Higher-order functional brain networks and anterior cingulate glutamate + glutamine (Glx) in antipsychotic-naïve first episode psychosis patients.

Human connectome studies have provided abundant data consistent with the hypothesis that functional dysconnectivity is predominant in psychosis spectrum disorders. Converging lines of evidence also suggest an interaction between dorsal anterior cingulate cortex (dACC) cortical glutamate with higher-order functional brain networks (FC) such as the default mode (DMN), dorsal attention (DAN), and executive control networks (ECN) in healthy controls (HC) and this mechanism may be impaired in psychosis. Data from 70 antipsychotic-medication naïve first-episode psychosis (FEP) and 52 HC were analyzed. 3T Proton magnetic resonance spectroscopy (1H-MRS) data were acquired from a voxel in the dACC and assessed correlations (positive FC) and anticorrelations (negative FC) of the DMN, DAN, and ECN. We then performed regressions to assess associations between glutamate + glutamine (Glx) with positive and negative FC of these same networks and compared them between groups. We found alterations in positive and negative FC in all networks (HC > FEP). A relationship between dACC Glx and positive and negative FC was found in both groups, but when comparing these relationships between groups, we found contrasting associations between these variables in FEP patients compared to HC. We demonstrated that both positive and negative FC in three higher-order resting state networks are already altered in antipsychotic-naïve FEP, underscoring the importance of also considering anticorrelations for optimal characterization of large-scale functional brain networks as these represent biological processes as well. Our data also adds to the growing body of evidence supporting the role of dACC cortical Glx as a mechanism underlying alterations in functional brain network connectivity. Overall, the implications for these findings are imperative as this particular mechanism may differ in untreated or chronic psychotic patients; therefore, understanding this mechanism prior to treatment could better inform clinicians.Clinical trial registration: Trajectories of Treatment Response as Window into the Heterogeneity of Psychosis: A Longitudinal Multimodal Imaging Study, NCT03442101 . Glutamate, Brain Connectivity and Duration of Untreated Psychosis (DUP), NCT02034253 .

Higher-Order Intrinsic Brain Network Trajectories After Antipsychotic Treatment in Medication-Naïve Patients With First-Episode Psychosis.

BACKGROUND: Intrinsic brain network connectivity is already altered in first-episode psychosis (FEP), but the longitudinal trajectories of network connectivity, especially in response to antipsychotic treatment, remain poorly understood. The goal of this study was to investigate how antipsychotic medications affect higher-order intrinsic brain network connectivity in FEP. METHODS: Data from 87 antipsychotic medication-naïve patients with FEP and 87 healthy control participants were used. Medication-naïve patients received antipsychotic treatment for 16 weeks. Resting-state functional connectivity (FC) of the default mode, salience, dorsal attention, and executive control networks were assessed prior to treatment and at 6 and 16 weeks after treatment. We evaluated baseline and FC changes using linear mixed models to test group × time interactions within each network. Associations between FC changes after 16 weeks and response to treatment were also evaluated. RESULTS: Prior to treatment, significant group differences in all networks were found. However, significant trajectory changes in FC were found only in the default mode and executive control networks. Changes in FC in these networks were associated with treatment response. Several sensitivity analyses showed a consistent normalization of executive control network FC in response to antipsychotic treatment. CONCLUSIONS: Here, we found that alterations in intrinsic brain network FC were not only alleviated with antipsychotic treatment, but the extent of this normalization was also associated with the degree of reduction in symptom severity. Taken together, our data suggest modulation of intrinsic brain network connectivity (mainly frontoparietal connectivity) as a mechanism underlying antipsychotic treatment response in FEP.

Structural Racism in Psychiatric Research Careers: Eradicating Barriers to a More Diverse Workforce.

Investigators from minoritized backgrounds are underrepresented in psychiatric research. That underrepresentation contributes to disparities in outcomes of access to mental health care. Drawing on lived experience, scholarly qualitative reports, and empirical data, the authors review how the underrepresentation of minoritized researchers arises from interlocking, self-reinforcing effects of structural biases in our research training and funding institutions. Minoritized researchers experience diminished early access to advanced training and opportunities, stereotype threats and microaggressions, isolation due to lack of peers and senior mentors, decreased access to early funding, and unique community and personal financial pressures. These represent structural racism-a system of institutional assumptions and practices that perpetuates race-based disparities, in spite of those institutions' efforts to increase diversity and in contradiction to the values that academic leaders outwardly espouse. The authors further review potential approaches to reversing these structural biases, including undergraduate-focused research experiences, financial support for faculty who lead training/mentoring programs, targeted mentoring through scholarly societies, better use of federal diversity supplement funding, support for scientific reentry, cohort building, diversity efforts targeting senior leadership, and rigorous examination of hiring, compensation, and promotion practices. Several of these approaches have empirically proven best practices and models for dissemination. If implemented alongside outcome measurement, they have the potential to reverse decades of structural bias in psychiatry and psychiatric research.

Hippocampal Hyperconnectivity to the Visual Cortex Predicts Treatment Response.

BACKGROUND: Converging lines of evidence point to hippocampal dysfunction in psychosis spectrum disorders, including altered functional connectivity. Evidence also suggests that antipsychotic medications can modulate hippocampal dysfunction. The goal of this project was to identify patterns of hippocampal connectivity predictive of response to antipsychotic treatment in 2 cohorts of patients with a psychosis spectrum disorder, one medication-naïve and the other one unmedicated. HYPOTHESIS: We hypothesized that we would identify reliable patterns of hippocampal connectivity in the 2 cohorts that were predictive of treatment response and that medications would modulate abnormal hippocampal connectivity after 6 weeks of treatment. STUDY DESIGN: We used a prospective design to collect resting-state fMRI scans prior to antipsychotic treatment and after 6 weeks of treatment with risperidone, a commonly used antipsychotic medication, in both cohorts. We enrolled 44 medication-naïve first-episode psychosis patients (FEP) and 39 unmedicated patients with schizophrenia (SZ). STUDY RESULTS: In both patient cohorts, we observed a similar pattern where greater hippocampal connectivity to regions of the occipital cortex was predictive of treatment response. Lower hippocampal connectivity of the frontal pole, orbitofrontal cortex, subcallosal area, and medial prefrontal cortex was predictive of treatment response in unmedicated SZ, but not in the medication-naïve cohort. Furthermore, greater reduction in hippocampal connectivity to the visual cortex with treatment was associated with better clinical response. CONCLUSIONS: Our results suggest that greater connectivity between the hippocampus and occipital cortex is not only predictive of better treatment response, but that antipsychotic medications have a modulatory effect by reducing hyperconnectivity.

Co-occurring opioid use disorder and serious mental illness: A selective literature review.

OBJECTIVE: The overarching goal of this review is to provide a clinical overview of epidemiology, diagnosis, and treatment, and to discuss the public health impact, social determinants including access to care, and implications for health care delivery and research. It is estimated that approximately 1 in 4 individuals suffering from a serious mental illness (SMI) may have a co-occurring opioid use disorder (OUD). In these individuals, the overall disease burden is higher and clinical outcomes are worse compared to those without a co-occurring illness, making an integrated approach to diagnosis and treatment an urgent priority. METHODS: We conducted a selective review of the literature to investigate prevalence, etiology for co-occurring OUD and SMI, and diagnostic and clinical guidelines in the United States, and consideration special populations. FINDINGS: Our findings suggest that, despite the high prevalence of co-occurring OUD and SMI, contemporary diagnostics and treatment approaches are underutilized in this patient population. The literature also suggests that both pharmacological and psychosocial treatment approaches need to be tailored to optimize clinical management, and that integrated treatment is pivotal for improving overall outcomes, yet comprehensive clinical guidelines for co-occurring OUD and SMI are lacking at this time.

In Search of Biomarkers to Guide Interventions in Autism Spectrum Disorder: A Systematic Review.

OBJECTIVE: The aim of this study was to catalog and evaluate response biomarkers correlated with autism spectrum disorder (ASD) symptoms to improve clinical trials. METHODS: A systematic review of MEDLINE, Embase, and Scopus was conducted in April 2020. Seven criteria were applied to focus on original research that includes quantifiable response biomarkers measured alongside ASD symptoms. Interventional studies or human studies that assessed the correlation between biomarkers and ASD-related behavioral measures were included. RESULTS: A total of 5,799 independent records yielded 280 articles for review that reported on 940 biomarkers, 755 of which were unique to a single publication. Molecular biomarkers were the most frequently assayed, including cytokines, growth factors, measures of oxidative stress, neurotransmitters, and hormones, followed by neurophysiology (e.g., EEG and eye tracking), neuroimaging (e.g., functional MRI), and other physiological measures. Studies were highly heterogeneous, including in phenotypes, demographic characteristics, tissues assayed, and methods for biomarker detection. With a median total sample size of 64, almost all of the reviewed studies were only powered to identify biomarkers with large effect sizes. Reporting of individual-level values and summary statistics was inconsistent, hampering mega- and meta-analysis. Biomarkers assayed in multiple studies yielded mostly inconsistent results, revealing a "replication crisis." CONCLUSIONS: There is currently no response biomarker with sufficient evidence to inform ASD clinical trials. This review highlights methodological imperatives for ASD biomarker research necessary to make definitive progress: consistent experimental design, correction for multiple comparisons, formal replication, sharing of sample-level data, and preregistration of study designs. Systematic "big data" analyses of multiple potential biomarkers could accelerate discovery.

Dorsal striatial hypoconnectivity predicts antipsychotic medication treatment response in first-episode psychosis and unmedicated patients with schizophrenia.

INTRODUCTION: The dorsal striatum, comprised of the caudate and putamen, is implicated in the pathophysiology of psychosis spectrum disorders. Given the high concentration of dopamine receptors in the striatum, striatal dopamine imbalance is a likely cause in cortico-striatal dysconnectivity. There is great interest in understanding the relationship between striatal abnormalities in psychosis and antipsychotic treatment response, but few studies have considered differential involvement of the caudate and putamen. This study's goals were twofold. First, identify patterns of dorsal striatal dysconnectivity for the caudate and putamen separately in patients with a psychosis spectrum disorder; second, determine if these dysconnectivity patterns were predictive of treatment response. METHODS: Using resting state functional connectivity, we evaluated dorsal striatal connectivity using separate bilateral caudate and putamen seed regions in two cohorts of subjects: a cohort of 71 medication-naïve first episode psychosis patients and a cohort of 42 unmedicated patients with schizophrenia (along with matched controls). Patient and control connectivity maps were contrasted for each cohort. After receiving 6 weeks of risperidone treatment, patients' clinical response was calculated. We used regression analyses to determine the relationship between baseline dysconnectivity and treatment response. RESULTS: This dysconnectivity was also predictive of treatment response in both cohorts. DISCUSSION: These findings suggest that the caudate may be more of a driving factor than the putamen in early cortico-striatal dysconnectivity.

The neural substrates of neurological soft signs in schizophrenia: a systematic review.

Neurological soft signs (NSS) are common in patients with schizophrenia. However, the neural substrates of NSS remain poorly understood. Using legacy PubMed, we performed a systematic review and included studies that assessed NSS and obtained neuroimaging data in patients with a schizophrenia spectrum disorder published up to June 2020. We systematically reviewed 35 relevant articles. Studies consistently implicate the basal ganglia and cerebellum as structural substrates of NSS and suggest that somatomotor and somatosensory regions as well as areas involved in visual processing and spatial orientation may underlie NSS in psychosis spectrum disorders. Additionally, dysfunction of frontoparietal and cerebellar networks has been implicated in the pathophysiology of NSS. The current literature outlines several structural and functional brain signatures that are relevant for NSS in schizophrenia spectrum disorder. The majority of studies assessed gray matter structure, but only a few studies leveraged other imaging methods such as diffusion weighted imaging, or molecular imaging. Due to this, it remains unclear if white matter integrity deficits or neurometabolic alterations contribute to NSS in the illness. While a substantial portion of the literature has been conducted in patients in the early illness stages, mitigating confounds of illness chronicity, few studies have been conducted in antipsychotic medication-naïve patients, which is a clear limitation. Furthermore, only little is known about the temporal evolution of NSS and associated brain signatures. Future studies addressing these pivotal gaps in our mechanistic understanding of NSS will be important.

Contrasting Frontoparietal Network Connectivity in Antipsychotic Medication-Naive First-Episode Psychosis Patients Who Do and Do Not Display Features of the Deficit Syndrome.

BACKGROUND: The deficit syndrome is a clinical subtype of schizophrenia that is characterized by enduring negative symptoms. Several lines of evidence point to frontoparietal involvement, but the frontoparietal control network (FPCN) and its subsystems (FPCNA and FPCNB) proposed by Yeo et al. have not been systematically characterized at rest in patients with the deficit syndrome. METHODS: We used resting-state fMRI to investigate the FPCN and its subnetworks in 72 healthy controls and 65 antipsychotic medication-naive, first-episode psychosis patients (22 displayed deficit syndrome features, 43 did not). To assess whole-brain FPCN connectivity, we used the right posterior parietal cortex as the seed region. We then performed region of interest analyses in FPCN subsystems. RESULTS: We found that patterns of FPCN dysconnectivity to the whole brain differed in patients who displayed deficit syndrome features compared with those who did not. Examining the FPCN on a more granular level revealed reduced within-FPCN(A) connectivity only in patients displaying deficit features. FPCNB connectivity did not differ between patient groups. DISCUSSION: Here, we describe a neurobiological signature of aberrant FPCN connectivity in antipsychotic-naive, first-episode patients who display clinical features of the deficit syndrome. Importantly, frontoparietal subnetwork connectivity differentiated subgroups, where the FPCNA is selectively involved in patients with deficit features. Our findings add to the growing body of literature supporting a neurobiological distinction between two clinical subtypes of schizophrenia, which has the potential to be leveraged for patient stratification in clinical trials and the development of novel treatments.

Hippocampal Dysconnectivity and Altered Glutamatergic Modulation of the Default Mode Network: A Combined Resting-State Connectivity and Magnetic Resonance Spectroscopy Study in Schizophrenia.

BACKGROUND: Converging lines of evidence point to hippocampal dysfunction in schizophrenia. It is thought that hippocampal dysfunction spreads across hippocampal subfields and to cortical regions by way of long-range efferent projections. Importantly, abnormalities in the excitation/inhibition balance could impair the long-range modulation of neural networks. The goal of this project was twofold. First, we sought to identify replicable patterns of hippocampal dysconnectivity in patients with a psychosis spectrum disorder. Second, we aimed to investigate a putative link between glutamatergic metabolism and hippocampal connectivity alterations. METHODS: We evaluated resting-state hippocampal functional connectivity alterations in two cohorts of patients with a psychosis spectrum disorder. The first cohort consisted of 55 medication-naïve patients with first-episode psychosis and 41 matched healthy control subjects, and the second cohort consisted of 42 unmedicated patients with schizophrenia and 41 matched control subjects. We also acquired measurements of glutamate + glutamine in the left hippocampus using magnetic resonance spectroscopy for 42 patients with first-episode psychosis and 37 healthy control subjects from our first cohort. RESULTS: We observed a pattern of hippocampal functional hypoconnectivity to regions of the default mode network and hyperconnectivity to the lateral occipital cortex in both cohorts. We also show that in healthy control subjects, greater hippocampal glutamate + glutamine levels predicted greater hippocampal functional connectivity to the anterior default mode network. Furthermore, this relationship was reversed in medication-naïve subjects with first-episode psychosis. CONCLUSIONS: These results suggest that an alteration in the relationship between glutamate and functional connectivity may disrupt the dynamic of major neural networks.

Risks and Benefits of Cannabis and Cannabinoids in Psychiatry.

OBJECTIVE: The United States is in the midst of rapidly changing laws regarding cannabis. The increasing availability of cannabis for recreational and medical use requires that mental health clinicians be knowledgeable about evidence to be considered when counseling both patients and colleagues. In this review, the authors outline the evidence from randomized double-blind placebo-controlled trials for therapeutic use of cannabinoids for specific medical conditions and the potential side effects associated with acute and chronic cannabis use. METHODS: Searches of PubMed and PsycInfo were conducted for articles published through July 2021 reporting on "cannabis" or "cannabinoids" or "medicinal cannabis." Additional articles were identified from the reference lists of published reviews. Articles that did not contain the terms "clinical trial" or "therapy" in the title or abstract were not reviewed. A total of 4,431 articles were screened, and 841 articles that met criteria for inclusion were reviewed by two or more authors. RESULTS: There are currently no psychiatric indications approved by the U.S. Food and Drug Administration (FDA) for cannabinoids, and there is limited evidence supporting the therapeutic use of cannabinoids for treatment of psychiatric disorders. To date, evidence supporting cannabinoid prescription beyond the FDA indications is strongest for the management of pain and spasticity. CONCLUSIONS: As cannabinoids become more available, the need for an evidence base adequately evaluating their safety and efficacy is increasingly important. There is considerable evidence that cannabinoids have a potential for harm in vulnerable populations such as adolescents and those with psychotic disorders. The current evidence base is insufficient to support the prescription of cannabinoids for the treatment of psychiatric disorders.

A multimodal neuroimaging study investigating resting-state connectivity, glutamate and GABA at 7 T in first-episode psychosis.

BACKGROUND: The major excitatory and inhibitory neurometabolites in the brain, glutamate and γ-aminobutyric acid (GABA), respectively, are related to the functional MRI signal. Disruption of resting-state functional MRI signals has been reported in psychosis spectrum disorders, but few studies have investigated the role of these metabolites in this context. METHODS: We included 19 patients with first-episode psychosis and 21 healthy controls in this combined magnetic resonance spectroscopy (MRS) and resting-state functional connectivity study. All imaging was performed on a Siemens Magnetom 7 T MRI scanner. Both the MRS voxel and the seed for functional connectivity analysis were located in the dorsal anterior cingulate cortex (ACC). We used multiple regressions to test for an interaction between ACC brain connectivity, diagnosis and neurometabolites. RESULTS: ACC brain connectivity was altered in first-episode psychosis. The relationship between ACC glutamate and ACC functional connectivity differed between patients with first-episode psychosis and healthy controls in the precuneus, retrosplenial cortex, supramarginal gyrus and angular gyrus. As well, the relationship between ACC GABA and ACC functional connectivity differed between groups in the caudate, putamen and supramarginal gyrus. LIMITATIONS: We used a small sample size. As well, although they were not chronically medicated, all participants were medicated during the study. CONCLUSION: We demonstrated a link between the major excitatory and inhibitory brain metabolites and resting-state functional connectivity in healthy participants, as well as an alteration in this relationship in patients with first-episode psychosis. Combining data from different imaging modalities may help our mechanistic understanding of the relationship between major neurometabolites and brain network dynamics, and shed light on the pathophysiology of first-episode psychosis.

Salience network glutamate and brain connectivity in medication-naïve first episode patients - A multimodal magnetic resonance spectroscopy and resting state functional connectivity MRI study.

BACKGROUND: Salience network (SN) connectivity is altered in schizophrenia, but the pathophysiological origin remains poorly understood. The goal of this multimodal neuroimaging study was to investigate the role of glutamatergic metabolism as putative mechanism underlying SN dysconnectivity in first episode psychosis (FEP) subjects. METHODS: We measured glutamate + glutamine (Glx) in the dorsal anterior cingulate cortex (dACC) from 70 antipsychotic-naïve FEP subjects and 52 healthy controls (HC). The dACC was then used as seed to define positive and negative resting state functional connectivity (FC) of the SN. We used multiple regression analyses to test main effects and group interactions of Glx and FC associations. RESULTS: dACC Glx levels did not differ between groups. Positive FC was significantly reduced in FEP compared to HC, and no group differences were found in negative FC. Group interactions of Glx-FC associations were found within the SN for positive FC, and in parietal cortices for negative FC. In HC, higher Glx levels predicted greater positive FC in the dACC and insula, and greater negative FC of the lateral parietal cortex. These relationships were weaker or absent in FEP. CONCLUSIONS: Here, we found that positive FC in the SN is already altered in medication-naïve FEP, underscoring the importance of considering both correlations and anticorrelations for characterization of pathology. Our data demonstrate that Glx and functional connectivity work differently in FEP than in HC, pointing to a possible mechanism underlying dysconnectivity in psychosis.

Structural and Functional Default Mode Network Connectivity and Antipsychotic Treatment Response in Medication-Naïve First Episode Psychosis Patients.

INTRODUCTION: Only a few studies have comprehensively characterized default mode network (DMN) pathology on a structural and functional level, and definite conclusions cannot be drawn due to antipsychotic medication exposure and illness chronicity. The objective of this study was to characterize DMN pathology in medication-naïve first episode psychosis (FEP) patients, and determine if DMN structural and functional connectivity (FC) have potential utility as a predictor for subsequent antipsychotic treatment response. METHODS: Diffusion imaging and resting state FC data from 42 controls and 52 FEP were analyzed. Patients then received 16 weeks of antipsychotic treatment. Using region of interest analyses, we quantified FC of the DMN and structural integrity of the white matter tracts supporting DMN function. We then did linear regressions between DMN structural and FC indices and antipsychotic treatment response. RESULTS: We detected reduced DMN fractional anisotropy and axial diffusivity in FEP compared to controls. No DMN FC abnormalities nor correlations between DMN structural and FC were found. Finally, DMN fractional anisotropy and radial diffusivity were associated with response to treatment. CONCLUSION: Our study highlights the critical role of the DMN in the pathophysiology suggesting that axonal damage may already be present in FEP patients. We also demonstrated that DMN pathology is clinically relevant, as greater structural DMN alterations were associated with a less favorable clinical response to antipsychotic medications.

Reinforcement learning abnormalities in the attenuated psychosis syndrome and first episode psychosis.

Prior studies indicate that chronic schizophrenia (SZ) is associated with a specific profile of reinforcement learning abnormalities. These impairments are characterized by: 1) reductions in learning rate, and 2) impaired Go learning and intact NoGo learning. Furthermore, each of these deficits are associated with greater severity of negative symptoms, consistent with theoretical perspectives positing that avolition and anhedonia are associated with impaired value representation. However, it is unclear whether these deficits extend to earlier phases of psychotic illness and when individuals are unmedicated. Two studies were conducted to examine reinforcement learning deficits in earlier phases of psychosis and in high risk patients. In study 1, participants included 35 participants with first episode psychosis (FEP) with limited antipsychotic medication exposure and 25 healthy controls (HC). Study 2 included 17 antipsychotic naïve individuals who were at clinical high-risk for psychosis (CHR) (i.e., attenuated psychosis syndrome) and 18 matched healthy controls (HC). In both studies, participants completed the Temporal Utility Integration Task, a measure of probabilistic reinforcement learning that contained Go and NoGo learning blocks. FEP displayed impaired Go and NoGo learning. In contrast, CHR did not display impairments in Go or NoGo learning. Impaired Go learning was not significantly associated with clinical outcomes in the CHR or FEP samples. Findings provide new evidence for areas of spared and impaired reinforcement learning in early phases of psychosis.

Neuroimaging Biomarkers in Schizophrenia.

Schizophrenia is a complex neuropsychiatric syndrome with a heterogeneous genetic, neurobiological, and phenotypic profile. Currently, no objective biological measures-that is, biomarkers-are available to inform diagnostic or treatment decisions. Neuroimaging is well positioned for biomarker development in schizophrenia, as it may capture phenotypic variations in molecular and cellular disease targets, or in brain circuits. These mechanistically based biomarkers may represent a direct measure of the pathophysiological underpinnings of the disease process and thus could serve as true intermediate or surrogate endpoints. Effective biomarkers could validate new treatment targets or pathways, predict response, aid in selection of patients for therapy, determine treatment regimens, and provide a rationale for personalized treatments. In this review, the authors discuss a range of mechanistically plausible neuroimaging biomarker candidates, including dopamine hyperactivity, N-methyl-d-aspartate receptor hypofunction, hippocampal hyperactivity, immune dysregulation, dysconnectivity, and cortical gray matter volume loss. They then focus on the putative neuroimaging biomarkers for disease risk, diagnosis, target engagement, and treatment response in schizophrenia. Finally, they highlight areas of unmet need and discuss strategies to advance biomarker development.

White matter and neurite morphology differ in psychogenic nonepileptic seizures.

OBJECTIVE: To further evaluate the relationship between the clinical profiles and limbic and motor brain regions and their connecting pathways in psychogenic nonepileptic seizures (PNES). Neurite Orientation Dispersion and Density Indices (NODDI) multicompartment modeling was used to test the relationships between tissue alterations in patients with traumatic brain injury (TBI) and multiple psychiatric symptoms. METHODS: The sample included participants with prior TBI (TBI; N = 37) but no PNES, and with TBI and PNES (TBI + PNES; N = 34). Participants completed 3T Siemens Prisma MRI high angular resolution imaging diffusion protocol. Statistical maps, including fractional anisotropy (FA), mean diffusivity (MD), neurite dispersion [orientation dispersion index (ODI)] and density [intracellular volume fraction (ICVF), and free water (i.e., isotropic) volume fraction (V-ISO)] signal intensity, were generated for each participant. Linear mixed-effects models identified clusters of between-group differences in indices of white matter changes. Pearson's r correlation tests assessed any relationship between signal intensity and psychiatric symptoms. RESULTS: Compared to TBI, TBI + PNES revealed decreases in FA, ICVF, and V-ISO and increases in MD for clusters within cingulum bundle, uncinate fasciculus, fornix/stria terminalis, and corticospinal tract pathways (cluster threshold α = 0.05). Indices of white matter changes for these clusters correlated with depressive, anxiety, PTSD, psychoticism, and somatization symptom severity (FDR threshold α = 0.05). A follow-up within-group analysis revealed that these correlations failed to reach the criteria for significance in the TBI + PNES group alone. INTERPRETATION: The results expand support for the hypothesis that alterations in pathways comprising the specific PNES network correspond to patient profiles. These findings implicate myelin-specific changes as possible contributors to PNES, thus introducing novel potential treatment targets.

A multimodal magnetoencephalography 7 T fMRI and 7 T proton MR spectroscopy study in first episode psychosis.

We combined magnetoencephalography (MEG), 7 T proton magnetic resonance spectroscopy (MRS), and 7 T fMRI during performance of a task in a group of 23 first episode psychosis (FEP) patients and 26 matched healthy controls (HC). We recorded both the auditory evoked response to 40 Hz tone clicks and the resting state in MEG. Neurometabolite levels were obtained from the anterior cingulate cortex (ACC). The fMRI BOLD response was obtained during the Stroop inhibitory control task. FEP showed a significant increase in resting state low frequency theta activity (p < 0.05; Cohen d = 0.69), but no significant difference in the 40 Hz auditory evoked response compared to HC. An across-groups whole brain analysis of the fMRI BOLD response identified eight regions that were significantly activated during task performance (p < 0.01, FDR-corrected); the mean signal extracted from those regions was significantly different between the groups (p = 0.0006; d = 1.19). In the combined FEP and HC group, there was a significant correlation between the BOLD signal during task performance and MEG resting state low frequency activity (p < 0.05). In FEP, we report significant alteration in resting state low frequency MEG activity, but no alterations in auditory evoked gamma band response, suggesting that the former is a more robust biomarker of early psychosis. There were no correlations between gamma oscillations and GABA levels in either HC or FEP. Finally, in this study, each of the three imaging modalities differentiated FEP from HC; fMRI with good and MEG and MRS with moderate effect size.

Hippocampal glutamate and hippocampus subfield volumes in antipsychotic-naive first episode psychosis subjects and relationships to duration of untreated psychosis.

Evidence points toward a relationship between longer duration of untreated psychosis (DUP) and worse long-term outcomes in patients with first episode psychosis (FEP), but the underlying neurobiology remains poorly understood. Proton magnetic resonance spectroscopy studies have reported altered hippocampus glutamatergic neurotransmission, and structural MRI as reported hippocampal atrophy that may be associated with memory impairment in schizophrenia. Here, we quantify left hippocampus glutamate (Glx) and left hippocampus subfield volumes in 54 antipsychotic-naive FEP and 41 healthy controls (HC), matched on age, sex, and parental occupation. While there were no significant group difference in Glx levels, hippocampal Glx levels were significantly higher in those who underwent a long DUP (>12 months) compared to those with a short DUP, and compared to HC. Compared to HC, FEP had significantly reduced whole hippocampus volume, as well as of CA1, CA4, granule cell layer, subiculum, and presubiculum subfields. Smaller whole hippocampal volume, as well as CA1, molecular layer, subiculum, presubiculum, and hippocampal tail volumes were significantly associated with longer DUP. However, we found no significant association between hippocampal Glx levels and hippocampal volume or subfields, suggesting that these alterations are not related, or their relationship does not follow a linear pattern. However, our results strongly suggest that one or several pathophysiological processes underlie the DUP. Importantly, our data highlight the critical need for reducing the DUP and for early pharmacological intervention with the hope to prevent structural deficits and, hopefully, improve clinical outcomes.