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Disconnected and Hyperactive: A Replication of Sensorimotor Cortex Abnormalities in Patients With Schizophrenia During Proactive Response Inhibition.

ABSTRACT: Inhibitory failure represents a core dysfunction in patients with schizophrenia (SP), which has predominantly been tested in the literature using reactive (ie, altering behavior after a stimulus) rather than proactive (ie, purposefully changing behavior before a stimulus) response inhibition tasks. The current study replicates/extends our previous findings of SP exhibiting sensorimotor cortex (SMC) hyperactivity and connectivity abnormalities in independent samples of patients and controls. Specifically, 49 clinically well-characterized SP and 54 matched healthy controls (HC) performed a proactive response inhibition task while undergoing functional magnetic resonance imaging and resting-state data collection. Results indicated that the majority of SP (84%) and HC (88%) successfully inhibited all overt motor responses following a cue, eliminating behavioral confounds frequently present in this population. Observations of left SMC hyperactivity during proactive response inhibition, reduced cortical connectivity with left SMC, and increased connectivity between left SMC and ventrolateral thalamus were replicated for SP relative to HC in the current study. Similarly, negative symptoms (eg, motor retardation) were again associated with SMC functional and connectivity abnormalities. In contrast, findings of a negative blood oxygenation level-dependent response in the SMC of HC did not replicate. Collectively, current and previous findings suggest that SMC connectivity abnormalities may be more robust relative to evoked hemodynamic signals during proactive response inhibition. In addition, there is strong support that these SMC abnormalities are a key component of SP pathology, along with dysfunction within other sensory cortices, and may be associated with certain clinical deficits such as negative symptoms.

SUBMITTER: Wertz CJ

PROVIDER: S-EPMC6483571 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Disconnected and Hyperactive: A Replication of Sensorimotor Cortex Abnormalities in Patients With Schizophrenia During Proactive Response Inhibition.

Wertz Christopher J CJ Hanlon Faith M FM Shaff Nicholas A NA Dodd Andrew B AB Bustillo Juan J Stromberg Shannon F SF Lin Denise S DS Abrams Swala S Yeo Ronald A RA Liu Jingyu J Calhoun Vince V Mayer Andrew R AR

Schizophrenia bulletin 20190401 3

Inhibitory failure represents a core dysfunction in patients with schizophrenia (SP), which has predominantly been tested in the literature using reactive (ie, altering behavior after a stimulus) rather than proactive (ie, purposefully changing behavior before a stimulus) response inhibition tasks. The current study replicates/extends our previous findings of SP exhibiting sensorimotor cortex (SMC) hyperactivity and connectivity abnormalities in independent samples of patients and controls. Spec ...[more]

PMID: 29939338

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Project description:ContextChondroitin sulfate proteoglycans (CSPGs), a main component of the brain extracellular matrix, regulate developmental and adult neural functions that are highly relevant to the pathogenesis of schizophrenia. Such functions, together with marked expression of CSPGs in astrocytes within the normal human amygdala and evidence of a disruption of astrocytic functions in this disease, point to involvement of CSPG-glial interactions in schizophrenia.HypothesisChondroitin sulfate proteoglycan-related abnormalities involve glial cells and extracellular matrix pericellular aggregates (perineuronal nets) in the amygdala and entorhinal cortex of subjects with schizophrenia.DesignPostmortem case-control study.SettingThe Translational Neuroscience Laboratory at McLean Hospital, Harvard Medical School. Specimens were obtained from the Harvard Brain Tissue Resource Center at McLean Hospital.ParticipantsTwo separate cohorts of healthy control (n = 15; n = 10) and schizophrenic (n = 11; n = 10) subjects and a cohort of subjects with bipolar disorder (n = 11).InterventionsQuantitative, immunocytological, and histological postmortem investigations.Main outcome measuresNumerical densities of CSPG-positive glial cells and perineuronal nets, glial fibrillary acidic protein-positive astrocytes, and total numbers of parvalbumin-positive neurons in the deep amygdala nuclei and entorhinal cortex.ResultsIn schizophrenia, massive increases in CSPG-positive glial cells were detected in the deep amygdala nuclei (419%-1162%) and entorhinal cortex (layer II; 480%-1560%). Perineuronal nets were reduced in the lateral nucleus of the amygdala and lateral entorhinal cortex (layer II). Numerical densities of glial fibrillary acidic protein-positive glial cells and total numbers of parvalbumin-positive neurons were unaltered. Changes in CSPG-positive elements were negligible in subjects with bipolar disorder.ConclusionsMarked changes in functionally relevant molecules in schizophrenia point to a pivotal role for extracellular matrix-glial interactions in the pathogenesis of this disease. Disruption of these interactions, unsuspected thus far, may represent a unifying factor contributing to disturbances of neuronal migration, synaptic connectivity, and GABAergic, glutamatergic, and dopaminergic neurotransmission in schizophrenia. The lack of CSPG abnormalities in bipolar disorder points to a distinctive aspect of the pathophysiology of schizophrenia in key medial temporal lobe regions.

Dataset Information

Disconnected and Hyperactive: A Replication of Sensorimotor Cortex Abnormalities in Patients With Schizophrenia During Proactive Response Inhibition.

Publications

Disconnected and Hyperactive: A Replication of Sensorimotor Cortex Abnormalities in Patients With Schizophrenia During Proactive Response Inhibition.

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