Antipsychotic Treatment and Functional Connectivity of the Striatum in First-Episode Schizophrenia

Sarpal, Deepak; Robinson, Delbert G.; Lencz, Todd; Árgyelán, Miklós; Ikuta, Toshikazu; Karlsgodt, Katherine H.; Gallego, Juan A.; Kane, John M.; Szeszko, Philip R.; Malhotra, Anil K.

doi:10.1001/jamapsychiatry.2014.1734

Cited by 270 publications

(228 citation statements)

References 41 publications

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“…More specifically, variations in corticostriatal association are seen in relation to treatment response in line with recent related findings (Sarpal et al, 2015); and striatonigral dysconnection is identified as a distinct feature of treatment-resistant illness. There is increasing interest in examining glutamatergic treatment options in schizophrenia (Papanastasiou et al, 2013) and elevated glutamate function has been observed in association with treatment resistance (Demjaha et al, 2014).…”

Section: Discussionsupporting

confidence: 84%

“…This provides an indication that these individuals are to some extent neurophysiologically responsive to antipsychotic medication despite its failure to treat their symptoms. Further support for the notion that the current effects are not purely medication derived is provided by the regional disparity between the current between-patient group FC effects and recent observations in responsive patients following medication (Sarpal et al, 2015). However, an incomplete understanding of the consequences of long-term antipsychotic treatment and interindividual variation in related phenomena limits this work.…”

Section: Discussionmentioning

confidence: 84%

“…A recent study has used this idea to examine prospective treatment response, identifying changes in striatal connectivity with prefrontal and limbic regions as important in symptomatic alleviation (Sarpal et al, 2015). Guided by these observations, the rationale that treatment-resistant individuals would differ from non-refractory patients in these brain substrates that track clinical improvement, and the idea that treatmentresistant individuals would exhibit striatal FC abnormalities indicative of their specific cognitive and behavioral impairments, we addressed two principal hypotheses.…”

Section: Introductionmentioning

confidence: 99%

“…First, treatment-resistant individuals with schizophrenia would display reduced connectivity along nigrostriatal pathways compared with non-refractory individuals, as learning and its influence on action can be impaired in treatment-resistant individuals (Dratcu et al, 2007;Kolakowska et al, 1985), and related processes are regulated by striatum and substantia nigra (Braver et al, 1999a;Braver and Cohen, 1999b;D'Ardenne et al, 2012). Second, frontostriatal disruptions observed when comparing patients with healthy individuals (Quide et al, 2013;Sarpal et al, 2015) would differ as a function of treatment resistance. In addition, as the persistence of positive symptoms is fundamental to treatment resistance, and with the aim of building on previous FEP observations (Fornito et al, 2013), we assessed the extent to which current positive symptom severity predicted striatal FC in treatment-resistant and non-refractory patients.…”

Section: Introductionmentioning

confidence: 99%

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Dysfunctional Striatal Systems in Treatment-Resistant Schizophrenia

White

Wigton

Joyce³

et al. 2015

Neuropsychopharmacol

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The prevalence of treatment-resistant schizophrenia points to a discrete illness subtype, but to date its pathophysiologic characteristics are undetermined. Information transfer from ventral to dorsal striatum depends on both striato-cortico-striatal and striato-nigro-striatal subcircuits, yet although the functional integrity of the former appears to track improvement of positive symptoms of schizophrenia, the latter have received little experimental attention in relation to the illness. Here, in a sample of individuals with schizophrenia stratified by treatment resistance and matched controls, functional pathways involving four foci along the striatal axis were assessed to test the hypothesis that treatment-resistant and non-refractory patients would exhibit contrasting patterns of resting striatal connectivity. Compared with non-refractory patients, treatment-resistant individuals exhibited reduced connectivity between ventral striatum and substantia nigra. Furthermore, disturbance to corticostriatal connectivity was more pervasive in treatment-resistant individuals. The occurrence of a more distributed pattern of abnormality may contribute to the failure of medication to treat symptoms in these individuals. This work strongly supports the notion of pathophysiologic divergence between individuals with schizophrenia classified by treatmentresistance criteria.

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Section: Discussionsupporting

confidence: 84%

Section: Discussionmentioning

confidence: 84%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Dysfunctional Striatal Systems in Treatment-Resistant Schizophrenia

White

Wigton

Joyce³

et al. 2015

Neuropsychopharmacol

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“…This is further evidenced by the association between accuracy on the mental animations and functional connectivity primarily between the left and right inferior frontal gyri, but also involving the left temporal lobe. Increased functional connectivity with the caudate nucleus may be a result of antipsychotic medication (Kraguljac, et al, 2016;Sarpal, et al, 2015), especially with the hippocampal region (Kraguljac, et al, 2016), and future studies should explore this association further using social cognitive tasks.…”

Section: Left Inferior Frontal Gyrus (Ifg) Functional Connectivitymentioning

confidence: 99%

Mentalizing in schizophrenia: A multivariate functional MRI study

et al. 2016

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Dopamine-Related Disruption of Functional Topography of Striatal Connections in Unmedicated Patients With Schizophrenia

Horga

Cassidy

et al. 2016

JAMA Psychiatry

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Importance Despite the well-established role of striatal dopamine in psychosis, current views generally agree that cortical dysfunction is likely necessary for the emergence of psychotic symptoms. The topographical organization of striatal-cortical connections is central to gating and integration of higher-order information, so a disruption of such topography via dysregulated dopamine could lead to cortical dysfunction in schizophrenia. However, this hypothesis remains to be tested using multivariate methods ascertaining the global pattern of striatal connectivity and without the confounding effects of anti-dopaminergic medication. Objective To determine whether the pattern of brain connectivity across striatal subregions is abnormal in unmedicated patients with schizophrenia, and whether this abnormality relates to psychotic symptoms and extrastriatal dopaminergic transmission. Design and Participants In this multimodal, case-control study, we obtained resting-state functional Magnetic Resonance Imaging (fMRI) data in 18 unmedicated patients with schizophrenia and 24 matched healthy controls. A subset of these (12 and 17, respectively) underwent Positron Emission Tomographic (PET) imaging with the dopamine D2-receptor radiotracer [11C]FLB457, before and after amphetamine. Data were acquired between June 16, 2011, and February 25, 2014. Main Outcomes (1) Group differences in the striatal connectivity pattern (assessed via multivariable logistic regression) across striatal subregions, and the relationship between the multivariate striatal connectivity pattern (2) with extrastriatal baseline D2-receptor binding potential and its change following amphetamine (BPND and ΔBPND), and (3) with severity of positive symptoms evaluated with the PANSS scale. Results Patients exhibited an abnormal pattern of striatal connectivity, which included abnormal caudate connections with a distributed set of associative cortex regions (p=0.0036). In patients, more deviation from the multivariate pattern of striatal connectivity found in controls correlated specifically with more severe positive symptoms (p=0.0021). Striatal connectivity also correlated with baseline BPND across cortical and extrastriatal subcortical regions (p=0.0116, Bonferroni-corrected) but not with ΔBPND. Conclusions and Relevance Using a multimodal, circuit-level interrogation of striatal-cortical connections, we provide a first demonstration that the functional topography of these connections is globally disrupted in unmedicated patients with schizophrenia. These findings suggest that striatal-cortical dysconnectivity may underlie the effects of dopamine dysregulation on the pathophysiology of psychotic symptoms.

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Antipsychotic Treatment and Functional Connectivity of the Striatum in First-Episode Schizophrenia

Cited by 270 publications

References 41 publications

Dysfunctional Striatal Systems in Treatment-Resistant Schizophrenia

Dysfunctional Striatal Systems in Treatment-Resistant Schizophrenia

Mentalizing in schizophrenia: A multivariate functional MRI study

Dopamine-Related Disruption of Functional Topography of Striatal Connections in Unmedicated Patients With Schizophrenia

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