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.

Aberrant static and dynamic functional patterns of frontoparietal control network in antipsychotic-naïve first-episode psychosis subjects.

Psychotic disorders are disabling clinical syndromes characterized by widespread alterations in cortical information processing. Disruption of frontoparietal network (FPN) connectivity has emerged as a common footprint across the psychosis spectrum. Our goal was to characterize the static and dynamic resting-state functional connectivity (FC) of the FPN in antipsychotic-naïve first-episode psychosis (FEP) subjects. We compared the static FC of the FPN in 40 FEP and 40 healthy control (HC) subjects, matched on age, sex, and socioeconomic status. To study the dynamic FC, we measured quasiperiodic patterns (QPPs) that consist of infraslow spatioemporal patterns embedded in the blood oxygen level-dependent signal that repeats over time, exhibiting alternation of high and low activity. Relative to HC, we found functional hypoconnectivity between the right middle frontal gyrus and the right middle temporal gyrus, as well as the left inferior temporal gyrus and the left inferior parietal gyrus in FEP (p < .05, false discovery rate corrected). The correlation of the QPP with all functional scans was significantly stronger for FEP compared to HC, suggesting a greater impact of the QPPs to intrinsic brain activity in psychotic population. Regressing the QPP from the functional scans erased all significant group differences in static FC, suggesting that abnormal connectivity in FEP could result from altered QPP. Our study supports that alterations of cortical information processing are not a function of psychotic chronicity or antipsychotic medication exposure and may be regarded as trait specific. In addition, static connectivity abnormality may be partly related to altered brain network temporal dynamics.

Baseline Functional Connectivity Predicts Connectivity Changes Due to a Small Dose of Midazolam in Older Adults.

BACKGROUND: In the perioperative context, benzodiazepines are widely used as anxiolytics. They affect cognition in general, but it is unclear whether the effects of a small dose of the short-acting benzodiazepine midazolam can be assessed objectively. To address this scientific question, we conducted a prospective observational study in adults 55-73 years of age. Using both validated psychometric and functional imaging techniques, we determined whether a 2-mg intravenous (IV) dose of midazolam affects cognitive function. METHODS: We measured the effect of 2 mg IV of midazolam with both the well-established Repeatable Battery for the Assessment of Neuropsychological Status test and resting-state functional magnetic imaging (rs-fMRI) in older adults. RESULTS: Midazolam reduces immediate and delayed memory and has a profound and robust effect on rs-fMRI. Baseline resting-state connectivity predicts memory decline after midazolam administration. CONCLUSIONS: Observed effects of midazolam on brain networks were statistically significant even in a small group of volunteers. If validated by other investigators, resting-state brain connectivity may have utility as a measure to predict sensitivity to midazolam in older adults.

A Prospective Longitudinal Investigation of Cortical Thickness and Gyrification in Schizophrenia.

BACKGROUND: Cortical thickness (CT) and gyrification are complementary indices that assess different aspects of gray matter structural integrity. Both neurodevelopment insults and acute tissue response to antipsychotic medication could underlie the known heterogeneity of treatment response and are well-suited for interrogation into the relationship between gray matter morphometry and clinical outcomes in schizophrenia (SZ). METHODS: Using a prospective design, we enrolled 34 unmedicated patients with SZ and 23 healthy controls. Patients were scanned at baseline and after a 6-week trial with risperidone. CT and local gyrification index (LGI) values were quantified from structural MRI scans using FreeSurfer 5.3. RESULTS: We found reduced CT and LGI in patients compared to controls. Vertex-wise analyses demonstrated that hypogyrification was most prominent in the inferior frontal cortex, temporal cortex, insula, pre/postcentral gyri, temporoparietal junction, and the supramarginal gyrus. Baseline CT was predictive of subsequent response to antipsychotic treatment, and increase in CT after 6 weeks was correlated with greater symptom reductions. CONCLUSIONS: In summary, we report evidence of reduced CT and LGI in unmedicated patients compared to controls, suggesting involvement of different aspects of gray matter morphometry in the pathophysiology of SZ. Importantly, we found that lower CT at baseline and greater increase of CT following 6 weeks of treatment with risperidone were associated with better clinical response. Our results suggest that cortical thinning may normalize as a result of a good response to antipsychotic medication, possibly by alleviating potential neurotoxic processes underlying gray matter deterioration.

A pilot study of combined endurance and resistance exercise rehabilitation for verbal memory and functional connectivity improvement in epilepsy.

Memory impairment is common in persons with epilepsy (PWE), and exercise may be a strategy for its improvement. In this pilot study, we hypothesized that exercise rehabilitation would improve physical fitness and verbal memory and induce changes in brain networks involved in memory processes. We examined the effects of combined endurance and resistance exercise rehabilitation on memory and resting state functional connectivity (rsFC). Participants were randomized to exercise (PWE-E) or control (PWE-noE). The exercise intervention consisted of 18 supervised sessions on nonconsecutive days over 6 weeks. Before and after the intervention period, both groups completed self-report assessments (Short Form-36 (SF-36), Baecke Questionnaire (BQ) of habitual physical activity, and Profile of Mood States (POMS)), cognitive testing (California Verbal Learning Test-II (CVLT-II)), and magnetic resonance imaging (MRI); PWE-E also completed exercise performance tests. After completing the study, PWE-noE were offered cross-over to the exercise arm. There were no differences in baseline demographic, clinical, or assessment variables between 8 PWE-noE and 9 PWE-E. Persons with epilepsy that participated in exercise intervention increased maximum voluntary strength (all strength tests p < 0.05) and exhibited nonsignificant improvement in cardiorespiratory fitness (p = 0.15). Groups did not show significant changes in quality of life (QOL) or habitual physical activity between visits. However, there was an effect of visit on POMS total mood disturbance (TMD) measure showing improvement from baseline to visit 2 (p = 0.023). There were significant group by visit interactions on CVLT-II learning score (p = 0.044) and total recognition discriminability (d') (p = 0.007). Persons with epilepsy that participated in exercise intervention had significant reductions in paracingulate rsFC with the anterior cingulate and increases in rsFC for the cerebellum, thalamus, posterior cingulate cortex (PCC), and left and right inferior parietal lobule (IPL) (corrected p < 0.05). Change in CVLT-II learning score was associated with rsFC changes for the paracingulate cortex (rS = -0.67; p = 0.0033), left IPL (rS = 0.70; p = 0.0019), and right IPL (rS = 0.71; p = 0.0015) while change in d' was associated with change in cerebellum rsFC to angular/middle occipital gyrus (rS = 0.68; p = 0.0025). Our conclusion is that exercise rehabilitation may facilitate verbal memory improvement and brain network functional connectivity changes in PWE and that improved memory performance is associated with changes in rsFC. A larger randomized controlled trial of exercise rehabilitation for cognitive improvement in PWE is warranted.

Four-way multimodal fusion of 7 T imaging data using an mCCA+jICA model in first-episode schizophrenia.

Acquisition of multimodal brain imaging data for the same subject has become more common leading to a growing interest in determining the intermodal relationships between imaging modalities to further elucidate the pathophysiology of schizophrenia. Multimodal data have previously been individually analyzed and subsequently integrated; however, these analysis techniques lack the ability to examine true modality inter-relationships. The utilization of a multiset canonical correlation and joint independent component analysis (mCCA + jICA) model for data fusion allows shared or distinct abnormalities between modalities to be examined. In this study, first-episode schizophrenia patients (nSZ =19) and matched controls (nHC =21) completed a resting-state functional magnetic resonance imaging (fMRI) scan at 7 T. Grey matter (GM), white matter (WM), cerebrospinal fluid (CSF), and amplitude of low frequency fluctuation (ALFF) maps were used as features in a mCCA + jICA model. Results of the mCCA + jICA model indicated three joint group-discriminating components (GM-CSF, WM-ALFF, GM-ALFF) and two modality-unique group-discriminating components (GM, WM). The joint component findings are highlighted by GM basal ganglia, somatosensory, parietal lobe, and thalamus abnormalities associated with ventricular CSF volume; WM occipital and frontal lobe abnormalities associated with temporal lobe function; and GM frontal, temporal, parietal, and occipital lobe abnormalities associated with caudate function. These results support and extend major findings throughout the literature using independent single modality analyses. The multimodal fusion of 7 T data in this study provides a more comprehensive illustration of the relationships between underlying neuronal abnormalities associated with schizophrenia than examination of imaging data independently.

Effective connectivity during episodic memory retrieval in schizophrenia participants before and after antipsychotic medication.

BACKGROUND: Impairment in episodic memory is one of the most robust findings in schizophrenia. Disruptions of fronto-temporal functional connectivity that could explain some aspects of these deficits have been reported. Recent work has identified abnormal hippocampal function in unmedicated patients with schizophrenia (SZ), such as increased metabolism and glutamate content that are not always seen in medicated SZ. For these reasons, we hypothesized that altered fronto-temporal connectivity might originate from the hippocampus and might be partially restored by antipsychotic medication. METHODS: Granger causality methods were used to evaluate the effective connectivity between frontal and temporal regions in 21 unmedicated SZ and 20 matched healthy controls (HC) during performance of an episodic memory retrieval task. In 16 SZ, effective connectivity between these regions was evaluated before and after 1-week of antipsychotic treatment. RESULTS: In HC, significant effective connectivity originating from the right hippocampus to frontal regions was identified. Compared to HC, unmedicated SZ showed significant altered fronto-temporal effective connectivity, including reduced right hippocampal to right medial frontal connectivity. After 1-week of antipsychotic treatment, connectivity more closely resembled the patterns observed in HC, including increased effective connectivity from the right hippocampus to frontal regions. CONCLUSIONS: These results support the notion that memory disruption in schizophrenia might originate from hippocampal dysfunction and that medication restores some aspects of fronto-temporal dysconnectivity. Patterns of fronto-temporal connectivity could provide valuable biomarkers to identify new treatments for the symptoms of schizophrenia, including memory deficits.

Expectancies for the effectiveness of different tobacco interventions account for racial and gender differences in motivation to quit and abstinence self-efficacy.

INTRODUCTION: Racial and gender disparities for smoking cessation might be accounted for by differences in expectancies for tobacco interventions, but few studies have investigated such differences or their relationships with motivation to quit and abstinence self-efficacy. METHODS: In this cross-sectional study, 673 smokers (African American: n = 443, 65.8%; women: n = 222, 33.0%) under criminal justice supervision who enrolled in a clinical smoking cessation trial in which all received bupropion and half received counseling. All participants completed pretreatment measures of expectancies for different tobacco interventions, motivation to quit, and abstinence self-efficacy. The indirect effects of race and gender on motivation to quit and abstinence self-efficacy through expectancies for different tobacco interventions were evaluated. RESULTS: African Americans' stronger expectancies that behavioral interventions would be effective accounted for their greater motivation to quit and abstinence self-efficacy. Women's stronger expectancies for the effectiveness of pharmacotherapy accounted for their greater motivation to quit, whereas their stronger expectancies for the effectiveness of behavioral treatments accounted for their greater abstinence self-efficacy. CONCLUSIONS: Findings point to the mediating role of expectancies for treatment effectiveness and suggest the importance of exploring expectancies among African Americans and women as a way to augment motivation and self-efficacy.

How low should you go? Determining the optimal cutoff for exhaled carbon monoxide to confirm smoking abstinence when using cotinine as reference.

INTRODUCTION: Confirming abstinence during smoking cessation clinical trials is critical for determining treatment effectiveness. Several biological methods exist for verifying abstinence (e.g., exhaled carbon monoxide [CO], cotinine), and while cotinine provides a longer window of detection, it is not easily used in trials involving nicotine replacement therapy. The Society for Research on Nicotine and Tobacco's Subcommittee on Biochemical Verification cite 8-10 parts per million (ppm) for CO as a viable cutoff to determine abstinence; however, recent literature suggests this cutoff is likely too high and may overestimate the efficacy of treatment. METHODS: This study examined the relationship between CO and cotinine in a sample of 662 individuals participating in a smoking cessation clinical trial. A receiver operating characteristics curve was calculated to determine the percentage of false positives and false negatives at given CO levels when using cotinine as confirmation of abstinence. Differences were also examined across race and gender. RESULTS: A CO cutoff of 3 ppm (97.1% correct classification) most accurately distinguished smokers from nonsmokers. This same cutoff was accurate for both racial and gender groups. The standard cutoffs of 8 ppm (14.0% misclassification of smokers as abstainers) and 10 ppm (20.6% misclassification of smokers as abstainers) produced very high false-negative rates and inaccurately identified a large part of the sample as being abstinent when their cotinine test identified them as still smoking. CONCLUSIONS: It is recommended that researchers and clinicians adopt a more stringent CO cutoff in the range of 3-4 ppm when complete abstinence from smoking is the goal.

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.

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 .

Functional magnetic resonance imaging in schizophrenia: current evidence, methodological advances, limitations and future directions.

Functional neuroimaging emerged with great promise and has provided fundamental insights into the neurobiology of schizophrenia. However, it has faced challenges and criticisms, most notably a lack of clinical translation. This paper provides a comprehensive review and critical summary of the literature on functional neuroimaging, in particular functional magnetic resonance imaging (fMRI), in schizophrenia. We begin by reviewing research on fMRI biomarkers in schizophrenia and the clinical high risk phase through a historical lens, moving from case-control regional brain activation to global connectivity and advanced analytical approaches, and more recent machine learning algorithms to identify predictive neuroimaging features. Findings from fMRI studies of negative symptoms as well as of neurocognitive and social cognitive deficits are then reviewed. Functional neural markers of these symptoms and deficits may represent promising treatment targets in schizophrenia. Next, we summarize fMRI research related to antipsychotic medication, psychotherapy and psychosocial interventions, and neurostimulation, including treatment response and resistance, therapeutic mechanisms, and treatment targeting. We also review the utility of fMRI and data-driven approaches to dissect the heterogeneity of schizophrenia, moving beyond case-control comparisons, as well as methodological considerations and advances, including consortia and precision fMRI. Lastly, limitations and future directions of research in the field are discussed. Our comprehensive review suggests that, in order for fMRI to be clinically useful in the care of patients with schizophrenia, research should address potentially actionable clinical decisions that are routine in schizophrenia treatment, such as which antipsychotic should be prescribed or whether a given patient is likely to have persistent functional impairment. The potential clinical utility of fMRI is influenced by and must be weighed against cost and accessibility factors. Future evaluations of the utility of fMRI in prognostic and treatment response studies may consider including a health economics analysis.

Discovery of early schizophrenia through neuroimaging.

In order to understand the pathophysiology of schizophrenia we carried out a number of brain imaging studies in both medicated and unmedicated patients. In addition, to help unravel the pathophysiological mechanisms without the confound of prior exposure to antipsychotic medication or chronicity, we enrolled a large group of antipsychotic medication-naïve first episode psychosis patients at first treatment contact, and performed longitudinal multimodal neuroimaging studies over several months. In unmedicated patients we found both functional and structural connectivity alterations. Similarly, in medication-naïve patients we replicated many of our prior findings, suggesting that functional and structural connectivity alterations are core pathological features of the illness. We found that a longer duration of untreated psychosis, i.e. the time between first symptom onset and initial treatment contact, was associated with greater structural and functional connectivity abnormalities, which in turn was associated with worse subsequent clinical response to treatment. These results underscore the critical importance of early identification and treatment in patients with psychosis spectrum disorders.

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.

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.

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.

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.

Ultrastructural evidence for glutamatergic dysregulation in schizophrenia.

The aim of this paper is to summarize ultrastructural evidence for glutamatergic dysregulation in several linked regions in postmortem schizophrenia brain. Following a brief summary of glutamate circuitry and how synapses are identified at the electron microscopic (EM) level, we will review EM pathology in the cortex and basal ganglia. We will include the effects of antipsychotic drugs and the relation of treatment response. We will discuss how these findings support or confirm other postmortem findings as well as imaging results. Briefly, synaptic and mitochondrial density in anterior cingulate cortex was decreased in schizophrenia, versus normal controls (NCs), in a selective layer specific pattern. In dorsal striatum, increases in excitatory synaptic density were detected in caudate matrix, a compartment associated with cognitive and motor function, and in the putamen patches, a region associated with limbic function and in the core of the nucleus accumbens. Patients who were treatment resistant or untreated had significantly elevated numbers of excitatory synapses in limbic striatal areas in comparison to NCs and responders. Protein levels of vGLUT2, found in subcortical glutamatergic neurons, were increased in the nucleus accumbens in schizophrenia. At the EM level, schizophrenia subjects had an increase in density of excitatory synapses in several areas of the basal ganglia. In the substantia nigra, the protein levels of vGLUT2 were elevated in untreated patients compared to NCs. The density of inhibitory synapses was decreased in schizophrenia versus NCs. In schizophrenia, glutamatergic synapses are differentially affected depending on the brain region, treatment status, and treatment response.

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.

In vivo Experience With NRT to Increase Adherence and Smoking Abstinence Among Individuals in the Criminal Legal System: Study Protocol for a Randomized Clinical Trial.

Background: While tobacco use among individuals involved in the criminal legal system remains 3-4 times higher than the general population, few interventions have been targeted for this population to aid in smoking cessation. Nicotine replacement therapy (NRT) is a relatively effective and accessible smoking cessation aid; however, individuals frequently stop use of NRT early due to side effects and misperceptions about the products. The present study aims to address low medication adherence by examining the efficacy of an "in vivo" NRT sampling experience in individuals under community criminal legal supervision. Methods: Following recruitment through community legal outlets, participants (N = 517) are randomized to either an "in vivo NRT sampling" group or a standard smoking cessation behavioral counseling group. The in vivo group uses NRT in session and discusses perceptions and experiences of using NRT in real time while the standard smoking cessation counseling group receives four sessions of standard behavioral smoking cessation counseling. Both groups receive four intervention sessions and 12 weeks of NRT following the intervention. The 6-month post-intervention primary outcome measures are smoking point-prevalence abstinence and medication adherence. Conclusion: This is a novel smoking cessation intervention specifically aimed at increasing NRT adherence and smoking cessation among those involved in the criminal legal system, a group of individuals with high smoking rates and low rates of pharmacotherapy use. If proven effective, the present treatment could be a novel intervention to implement in criminal legal settings given the minimal requirement of resources and training.This trial is registered with www.clinicaltrials.gov-NCT02938403.