory and cerebellar networks, are also likely to contribute to symptom onset (

      Horga G, Abi-Dargham A (2019): An integrative framework for perceptual disturbances in psychosis. Nature Reviews Neuroscience, vol. 20. Springer US, pp 763–778.

      ,
      • Schmack K.
      • Bosc M.
      • Ott T.
      • Sturgill J.F.
      • Kepecs A.
      Striatal dopamine mediates hallucination-like perception in mice.
      ,
      • Andreasen N.C.
      • Pierson R.
      The Role of the Cerebellum in Schizophrenia.
      ), but these are beyond the present scope.
      It is probable that there is no single pattern of dysfunction that inevitably leads to psychotic illness; instead, genetic, environmental, and neurodevelopmental factors are likely to conspire to distinctly alter the function of CST circuit elements in any individual patient. Thus, much like plucking different strings of a guitar gives rise to a specific melody, it is probable that dysfunction at different points within the ventral and dorsal CST circuit, in combination with alterations to other neural systems, ultimately determines the unique constellation of symptoms expressed by any individual patient.

      Disclosures

      The authors report no biomedical financial interests or potential conflicts of interest.

      Acknowledgments

      This work was supported by the National Health and Medical Research Council (NHMRC) (ID: 1050504), Australian Research Council (ID: FT130100589) and the Charles and Sylvia Viertel Charitable Foundation.

      Supplementary Material

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