Publications by authors named "Peter Kochunov"

197 Publications

Bayes estimate of primary threshold in clusterwise functional magnetic resonance imaging inferences.

Stat Med 2021 Jul 26. Epub 2021 Jul 26.

Maryland Psychiatric Research Center, Department of Psychiatry, School of Medicine, University of Maryland, Baltimore, Maryland, USA.

Clusterwise statistical inference is the most widely used technique for functional magnetic resonance imaging (fMRI) data analyses. Clusterwise statistical inference consists of two steps: (i) primary thresholding that excludes less significant voxels by a prespecified cut-off (eg, ); and (ii) clusterwise thresholding that controls the familywise error rate caused by clusters consisting of false positive suprathreshold voxels. The selection of the primary threshold is critical because it determines both statistical power and false discovery rate (FDR). However, in most existing statistical packages, the primary threshold is selected based on prior knowledge (eg, ) without taking into account the information in the data. In this article, we propose a data-driven approach to algorithmically select the optimal primary threshold based on an empirical Bayes framework. We evaluate the proposed model using extensive simulation studies and real fMRI data. In the simulation, we show that our method can effectively increase statistical power by 20% to over 100% while effectively controlling the FDR. We then investigate the brain response to the dose-effect of chlorpromazine in patients with schizophrenia by analyzing fMRI scans and generate consistent results.
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http://dx.doi.org/10.1002/sim.9147DOI Listing
July 2021

White matter in prolonged glucocorticoid response to psychological stress in schizophrenia.

Neuropsychopharmacology 2021 Jul 1. Epub 2021 Jul 1.

Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA.

Stress is implicated in psychosis etiology and exacerbation, but pathogenesis toward brain network alterations in schizophrenia remain unclear. White matter connects limbic and prefrontal regions responsible for stress response regulation, and white matter tissues are also vulnerable to glucocorticoid aberrancies. Using a novel psychological stressor task, we studied cortisol stress responses over time and white matter microstructural deficits in schizophrenia spectrum disorder (SSD). Cortisol was measured at baseline, 0-, 20-, and 40-min after distress induction by a psychological stressor task in 121 SSD patients and 117 healthy controls (HC). White matter microstructural integrity was measured by 64-direction diffusion tensor imaging. Fractional anisotropy (FA) in white matter tracts were related to cortisol responses and then compared to general patterns of white matter tract deficits in SSD identified by mega-analysis. Differences between 40-min post-stress and baseline, but not acute reactivity post-stress, was significantly elevated in SSD vs HC, time × diagnosis interaction F = 4.1, p = 0.013. All SSD white matter tracts were negatively associated with prolonged cortisol reactivity but all tracts were positively associated with prolonged cortisol reactivity in HC. Individual tracts most strongly associated with prolonged cortisol reactivity were also most impacted in schizophrenia in general as established by the largest schizophrenia white matter study (r = -0.56, p = 0.006). Challenged with psychological stress, SSD and HC mount similar cortisol responses, and impairments arise in the resolution timeframe. Prolonged cortisol elevations are associated with the white matter deficits in SSD, in a pattern previously associated with schizophrenia in general.
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http://dx.doi.org/10.1038/s41386-021-01077-4DOI Listing
July 2021

White Matter Disruption in Pediatric Traumatic Brain Injury: Results from ENIGMA Pediatric Moderate to Severe Traumatic Brain Injury.

Neurology 2021 May 28. Epub 2021 May 28.

Hospital for Sick Children, Neuroscience and Mental Health Program, Toronto, Canada.

Objective: Our study addressed aims: (1) test the hypothesis that moderate-severe TBI in pediatric patients is associated with widespread white matter (WM) disruption; (2) test the hypothesis that age and sex impact WM organization after injury; and (3) examine associations between WM organization and neurobehavioral outcomes.

Methods: Data from ten previously enrolled, existing cohorts recruited from local hospitals and clinics were shared with the ENIGMA (Enhancing NeuroImaging Genetics through Meta-Analysis) Pediatric msTBI working group. We conducted a coordinated analysis of diffusion MRI (dMRI) data using the ENIGMA dMRI processing pipeline.

Results: Five hundred and seven children and adolescents (244 with complicated mild to severe TBI [msTBI] and 263 controls) were included. Patients were clustered into three post-injury intervals: acute/subacute - <2 months, post-acute - 2-6 months, chronic - 6+ months. Outcomes were dMRI metrics and post-injury behavioral problems as indexed by the Child Behavior Checklist (CBCL). Our analyses revealed altered WM diffusion metrics across multiple tracts and all post-injury intervals (effect sizes ranging between =-0.5 to -1.3). Injury severity is a significant contributor to the extent of WM alterations but explained less variance in dMRI measures with increasing time post-injury. We observed a sex-by-group interaction: females with TBI had significantly lower fractional anisotropy in the uncinate fasciculus than controls (𝞫=0.043), which coincided with more parent-reported behavioral problems (𝞫=-0.0027).

Conclusions: WM disruption after msTBI is widespread, persistent, and influenced by demographic and clinical variables. Future work will test techniques for harmonizing neurocognitive data, enabling more advanced analyses to identify symptom clusters and clinically-meaningful patient subtypes.
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http://dx.doi.org/10.1212/WNL.0000000000012222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8302152PMC
May 2021

Aberrant anterior cingulate processing of anticipated threat as a mechanism for psychosis.

Psychiatry Res Neuroimaging 2021 07 12;313:111300. Epub 2021 May 12.

Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD 21228 , United States.

Stress and abnormal stress response are associated with schizophrenia spectrum disorder (SSD), but the brain mechanisms linking stress to symptomatology remain unclear. In this study, we used a stress-based functional neuroimaging task, reverse-translated from preclinical studies, to test the hypothesis that abnormal corticolimbic processing of stressful threat anticipation is associated with psychosis and affective symptoms in SSD. Participants underwent an MRI-compatible ankle-shock task (AST) in which the threat of mild electrical shock was anticipated. We compared functional brain activations during anticipatory threat periods from N = 18 participants with SSD (10 M/8F) to those from N = 12 community controls (9 M/3F). After family-wise error correction, only one region, the ventral anterior cingulate cortex (vACC), showed significantly reduced activation compared with controls. vACC activation significantly correlated with clinical symptoms measured by the Brief Psychiatric Rating Scale total score (r = 0.54) and the psychosis subscale (r = 0.71), and inversely correlated with trait depression measured by the Maryland Trait and State Depression scale (r=-0.48). Deficient activation in vACC under stress of anticipated threat may lead to aberrant interpretation of such threat, contributing to psychosis and mood symptoms in SSD. This experimental paradigm has translational potential and may identify circuitry-level mechanisms of stress-related mental illness, leading to more targeted treatment.
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http://dx.doi.org/10.1016/j.pscychresns.2021.111300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8206034PMC
July 2021

Neuroretinal Biomarkers for Schizophrenia Spectrum Disorders.

Transl Vis Sci Technol 2021 04;10(4):29

Department of Ophthalmology and Visual Sciences, University of Maryland School of Medicine, Baltimore, MD, USA.

Purpose: We evaluated the patient-control differences and predictive value of the retina as potential biomarkers for schizophrenia.

Methods: The institutional study included both eyes of 58 schizophrenia spectrum disorder (SSD) patients (age 37.2 ± 12.3 years) and 35 controls (age 41.1 ± 15.2 years). Retinal nerve fiber layer (RNFL), ganglion cell-inner plexiform layer, outer retinal photoreceptor complex, and total macula thicknesses were measured by optical coherence tomography (OCT). Anterior segment parameters including central corneal thickness, anterior chamber depth, and axial length were measured to rule out confounds on the retinal measures.

Results: The peripapillary RNFL was overall significantly thinner in SSD relative to controls (F = 3.97, P = 0.049), most pronounced in the temporal (5.2 µm difference, F = 6.95, P = 0.010) and inferior quadrants (12.1 µm difference, F = 7.32, P = 0.009). There were no significant group differences in thickness for the macular RNFL, ganglion, or photoreceptor cell related measures (P > 0.05). Peripapillary RNFL, central macula, and outer photoreceptor complex thicknesses were together able to classify SSD patients with 80% sensitivity and 71% specificity; area under the curve = 0.82 (95% confidence interval, 0.75-0.88).

Conclusions: SSD patients exhibited significant RNFL thinning relative to controls. Notably, retinal thickness measures including both peripapillary and macular data exhibited improved diagnostic accuracy for SSD as compared to these regions alone.

Translational Relevance: This is the first study to evaluate the predictive value of both the inner and outer retina in SSD. OCT retinal thickness measures including peripapillary data in conjunction with macular data may provide an informative, noninvasive in vivo ocular biomarker for schizophrenia.
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http://dx.doi.org/10.1167/tvst.10.4.29DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8083086PMC
April 2021

Mapping local and long-distance resting connectivity markers of TMS-related inhibition reduction in schizophrenia.

Neuroimage Clin 2021 Apr 30;31:102688. Epub 2021 Apr 30.

Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, United States.

Short interval intracortical inhibition (SICI) is a biomarker for altered motor inhibition in schizophrenia, but the manner in which distant sites influence the inhibitory cortical-effector response remains elusive. Our study investigated local and long-distance resting state functional connectivity (rsFC) markers of SICI in a sample of N = 23 patients with schizophrenia and N = 29 controls. Local functional connectivity was quantified using regional homogeneity (ReHo) analysis and long-range connectivity was estimated using seed-based rsFC analysis. Direct and indirect effects of connectivity measures on SICI were modeled using mediation analysis. Higher SICI ratios (indicating reduced inhibition) in patients were associated with lower ReHo in the right insula. Follow-up rsFC analyses showed that higher SICI scores (indicating reduced inhibition) were associated with reduced connectivity between right insula and hubs of the corticospinal pathway: sensorimotor cortex and basal ganglia. Mediation analysis supported a model in which the direct effect of local insular connectivity strength on SICI is mediated by the interhemispheric connectivity between insula and left sensorimotor cortex. The broader clinical implications of these findings are discussed with emphasis on how these preliminary findings might inform novel interventions designed to restore or improve SICI in schizophrenia and deepen our understanding of motor inhibitory control and impact of abnormal signaling in motor-inhibitory pathways in schizophrenia.
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http://dx.doi.org/10.1016/j.nicl.2021.102688DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8135038PMC
April 2021

Multiple dimensions of stress vs. genetic effects on depression.

Transl Psychiatry 2021 04 29;11(1):254. Epub 2021 Apr 29.

Maryland Psychiatric Research Center, Department of Psychiatry, , University of Maryland School of Medicine, Baltimore, MD, 21201, USA.

Many psychiatric disorders including depression involve complex interactions of genetics and environmental stressors. Environmental influence is challenging to measure objectively and account for in genetic studies because the necessary large population samples in these studies involve individuals with varying cultures and life experiences, clouding genetic findings. In a unique population with relative sociocultural homogeneity and a narrower range of types of stress experiences, we quantitatively assessed multiple stress dimensions and measured their potential influence in biasing the heritability estimate of depression. We quantified depressive symptoms, major lifetime stressors, current perceived stress, and a culturally specific community stress measure in individuals with depression-related diagnoses and community controls in Old Order Amish and Mennonite populations. Results showed that lifetime stressors measured by lifetime stressor inventory (R= 0.06, p = 2 × 10) and current stress measured by Perceived Stress Scale (R= 0.13, p < 1 × 10) were both associated with current depressive symptoms quantified by Beck Depression Inventory in community controls, but current stress was the only measure associated with current depressive symptoms in individuals with a depression diagnosis, and to a greater degree (R = 0.41, p < 1 × 10). A novel, culturally specific community stress measure demonstrated internal reliability and was associated with current stress but was not significantly related to depression. Heritability (h) for depression diagnosis (0.46 ± 0.14) and quantitative depression severity as measured by Beck Depression Inventory (0.45 ± 0.12) were significant, but h for depression diagnosis decreased to 0.25 ± 0.14 once stressors were accounted for in the model. This quantifies and demonstrates the importance of accounting for environmental influence in reducing phenotypic heterogeneity of depression and improving the power and replicability of genetic association findings that can be better translated to patient groups.
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http://dx.doi.org/10.1038/s41398-021-01369-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8085217PMC
April 2021

ENIGMA-Sleep: Challenges, opportunities, and the road map.

J Sleep Res 2021 Apr 28:e13347. Epub 2021 Apr 28.

Department of Sleep and Cognition, Netherlands Institute for Neuroscience (NIN), an Institute of the Royal Netherlands Academy of Arts and Sciences, Amsterdam, The Netherlands.

Neuroimaging and genetics studies have advanced our understanding of the neurobiology of sleep and its disorders. However, individual studies usually have limitations to identifying consistent and reproducible effects, including modest sample sizes, heterogeneous clinical characteristics and varied methodologies. These issues call for a large-scale multi-centre effort in sleep research, in order to increase the number of samples, and harmonize the methods of data collection, preprocessing and analysis using pre-registered well-established protocols. The Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) consortium provides a powerful collaborative framework for combining datasets across individual sites. Recently, we have launched the ENIGMA-Sleep working group with the collaboration of several institutes from 15 countries to perform large-scale worldwide neuroimaging and genetics studies for better understanding the neurobiology of impaired sleep quality in population-based healthy individuals, the neural consequences of sleep deprivation, pathophysiology of sleep disorders, as well as neural correlates of sleep disturbances across various neuropsychiatric disorders. In this introductory review, we describe the details of our currently available datasets and our ongoing projects in the ENIGMA-Sleep group, and discuss both the potential challenges and opportunities of a collaborative initiative in sleep medicine.
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http://dx.doi.org/10.1111/jsr.13347DOI Listing
April 2021

Effects of neuroactive metabolites of the tryptophan pathway on working memory and cortical thickness in schizophrenia.

Transl Psychiatry 2021 04 1;11(1):198. Epub 2021 Apr 1.

Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA.

A number of tryptophan metabolites known to be neuroactive have been examined for their potential associations with cognitive deficits in schizophrenia. Among these metabolites, kynurenic acid (KYNA), 5-hydroxyindole (5-HI), and quinolinic acid (QUIN) are documented in their diverse effects on α-7 nicotinic acetylcholine receptor (α7nAChR) and/or N-methyl-D-aspartate receptor (NMDAR), two of the receptor types thought to contribute to cognitive impairment in schizophrenia. In this study, serum levels of KYNA, 5-HI, and QUIN were measured in 195 patients with schizophrenia and in 70 healthy controls using liquid chromatography-tandem mass spectrometry; cognitive performance in MATRICS Consensus Cognitive Battery and cortical thickness measured by magnetic resonance imaging were obtained. Patients with schizophrenia had significantly lower serum KYNA (p < 0.001) and QUIN (p = 0.02) levels, and increased 5-HI/KYNA (p < 0.001) and QUIN/KYNA ratios (p < 0.001) compared with healthy controls. Multiple linear regression showed that working memory was positively correlated with serum 5-HI levels (t = 2.10, p = 0.04), but inversely correlated with KYNA concentrations (t = -2.01, p = 0.05) in patients. Patients with high 5-HI and low KYNA had better working memory than other subgroups (p = 0.01). Higher 5-HI levels were associated with thicker left lateral orbitofrontal cortex (t = 3.71, p = 2.94 × 10) in patients. The different effects of 5-HI and KYNA on working memory may appear consistent with their opposite receptor level mechanisms. Our findings appear to provide a new insight into the dynamic roles of tryptophan pathway metabolites on cognition, which may benefit novel therapeutic development that targets cognitive impairment in schizophrenia.
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http://dx.doi.org/10.1038/s41398-021-01311-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8016899PMC
April 2021

White matter microstructure and its relation to clinical features of obsessive-compulsive disorder: findings from the ENIGMA OCD Working Group.

Transl Psychiatry 2021 03 17;11(1):173. Epub 2021 Mar 17.

Department of Psychiatry, Oxford University, Oxford, UK.

Microstructural alterations in cortico-subcortical connections are thought to be present in obsessive-compulsive disorder (OCD). However, prior studies have yielded inconsistent findings, perhaps because small sample sizes provided insufficient power to detect subtle abnormalities. Here we investigated microstructural white matter alterations and their relation to clinical features in the largest dataset of adult and pediatric OCD to date. We analyzed diffusion tensor imaging metrics from 700 adult patients and 645 adult controls, as well as 174 pediatric patients and 144 pediatric controls across 19 sites participating in the ENIGMA OCD Working Group, in a cross-sectional case-control magnetic resonance study. We extracted measures of fractional anisotropy (FA) as main outcome, and mean diffusivity, radial diffusivity, and axial diffusivity as secondary outcomes for 25 white matter regions. We meta-analyzed patient-control group differences (Cohen's d) across sites, after adjusting for age and sex, and investigated associations with clinical characteristics. Adult OCD patients showed significant FA reduction in the sagittal stratum (d = -0.21, z = -3.21, p = 0.001) and posterior thalamic radiation (d = -0.26, z = -4.57, p < 0.0001). In the sagittal stratum, lower FA was associated with a younger age of onset (z = 2.71, p = 0.006), longer duration of illness (z = -2.086, p = 0.036), and a higher percentage of medicated patients in the cohorts studied (z = -1.98, p = 0.047). No significant association with symptom severity was found. Pediatric OCD patients did not show any detectable microstructural abnormalities compared to controls. Our findings of microstructural alterations in projection and association fibers to posterior brain regions in OCD are consistent with models emphasizing deficits in connectivity as an important feature of this disorder.
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http://dx.doi.org/10.1038/s41398-021-01276-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7969744PMC
March 2021

White matter brain aging in relationship to schizophrenia and its cognitive deficit.

Schizophr Res 2021 04 2;230:9-16. Epub 2021 Mar 2.

Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA; Division of Biostatistics and Bioinformatics, Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, MD, USA. Electronic address:

We hypothesized that cerebral white matter deficits in schizophrenia (SZ) are driven in part by accelerated white matter aging and are associated with cognitive deficits. We used a machine learning model to predict individual age from diffusion tensor imaging features and calculated the delta age (Δage) as the difference between predicted and chronological age. Through this approach, we translated multivariate white matter imaging features into an age-scaled metric and used it to test the temporal trends of accelerated aging-related white matter deficit in SZ and its association with the cognition. A feature selection procedure was first employed to choose fractional anisotropy values in 34 of 43 white fiber tracts. Using these features, a machine learning model was trained based on a training set consisted of 107 healthy controls (HC). The brain age of 166 SZs and 107 HCs in the testing set were calculated using this model. Then, we examined the SZ-HC group effect on Δage and whether this effect was moderated by chronological age using the regression spline model. The results showed that Δage was significantly elevated in the age > 30 group in patients (p < 0.001) but not in age ≤ 30 group (p = 0.364). Δage in patients was significantly and negatively associated with both working memory (β = -0.176, p = 0.007) and processing speed (β = -0.519, p = 0.035) while adjusting sex and chronological age. Overall, these findings indicate that the Δage is elevated in SZs and become significantly from the third decade of life; the increase of Δage in SZs is associated with the declined neurocognitive performance.
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http://dx.doi.org/10.1016/j.schres.2021.02.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8222174PMC
April 2021

Association of working memory and elevated overnight urinary norepinephrine in patients with schizophrenia.

J Psychiatr Res 2021 05 13;137:89-95. Epub 2021 Feb 13.

Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA. Electronic address:

Introduction: Norepinephrine has both central and peripheral origins and is known to influence cognitive processes in attention, learning, and working memory, but the research regarding the impact of norepinephrine on cognition in schizophrenia remains sparse, and mainly focuses on centrally regulated noradrenergic effects. This study examined the relationship between cumulative overnight norepinephrine levels in the urine and working memory in patients with schizophrenia and healthy controls.

Methods: Urinary catecholamines were collected overnight in patients with schizophrenia (n = 75) and healthy controls (n = 33). Working memory was assessed using the digit sequencing task.

Results: Patients showed significantly higher average levels of overnight norepinephrine (t(103.10) = -3.16, p = 0.002) and reduced working memory performance (t(90) = 3.87, p = 0.001) compared with healthy individuals. There was a significant negative correlation between norepinephrine and working memory in patients (r = -0.38, p = 0.005), but not in controls (r = 0.08, p = 0.67). After controlling for age, sex, antipsychotic medications, and serotonin-norepinephrine reuptake inhibitor-based antidepressants, the correlation remained significant (r = -0.41, p = 0.004).

Conclusions: High peripheral overnight levels of urinary norepinephrine are associated with lower working memory performance in patients with schizophrenia. These results parallel previous studies suggesting that high levels of central norepinephrine may result in working memory impairments. As norepinephrine rapidly breaks down and usually does not pass through the blood-brain barrier, the potential effect of peripheral cumulative norepinephrine on working memory is intriguing, and needs to be further investigated.
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http://dx.doi.org/10.1016/j.jpsychires.2021.02.005DOI Listing
May 2021

Genetic versus stress and mood determinants of sleep in the Amish.

Am J Med Genet B Neuropsychiatr Genet 2021 03 1;186(2):113-121. Epub 2021 Mar 1.

Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, Maryland, USA.

Sleep is essential to the human brain and is regulated by genetics with many features conserved across species. Sleep is also influenced by health and environmental factors; identifying replicable genetic variants contributing to sleep may require accounting for these factors. We examined how stress and mood disorder contribute to sleep and impact its heritability. Our sample included 326 Amish/Mennonite individuals with a lifestyle with limited technological interferences with sleep. Sleep measures included Pittsburgh Sleep Quality Index (PSQI), bedtime, wake time, and time to sleep onset. Current stress level, cumulative life stressors, and mood disorder were also evaluated. We estimated the heritability of sleep features and examined the impact of current stress, lifetime stress, mood diagnosis on sleep quality. The results showed current stress, lifetime stress, and mood disorder were independently associated with PSQI score (p < .05). Heritability of PSQI was low (0-0.23) before and after accounting for stress and mood. Bedtime, wake time, and minutes to sleep time did show significant heritability at 0.44, 0.42, and 0.29. However, after adjusting for shared environment, only heritability of wake time remained significant. Sleep is affected by environmental stress and mental health factors even in a society with limited technological interference with sleep. Wake time may be a more biological marker of sleep as compared to the evening measures which are more influenced by other household members. Accounting for nongenetic and partially genetic determinants of sleep particularly stress and mood disorder is likely important for improving the precision of genetic studies of sleep.
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http://dx.doi.org/10.1002/ajmg.b.32840DOI Listing
March 2021

The microRNA-195 - BDNF pathway and cognitive deficits in schizophrenia patients with minimal antipsychotic medication exposure.

Transl Psychiatry 2021 02 8;11(1):117. Epub 2021 Feb 8.

Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA.

Cognitive impairment is a core characteristic of schizophrenia, but its underlying neural mechanisms remain poorly understood. Reduced brain-derived neurotrophic factor (BDNF), a protein critical for neural plasticity and synaptic signaling, is one of the few molecules consistently associated with cognitive deficits in schizophrenia although the etiological pathway leading to BDNF reduction in schizophrenia is unclear. We examined microRNA-195 (miR-195), a known modulator of BDNF protein expression, as a potential mechanistic component. One-hundred and eighteen first-episode patients with schizophrenia either antipsychotic medication-naïve or within two weeks of antipsychotic medication exposure and forty-seven age- and sex-matched healthy controls were enrolled. MiR-195 and BDNF mRNA and BDNF protein levels in peripheral blood were tested. Cognitive function was assessed using the MATRICS Consensus Cognitive Battery (MCCB). MiR-195 was significantly higher (p = 0.01) whereas BDNF mRNA (p < 0.001) and protein (p = 0.016) levels were significantly lower in patients compared with controls. Higher miR-195 expression was significantly correlated to lower BDNF protein levels in patients (partial r = -0.28, p = 0.003) and lower BDNF protein levels were significantly associated with poorer overall cognitive performance by MCCB and also in speed of processing, working memory, and attention/vigilance domains composite score (p = 0.002-0.004). The subgroup of patients with high miR-195 and low BDNF protein showed the lowest level of cognitive functions, and miR-195 showed significant mediation effects on cognitive functions through BDNF protein. Elevated miR-195 may play a role in regulating BDNF protein expression thereby influencing cognitive impairments in schizophrenia, suggesting that development of cognition enhancing treatment for schizophrenia may consider a micro-RNA based strategy.
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http://dx.doi.org/10.1038/s41398-021-01240-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7870897PMC
February 2021

Comparison of regional brain deficit patterns in common psychiatric and neurological disorders as revealed by big data.

Neuroimage Clin 2021 26;29:102574. Epub 2021 Jan 26.

Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA. Electronic address:

Neurological and psychiatric illnesses are associated with regional brain deficit patterns that bear unique signatures and capture illness-specific characteristics. The Regional Vulnerability Index (RVI) was developed toquantify brain similarity by comparing individual white matter microstructure, cortical gray matter thickness and subcortical gray matter structural volume measures with neuroanatomical deficit patterns derived from large-scale meta-analytic studies. We tested the specificity of the RVI approach for major depressive disorder (MDD) and Alzheimer's disease (AD) in a large epidemiological sample of UK Biobank (UKBB) participants (N = 19,393; 9138 M/10,255F; age = 64.8 ± 7.4 years). Compared to controls free of neuropsychiatric disorders, participants with MDD (N = 2,248; 805 M/1443F; age = 63.4 ± 7.4) had significantly higher RVI-MDD values (t = 5.6, p = 1·10), but showed no detectable difference in RVI-AD (t = 2.0, p = 0.10). Subjects with dementia (N = 7; 4 M/3F; age = 68.6 ± 8.6 years) showed significant elevation in RVI-AD (t = 4.2, p = 3·10) but not RVI-MDD (t = 2.1, p = 0.10) compared to controls. Even within affective illnesses, participants with bipolar disorder (N = 54) and anxiety disorder (N = 773) showed no significant elevation in whole-brain RVI-MDD. Participants with Parkinson's disease (N = 37) showed elevation in RVI-AD (t = 2.4, p = 0.01) while subjects with stroke (N = 247) showed no such elevation (t = 1.1, p = 0.3). In summary, we demonstrated elevation in RVI-MDD and RVI-AD measures in the respective illnesses with strong replicability that is relatively specific to the respective diagnoses. These neuroanatomic deviation patterns offer a useful biomarker for population-wide assessments of similarity to neuropsychiatric illnesses.
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http://dx.doi.org/10.1016/j.nicl.2021.102574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851406PMC
June 2021

N-methyl-D-aspartate Receptor Antibody and White Matter Deficits in Schizophrenia Treatment-Resistance.

Schizophr Bull 2021 Jan 30. Epub 2021 Jan 30.

Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA.

Insufficient or lack of response to antipsychotic medications in some patients with schizophrenia is a major challenge in psychiatry, but the underlying mechanisms remain unclear. Two seemingly unrelated observations, cerebral white matter and N-methyl-D-aspartate receptor (NMDAR) hypofunction, have been linked to treatment-resistant schizophrenia (TRS). As NMDARs are critical to axonal myelination and signal transduction, we hypothesized that NMDAR antibody (Ab), when present in schizophrenia, may impair NMDAR functions and white matter microstructures, contributing to TRS. In this study, 50 patients with TRS, 45 patients with nontreatment-resistant schizophrenia (NTRS), 53 patients with schizophrenia at treatment initiation schizophrenia (TIS), and 90 healthy controls were enrolled. Serum NMDAR Ab levels and white matter diffusion tensor imaging fractional anisotropy (FA) were assessed. The white matter specificity effects by NMDAR Ab were assessed by comparing with effects on cortical and subcortical gray matter. Serum NMDAR Ab levels of the TRS were significantly higher than those of the NTRS (P = .035). In patients with TRS, higher NMDAR Ab levels were significantly associated with reduced whole-brain average FA (r = -.37; P = .026), with the strongest effect at the genu of corpus callosum (r = -.50; P = .0021, significant after correction for multiple comparisons). Conversely, there was no significant correlation between whole-brain or regional cortical thickness or any subcortical gray matter structural volume and NMDAR Ab levels in TRS. Our finding highlights a potential NMDAR mechanism on white matter microstructure impairment in schizophrenia that may contribute to their treatment resistance to antipsychotic medications.
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http://dx.doi.org/10.1093/schbul/sbab003DOI Listing
January 2021

Allostatic Load Effects on Cortical and Cognitive Deficits in Essentially Normotensive, Normoweight Patients with Schizophrenia.

Schizophr Bull 2021 Jul;47(4):1048-1057

Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD.

Reduced cortical gray matter integrity and cognitive abilities are among core deficits in schizophrenia. We hypothesized that higher allostatic load (AL) that accounts for exposure to chronic stress is a contributor to structural and cognitive deficits in schizophrenia. One hundred and sixty-seven schizophrenia patients who were on average with normal weight, normal systolic, and diastolic blood pressure and 72 healthy controls were enrolled in the study. Group differences in subclinical cardiovascular, metabolic, immune, and neuroendocrine biological markers as indexed by AL and contribution of AL components to the structural and cognitive deficits in schizophrenia were explored. Compared with controls, schizophrenia patients who were normotensive, normoweight, and had low total cholesterol levels still had significantly higher AL mainly due to lower high-density lipoprotein cholesterol and higher heart rate, waist-hip ratio, hemoglobinA1c, hypersensitive C-reactive protein, and overnight-urine cortisol levels. Patients also had decreased whole-brain mean cortical thickness, and lower cognition assessed by the MATRICS consensus cognitive battery. AL was inversely correlated with mean cortical thickness and cognition in schizophrenia, while none of these relationships existed in controls. Mediation analyses showed the effect of AL on cognitive deficits in schizophrenia was significantly mediated by cortical thinning, and the most significant mediating cortical area was the left superior frontal gyrus. Cortical thickness may act as a mediator between AL and cognitive deficits in schizophrenia. Early intervention strategies to reduce cortical thinning and cognitive dysfunction in schizophrenia should target specific aspects of their high AL in addition to weight gain, hypertension and high cholesterol levels.
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http://dx.doi.org/10.1093/schbul/sbaa196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8266595PMC
July 2021

Local versus long-range connectivity patterns of auditory disturbance in schizophrenia.

Schizophr Res 2021 02 22;228:262-270. Epub 2021 Jan 22.

Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA; Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, MD, USA. Electronic address:

Auditory hallucinations are a debilitating symptom of schizophrenia. Effective treatment is limited because the underlying neural mechanisms remain unknown. Our study investigates how local and long-range functional connectivity is associated with auditory perceptual disturbances (APD) in schizophrenia. APD was assessed using the Auditory Perceptual Trait and State Scale. Resting state fMRI data were collected for N=99 patients with schizophrenia. Local functional connectivity was estimated using regional homogeneity (ReHo) analysis; long-range connectivity was estimated using resting state functional connectivity (rsFC) analysis. Mediation analyses tested whether local (ReHo) connectivity significantly mediated associations between long-distance rsFC and APD. Severity of APD was significantly associated with reduced ReHo in left and right putamen, left temporoparietal junction (TPJ), and right hippocampus-pallidum. Higher APD was also associated with reduced rsFC between the right putamen and the contralateral putamen and auditory cortex. Local and long-distance connectivity measures together explained 40.3% of variance in APD (P < 0.001), with the strongest predictor being the left TPJ ReHo (P < 0.001). Additionally, TPJ ReHo significantly mediated the relationship between right putamen - left putamen rsFC and APD (Sobel test, P = 0.001). Our findings suggest that both local and long-range functional connectivity deficits contribute to APD, emphasizing the role of striatum and auditory cortex. Considering the translational impact of these circuit-based findings within the context of prior clinical trials to treat auditory hallucinations, we propose a model in which correction of both local and long-distance functional connectivity deficits may be necessary to treat auditory hallucinations.
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http://dx.doi.org/10.1016/j.schres.2020.11.052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987759PMC
February 2021

Characterizing the Complexity of Weighted Networks via Graph Embedding and Point Pattern Analysis.

Entropy (Basel) 2020 Aug 23;22(9). Epub 2020 Aug 23.

Maryland Psychiatric Research Center, Department of Psychiatry, School of Medicine, University of Maryland, Baltimore, MD 21228, USA.

We propose a new metric to characterize the complexity of weighted complex networks. Weighted complex networks represent a highly organized interactive process, for example, co-varying returns between stocks (financial networks) and coordination between brain regions (brain connectivity networks). Although network entropy methods have been developed for binary networks, the measurement of non-randomness and complexity for large weighted networks remains challenging. We develop a new analytical framework to measure the complexity of a weighted network via graph embedding and point pattern analysis techniques in order to address this unmet need. We first perform graph embedding to project all nodes of the weighted adjacency matrix to a low dimensional vector space. Next, we analyze the point distribution pattern in the projected space, and measure its deviation from the complete spatial randomness. We evaluate our method via extensive simulation studies and find that our method can sensitively detect the difference of complexity and is robust to noise. Last, we apply the approach to a functional magnetic resonance imaging study and compare the complexity metrics of functional brain connectivity networks from 124 patients with schizophrenia and 103 healthy controls. The results show that the brain circuitry is more organized in healthy controls than schizophrenic patients for male subjects while the difference is minimal in female subjects. These findings are well aligned with the established sex difference in schizophrenia.
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http://dx.doi.org/10.3390/e22090925DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7597178PMC
August 2020

Assessment of brain cholesterol metabolism biomarker 24S-hydroxycholesterol in schizophrenia.

NPJ Schizophr 2020 Nov 20;6(1):34. Epub 2020 Nov 20.

Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA.

Plasma 24S-hydroxycholesterol mostly originates in brain tissue and likely reflects the turnover of cholesterol in the central nervous system. As cholesterol is disproportionally enriched in many key brain structures, 24S-hydroxycholesterol is a promising biomarker for psychiatric and neurologic disorders that impact brain structure. We hypothesized that, as schizophrenia patients have widely reported gray and white matter deficits, they would have abnormal levels of plasma 24S-hydroxycholesterol, and that plasma levels of 24S-hydroxycholesterol would be associated with brain structural and functional biomarkers for schizophrenia. Plasma levels of 24S-hydroxycholesterol were measured in 226 individuals with schizophrenia and 204 healthy controls. The results showed that levels of 24S-hydroxycholesterol were not significantly different between patients and controls. Age was significantly and negatively correlated with 24S-hydroxycholesterol in both groups, and in both groups, females had significantly higher levels of 24S-hydroxycholesterol compared to males. Levels of 24S-hydroxycholesterol were not related to average fractional anisotropy of white matter or cortical thickness, or to cognitive deficits in schizophrenia. Based on these results from a large sample and using multiple brain biomarkers, we conclude there is little to no value of plasma 24S-hydroxycholesterol as a brain metabolite biomarker for schizophrenia.
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http://dx.doi.org/10.1038/s41537-020-00121-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7680117PMC
November 2020

Intracranial and subcortical volumes in adolescents with early-onset psychosis: A multisite mega-analysis from the ENIGMA consortium.

Hum Brain Mapp 2020 Oct 5. Epub 2020 Oct 5.

Hurvitz Brain Sciences, Sunnybrook Research Institute, Toronto, Ontario, Canada.

Early-onset psychosis disorders are serious mental disorders arising before the age of 18 years. Here, we investigate the largest neuroimaging dataset, to date, of patients with early-onset psychosis and healthy controls for differences in intracranial and subcortical brain volumes. The sample included 263 patients with early-onset psychosis (mean age: 16.4 ± 1.4 years, mean illness duration: 1.5 ± 1.4 years, 39.2% female) and 359 healthy controls (mean age: 15.9 ± 1.7 years, 45.4% female) with magnetic resonance imaging data, pooled from 11 clinical cohorts. Patients were diagnosed with early-onset schizophrenia (n = 183), affective psychosis (n = 39), or other psychotic disorders (n = 41). We used linear mixed-effects models to investigate differences in intracranial and subcortical volumes across the patient sample, diagnostic subgroup and antipsychotic medication, relative to controls. We observed significantly lower intracranial (Cohen's d = -0.39) and hippocampal (d = -0.25) volumes, and higher caudate (d = 0.25) and pallidum (d = 0.24) volumes in patients relative to controls. Intracranial volume was lower in both early-onset schizophrenia (d = -0.34) and affective psychosis (d = -0.42), and early-onset schizophrenia showed lower hippocampal (d = -0.24) and higher pallidum (d = 0.29) volumes. Patients who were currently treated with antipsychotic medication (n = 193) had significantly lower intracranial volume (d = -0.42). The findings demonstrate a similar pattern of brain alterations in early-onset psychosis as previously reported in adult psychosis, but with notably low intracranial volume. The low intracranial volume suggests disrupted neurodevelopment in adolescent early-onset psychosis.
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http://dx.doi.org/10.1002/hbm.25212DOI Listing
October 2020

Shaping brain structure: Genetic and phylogenetic axes of macroscale organization of cortical thickness.

Sci Adv 2020 Sep 25;6(39). Epub 2020 Sep 25.

Institute of Neuroscience and Medicine (INM-7: Brain and Behavior), Research Centre Jülich, Jülich, Germany.

The topology of the cerebral cortex has been proposed to provide an important source of constraint for the organization of cognition. In a sample of twins ( = 1113), we determined structural covariance of thickness to be organized along both a posterior-to-anterior and an inferior-to-superior axis. Both organizational axes were present when investigating the genetic correlation of cortical thickness, suggesting a strong genetic component in humans, and had a comparable organization in macaques, demonstrating they are phylogenetically conserved in primates. In both species, the inferior-superior dimension of cortical organization aligned with the predictions of dual-origin theory, and in humans, we found that the posterior-to-anterior axis related to a functional topography describing a continuum of functions from basic processes involved in perception and action to more abstract features of human cognition. Together, our study provides important insights into how functional and evolutionary patterns converge at the level of macroscale cortical structural organization.
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http://dx.doi.org/10.1126/sciadv.abb3417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7518868PMC
September 2020

NeuroMark: An automated and adaptive ICA based pipeline to identify reproducible fMRI markers of brain disorders.

Neuroimage Clin 2020 11;28:102375. Epub 2020 Aug 11.

Tri-Institutional Center for Translational Research in Neuroimaging and Data Science (TReNDS), Georgia State University, Georgia Institute of Technology, Emory University, Atlanta, USA; School of Electrical & Computer Engineering, Georgia Institute of Technology, Atlanta, USA.

Many mental illnesses share overlapping or similar clinical symptoms, confounding the diagnosis. It is important to systematically characterize the degree to which unique and similar changing patterns are reflective of brain disorders. Increasing sharing initiatives on neuroimaging data have provided unprecedented opportunities to study brain disorders. However, it is still an open question on replicating and translating findings across studies. Standardized approaches for capturing reproducible and comparable imaging markers are greatly needed. Here, we propose a pipeline based on the priori-driven independent component analysis, NeuroMark, which is capable of estimating brain functional network measures from functional magnetic resonance imaging (fMRI) data that can be used to link brain network abnormalities among different datasets, studies, and disorders. NeuroMark automatically estimates features adaptable to each individual subject and comparable across datasets/studies/disorders by taking advantage of the reliable brain network templates extracted from 1828 healthy controls as guidance. Four studies including 2442 subjects were conducted spanning six brain disorders (schizophrenia, autism spectrum disorder, mild cognitive impairment, Alzheimer's disease, bipolar disorder, and major depressive disorder) to evaluate validity of the proposed pipeline from different perspectives (replication of brain abnormalities, cross-study comparison, identification of subtle brain changes, and multi-disorder classification using identified biomarkers). Our results highlight that NeuroMark effectively identified replicated brain network abnormalities of schizophrenia across different datasets; revealed interesting neural clues on the overlap and specificity between autism and schizophrenia; demonstrated brain functional impairments present to varying degrees in mild cognitive impairments and Alzheimer's disease; and captured biomarkers that achieved good performance in classifying bipolar disorder and major depressive disorder.
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http://dx.doi.org/10.1016/j.nicl.2020.102375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7509081PMC
June 2021

The reliability and heritability of cortical folds and their genetic correlations across hemispheres.

Commun Biol 2020 09 15;3(1):510. Epub 2020 Sep 15.

Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine of USC, Marina del Rey, CA, USA.

Cortical folds help drive the parcellation of the human cortex into functionally specific regions. Variations in the length, depth, width, and surface area of these sulcal landmarks have been associated with disease, and may be genetically mediated. Before estimating the heritability of sulcal variation, the extent to which these metrics can be reliably extracted from in-vivo MRI must be established. Using four independent test-retest datasets, we found high reliability across the brain (intraclass correlation interquartile range: 0.65-0.85). Heritability estimates were derived for three family-based cohorts using variance components analysis and pooled (total N > 3000); the overall sulcal heritability pattern was correlated to that derived for a large population cohort (N > 9000) calculated using genomic complex trait analysis. Overall, sulcal width was the most heritable metric, and earlier forming sulci showed higher heritability. The inter-hemispheric genetic correlations were high, yet select sulci showed incomplete pleiotropy, suggesting hemisphere-specific genetic influences.
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http://dx.doi.org/10.1038/s42003-020-01163-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7493906PMC
September 2020

Virtual Histology of Cortical Thickness and Shared Neurobiology in 6 Psychiatric Disorders.

JAMA Psychiatry 2021 Jan;78(1):47-63

Department of Psychiatry and Neuropsychology, School of Mental Health and Neuroscience, Maastricht University, the Netherlands.

Importance: Large-scale neuroimaging studies have revealed group differences in cortical thickness across many psychiatric disorders. The underlying neurobiology behind these differences is not well understood.

Objective: To determine neurobiologic correlates of group differences in cortical thickness between cases and controls in 6 disorders: attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), bipolar disorder (BD), major depressive disorder (MDD), obsessive-compulsive disorder (OCD), and schizophrenia.

Design, Setting, And Participants: Profiles of group differences in cortical thickness between cases and controls were generated using T1-weighted magnetic resonance images. Similarity between interregional profiles of cell-specific gene expression and those in the group differences in cortical thickness were investigated in each disorder. Next, principal component analysis was used to reveal a shared profile of group difference in thickness across the disorders. Analysis for gene coexpression, clustering, and enrichment for genes associated with these disorders were conducted. Data analysis was conducted between June and December 2019. The analysis included 145 cohorts across 6 psychiatric disorders drawn from the ENIGMA consortium. The numbers of cases and controls in each of the 6 disorders were as follows: ADHD: 1814 and 1602; ASD: 1748 and 1770; BD: 1547 and 3405; MDD: 2658 and 3572; OCD: 2266 and 2007; and schizophrenia: 2688 and 3244.

Main Outcomes And Measures: Interregional profiles of group difference in cortical thickness between cases and controls.

Results: A total of 12 721 cases and 15 600 controls, ranging from ages 2 to 89 years, were included in this study. Interregional profiles of group differences in cortical thickness for each of the 6 psychiatric disorders were associated with profiles of gene expression specific to pyramidal (CA1) cells, astrocytes (except for BD), and microglia (except for OCD); collectively, gene-expression profiles of the 3 cell types explain between 25% and 54% of variance in interregional profiles of group differences in cortical thickness. Principal component analysis revealed a shared profile of difference in cortical thickness across the 6 disorders (48% variance explained); interregional profile of this principal component 1 was associated with that of the pyramidal-cell gene expression (explaining 56% of interregional variation). Coexpression analyses of these genes revealed 2 clusters: (1) a prenatal cluster enriched with genes involved in neurodevelopmental (axon guidance) processes and (2) a postnatal cluster enriched with genes involved in synaptic activity and plasticity-related processes. These clusters were enriched with genes associated with all 6 psychiatric disorders.

Conclusions And Relevance: In this study, shared neurobiologic processes were associated with differences in cortical thickness across multiple psychiatric disorders. These processes implicate a common role of prenatal development and postnatal functioning of the cerebral cortex in these disorders.
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http://dx.doi.org/10.1001/jamapsychiatry.2020.2694DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7450410PMC
January 2021

White matter abnormalities across different epilepsy syndromes in adults: an ENIGMA-Epilepsy study.

Brain 2020 08;143(8):2454-2473

Department of Neurology, Medical University of South Carolina, Charleston 29425 SC, USA.

The epilepsies are commonly accompanied by widespread abnormalities in cerebral white matter. ENIGMA-Epilepsy is a large quantitative brain imaging consortium, aggregating data to investigate patterns of neuroimaging abnormalities in common epilepsy syndromes, including temporal lobe epilepsy, extratemporal epilepsy, and genetic generalized epilepsy. Our goal was to rank the most robust white matter microstructural differences across and within syndromes in a multicentre sample of adult epilepsy patients. Diffusion-weighted MRI data were analysed from 1069 healthy controls and 1249 patients: temporal lobe epilepsy with hippocampal sclerosis (n = 599), temporal lobe epilepsy with normal MRI (n = 275), genetic generalized epilepsy (n = 182) and non-lesional extratemporal epilepsy (n = 193). A harmonized protocol using tract-based spatial statistics was used to derive skeletonized maps of fractional anisotropy and mean diffusivity for each participant, and fibre tracts were segmented using a diffusion MRI atlas. Data were harmonized to correct for scanner-specific variations in diffusion measures using a batch-effect correction tool (ComBat). Analyses of covariance, adjusting for age and sex, examined differences between each epilepsy syndrome and controls for each white matter tract (Bonferroni corrected at P < 0.001). Across 'all epilepsies' lower fractional anisotropy was observed in most fibre tracts with small to medium effect sizes, especially in the corpus callosum, cingulum and external capsule. There were also less robust increases in mean diffusivity. Syndrome-specific fractional anisotropy and mean diffusivity differences were most pronounced in patients with hippocampal sclerosis in the ipsilateral parahippocampal cingulum and external capsule, with smaller effects across most other tracts. Individuals with temporal lobe epilepsy and normal MRI showed a similar pattern of greater ipsilateral than contralateral abnormalities, but less marked than those in patients with hippocampal sclerosis. Patients with generalized and extratemporal epilepsies had pronounced reductions in fractional anisotropy in the corpus callosum, corona radiata and external capsule, and increased mean diffusivity of the anterior corona radiata. Earlier age of seizure onset and longer disease duration were associated with a greater extent of diffusion abnormalities in patients with hippocampal sclerosis. We demonstrate microstructural abnormalities across major association, commissural, and projection fibres in a large multicentre study of epilepsy. Overall, patients with epilepsy showed white matter abnormalities in the corpus callosum, cingulum and external capsule, with differing severity across epilepsy syndromes. These data further define the spectrum of white matter abnormalities in common epilepsy syndromes, yielding more detailed insights into pathological substrates that may explain cognitive and psychiatric co-morbidities and be used to guide biomarker studies of treatment outcomes and/or genetic research.
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http://dx.doi.org/10.1093/brain/awaa200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7567169PMC
August 2020

A White Matter Connection of Schizophrenia and Alzheimer's Disease.

Schizophr Bull 2021 01;47(1):197-206

Department of Psychiatry, Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, MD.

Schizophrenia (SZ) is a severe psychiatric illness associated with an elevated risk for developing Alzheimer's disease (AD). Both SZ and AD have white matter abnormalities and cognitive deficits as core disease features. We hypothesized that aging in SZ patients may be associated with the development of cerebral white matter deficit patterns similar to those observed in AD. We identified and replicated aging-related increases in the similarity between white matter deficit patterns in patients with SZ and AD. The white matter "regional vulnerability index" (RVI) for AD was significantly higher in SZ patients compared with healthy controls in both the independent discovery (Cohen's d = 0.44, P = 1·10-5, N = 173 patients/230 control) and replication (Cohen's d = 0.78, P = 9·10-7, N = 122 patients/64 controls) samples. The degree of overlap with the AD deficit pattern was significantly correlated with age in patients (r = .21 and .29, P < .01 in discovery and replication cohorts, respectively) but not in controls. Elevated RVI-AD was significantly associated with cognitive measures in both SZ and AD. Disease and cognitive specificities were also tested in patients with mild cognitive impairment and showed intermediate overlap. SZ and AD have diverse etiologies and clinical courses; our findings suggest that white matter deficits may represent a key intersecting point for these 2 otherwise distinct diseases. Identifying mechanisms underlying this white matter deficit pattern may yield preventative and treatment targets for cognitive deficits in both SZ and AD patients.
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http://dx.doi.org/10.1093/schbul/sbaa078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7825012PMC
January 2021

White matter alterations and the conversion to psychosis: A combined diffusion tensor imaging and glutamate H MRS study.

Schizophr Res 2020 Jun 25. Epub 2020 Jun 25.

Laboratory of Experimental Psychiatry, Instituto Nacional de Neurología y Neurocirugía, Mexico City, Mexico; Neuropsychiatry Department, Instituto Nacional de Neurología y Neurocirugía, Mexico City, Mexico. Electronic address:

Introduction: Widespread white matter abnormalities and alterations in glutamate levels have been reported in patients with schizophrenia. We hypothesized that alterations in white matter integrity and glutamate levels in individuals at clinical high risk (CHR) for psychosis are associated with the subsequent development of psychosis.

Methods: Participants included 33 antipsychotic naïve CHR (Female 7/Male 26, Age 19.55 (4.14) years) and 38 healthy controls (Female 10/Male 28, Age 20.92 (3.37) years). Whole brain diffusion tensor imaging for fractional anisotropy (FA) and right frontal white matter proton magnetic resonance spectroscopy for glutamate levels were acquired. CHR participants were clinically followed for 2 years to determine conversion to psychosis.

Results: CHR participants that transitioned to psychosis (N = 7, 21%) were characterized by significantly lower FA values in the posterior thalamic radiation compared to those who did not transition and healthy controls. In the CHR group that transitioned to psychosis only, positive exploratory correlations between glutamate levels and FA values of the posterior thalamic radiation and the retrolenticular part of the internal capsule and a negative correlation between glutamate levels and the cingulum FA values were found.

Conclusion: The results of the present study highlight that alterations in white matter structure and glutamate are related with the conversion to psychosis.
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http://dx.doi.org/10.1016/j.schres.2020.06.006DOI Listing
June 2020

Personality and local brain structure: Their shared genetic basis and reproducibility.

Neuroimage 2020 10 20;220:117067. Epub 2020 Jun 20.

Institute of Neuroscience and Medicine (INM-7: Brain and Behaviour), Research Centre Jülich, 52425, Jülich, Germany; Institute of Systems Neuroscience, Heinrich Heine University Düsseldorf, 40225, Düsseldorf, Germany.

Local cortical architecture is highly heritable and distinct genes are associated with specific cortical regions. Total surface area has been shown to be genetically correlated with complex cognitive capacities, suggesting cortical brain structure is a viable endophenotype linking genes to behavior. However, to what extend local brain structure has a genetic association with cognitive and emotional functioning is incompletely understood. Here, we study the genetic correlation between personality traits and local cortical structure in a large-scale twin sample (Human Connectome Project, n ​= ​1102, 22-37y) and we evaluated whether observed associations reflect generalizable relationships between personality and local brain structure two independent age-matched samples (Brain Genomics Superstructure Project: n ​= ​925, age ​= ​19-35y, enhanced Nathan Kline Institute dataset: n ​= ​209, age: 19-39y). We found a genetic overlap between personality traits and local cortical structure in 10 of 18 observed phenotypic associations in predominantly frontal cortices. However, we only observed evidence in favor of replication for the negative association between surface area in medial prefrontal cortex and Neuroticism in both replication samples. Quantitative functional decoding indicated this region is implicated in emotional and socio-cognitive functional processes. In sum, our observations suggest that associations between local brain structure and personality are, in part, under genetic control. However, associations are weak and only the relation between frontal surface area and Neuroticism was consistently observed across three independent samples of young adults.
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http://dx.doi.org/10.1016/j.neuroimage.2020.117067DOI Listing
October 2020

Author Correction: The interrelation of sleep and mental and physical health is anchored in grey-matter neuroanatomy and under genetic control.

Commun Biol 2020 Jun 2;3(1):290. Epub 2020 Jun 2.

Institute of Neuroscience and Medicine (INM-7: Brain and Behaviour), Research Centre Jülich, 52425, Jülich, Germany.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s42003-020-1017-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7265545PMC
June 2020
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