Publications by authors named "Fabio Sambataro"

129 Publications

A neurodevelopmental signature of parkinsonism in schizophrenia.

Schizophr Res 2021 Mar 23;231:54-60. Epub 2021 Mar 23.

Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.

While sensorimotor abnormalities in schizophrenia (SZ) are of increasing scientific interest, little is known about structural changes and their developmental origins that may underlie parkinsonism. This multimodal magnetic resonance imaging (MRI) study examined healthy controls (HC, n = 20) and SZ patients with (SZ-P, n = 38) and without (SZ-nonP, n = 35) parkinsonism, as defined by Simpson-Angus Scale total scores of ≥4 or ≤1, respectively. Using the Computational Anatomy Toolbox (CAT12), voxel- and surface-based morphometry were applied to investigate cortical and subcortical gray matter volume (GMV) and three cortical surface markers of distinct neurodevelopmental origin: cortical thickness (CTh), complexity of cortical folding (CCF) and sulcus depth. In a subgroup of patients (29 SZ-nonP, 25 SZ-P), resting-state fMRI data were also analyzed using a regions-of-interest approach based on fractional amplitude of low frequency fluctuations (fALFF). SZ-P patients showed increased CCF in the left supplementary motor cortex (SMC) and decreased left postcentral sulcus (PCS) depth compared to SZ-nonP patients (p < 0.05, FWE-corrected at cluster level). In SMC, CCF was associated negatively with activity, which also differed significantly between the patient groups and between patients and HC. In regression models, severity of parkinsonism was associated negatively with left middle frontal CCF and left anterior cingulate CTh. These data provide novel insights into altered trajectories of cortical development in SZ patients with parkinsonism. These cortical surface changes involve the sensorimotor system, suggesting abnormal neurodevelopmental processes tightly coupled with cortical activity and subcortical morphology that convey increased risk for sensorimotor abnormalities in SZ.
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http://dx.doi.org/10.1016/j.schres.2021.03.004DOI Listing
March 2021

Neural Responses of Benefiting From the Prosocial Exchange: The Effect of Helping Behavior.

Front Psychol 2021 4;12:606858. Epub 2021 Mar 4.

Department of Neuroscience (DNS), University of Padua, Padua, Italy.

Prosocial behavior is critical for the natural development of an individual as well as for promoting social relationships. Although this complex behavior results from gratuitous acts occurring between an agent and a recipient and a wealth of literature on prosocial behavior has investigated these actions, little is known about the effects on the recipient and the neurobiology underlying them. In this study, we used functional magnetic resonance imaging to identify neural correlates of receiving prosocial behavior in the context of real-world experiences, with different types of action provided by the agent, including practical help and effort appreciation. Practical help was associated with increased activation in a network of regions spanning across bilateral superior temporal sulcus, temporoparietal junction, temporal pole, and medial prefrontal cortex. Effort appreciation was associated with activation and increased task-modulated connectivity of the occipital cortex. Prosocial-dependent brain responses were associated with positive affect. Our results support the role of the theory of mind network and the visual cortices in mediating the positive effects of receiving gratuitous help. Moreover, they indicate that specific types of prosocial behavior are mediated by distinct brain networks, which further demonstrates the uniqueness of the psychological processes underlying prosocial actions.
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http://dx.doi.org/10.3389/fpsyg.2021.606858DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7969530PMC
March 2021

Long-Acting Aripiprazole in the Management of Violence in Treatment Nonadherent Schizophrenia.

Prim Care Companion CNS Disord 2021 Jan 14;23(1). Epub 2021 Jan 14.

Department of Neurosciences, Psychiatry Unit, University-Hospital of Padova, Padova, Italy.

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http://dx.doi.org/10.4088/PCC.20l02623DOI Listing
January 2021

Effortful control is associated with executive attention: A computational study.

J Pers 2020 Dec 20. Epub 2020 Dec 20.

Department of Medicine and Surgery, Università di Parma, Parma, Italy.

Introduction: Effortful control (EC) is the self-regulatory aspect of temperament that is thought to reflect the efficiency of executive attention (EA). Findings on relationship between EC and performance on EA tasks among adults are still contradictory. This study used a computational approach to clarify whether greater self-reported EC reflects better EA.

Methods: Four hundred twenty-seven healthy subjects completed the Adult Temperament Questionnaires and the Attention Network Task-revised, a conflict resolution task that gauges EA as the flanker effect (FE), that is, the difference in performances between incongruent and congruent trials. Here we also employed a drift-diffusion model in which parameters reflecting the actual decisional process (drift rate) and the extra-decisional time are extracted for congruent and incongruent trials.

Results: EC was not correlated with the FE computed with the classic approach, but correlated positively with drift rate for the incongruent trials, even when controlling for the drift rate in the congruent condition and the extra-decisional time in the incongruent condition.

Conclusion: This study demonstrates an association between self-reported EC and EA among adults. Specifically, EC is not associated with overall response facilitation but specifically with a greater ability to make goal-oriented decisions when facing conflicting information.
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http://dx.doi.org/10.1111/jopy.12614DOI Listing
December 2020

Neurological Soft Signs Predict Auditory Verbal Hallucinations in Patients With Schizophrenia.

Schizophr Bull 2021 Mar;47(2):433-443

Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.

Neurological soft signs (NSS) are well documented in individuals with schizophrenia (SZ), yet so far, the relationship between NSS and specific symptom expression is unclear. We studied 76 SZ patients using magnetic resonance imaging (MRI) to determine associations between NSS, positive symptoms, gray matter volume (GMV), and neural activity at rest. SZ patients were hypothesis-driven stratified according to the presence or absence of auditory verbal hallucinations (AVH; n = 34 without vs 42 with AVH) according to the Brief Psychiatric Rating Scale. Structural MRI data were analyzed using voxel-based morphometry, whereas intrinsic neural activity was investigated using regional homogeneity (ReHo) measures. Using ANCOVA, AVH patients showed significantly higher NSS in motor and integrative functions (IF) compared with non-hallucinating (nAVH) patients. Partial correlation revealed that NSS IF were positively associated with AVH symptom severity in AVH patients. Such associations were not confirmed for delusions. In region-of-interest ANCOVAs comprising the left middle and superior temporal gyri, right paracentral lobule, and right inferior parietal lobule (IPL) structure and function, significant differences between AVH and nAVH subgroups were not detected. In a binary logistic regression model, IF scores and right IPL ReHo were significant predictors of AVH. These data suggest significant interrelationships between sensorimotor integration abilities, brain structure and function, and AVH symptom expression.
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http://dx.doi.org/10.1093/schbul/sbaa146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7965075PMC
March 2021

How to improve adherence to antidepressant treatments in patients with major depression: a psychoeducational consensus checklist.

Ann Gen Psychiatry 2020 12;19:61. Epub 2020 Oct 12.

Department of Psychiatry, University of Campania "L. Vanvitelli", Naples, Italy.

Studies conducted in primary care as well as in psychiatric settings show that more than half of patients suffering from major depressive disorder (MDD) have poor adherence to antidepressants. Patients prematurely discontinue antidepressant therapy for various reasons, including patient-related (e.g., misperceptions about antidepressants, side-effects, and lack of tolerability), clinician-related (e.g., insufficient instruction received by clinicians about the medication, lack of shared decision-making, and follow-up care), as well as structural factors (e.g., access, cost, and stigma). The high rate of poor adherence to antidepressant treatments provides the impetus for identifying factors that are contributing to noncompliance in an individual patient, to implement a careful education about this phenomenon. As adherence to antidepressants is one of the major unmet needs in MDD treatment, being associated with negative outcomes, we sought to identify a series of priorities to be discussed with persons with MDD with the larger aim to improve treatment adherence. To do so, we analyzed a series of epidemiological findings and clinical reasons for this phenomenon, and then proceeded to define through a multi-step consensus a set of recommendations to be provided by psychiatrists and other practitioners at the time of the first (prescription) visit with patients. Herein, we report the results of this initiative.
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http://dx.doi.org/10.1186/s12991-020-00306-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7552507PMC
October 2020

Movement disorder and sensorimotor abnormalities in schizophrenia and other psychoses - European consensus on assessment and perspectives.

Eur Neuropsychopharmacol 2020 09 23;38:25-39. Epub 2020 Jul 23.

Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. Electronic address:

Over the last three decades, movement disorder as well as sensorimotor and psychomotor functioning in schizophrenia (SZ) and other psychoses has gained greater scientific and clinical relevance as an intrinsic component of the disease process of psychotic illness; this extends to early psychosis prediction, early detection of motor side effects of antipsychotic medication, clinical outcome monitoring, treatment of psychomotor syndromes (e.g. catatonia), and identification of new targets for non-invasive brain stimulation. In 2017, a systematic cooperation between working groups interested in movement disorder and sensorimotor/psychomotor functioning in psychoses was initiated across European universities. As a first step, the members of this group would like to introduce and define the theoretical aspects of the sensorimotor domain in SZ and other psychoses. This consensus paper is based on a synthesis of scientific evidence, good clinical practice and expert opinions that were discussed during recent conferences hosted by national and international psychiatric associations. While reviewing and discussing the recent theoretical and experimental work on neural mechanisms and clinical implications of sensorimotor behavior, we here seek to define the key principles and elements of research on movement disorder and sensorimotor/psychomotor functioning in psychotic illness. Finally, the members of this European group anticipate that this consensus paper will stimulate further multimodal and prospective studies on hypo- and hyperkinetic movement disorders and sensorimotor/psychomotor functioning in SZ and other psychotic disorders.
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http://dx.doi.org/10.1016/j.euroneuro.2020.07.003DOI Listing
September 2020

Aripiprazole for the treatment of delusional disorders: A systematic review.

Gen Hosp Psychiatry 2020 Sep - Oct;66:34-43. Epub 2020 Jun 26.

Padua University Hospital, Padua, Italy.

Background: Delusional disorder is an uncommon psychotic disorder. The first-line treatments for this chronic and resistant condition are antipsychotic medications, usually associated with several side effects that can exacerbate poor adherence. Conversely, aripiprazole is a well-tolerated antipsychotic drug that is effective in the treatment of other psychotic disorders. Here, we aimed to systematically review and summarize the currently available literature to evaluate the effectiveness and tolerability of aripiprazole in delusional disorders.

Methods: A comprehensive literature search from inception until February 2020 was performed in PubMed, Cochrane Database of Systematic Reviews, and Scopus databases using The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.

Results: We identified 21 single cases of delusional disorders, mostly somatic type, treated with aripiprazole. All studies reported patient clinical improvements after the beginning of the treatment with aripiprazole. The average dose of aripiprazole was 11.1 mg/day, and the average time to achieve a clinical response was 5.7 weeks. Few adverse effects were reported, including asthenia, extrapyramidal symptoms, hyperprolactinemia, and insomnia.

Conclusions: Our findings suggest that aripiprazole may be an effective treatment for delusional disorders with good tolerability. Further studies comparing aripiprazole with other antipsychotics in the treatment of delusional disorders are needed.
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http://dx.doi.org/10.1016/j.genhosppsych.2020.06.012DOI Listing
June 2020

Moving forward: distinct sensorimotor abnormalities predict clinical outcome after 6 months in patients with schizophrenia.

Eur Neuropsychopharmacol 2020 07 7;36:72-82. Epub 2020 Jun 7.

Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, D-68159, Germany. Electronic address:

Despite substantial efforts in the last decades, objective measures that can predict clinical outcome in patients with schizophrenia (SZ) after an acute psychotic episode are still lacking. Here, we introduced a comprehensive assessment of sensorimotor function to predict mid-term clinical outcome following an acute psychotic episode. This naturalistic follow-up of 43 patients with DSM-IV-TR diagnosis of SZ examined sensorimotor abnormalities (i.e. Neurological Soft Signs (NSS), parkinsonism, akathisia, catatonia and acute dyskinesia), psychopathology, cognition and psychosocial functioning using well-established instruments. A collection of statistical methods was used to examine the relationship between sensorimotor domain, psychopathology, cognition and psychosocial functioning. We also tested the clinical feasibility of this relationship when predicting clinical outcome after an acute psychotic episode. Longitudinal data were collected on 43 individuals after a follow-up period of >6 months. At follow-up, patients showed significantly reduced general symptom severity, as well as decreased levels of NSS, parkinsonism and catatonia. Further, NSS scores at baseline predicted PANSS negative scores and cognitive functioning at baseline. Finally, NSS scores at baseline predicted symptom change (reduction of PANSS positive and negative scores) at follow-up. In conclusion, our results suggest that NSS are significant predictors of poor clinical outcome in SZ at baseline and >6 months after an acute psychotic episode. These findings propose sensorimotor domain as state biomarker of SZ and support its predictive power with respect to treatment outcome.
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http://dx.doi.org/10.1016/j.euroneuro.2020.05.002DOI Listing
July 2020

Functional Decoupling of Language and Self-Reference Networks in Patients with Persistent Auditory Verbal Hallucinations.

Neuropsychobiology 2020 2;79(4-5):345-351. Epub 2020 Jun 2.

Center for Psychosocial Medicine, Department of General Psychiatry, Heidelberg University, Heidelberg, Germany,

Background: Accumulating neuroimaging evidence suggests that abnormal intrinsic neural activity could underlie auditory verbal hallucinations (AVH) in patients with schizophrenia. However, little is known about the functional interplay between distinct intrinsic neural networks and their association with AVH.

Methods: We investigated functional network connectivity (FNC) of distinct resting-state networks as well as the relationship between FNC strength and AVH symptom severity. Resting-state functional MRI data at 3 T were obtained for 14 healthy controls and 10 patients with schizophrenia presenting with persistent AVH. The data were analyzed using a spatial group independent component analysis, followed by constrained maximal lag correlations to determine FNC within and between groups.

Results: Four components of interest, comprising language, attention, executive control networks, as well as the default-mode network (DMN), were selected for subsequent FNC analyses. Patients with persistent AVH showed lower FNC between the language network and the DMN (p < 0.05, corrected for false discovery rate). FNC strength, however, was not significantly related to symptom severity, as measured by the Psychotic Symptom Rating Scale.

Conclusion: These findings suggest that disrupted FNC between a speech-related system and a network subserving self-referential processing is associated with AVH. The data are consistent with a model of disrupted self-attribution of speech generation and perception.
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http://dx.doi.org/10.1159/000507630DOI Listing
April 2021

Neural correlates of cue reactivity in individuals with smartphone addiction.

Addict Behav 2020 09 29;108:106422. Epub 2020 Mar 29.

Department of General Psychiatry, Center for Psychosocial Medicine, Heidelberg University, Germany. Electronic address:

Popularity of smartphones has dramatically increased in the past years, accompanied by increased concerns regarding potentially adverse effects on physical and mental health. Addictive behavior associated with excessive smartphone use, frequently referred to as "smartphone addiction" (SPA), has attracted increased scientific interest. However the neural correlates of SPA are unknown. We used functional magnetic resonance imaging at 3T to investigate the neural correlates of cue reactivity (CR) in individuals with SPA (n = 21) compared to controls (n = 21). SPA was assessed using the Smartphone Addiction Inventory (SPAI), and neural activity was measured by a modified CR task. Contrasts of images of smartphones vs. neutral stimuli and stimuli including active vs. inactive smartphones (p < 0.001, uncorrected for height, followed by correction for spatial extent) were analyzed. In the first contrast, group differences in medial prefrontal (MPFC), occipital, temporal, and anterior cingulate (ACC) cortices, in temporoparietal regions, and cerebellum were found. For active vs. inactive smartphones, group differences were found in frontal operculum/anterior insula and precentral gyrus. Negative correlations were found between MPFC, ACC, precuneus, and precentral gyrus and specific SPAI subscores, i.e. compulsive behavior, functional impairment and withdrawal. This study suggests spatial similarities of CR-related brain activation between addictive smartphone use and other well-known addictive disorders.
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http://dx.doi.org/10.1016/j.addbeh.2020.106422DOI Listing
September 2020

A Neural Signature of Parkinsonism in Patients With Schizophrenia Spectrum Disorders: A Multimodal MRI Study Using Parallel ICA.

Schizophr Bull 2020 07;46(4):999-1008

Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.

Motor abnormalities in schizophrenia spectrum disorders (SSD) have increasingly attracted scientific interest in the past years. However, the neural mechanisms underlying parkinsonism in SSD are unclear. The present multimodal magnetic resonance imaging (MRI) study examined SSD patients with and without parkinsonism, as defined by a Simpson and Angus Scale (SAS) total score of ≥4 (SAS group, n = 22) or <4 (non-SAS group, n = 22). Parallel independent component analysis (p-ICA) was used to examine the covarying components among gray matter volume maps computed from structural MRI (sMRI) and fractional amplitude of low-frequency fluctuations (fALFF) maps computed from resting-state functional MRI (rs-fMRI) patient data. We found a significant correlation (P = .020, false discovery rate [FDR] corrected) between an sMRI component and an rs-fMRI component, which also significantly differed between the SAS and non-SAS group (P = .042, z = -2.04). The rs-fMRI component comprised the cortical sensorimotor network, and the sMRI component included predominantly a frontothalamic/cerebellar network. Across the patient sample, correlations adjusted for the Positive and Negative Syndrome Scale (PANSS) total scores showed a significant relationship between tremor score and loadings of the cortical sensorimotor network, as well as between glabella-salivation score, frontothalamic/cerebellar and cortical sensorimotor network loadings. These data provide novel insights into neural mechanisms of parkinsonism in SSD. Aberrant bottom-up modulation of cortical motor regions may account for these specific motor symptoms, at least in patients with SSD.
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http://dx.doi.org/10.1093/schbul/sbaa007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7345812PMC
July 2020

Structural and functional correlates of smartphone addiction.

Addict Behav 2020 06 1;105:106334. Epub 2020 Feb 1.

Department of General Psychiatry, Center for Psychosocial Medicine, Heidelberg University, Germany. Electronic address:

Popularity and availability of smartphones have dramatically increased in the past years. This trend is accompanied by increased concerns regarding potentially adverse effects of excessive smartphone use, particularly with respect to physical and mental health. Recently, the term "smartphone addiction" (SPA) has been introduced to describe smartphone-related addictive behavior and associated physical and psychosocial impairment. Here, we used structural and functional magnetic resonance imaging (MRI) at 3 T to investigate gray matter volume (GMV) and intrinsic neural activity in individuals with SPA (n = 22) compared to a control group (n = 26). SPA was assessed using the Smartphone Addiction Inventory (SPAI), GMV was investigated by means of voxel-based morphometry, and intrinsic neural activity was measured by the amplitude of low frequency fluctuations (ALFF). Compared to controls, individuals with SPA showed lower GMV in left anterior insula, inferior temporal and parahippocampal cortex (p < 0.001, uncorrected for height, followed by correction for spatial extent). Lower intrinsic activity in SPA was found in the right anterior cingulate cortex (ACC). A significant negative association was found between SPAI and both ACC volume and activity. In addition, a significant negative association between SPAI scores and left orbitofrontal GMV was found. This study provides first evidence for distinct structural and functional correlates of behavioral addiction in individuals meeting psychometric criteria for SPA. Given their widespread use and increasing popularity, the present study questions the harmlessness of smartphones, at least in individuals that may be at increased risk for developing smartphone-related addictive behaviors.
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http://dx.doi.org/10.1016/j.addbeh.2020.106334DOI Listing
June 2020

A Case of Visual Illusions Secondary to Mirtazapine Treatment.

Prim Care Companion CNS Disord 2020 Feb 6;22(1). Epub 2020 Feb 6.

Department of Neuroscience, University of Padova, Via Giustiniani 2, Padua, Italy.

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http://dx.doi.org/10.4088/PCC.19l02500DOI Listing
February 2020

Polyglutamine-Expanded Androgen Receptor Alteration of Skeletal Muscle Homeostasis and Myonuclear Aggregation Are Affected by Sex, Age and Muscle Metabolism.

Cells 2020 01 30;9(2). Epub 2020 Jan 30.

Dulbecco Telethon Institute, Centre for Integrative Biology (CIBIO), University of Trento, 38123 Trento, Italy.

Polyglutamine (polyQ) expansions in the androgen receptor (AR) gene cause spinal and bulbar muscular atrophy (SBMA), a neuromuscular disease characterized by lower motor neuron (MN) loss and skeletal muscle atrophy, with an unknown mechanism. We generated new mouse models of SBMA for constitutive and inducible expression of mutant AR and performed biochemical, histological and functional analyses of phenotype. We show that polyQ-expanded AR causes motor dysfunction, premature death, IIb-to-IIa/IIx fiber-type change, glycolytic-to-oxidative fiber-type switching, upregulation of atrogenes and autophagy genes and mitochondrial dysfunction in skeletal muscle, together with signs of muscle denervation at late stage of disease. PolyQ expansions in the AR resulted in nuclear enrichment. Within the nucleus, mutant AR formed 2% sodium dodecyl sulfate (SDS)-resistant aggregates and inclusion bodies in myofibers, but not spinal cord and brainstem, in a process exacerbated by age and sex. Finally, we found that two-week induction of expression of polyQ-expanded AR in adult mice was sufficient to cause premature death, body weight loss and muscle atrophy, but not aggregation, metabolic alterations, motor coordination and fiber-type switch, indicating that expression of the disease protein in the adulthood is sufficient to recapitulate several, but not all SBMA manifestations in mice. These results imply that chronic expression of polyQ-expanded AR, i.e. during development and prepuberty, is key to induce the full SBMA muscle pathology observed in patients. Our data support a model whereby chronic expression of polyQ-expanded AR triggers muscle atrophy through toxic (neomorphic) gain of function mechanisms distinct from normal (hypermorphic) gain of function mechanisms.
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http://dx.doi.org/10.3390/cells9020325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072234PMC
January 2020

Neurological soft signs in schizophrenia spectrum disorders are not confounded by current antipsychotic dosage.

Eur Neuropsychopharmacol 2020 02 25;31:47-57. Epub 2019 Nov 25.

Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. Electronic address:

Neurological soft signs (NSS) have garnered increasing attention in psychiatric research on motor abnormalities in schizophrenia spectrum disorders (SSD). However, it remains unclear whether the assessment of NSS severity could have been confounded by current antipsychotic dosage. In this study, we recruited 105 patients with SSD that underwent a comprehensive motor assessment evaluating NSS and extrapyramidal motor symptoms (EPMS) by means of standardized instruments. Current antipsychotic dosage equivalence estimates were determined by the classical mean dose method (doses equivalent to 1 mg/d olanzapine). We used multiple regression analyses to describe the relationship between NSS, EPMS and antipsychotic medication. In line with our expectations, current antipsychotic dosage had no significant effects on NSS total score (p = 0.27), abnormal involuntary movements (p = 0.17), akathisia (p = 0.32) and parkinsonism (p = 0.26). Further, NSS total score had a significant effect on akathisia (p = 0.003) and parkinsonism (p = 0.0001, Bonferroni corr.), but only marginal effect on abnormal involuntary movements (p = 0.08). Our results support the notion that NSS are not significantly modulated by current antipsychotic dosage in SSD. The associations between NSS, akathisia and parkinsonism, as revealed by this study, support the genuine rather than medication-dependent origin of particular motor abnormalities in SSD.
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http://dx.doi.org/10.1016/j.euroneuro.2019.11.001DOI Listing
February 2020

Large scale networks for human hand-object interaction: Functionally distinct roles for two premotor regions identified intraoperatively.

Neuroimage 2020 01 24;204:116215. Epub 2019 Sep 24.

Laboratory of Motor Control, Department of Medical Biotechnologies and Translational Medicine, Università degli Studi di Milano, Humanitas Reasearch Hospital, IRCCS, Milan, Italy.

The development of awake intraoperative brain-mapping procedures for resection of brain tumors is of growing interest in neuroscience, because it enables direct testing of brain tissue, previously only possible in non-human primates. In a recent study performed in this setting specific effects can be induced by direct electrical stimulation on different sectors of premotor cortex during the execution of a hand manipulation task. Specifically, direct electrical stimulation applied on a dorsal sector of precentral cortex led to an increase in motor unit recruitment in hand muscles during execution of a hand manipulation task (Recruitment sector). The opposite effect was elicited when electrical stimulation was delivered more ventrally on the precentral cortex (Suppression sector). We studied whether the different effects on motor behavior induced by direct electrical stimulation applied on the two sites of the precentral cortex underlie differences in their functional connectivity with other brain areas, measured using resting state fMRI. Using healthy adults scanned as part of the Human Connectome Project, we computed the functional connectivity of each sector used as seeds. The functional connectivity patterns of the two intraoperative seeds was similar but cross-comparison revealed that the left and right Recruitment sectors had stronger functional connections with the hand region of the sensorimotor cortex, while the right Suppression region displayed stronger functional connectivity with a bilateral set of parieto-frontal areas crucial for the integration of perceptual and cognitive hand-related sensorimotor processes required for goal-related hand actions. Our results suggest that analyzing data obtained in the intraoperative setting with resting state functional magnetic resonance imaging in healthy brains can yield useful insight into the roles of different premotor sectors directly involved in hand-object interaction.
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http://dx.doi.org/10.1016/j.neuroimage.2019.116215DOI Listing
January 2020

Cognitive remediation therapy modulates intrinsic neural activity in patients with major depression.

Psychol Med 2020 10 16;50(14):2335-2345. Epub 2019 Sep 16.

Department of General Psychiatry, Center for Psychosocial Medicine, University of Heidelberg, Heidelberg Germany, Voßstr. 4, 69115Heidelberg, Germany.

Background: Cognitive impairment is a core feature of major depressive disorder (MDD). Cognitive remediation may improve cognition in MDD, yet so far, the underlying neural mechanisms are unclear. This study investigated changes in intrinsic neural activity in MDD after a cognitive remediation trial.

Methods: In a longitudinal design, 20 patients with MDD and pronounced cognitive deficits and 18 healthy controls (HC) were examined using resting-state functional magnetic resonance imaging. MDD patients received structured cognitive remediation therapy (CRT) over 5 weeks. The whole-brain fractional amplitude of low-frequency fluctuations was computed before the first and after the last training session. Univariate methods were used to address regionally-specific effects, and a multivariate data analysis strategy was employed to investigate functional network strength (FNS).

Results: MDD patients significantly improved in cognitive function after CRT. Baseline comparisons revealed increased right caudate activity and reduced activity in the left frontal cortex, parietal lobule, insula, and precuneus in MDD compared to HC. In patients, reduced FNS was found in a bilateral prefrontal system at baseline (p < 0.05, uncorrected). In MDD, intrinsic neural activity increased in right inferior frontal gyrus after CRT (p < 0.05, small volume corrected). Left inferior parietal lobule, left insula, left precuneus, and right caudate activity showed associations with cognitive improvement (p < 0.05, uncorrected). Prefrontal network strength increased in patients after CRT, but this increase was not associated with improved cognitive performance.

Conclusions: Our findings support the role of intrinsic neural activity of the prefrontal cortex as a possible mediator of cognitive improvement following CRT in MDD.
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http://dx.doi.org/10.1017/S003329171900240XDOI Listing
October 2020

Patterns of co-altered brain structure and function underlying neurological soft signs in schizophrenia spectrum disorders.

Hum Brain Mapp 2019 12 12;40(17):5029-5041. Epub 2019 Aug 12.

Center for Psychosocial Medicine, Department of General Psychiatry, Heidelberg University, Heidelberg, Germany.

Neurological soft signs (NSS) comprise a broad range of subtle neurological deficits and are considered to represent external markers of sensorimotor dysfunction frequently found in mental disorders of presumed neurodevelopmental origin. Although NSS frequently occur in schizophrenia spectrum disorders (SSD), specific patterns of co-altered brain structure and function underlying NSS in SSD have not been investigated so far. It is unclear whether gray matter volume (GMV) alterations or aberrant brain activity or a combination of both, are associated with NSS in SSD. Here, 37 right-handed SSD patients and 37 matched healthy controls underwent motor assessment and magnetic resonance imaging (MRI) at 3 T. NSS were examined on the Heidelberg NSS scale. We used a multivariate data fusion technique for multimodal MRI data-multiset canonical correlation and joint independent component analysis (mCCA + jICA)-to investigate co-altered patterns of GMV and intrinsic neural fluctuations (INF) in SSD patients exhibiting NSS. The mCCA + jICA model indicated two joint group-discriminating components (temporoparietal/cortical sensorimotor and frontocerebellar/frontoparietal networks) and one modality-specific group-discriminating component (p < .05, FDR corrected). NSS motor score was associated with joint frontocerebellar/frontoparietal networks in SSD patients. This study highlights complex neural pathomechanisms underlying NSS in SSD suggesting aberrant structure and function, predominantly in cortical and cerebellar systems that critically subserve sensorimotor dynamics and psychomotor organization.
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http://dx.doi.org/10.1002/hbm.24755DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6865492PMC
December 2019

Transdiagnostic modulation of brain networks by electroconvulsive therapy in schizophrenia and major depression.

Eur Neuropsychopharmacol 2019 08 3;29(8):925-935. Epub 2019 Jul 3.

Center for Psychosocial Medicine, Department of General Psychiatry, Heidelberg University, 69115 Heidelberg, Germany. Electronic address:

Major depressive disorder (MDD) and schizophrenia (SCZ) share neurobiological and clinical commonalities. Altered functional connectivity of large-scale brain networks has been associated with both disorders. Electroconvulsive therapy (ECT) has proven to be an effective treatment in severe forms of MDD and SCZ. However, the role of ECT on the modulation of the dynamics of brain networks is still unknown. In this study, we used resting state functional magnetic resonance imaging (rs-fMRI) to investigate functional connectivity in 16 pharmacoresistant patients with SCZ or MDD and a matched group of normal controls. Patients were scanned before and after right-sided unilateral ECT. Group spatial independent component analysis was carried out with a multiple analysis of covariance (MANCOVA) approach to estimate the effects of ECT treatment on intrinsic components (INs). Functional network connectivity (FNC) was calculated between pairs of INs. Patients had reduced connectivity within a striato-thalamic network in the thalamus as well as increased low frequency oscillations in a striatal network. ECT reduced low frequency oscillations (LFOs) on a striatal network along with increasing functional connectivity in the medial prefrontal cortex within the DMN. Following ECT treatment, the FNC of the executive network was reduced with the DMN and increased with the salience network, respectively. Our findings suggest transnosological effects of ECT on the connectivity of large-scale networks as well as at the level of their interplay. Furthermore, they support a transnosological approach for the investigation not only of the neural correlates of the disease but also of the brain mechanism of treatment of mental disorders.
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http://dx.doi.org/10.1016/j.euroneuro.2019.06.002DOI Listing
August 2019

Exploring cortical predictors of clinical response to electroconvulsive therapy in major depression.

Eur Arch Psychiatry Clin Neurosci 2020 Mar 5;270(2):253-261. Epub 2019 Jul 5.

Department of General Psychiatry, Center for Psychosocial Medicine, University of Heidelberg, Vosstrasse 4, 69115, Heidelberg, Germany.

Electroconvulsive therapy (ECT) is a rapid and highly effective treatment option for treatment-resistant major depressive disorder (TRD). The neural mechanisms underlying such beneficial effects are poorly understood. Exploring associations between changes of brain structure and clinical response is crucial for understanding ECT mechanisms of action and relevant for the validation of potential biomarkers that can facilitate the prediction of ECT efficacy. The aim of this explorative study was to identify cortical predictors of clinical response in TRD patients treated with ECT. We longitudinally investigated 12 TRD patients before and after ECT. Twelve matched healthy controls were studied cross sectionally. Demographical, clinical, and structural magnetic resonance imaging data at 3 T and multiple cortical markers derived from surface-based morphometry (SBM) analyses were considered. Multiple regression models were computed to identify predictors of clinical response to ECT, as reflected by Hamilton Depression Rating Scale (HAMD) score changes. Symptom severity differences pre-post-ECT were predicted by models including demographic data, clinical data and SBM of frontal, cingulate, and entorhinal structures. Using all-subsets regression, a model comprising HAMD score at baseline and cortical thickness of the left rostral anterior cingulate gyrus explained most variance in the data (multiple R = 0.82). The data suggest that SBM provides powerful measures for identifying biomarkers for ECT response in TRD. Rostral anterior cingulate thickness and HAMD score at baseline showed the greatest predictive power of clinical response, in contrast to cortical complexity, cortical gyrification, or demographical data.
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http://dx.doi.org/10.1007/s00406-019-01033-wDOI Listing
March 2020

Functional neuroimaging in treatment resistant schizophrenia: A systematic review.

Neurosci Biobehav Rev 2019 09 2;104:178-190. Epub 2019 Jul 2.

Department of Medicine (DAME), University of Udine, Udine, Italy; Department of Neuroscience (DNS), University of Padova, Padua, Italy. Electronic address:

Despite the availability of several drugs, about 30% of patients with schizophrenia still fail to respond properly to a course of appropriate antipsychotic treatment. Functional neuroimaging studies have shown widespread patterns of altered activation and functional connectivity in treatment-resistant schizophrenia (TRS). The aim of the present study was to examine the available functional magnetic resonance imaging studies investigating TRS and to identify common patterns of altered brain function that could predict the lack of response to antipsychotic treatment in this disorder. Alterations of activation and functional connectivity in fronto-temporal, cortico-striatal, default mode network and salience networks, and of their interplay, were associated with TRS. Our findings support the notion that large-scale network alterations present in schizophrenia lie in a continuum within treatment response with the most severe dysfunction in TRS. Few studies with small sample size and without adequate control group limit the generalizability of current literature. Future controlled longitudinal studies are needed to identify neuroimaging biomarkers of pharmacotherapy response to inform individual treatment selection and facilitate early clinical response.
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http://dx.doi.org/10.1016/j.neubiorev.2019.07.001DOI Listing
September 2019

Motor domain in psychotic disorders: the rebirth of a concept.

Eur Arch Psychiatry Clin Neurosci 2020 04 25;270(3):399-400. Epub 2019 Jun 25.

Department of General Psychiatry, Center for Psychosocial Medicine, Heidelberg University, Heidelberg, Germany.

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http://dx.doi.org/10.1007/s00406-019-01036-7DOI Listing
April 2020

Embarking on antidepressant response prediction using brain perfusion estimation.

EClinicalMedicine 2019 Apr 3;10:4-5. Epub 2019 May 3.

Department of General Psychiatry, Center for Psychosocial Medicine, University of Heidelberg, Heidelberg, Germany.

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http://dx.doi.org/10.1016/j.eclinm.2019.04.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6543176PMC
April 2019

Multimodal Magnetic Resonance Imaging Data Fusion Reveals Distinct Patterns of Abnormal Brain Structure and Function in Catatonia.

Schizophr Bull 2020 01;46(1):202-210

Center for Psychosocial Medicine, Department of General Psychiatry, Heidelberg University, Heidelberg, Germany.

Catatonia is a nosologically unspecific syndrome, which subsumes a plethora of mostly complex affective, motor, and behavioral phenomena. Although catatonia frequently occurs in schizophrenia spectrum disorders (SSD), specific patterns of abnormal brain structure and function underlying catatonia are unclear at present. Here, we used a multivariate data fusion technique for multimodal magnetic resonance imaging (MRI) data to investigate patterns of aberrant intrinsic neural activity (INA) and gray matter volume (GMV) in SSD patients with and without catatonia. Resting-state functional MRI and structural MRI data were collected from 87 right-handed SSD patients. Catatonic symptoms were examined on the Northoff Catatonia Rating Scale (NCRS). A multivariate analysis approach was used to examine co-altered patterns of INA and GMV. Following a categorical approach, we found predominantly frontothalamic and corticostriatal abnormalities in SSD patients with catatonia (NCRS total score ≥ 3; n = 24) when compared to SSD patients without catatonia (NCRS total score = 0; n = 22) matched for age, gender, education, and medication. Corticostriatal network was associated with NCRS affective scores. Following a dimensional approach, 33 SSD patients with catatonia according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision were identified. NCRS behavioral scores were associated with a joint structural and functional system that predominantly included cerebellar and prefrontal/cortical motor regions. NCRS affective scores were associated with frontoparietal INA. This study provides novel neuromechanistic insights into catatonia in SSD suggesting co-altered structure/function-interactions in neural systems subserving coordinated visuospatial functions and motor behavior.
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http://dx.doi.org/10.1093/schbul/sbz042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6942158PMC
January 2020

A search for cortical correlates of trait impulsivity in Parkinson´s disease.

Behav Brain Res 2019 09 13;369:111911. Epub 2019 Apr 13.

Center for Psychosocial Medicine, Department of General Psychiatry, University of Heidelberg, Germany.

Background: Impulsivity is an enduring personality trait that is highly relevant for the development of neuropsychiatric disorders. Although impulse control disorders (ICD) are well-characterized non-motor features in Parkinson's disease (PD), mainly related to medication, little is known about neural correlates reflecting trait aspects of impulsivity in PD patients. Here, we address the question whether motor, attentional and non-planning components, measured by the Barratt Impulsiveness Scale (BIS-11), are distinctly related to cortical thickness and cortical folding abnormalities in PD when compared to age-matched healthy controls (HC).

Method: We investigated cortical thickness (CT) and complexity of cortical folding (CCF) in 22 PD patients with moderately advanced disease stages without ICD and 18 HC using high-resolution structural magnetic resonance imaging (MRI) data. Surface-based data analysis was driven by CAT12 toolbox.

Results: PD patients showed widespread CT loss in frontal, cingulate, temporo-parietal and occipital regions (FDR corrected at p < 0.05 using threshold-free cluster enhancement). Significant differences in CCF between groups were not found. Using a multiple regression model, CT in inferior and superior frontal, anterior cingulate and precentral regions significantly predicted BIS attentional subscores (p = 0.041).

Conclusion: These data suggest a specific cortical trajectory associated with impulsivity in moderately advanced staged PD patients. The attentional dimension of trait impulsivity appears to be specifically related to CT, in contrast to alterations of early neurodevelopmental markers, i. e. CCF. Our results shed light on structural correlates of trait impulsivity in PD patients and establish a baseline for future research into neural risk factors potentially predisposing to ICD development.
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http://dx.doi.org/10.1016/j.bbr.2019.111911DOI Listing
September 2019

The Combination of DAT-SPECT, Structural and Diffusion MRI Predicts Clinical Progression in Parkinson's Disease.

Front Aging Neurosci 2019 15;11:57. Epub 2019 Mar 15.

Roche Pharma and Early Development, Neuroscience, Ophthalmology and Rare Diseases, F. Hoffmann-La Roche Ltd., Basel, Switzerland.

There is an increasing interest in identifying non-invasive biomarkers of disease severity and prognosis in idiopathic Parkinson's disease (PD). Dopamine-transporter SPECT (DAT-SPECT), diffusion tensor imaging (DTI), and structural magnetic resonance imaging (sMRI) provide unique information about the brain's neurotransmitter and microstructural properties. In this study, we evaluate the relative and combined capability of these imaging modalities to predict symptom severity and clinical progression in PD patients. To this end, we used MRI, SPECT, and clinical data of drug-naïve PD patients ( = 205, mean age 61 ± 10) and age-, sex-matched healthy controls ( = 105, mean age 58 ± 12) acquired at baseline. Moreover, we employed clinical data acquired at 1 year follow-up for PD patients with or without L-Dopa treatment in order to predict the progression symptoms severity. Voxel-based group comparisons and covariance analyses were applied to characterize baseline disease-related alterations for DAT-SPECT, DTI, and sMRI. Cortical and subcortical alterations in PD patients were found in all evaluated imaging modalities, in line with previously reported midbrain-striato-cortical network alterations. The combination of these imaging alterations was reliably linked to clinical severity and disease progression at 1 year follow-up in this patient population, providing evidence for the potential use of these modalities as imaging biomarkers for disease severity and prognosis that can be integrated into clinical trials.
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http://dx.doi.org/10.3389/fnagi.2019.00057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6428714PMC
March 2019

Mindfulness-based therapy modulates default-mode network connectivity in patients with opioid dependence.

Eur Neuropsychopharmacol 2019 05 26;29(5):662-671. Epub 2019 Mar 26.

Center for Psychosocial Medicine, Department of General Psychiatry, Heidelberg University, Voßstraße 4, 69115 Heidelberg, Germany. Electronic address:

Recently, mindfulness-based programs have shown promising clinical effects in the treatment of substance-use disorders (SUD). While several studies linked mindfulness to decreased default mode network (DMN) connectivity in meditators, only a few studies investigated its effects in patients with SUD. This study aimed to detect changes in DMN connectivity in opiate dependent patients receiving mindfulness based therapy (MBT) during their first month of treatment. Data from 32 patients that were assigned to MBT or treatment as usual (TAU) groups was investigated using resting-state functional MRI at 1.5 T before and after four weeks of treatment. Independent Component Analysis was used to investigate distinct (anterior vs. posterior) DMN subsystems. Connectivity changes after treatment were related to measures of impulsivity, distress tolerance and mindfulness. Increased mindfulness scores after treatment were found in patients receiving MBT compared to TAU. Within the anterior DMN, decreased right inferior frontal cortical connectivity was detected in patients who received MBT compared to TAU. In addition, within the MBT-group decreased right superior frontal cortex connectivity was detected after treatment. Inferior frontal cortex function was significantly associated with mindfulness measures. The data suggest that MBT can be useful during abstinence from opiates. In opiate-dependent patients distinct functional connectivity changes within the DMN are associated with MBT.
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http://dx.doi.org/10.1016/j.euroneuro.2019.03.002DOI Listing
May 2019

Structure/function interrelationships in patients with schizophrenia who have persistent auditory verbal hallucinations: A multimodal MRI study using parallel ICA.

Prog Neuropsychopharmacol Biol Psychiatry 2019 07 16;93:114-121. Epub 2019 Mar 16.

Center for Psychosocial Medicine, Department of General Psychiatry, University of Heidelberg, Germany. Electronic address:

There is accumulating neuroimaging evidence for both structural and functional abnormalities in schizophrenia patients with persistent auditory verbal hallucinations (AVH). So far, the direct interrelationships between altered structural and functional changes underlying AVH are unknown. Recently, it has become possible to reveal hidden patterns of neural dysfunction not sufficiently captured by separate analysis of these two modalities. A data-driven fusion method called parallel independent component analysis (p-ICA) is able to identify maximally independent components of each imaging modality as well as the link between them. In the present study, we utilized p-ICA to study covarying components among gray matter volume maps computed from structural MRI (sMRI) and fractional amplitude of low-frequency fluctuations (fALFF) maps computed from resting-state functional MRI (rs-fMRI) data of 15 schizophrenia patients with AVH, 16 non-hallucinating schizophrenia patients (nAVH), and 19 healthy controls (HC). We found a significant correlation (r = 0.548, n = 50, p < .001) between a sMRI component and a rs-fMRI component, which was significantly different between the AVH and non AVH group (nAVH). The rs-fMRI component comprised temporal cortex and cortical midline regions, the sMRI component included predominantly fronto-temporo-parietal regions. Distinct clinical features, as measured by the Psychotic Symptoms Rating Scale (PSYRATS), were associated with two different modality specific rs-fMRI components. There was a significant correlation between a predominantly parietal resting-state network and the physical dimension of PSYRATS and the posterior cingulate/temporal cortex network and the emotional dimension of PSYRATS. These data suggest AVH-specific interrelationships between intrinsic network activity and GMV, together with modality-specific associations with distinct symptom dimensions of AVH.
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http://dx.doi.org/10.1016/j.pnpbp.2019.03.007DOI Listing
July 2019

Thalamic connectivity measured with fMRI is associated with a polygenic index predicting thalamo-prefrontal gene co-expression.

Brain Struct Funct 2019 Apr 6;224(3):1331-1344. Epub 2019 Feb 6.

Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari Aldo Moro, Piazza Giulio Cesare, 11, 70124, Bari, Italy.

The functional connectivity between thalamic medio-dorsal nucleus (MD) and cortical regions, especially the dorsolateral prefrontal cortex (DLPFC), is implicated in attentional processing and is anomalous in schizophrenia, a brain disease associated with polygenic risk and attentional deficits. However, the molecular and genetic underpinnings of thalamic connectivity anomalies are unclear. Given that gene co-expression across brain areas promotes synchronous interregional activity, our aim was to investigate whether coordinated expression of genes relevant to schizophrenia in MD and DLPFC may reflect thalamic connectivity anomalies in an attention-related network including the DLPFC. With this aim, we identified in datasets of post-mortem prefrontal mRNA expression from healthy controls a gene module with robust overrepresentation of genes with coordinated MD-DLPFC expression and enriched for schizophrenia genes according to the largest genome-wide association study to date. To link this gene cluster with imaging phenotypes, we computed a Polygenic Co-Expression Index (PCI) combining single-nucleotide polymorphisms predicting module co-expression. Finally, we investigated the association between PCI and thalamic functional connectivity during attention through fMRI Independent Component Analysis in 265 healthy participants. We found that PCI was positively associated with connectivity strength of a thalamic region overlapping with the MD within an attention brain circuit. These findings identify a novel association between schizophrenia-related genes and thalamic functional connectivity. Furthermore, they highlight the association between gene expression co-regulation and brain connectivity, such that genes with coordinated MD-DLPFC expression are associated with coordinated activity between the same brain regions. We suggest that gene co-expression is a plausible mechanism underlying biological phenotypes of schizophrenia.
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http://dx.doi.org/10.1007/s00429-019-01843-7DOI Listing
April 2019