The design and baseline characteristics for the HOPE Consortium Trial to reduce pain and opioid use in hemodialysis.

The HOPE Consortium Trial to Reduce Pain and Opioid Use in Hemodialysis (HOPE Trial) is a multicenter randomized trial addressing chronic pain among patients receiving maintenance hemodialysis for end-stage kidney disease. The trial uses a sequential, multiple assignment design with a randomized component for all participants (Phase 1) and a non-randomized component for a subset of participants (Phase 2). During Phase 1, participants are randomized to Pain Coping Skills Training (PCST), an intervention designed to increase self-efficacy for managing pain, or Usual Care. PCST consists of weekly, live, coach-led cognitive behavioral therapy sessions delivered by video- or tele-conferencing for 12 weeks followed by daily interactive voice response sessions delivered by telephone for an additional 12 weeks. At 24 weeks (Phase 2), participants in both the PCST and Usual Care groups taking prescription opioid medications at an average dose of ≥20 morphine milligram equivalents per day are offered buprenorphine, a partial opioid agonist with a more favorable safety profile than full-agonist opioids. All participants are followed for 36 weeks. The primary outcome is pain interference ascertained, for the primary analysis, at 12 weeks. Secondary outcomes include additional patient-reported measures and clinical outcomes including falls, hospitalizations, and death. Exploratory outcomes include acceptability, tolerability, and efficacy of buprenorphine. The enrollment target of 640 participants was met 27 months after trial initiation. The findings of the trial will inform the management of chronic pain, a common and challenging issue for patients treated with maintenance hemodialysis. NCT04571619.

Development of a Patient Preference Survey for Wearable Kidney Replacement Therapy Devices.

Background: Recent innovations have the potential to disrupt the current paradigm for kidney failure treatment. The US Food and Drug Administration is committed to incorporating valid scientific evidence about how patients weigh the benefits and risks of new devices into their decision making, but to date, premarket submission of patient preference information (PPI) has been limited for kidney devices. With input from stakeholders, we developed a survey intended to yield valid PPI, capturing how patients trade off the potential benefits and risks of wearable dialysis devices and in-center hemodialysis. Methods: We conducted concept elicitation interviews with individuals receiving dialysis to inform instrument content. After instrument drafting, we conducted two rounds of pretest interviews to evaluate survey face validity, comprehensibility, and perceived relevance. We pilot tested the survey with in-center hemodialysis patients to assess comprehensibility and usability further. Throughout, we used participant input to guide survey refinements. Results: Thirty-six individuals receiving in-center or home dialysis participated in concept elicitation (N=20) and pretest (N=16) interviews. Participants identified reduced fatigue, lower treatment burden, and enhanced freedom as important benefits of a wearable device, and many expressed concerns about risks related to device disconnection-specifically bleeding and infection. We drafted a survey that included descriptions of the risks of serious bleeding and serious infection and an assessment of respondent willingness to wait for a safer device. Input from pretest interviewees led to various instrument modifications, including treatment descriptions, item wording, and risk-level explanations. Pilot testing of the updated survey among 24 in-center hemodialysis patients demonstrated acceptable survey comprehensibility and usability, although 50% of patients required some assistance. Conclusions: The final survey is a 54-item web-based instrument that will yield estimates of the maximal acceptable risk for the described wearable device and willingness to wait for wearable devices with lower risk.

Critically important outcomes for infection in trials in kidney transplantation: An international survey of patients, caregivers, and health professionals.

BACKGROUND: Infections are a common complication following kidney transplantation, but are reported inconsistently in clinical trials. This study aimed to identify the infection outcomes of highest priority for patients/caregivers and health professionals to inform a core outcome set to be reported in all kidney transplant clinical trials. METHODS: In an international online survey, participants rated the absolute importance of 16 infections and eight severity dimensions on 9-point Likert Scales, with 7-9 being critically important. Relative importance was determined using a best-worst scale. Means and proportions of the Likert-scale ratings and best-worst preference scores were calculated. RESULTS: 353 healthcare professionals (19 who identified as both patients/caregiver and healthcare professionals) and 220 patients/caregivers (190 patients, 22 caregivers, eight who identified as both) from 55 countries completed the survey. Both healthcare professionals and patients/caregivers rated bloodstream (mean 8.4 and 8.5, respectively; aggregate 8.5), kidney/bladder (mean 7.9 and 8.4; aggregate 8.1), and BK virus (mean 8.1 and 8.6; aggregate 8.3) as the top three most critically important infection outcomes, whilst infectious death (mean 8.8 and 8.6; aggregate 8.7), impaired graft function (mean 8.4 and 8.7; aggregate 8.5) and admission to the intensive care unit (mean 8.2 and 8.3; aggregate 8.2) were the top three severity dimensions. Relative importance (best-worst) scores were consistent. CONCLUSIONS: Healthcare professionals and patients/caregivers consistently identified bloodstream infection, kidney/bladder infections, and BK virus as the three most important infection outcomes, and infectious death, admission to intensive care unit and infection impairing graft function as the three most important infection severity outcomes.

Range and Consistency of Infection Outcomes Reported in Trials Conducted in Kidney Transplant Recipients: A Systematic Review.

BACKGROUND: Infection remains a leading cause of death in kidney transplant recipients. This study aimed to assess the scope and consistency of infection outcomes reported in contemporary trials conducted in kidney transplant recipients. METHODS: A literature review of all randomized trials and trial protocols reporting infection outcomes in adult kidney transplant recipients was identified in the Cochrane Kidney and Transplant Specialized Register from January 2014 to July 2019. Characteristics and infection outcomes from the trials were analyzed. RESULTS: From 102 included trials, 772 outcome measures were extracted and categorized into 216 unique measures with a median of 3.2 outcome measures per trial (range: 1-9). Measures were further grouped into 32 outcomes based on site of infection (14 outcomes) and organism (18 outcomes). The most commonly reported site-specific outcome and organism-specific outcome were systemic infection (71% trials) and cytomegalovirus infection (62% trials), respectively. Outcome metric and methods of aggregation included mean, median, proportion, proportional change, and number of patients with at least 1 episode. Across all trials, measures were assessed at 55 different time points with a range of 1-11 time points per trial. CONCLUSIONS: Infection outcomes in kidney transplant recipients were frequently reported by site and organism but varied widely in terms of outcome, metrics, method of aggregation, and time point of measurement. Establishment of core outcomes for infection based on the shared priorities of patients/caregivers and health professionals may improve the consistency, comparability, and usefulness of trial evidence.

Adolescent driving behavior before and during restrictions related to COVID-19.

INTRODUCTION: Understanding who heeds the driving-related COVID-19 restrictions is critical for assisting public health professionals improve response to this and future pandemic events. The purpose of the current study was to characterize driving behavior changes among adolescents as a function of COVID-19 restrictions. It was hypothesized that adolescent driving would be reduced by COVID-19 restrictions, especially for younger teens, non-minorities, females, non-working teens, and those with higher prosocial tendencies. METHODS: Participants were licensed drivers in "REACT," a longitudinal study of adolescent driving attention. Upon enrollment in REACT, drivers were required to be age 16 or 18, have been issued a driver's license within the last two weeks, and be fluent in written/spoken English. The current observational cohort study was of drivers reporting driving exposure between February 8 and April 22, 2020. Linear mixed-effects models estimated differences in driving changes between COVID-19 periods. RESULTS: Results indicated a decrease across pre-COVID-19 period (February 8 - March 13, 2020) in days driven per week and vehicle miles driven (VMD) was explained by the change of slope post-COVID-19 restrictions (March 14 - April 22, 2020). Post-COVID-19, driving days per week decreased by 37 % and VMD decreased by 35 %. This decrease was lower in ethnic minorities, older adolescents, and employed adolescents. Those with greater dire prosocial tendencies showed greater post-COVID-19 driving decline. DISCUSSION: Findings provide early evidence of COVID-19 restriction-related adolescent driving changes suggesting older, employed, minority teens and teens with lower prosocial tendencies are less likely to reduce driving behavior. These observations provide a foundation for more extensive studies of adolescent drivers during various driving and contact restrictions and inform future public health campaigns for social distancing.

Patient and Caregiver Perspectives on Terms Used to Describe Kidney Health.

BACKGROUND AND OBJECTIVES: The language used to communicate important aspects of kidney health is inconsistent and may be conceptualized differently by patients and health professionals. These problems may impair the quality of communication, care, and patient outcomes. We aimed to describe the perspectives of patients on terms used to describe kidney health. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Patients with CKD (n=54) and caregivers (n=13) from the United States, United Kingdom, and Australia participated in ten focus groups to discuss terms for kidney health (including kidney, renal, CKD, ESKD, kidney failure, and descriptors for kidney function). We analyzed the data using thematic analysis. RESULTS: We identified four themes: provoking and exacerbating undue trauma (fear of the unknown, denoting impending death, despair in having incurable or untreatable disease, premature labeling and assumptions, judgment, stigma, and failure of self); frustrated by ambiguity (confused by medicalized language, lacking personal relevance, baffled by imprecision in meaning, and/or opposed to obsolete terms); making sense of the prognostic enigma (conceptualizing level of kidney function, correlating with symptoms and effect on life, predicting progression, and need for intervention); and mobilizing self-management (confronting reality, enabling planning and preparation, taking ownership for change, learning medical terms for self-advocacy, and educating others). CONCLUSIONS: The obscurity and imprecision of terms in CKD can be unduly distressing and traumatizing for patients, which can impair decision making and self-management. Consistent and meaningful patient-centered terminology may improve patient autonomy, satisfaction, and outcomes.

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.

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 longitudinal magnetic resonance spectroscopy study investigating effects of risperidone in the anterior cingulate cortex and hippocampus in schizophrenia.

Magnetic Resonance Spectroscopy is a popular approach to probe brain chemistry in schizophrenia (SZ), but no consensus exists as to the extent of alterations. This may be attributable to differential effects of populations studied, brain regions examined, or antipsychotic medication effects. Here, we measured neurometabolites in the anterior cingulate cortex (ACC) and hippocampus, two structurally dissimilar brain regions implicated in the SZ pathophysiology. We enrolled 61 SZ with the goal to scan them before and after six weeks of treatment with risperidone. We also scanned 31 matched healthy controls twice, six weeks apart. Using mixed effect repeated measures linear models to examine the effect of group and time on metabolite levels in each voxel, we report an increase in hippocampal glutamate + glutamine (Glx) in SZ compared to controls (p = 0.043), but no effect of antipsychotic medication (p = 0.330). In the ACC, we did not find metabolite alterations or antipsychotic medication related changes after six weeks of treatment with risperidone. The coefficients for the discriminant function (differentiating SZ from HC) in the ACC were greatest for NAA (-0.83), and in the hippocampus for Glx (0.76), the same metabolites were associated with greater treatment response in patients at trend level. Taken together, our data extends the existing literature by demonstrating regionally distinct metabolite alterations in the same patient group and suggests that antipsychotic medications may have limited effects on metabolite levels in these regions.

7T Proton Magnetic Resonance Spectroscopy of the Anterior Cingulate Cortex in First-Episode Schizophrenia.

Recent magnetic resonance spectroscopy (MRS) studies suggest that abnormalities of the glutamatergic system in schizophrenia may be dependent on illness stage, medication status, and symptomatology. Glutamatergic metabolites appear to be elevated in the prodromal and early stages of schizophrenia but unchanged or reduced below normal in chronic, medicated patients. However, few of these studies have measured metabolites with high-field 7T MR scanners, which offer higher signal-to-noise ratio and better spectral resolution than 3T scanners and facilitate separation of glutamate and glutamine into distinct signals. In this study, we examined glutamate and other metabolites in the dorsal anterior cingulate cortex (ACC) of first-episode schizophrenia patients. Glutamate and N-acetylaspartate (NAA) were significantly lower in schizophrenia patients vs controls. No differences were observed in levels of glutamine, GABA, or other metabolites. In schizophrenia patients but not controls, GABA was negatively correlated with the total score on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) as well as the immediate memory and language subscales. Our findings suggest that glutamate and NAA reductions in the ACC may be present early in the illness, but additional large-scale studies are needed to confirm these results as well as longitudinal studies to determine the effect of illness progression and treatment. The correlation between GABA and cognitive function suggests that MRS may be an important technique for investigating the neurobiology underlying cognitive deficits in schizophrenia.

Cognitive control network dysconnectivity and response to antipsychotic treatment in schizophrenia.

To better understand cognitive control impairment in schizophrenia, it is vital to determine the extent of dysfunctional connectivity in the associated fronto-striatal brain network, with a focus on the connections with the anterior cingulate cortex (ACC), prior to the potential confounding effect of medication. It is also essential to determine the effects following antipsychotic medication and the relationship of those effects on psychosis improvement. Twenty-two patients with schizophrenia, initially unmedicated and after a 6-week course of risperidone, and 20 matched healthy controls (HC) performed a fMRI task twice, six weeks apart. We investigated group and longitudinal differences in ACC-related functional connectivity during performance of a Stroop color task as well as connectivity patterns associated with improvement in psychosis symptoms. Unmedicated patients with schizophrenia showed greater functional connectivity between ACC and bilateral caudate and midbrain and lower connectivity with left putamen compared to healthy controls. At baseline, greater functional connectivity between ACC and bilateral putamen predicted subsequent better treatment response. Change in functional connectivity between ACC and left putamen positively correlated with better treatment response. These results suggest that patterns of functional connectivity in fronto-striatal networks can be utilized to predict potential response to antipsychotic medication. Prior to treatment, brain function may be structured with a predisposition that favors or not treatment response.

Relationship Between Cortical Excitation and Inhibition and Task-Induced Activation and Deactivation: A Combined Magnetic Resonance Spectroscopy and Functional Magnetic Resonance Imaging Study at 7T in First-Episode Psychosis.

BACKGROUND: Schizophrenia is thought to be a disorder of brain dysconnectivity. An imbalance between cortical excitation/inhibition is also implicated, but the link between these abnormalities remains unclear. The present study used magnetic resonance spectroscopy and functional magnetic resonance imaging at 7T to investigate how measurements of glutamate and gamma-aminobutyric acid (GABA) relate to the blood oxygen level-dependent (BOLD) response during a cognitive task, and how these relationships are altered in schizophrenia. METHODS: Usable functional magnetic resonance imaging data from 17 first-episode psychosis (FEP) patients (4 women, 13 men) and 21 matched healthy control subjects (HCs) (5 women, 16 men) were acquired during a Stroop task. Within- and between-group comparisons of the BOLD response were performed. Neurometabolite levels were measured in the dorsal anterior cingulate cortex. Two multiple regressions investigated how glutamate, glutamine, and GABA related to the BOLD response in HCs and FEP patients separately. A third investigated between-group differences in the relationships between the BOLD response and each of these neurometabolites. RESULTS: Compared with HCs, FEP patients showed an increased BOLD response within regions of the executive and default mode networks. In FEP patients, the relationship between anterior cingulate cortex glutamate levels and the BOLD response in regions of the posterior default mode network was opposite to that of HCs. In FEP patients but not HCs, anterior cingulate cortex GABA levels correlated with the local BOLD response and with the Stroop reaction time. CONCLUSION: These results suggest a mechanism whereby alterations in the relationship between cortical glutamate/GABA and BOLD response is disrupting the dynamic of major neural networks, possibly affecting cognition.

A Longitudinal Multimodal Neuroimaging Study to Examine Relationships Between Resting State Glutamate and Task Related BOLD Response in Schizophrenia.

Previous studies have observed impairments in both brain function and neurometabolite levels in schizophrenia. In this study, we investigated the relationship between brain activity and neurochemistry in off-medication patients with schizophrenia and if this relationship is altered following antipsychotic medication by combining proton magnetic resonance spectroscopy (1H-MRS) with functional magnetic resonance imaging (fMRI). We used single voxel MRS acquired in the bilateral dorsal anterior cingulate cortex (ACC) and fMRI during performance of a Stroop color-naming task in 22 patients with schizophrenia (SZ), initially off-medication and after a 6-week course of risperidone, and 20 matched healthy controls (HC) twice, 6 weeks apart. We observed a significant decrease in ACC glutamate + glutamine (Glx)/Creatine (Cr) levels in medicated SZ patients compared to HC but not compared to their off-medication baseline. In off-medication SZ, the relationship between ACC Glx/Cr levels and the blood oxygen level-dependent (BOLD) response in regions of the salience network (SN) and posterior default mode network (DMN) was opposite than of HC. After 6 weeks, the relationship between Glx and the BOLD response was still opposite between the groups; however for both groups the direction of the relationship changed from baseline to week 6. These results suggest a mechanism whereby alterations in the relationship between cortical glutamate and BOLD response is disrupting the modulation of major neural networks subserving cognitive processes, potentially affecting cognition. While these relationships appear to normalize with treatment in patients, the interpretations of the results are confounded by significant group differences in Glx levels, as well as the variability of the relationship between Glx and BOLD response in HC over time, which may be driven by factors including habituation to task or scanner environment.

Neurometabolic abnormalities in the associative striatum in antipsychotic-naïve first episode psychosis patients.

Schizophrenia is a chronic, often progressive, disorder. Understanding the underlying neurobiology present in the early stages of the illness is as a pivotal step in designing targeted interventions aimed at arresting disease progression. The aim of our study was to examine neurometabolic changes in the dopamine rich associative striatum in medication-naïve first episode psychosis (FEP). We quantified neurometabolites in 14 FEP and 18 healthy controls (HC) matched on key demographic characteristics. Spectra from the voxel in the left associative striatum were acquired using a PRESS sequence (TR/TE = 2000/80 ms; 512 averages). MRS data were quantified in the time domain with AMARES in jMRUI. Choline was significantly elevated in FEP compared to HC. No significant alterations in other metabolites were observed. We did not observe correlations between metabolite levels and clinical characteristics in FEP. Here, we demonstrated elevated choline and a disruption of the relationship between N-acetyl-aspartate and Glx (glutamate + glutamine) in medication-naïve FEP patients in the left striatum indicating possible mitochondrial, membrane and glial dysfunction as an underlying pathological phenomenon. In addition, striatal choline shows promise as a biomarker for FEP that may have utility in clinical trials investigating target engagement in experimental regimens.

Evaluation of fronto-striatal networks during cognitive control in unmedicated patients with schizophrenia and the effect of antipsychotic medication.

To understand the mechanism of cognitive control dysfunction in schizophrenia, it is critical to characterize brain function without the confounding effect of medication. It is also important to establish the extent to which antipsychotic medication restores brain function and whether those changes are related to psychosis improvement. Twenty-two patients with schizophrenia, initially unmedicated and after a 6-week course of risperidone, and 20 healthy controls (HC) studied twice, 6 weeks apart, performed an fMRI task. We examined group and longitudinal differences in anterior cingulate cortex (ACC), striatum, and midbrain functional activity during performance of a Stroop color task as well as activity patterns associated with improvement in psychosis symptoms. Unmedicated patients showed reduced functional activity in the ACC, striatum, and midbrain compared to HC. Post hoc contrasts from significant group-by-time interactions indicated that, in patients, drug administration was associated with both activity increases and decreases. In unmedicated patients, greater baseline functional activity in the striatum and midbrain predicted subsequent better treatment response. Greater changes in functional activity in ACC and ventral putamen over the course of 6 weeks positively correlated with better treatment response. Unmedicated patients show reduced activity in brain networks pivotal for cognitive control and medication is associated with functional changes in these regions. These results suggest a mechanism by which antipsychotic medication has a beneficial effect on cognition. Our results also support the notion that treatment response is determined by a combination of the baseline pattern of brain function and by the pharmacological modulation of these regions.

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.

Gyrification Connectomes in Unmedicated Patients With Schizophrenia and Following a Short Course of Antipsychotic Drug Treatment.

Schizophrenia (SZ) is a d isease characterized by brain dysconnectivity and abnormal brain development. The study of cortical gyrification in schizophrenia may capture underlying alterations reflective of neurodevelopmental abnormalities more accurately than other imaging modalities. Graph-based connectomic approaches have been previously used in schizophrenia to study structural and functional brain covariance using a diversity of techniques. The goal of the present study was to evaluate morphological covariance using a measure of local gyrification index in patients with schizophrenia. The aims of this study were two-fold: (1) Evaluate the structural covariance of local gyrification index using graph theory measures of integration and segregation in unmedicated patients with schizophrenia compared to healthy controls and (2) investigate changes in these measures following a short antipsychotic drug (APD) treatment. Using a longitudinal prospective design, structural scans were obtained prior to treatment in 34 unmedicated patients with SZ and after 6 weeks of treatment with risperidone. To control for the effect of time, 23 matched healthy controls (HC) were also scanned twice, 6 weeks apart. The cortical surface of each structural image was reconstructed and local gyrification index values were computed using FreeSurfer. Local gyrification index values where then parcellated into atlas based regions and entered into a 68 × 68 correlation matrix to construct local gyrification index connectomes for each group at each time point. Longitudinal comparisons showed significant group by time interactions for measures of segregation (clustering, local efficiency) and modularity, but not for measures of integration (path length, global efficiency). Post-hoc tests showed increased clustering, local efficiency, and modularity connectomes in unmedicated patients with SZ at baseline compared to HC. Post-hoc tests did not show significant within group differences for HCs or patients with SZ. After 6 weeks of treatment, there were no significant differences between the groups on these measures. Abnormal cortical topography is detected in schizophrenia and is modified by short term APD treatment reflective of decreases in hyper-specialization in network connectivity. We speculate that changes in the structural organization of the brain is achieved through the neuroplastic effects that APDs have on brain tissue, thus promoting more efficient brain connections and, possibly, a therapeutic effect.

Risperidone Effects on Brain Dynamic Connectivity-A Prospective Resting-State fMRI Study in Schizophrenia.

Resting-state functional connectivity studies in schizophrenia evaluating average connectivity over the entire experiment have reported aberrant network integration, but findings are variable. Examining time-varying (dynamic) functional connectivity may help explain some inconsistencies. We assessed dynamic network connectivity using resting-state functional MRI in patients with schizophrenia, while unmedicated (n = 34), after 1 week (n = 29) and 6 weeks of treatment with risperidone (n = 24), as well as matched controls at baseline (n = 35) and after 6 weeks (n = 19). After identifying 41 independent components (ICs) comprising resting-state networks, sliding window analysis was performed on IC timecourses using an optimal window size validated with linear support vector machines. Windowed correlation matrices were then clustered into three discrete connectivity states (a relatively sparsely connected state, a relatively abundantly connected state, and an intermediately connected state). In unmedicated patients, static connectivity was increased between five pairs of ICs and decreased between two pairs of ICs when compared to controls, dynamic connectivity showed increased connectivity between the thalamus and somatomotor network in one of the three states. State statistics indicated that, in comparison to controls, unmedicated patients had shorter mean dwell times and fraction of time spent in the sparsely connected state, and longer dwell times and fraction of time spent in the intermediately connected state. Risperidone appeared to normalize mean dwell times after 6 weeks, but not fraction of time. Results suggest that static connectivity abnormalities in schizophrenia may partly be related to altered brain network temporal dynamics rather than consistent dysconnectivity within and between functional networks and demonstrate the importance of implementing complementary data analysis techniques.