Data-driven, connectome-wide analysis identifies psychosis-specific brain correlates of fear and anxiety.

Decades of psychosis research highlight the prevalence and the clinical significance of negative emotions, such as fear and anxiety. Translational evidence demonstrates the pivotal role of the amygdala in fear and anxiety. However, most of these approaches have used hypothesis-driven analyses with predefined regions of interest. A data-driven analysis may provide a complimentary, unbiased approach to identifying brain correlates of fear and anxiety. The aim of the current study was to identify the brain basis of fear and anxiety in early psychosis and controls using a data-driven approach. We analyzed data from the Human Connectome Project for Early Psychosis, a multi-site study of 125 people with psychosis and 58 controls with resting-state fMRI and clinical characterization. Multivariate pattern analysis of whole-connectome data was used to identify shared and psychosis-specific brain correlates of fear and anxiety using the NIH Toolbox Fear-Affect and Fear-Somatic Arousal scales. We then examined clinical correlations of Fear-Affect scores and connectivity patterns. Individuals with psychosis had higher levels of Fear-Affect scores than controls (p < 0.05). The data-driven analysis identified a cluster encompassing the amygdala and hippocampus where connectivity was correlated with Fear-Affect score (p < 0.005) in the entire sample. The strongest correlate of Fear-Affect was between this cluster and the anterior insula and stronger connectivity was associated with higher Fear-Affect scores (r = 0.31, p = 0.0003). The multivariate pattern analysis also identified a psychosis-specific correlate of Fear-Affect score between the amygdala/hippocampus cluster and a cluster in the ventromedial prefrontal cortex (VMPFC). Higher Fear-Affect scores were correlated with stronger amygdala/hippocampal-VMPFC connectivity in the early psychosis group (r = 0.33, p = 0.002), but not in controls (r = -0.15, p = 0.28). The current study provides evidence for the transdiagnostic role of the amygdala, hippocampus, and anterior insula in the neural basis of fear and anxiety and suggests a psychosis-specific relationship between fear and anxiety symptoms and amygdala/hippocampal-VMPFC connectivity. Our novel data-driven approach identifies novel, psychosis-specific treatment targets for fear and anxiety symptoms and provides complimentary evidence to decades of hypothesis-driven approaches examining the brain basis of threat processing.

Isolation of Distinct Networks Driving Action and Cognition in Psychomotor Processes.

BACKGROUND: Psychomotor disturbances are observed across psychiatric disorders and often manifest as psychomotor slowing, agitation, disorganized behavior, or catatonia. Psychomotor function includes both cognitive and motor components, but the neural circuits driving these subprocesses and how they relate to symptoms have remained elusive for centuries. METHODS: We analyzed data from the HCP-EP (Human Connectome Project for Early Psychosis), a multisite study of 125 participants with early psychosis and 58 healthy participants with resting-state functional magnetic resonance imaging and clinical characterization. Psychomotor function was assessed using the 9-hole pegboard task, a timed motor task that engages mechanical and psychomotor components of action, and tasks assessing processing speed and task switching. We used multivariate pattern analysis of whole-connectome data to identify brain correlates of psychomotor function. RESULTS: We identified discrete brain circuits driving the cognitive and motor components of psychomotor function. In our combined sample of participants with psychosis (n = 89) and healthy control participants (n = 52), the strongest correlates of psychomotor function (pegboard performance) (p < .005) were between a midline cerebellar region and left frontal region and presupplementary motor area. Psychomotor function was correlated with both cerebellar-frontal connectivity (r = 0.33) and cerebellar-presupplementary motor area connectivity (r = 0.27). However, the cognitive component of psychomotor performance (task switching) was correlated only with cerebellar-frontal connectivity (r = 0.19), whereas the motor component (processing speed) was correlated only with cerebellar-presupplementary motor area connectivity (r = 0.15), suggesting distinct circuits driving unique subprocesses of psychomotor function. CONCLUSIONS: We identified cerebellar-cortical circuits that drive distinct subprocesses of psychomotor function. Future studies should probe relationships between cerebellar connectivity and psychomotor performance using neuromodulation.

Brain morphometry in former American football players: Findings from the DIAGNOSE CTE research project.

Exposure to repetitive head impacts (RHIs) in contact sports is associated with neurodegenerative disorders including chronic traumatic encephalopathy (CTE) which currently can be diagnosed only at postmortem. American football players are at higher risk of developing CTE given their exposure to RHIs. One promising approach for diagnosing CTE in vivo is to explore known neuropathological abnormalities at postmortem in living individuals using structural magnetic resonance imaging (MRI). MRI brain morphometry was evaluated in 170 male former American football players ages 45-74 years (n = 114 professional; n = 56 college) and 54 same-age unexposed asymptomatic male controls (n = 58 age range 45-74). Cortical thickness and volume of regions of interest were selected based on established CTE pathology findings and were assessed using FreeSurfer. Group differences and interactions with age and exposure factors were evaluated using a generalized least squares model. A separate logistic regression and independent multinomial model were performed to predict each Traumatic Encephalopathy Syndrome (TES) diagnosis core clinical features and provisional level of certainty for CTE pathology using brain regions of interest. Former college and professional American football players (combined) showed significant cortical thickness and/or volume reductions compared to unexposed asymptomatic controls in the hippocampus amygdala entorhinal cortex parahippocampal gyrus insula temporal pole and superior frontal gyrus. Post-hoc analyses identified group-level differences between former professional players and unexposed asymptomatic controls in the hippocampus amygdala entorhinal cortex parahippocampal gyrus insula and superior frontal gyrus. Former college players showed significant volume reductions in the hippocampus amygdala and superior frontal gyrus compared to the unexposed asymptomatic controls. We did not observe age-by-group interactions for brain morphometric measures. Interactions between morphometry and exposure measures were limited to a single significant positive association between the age of first exposure to organized tackle football and right insular volume. We found no significant relationship between brain morphometric measures and the TES diagnosis core clinical features and provisional level of certainty for CTE pathology outcomes. These findings suggest that MRI morphometrics detects abnormalities in individuals with a history of RHI exposure that resemble the anatomic distribution of pathological findings from postmortem CTE studies. The lack of findings associating MRI measures with exposure metrics (except for one significant relationship) or TES diagnosis and core clinical features suggests that brain morphometry must be complemented by other types of measures to characterize individuals with RHIs.

Executive functioning, behavior, and white matter microstructure in the chronic phase after pediatric mild traumatic brain injury: results from the adolescent brain cognitive development study.

BACKGROUND: Mild traumatic brain injury (mTBI) is common in children. Long-term cognitive and behavioral outcomes as well as underlying structural brain alterations following pediatric mTBI have yet to be determined. In addition, the effect of age-at-injury on long-term outcomes is largely unknown. METHODS: Children with a history of mTBI (n = 406; Mage = 10 years, SDage = 0.63 years) who participated in the Adolescent Brain Cognitive Development (ABCD) study were matched (1:2 ratio) with typically developing children (TDC; n = 812) and orthopedic injury (OI) controls (n = 812). Task-based executive functioning, parent-rated executive functioning and emotion-regulation, and self-reported impulsivity were assessed cross-sectionally. Regression models were used to examine the effect of mTBI on these domains. The effect of age-at-injury was assessed by comparing children with their first mTBI at either 0-3, 4-7, or 8-10 years to the respective matched TDC controls. Fractional anisotropy (FA) and mean diffusivity (MD), both MRI-based measures of white matter microstructure, were compared between children with mTBI and controls. RESULTS: Children with a history of mTBI displayed higher parent-rated executive dysfunction, higher impulsivity, and poorer self-regulation compared to both control groups. At closer investigation, these differences to TDC were only present in one respective age-at-injury group. No alterations were found in task-based executive functioning or white matter microstructure. CONCLUSIONS: Findings suggest that everyday executive function, impulsivity, and emotion-regulation are affected years after pediatric mTBI. Outcomes were specific to the age at which the injury occurred, suggesting that functioning is differently affected by pediatric mTBI during vulnerable periods. Groups did not differ in white matter microstructure.

Clinical Outcomes and Tau Pathology in Retired Football Players: Associations With Diagnosed and Witnessed Sleep Apnea.

Background and Objectives: Obstructive sleep apnea (SA) is common in older men and a contributor to negative cognitive, psychiatric, and brain health outcomes. Little is known about SA in those who played contact sports and are at increased risk of neurodegenerative disease(s) and other neuropathologies associated with repetitive head impacts (RHI). In this study, we investigated the frequency of diagnosed and witnessed SA and its contribution to clinical symptoms and tau pathology using PET imaging among male former college and former professional American football players. Methods: The sample included 120 former National Football League (NFL) players, 60 former college players, and 60 asymptomatic men without exposure to RHI (i.e., controls). Diagnosed SA was self-reported, and all participants completed the Mayo Sleep Questionnaire (MSQ, informant version), the Epworth Sleepiness Scale (ESS), neuropsychological testing, and tau (flortaucipir) PET imaging. Associations between sleep indices (diagnosed SA, MSQ items, and the ESS) and derived neuropsychological factor scores, self-reported depression (Beck Depression Inventory-II [BDI-II]), informant-reported neurobehavioral dysregulation (Behavior Rating Inventory of Executive Function-Adult Version [BRIEF-A] Behavioral Regulation Index [BRI]), and tau PET uptake, were tested. Results: Approximately 36.7% of NFL players had diagnosed SA compared with 30% of the former college football players and 16.7% of the controls. Former NFL players and college football players also had higher ESS scores compared with the controls. Years of football play was not associated with any of the sleep metrics. Among the former NFL players, diagnosed SA was associated with worse Executive Function and Psychomotor Speed factor scores, greater BDI-II scores, and higher flortaucipir PET standard uptake value ratios, independent of age, race, body mass index, and APOE ε4 gene carrier status. Higher ESS scores correlated with higher BDI-II and BRIEF-A BRI scores. Continuous positive airway pressure use mitigated all of the abovementioned associations. Among the former college football players, witnessed apnea and higher ESS scores were associated with higher BRIEF-A BRI and BDI-II scores, respectively. No other associations were observed in this subgroup. Discussion: Former elite American football players are at risk of SA. Our findings suggest that SA might contribute to cognitive, neuropsychiatric, and tau outcomes in this population. Like all neurodegenerative diseases, this study emphasizes the multifactorial contributions to negative brain health outcomes and the importance of sleep for optimal brain health.

Inflammatory biomarkers for neurobehavioral dysregulation in former American football players: findings from the DIAGNOSE CTE Research Project.

BACKGROUND: Traumatic encephalopathy syndrome (TES) is defined as the clinical manifestation of the neuropathological entity chronic traumatic encephalopathy (CTE). A core feature of TES is neurobehavioral dysregulation (NBD), a neuropsychiatric syndrome in repetitive head impact (RHI)-exposed individuals, characterized by a poor regulation of emotions/behavior. To discover biological correlates for NBD, we investigated the association between biomarkers of inflammation (interleukin (IL)-1ß, IL-6, IL-8, IL-10, C-reactive protein (CRP), tumor necrosis factor (TNF)-α) in cerebrospinal fluid (CSF) and NBD symptoms in former American football players and unexposed individuals. METHODS: Our cohort consisted of former American football players, with (n = 104) or without (n = 76) NBD diagnosis, as well as asymptomatic unexposed individuals (n = 55) from the DIAGNOSE CTE Research Project. Specific measures for NBD were derived (i.e., explosivity, emotional dyscontrol, impulsivity, affective lability, and a total NBD score) from a factor analysis of multiple self-report neuropsychiatric measures. Analyses of covariance tested differences in biomarker concentrations between the three groups. Within former football players, multivariable linear regression models assessed relationships among log-transformed inflammatory biomarkers, proxies for RHI exposure (total years of football, cumulative head impact index), and NBD factor scores, adjusted for relevant confounding variables. Sensitivity analyses tested (1) differences in age subgroups (< 60, ≥ 60 years); (2) whether associations could be identified with plasma inflammatory biomarkers; (3) associations between neurodegeneration and NBD, using plasma neurofilament light (NfL) chain protein; and (4) associations between biomarkers and cognitive performance to explore broader clinical symptoms related to TES. RESULTS: CSF IL-6 was higher in former American football players with NBD diagnosis compared to players without NBD. Furthermore, elevated levels of CSF IL-6 were significantly associated with higher emotional dyscontrol, affective lability, impulsivity, and total NBD scores. In older football players, plasma NfL was associated with higher emotional dyscontrol and impulsivity, but also with worse executive function and processing speed. Proxies for RHI exposure were not significantly associated with biomarker concentrations. CONCLUSION: Specific NBD symptoms in former American football players may result from multiple factors, including neuroinflammation and neurodegeneration. Future studies need to unravel the exact link between NBD and RHI exposure, including the role of other pathophysiological pathways.

Association of Vascular Risk Factors and CSF and Imaging Biomarkers With White Matter Hyperintensities in Former American Football Players.

BACKGROUND AND OBJECTIVES: Recent data link exposure to repetitive head impacts (RHIs) from American football with increased white matter hyperintensity (WMH) burden. WMH might have unique characteristics in the context of RHI beyond vascular risk and normal aging processes. We evaluated biological correlates of WMH in former American football players, including markers of amyloid, tau, inflammation, axonal injury, neurodegeneration, and vascular health. METHODS: Participants underwent clinical interviews, MRI, and lumbar puncture as part of the Diagnostics, Imaging, and Genetics Network for the Objective Study and Evaluation of Chronic Traumatic Encephalopathy Research Project. Structural equation modeling tested direct and indirect effects between log-transformed total fluid-attenuated inversion recovery (FLAIR) lesion volumes (TLV) and the revised Framingham stroke risk profile (rFSRP), MRI-derived global metrics of cortical thickness and fractional anisotropy (FA), and CSF levels of amyloid ß1-42, p-tau181, soluble triggering receptor expressed on myeloid cells 2 (sTREM2), and neurofilament light. Covariates included age, race, education, body mass index, APOE ε4 carrier status, and evaluation site. Models were performed separately for former football players and a control group of asymptomatic men unexposed to RHI. RESULTS: In 180 former football players (mean age = 57.2, 36% Black), higher log(TLV) had direct associations with the following: higher rFSRP score (B = 0.26, 95% CI 0.07-0.40), higher p-tau181 (B = 0.17, 95% CI 0.01-0.43), lower FA (B = -0.28, 95% CI -0.42 to -0.13), and reduced cortical thickness (B = -0.25, 95% CI -0.45 to -0.08). In 60 asymptomatic unexposed men (mean age = 59.3, 40% Black), there were no direct effects on log(TLV) (rFSRP: B = -0.03, 95% CI -0.48 to 0.57; p-tau181: B = -0.30, 95% CI -1.14 to 0.37; FA: B = -0.07, 95% CI -0.48 to 0.42; or cortical thickness: B = -0.28, 95% CI -0.64 to 0.10). The former football players showed stronger associations between log(TLV) and rFSRP (1,069% difference in estimates), p-tau181 (158%), and FA (287%) than the unexposed men. DISCUSSION: Risk factors and biological correlates of WMH differed between former American football players and asymptomatic unexposed men. In addition to vascular health, p-tau181 and diffusion tensor imaging indices of white matter integrity showed stronger associations with WMH in the former football players. FLAIR WMH may have specific risk factors and pathologic underpinnings in RHI-exposed individuals.

More organized white matter is associated with positivity bias in older adults.

On average, healthy older adults prefer positive over neutral or negative stimuli. This positivity bias is related to memory and attention processes and is linked to the function and structure of several interconnected brain areas. However, the relationship between the positivity bias and white matter integrity remains elusive. The present study examines how white matter organization relates to the degree of the positivity bias among older adults. We collected imaging and behavioral data from 25 individuals (12 females, 13 males, and a mean age of 77.32). Based on a functional memory task, we calculated a Pos-Neg score, reflecting the memory for positively valenced information over negative information, and a Pos-Neu score, reflecting the memory for positively valenced information over neutral information. Diffusion-weighted magnetic resonance imaging data were processed using Tract-Based Spatial Statistics. We performed two non-parametric permutation tests to correlate whole brain white matter integrity and the Pos-Neg and Pos-Neu scores while controlling for age, sex, and years of education. We observed a statistically significant positive association between the Pos-Neu score and white matter integrity in multiple brain connections, mostly frontal. The results did not remain significant when including verbal episodic memory as an additional covariate. Our study indicates that the positivity bias in memory in older adults is associated with more organized white matter in the connections of the frontal brain. While these frontal areas are critical for memory and executive processes and have been related to pathological aging, more extensive studies are needed to fully understand their role in the positivity bias and the potential for therapeutic interventions.

Examination of parkinsonism in former elite American football players.

BACKGROUND: Former American football players are at risk for chronic traumatic encephalopathy (CTE) which may have parkinsonism as a clinical feature. OBJECTIVE: Former football players were prospectively assessed for parkinsonism. METHODS: 120 former professional football players, 58 former college football players, and 60 same-age asymptomatic men without repetitive head impacts, 45-74 years, were studied using the MDS-UPDRS to assess for parkinsonism, and the Timed Up and Go (TUG). Traumatic encephalopathy syndrome (TES), the clinical syndrome of CTE, was adjudicated and includes parkinsonism diagnosis. Fisher's Exact Test compared groups on parkinsonism due to small cell sizes; analysis of covariance or linear regressions controlling for age and body mass index were used otherwise. RESULTS: Twenty-two (12.4%) football players (13.3% professional, 10.3% college) met parkinsonism criteria compared with two (3.3%) in the unexposed group. Parkinsonism was higher in professional (p = 0.037) but not college players (p = 0.16). There were no differences on the MDS-UPDRS Part III total scores. Scores on the individual MDS-UPDRS items were low. TUG times were longer in former professional but not college players compared with unexposed men (13.09 versus 11.35 s, p < 0.01). There were no associations between years of football, age of first exposure, position or level of play on motor outcomes. TES status was not associated with motor outcomes. CONCLUSIONS: Parkinsonism rates in this sample of football players was low and highest in the professional football players. The association between football and parkinsonism is inconclusive and depends on factors related to sample selection, comparison groups, and exposure characteristics.

Flortaucipir tau PET findings from former professional and college American football players in the DIAGNOSE CTE research project.

INTRODUCTION: Tau is a key pathology in chronic traumatic encephalopathy (CTE). Here, we report our findings in tau positron emission tomography (PET) measurements from the DIAGNOSE CTE Research Project. METHOD: We compare flortaucipir PET measures from 104 former professional players (PRO), 58 former college football players (COL), and 56 same-age men without exposure to repetitive head impacts (RHI) or traumatic brain injury (unexposed [UE]); characterize their associations with RHI exposure; and compare players who did or did not meet diagnostic criteria for traumatic encephalopathy syndrome (TES). RESULTS: Significantly elevated flortaucipir uptake was observed in former football players (PRO+COL) in prespecified regions (p < 0.05). Association between regional flortaucipir uptake and estimated cumulative head impact exposure was only observed in the superior frontal region in former players over 60 years old. Flortaucipir PET was not able to differentiate TES groups. DISCUSSION: Additional studies are needed to further understand tau pathology in CTE and other individuals with a history of RHI.

Structural connectivity of cytoarchitectonically distinct human left temporal pole subregions: a diffusion MRI tractography study.

The temporal pole (TP) is considered one of the major paralimbic cortical regions, and is involved in a variety of functions such as sensory perception, emotion, semantic processing, and social cognition. Based on differences in cytoarchitecture, the TP can be further subdivided into smaller regions (dorsal, ventrolateral and ventromedial), each forming key nodes of distinct functional networks. However, the brain structural connectivity profile of TP subregions is not fully clarified. Using diffusion MRI data in a set of 31 healthy subjects, we aimed to elucidate the comprehensive structural connectivity of three cytoarchitectonically distinct TP subregions. Diffusion tensor imaging (DTI) analysis suggested that major association fiber pathways such as the inferior longitudinal, middle longitudinal, arcuate, and uncinate fasciculi provide structural connectivity to the TP. Further analysis suggested partially overlapping yet still distinct structural connectivity patterns across the TP subregions. Specifically, the dorsal subregion is strongly connected with wide areas in the parietal lobe, the ventrolateral subregion with areas including constituents of the default-semantic network, and the ventromedial subregion with limbic and paralimbic areas. Our results suggest the involvement of the TP in a set of extensive but distinct networks of cortical regions, consistent with its functional roles.

Amyloid PET across the cognitive spectrum in former professional and college American football players: findings from the DIAGNOSE CTE Research Project.

BACKGROUND: Exposure to repetitive head impacts (RHI) in American football players can lead to cognitive impairment and dementia due to neurodegenerative disease, particularly chronic traumatic encephalopathy (CTE). The pathognomonic lesion of CTE consists of perivascular aggregates of hyper-phosphorylated tau in neurons at the depths of cortical sulci. However, it is unclear whether exposure to RHI accelerates amyloid-ß (Aß) plaque formation and increases the risk for Alzheimer's disease (AD). Although the Aß neuritic plaques characteristic of AD are observed in a minority of later-stage CTE cases, diffuse plaques are more common. This study examined whether former professional and college American football players, including those with cognitive impairment and dementia, have elevated neuritic Aß plaque density, as measured by florbetapir PET. Regardless of cognitive and functional status, elevated levels of florbetapir uptake were not expected. METHODS: We examined 237 men ages 45-74, including 119 former professional (PRO) and 60 former college (COL) football players, with and without cognitive impairment and dementia, and 58 same-age men without a history of contact sports or TBI (unexposed; UE) and who denied cognitive or behavioral symptoms at telephone screening. Former players were categorized into four diagnostic groups: normal cognition, subjective memory impairment, mild cognitive impairment, and dementia. Positive florbetapir PET was defined by cortical-cerebellar average SUVR of ≥ 1.10. Multivariable linear regression and analysis of covariance (ANCOVA) compared florbetapir average SUVR across diagnostic and exposure groups. Multivariable logistic regression compared florbetapir positivity. Race, education, age, and APOE4 were covariates. RESULTS: There were no diagnostic group differences either in florbetapir average SUVR or the proportion of elevated florbetapir uptake. Average SUVR means also did not differ between exposure groups: PRO-COL (p = 0.94, 95% C.I. = [- 0.033, 0.025]), PRO-UE (p = 0.40, 95% C.I. = [- 0.010, 0.029]), COL-UE (p = 0.36, 95% CI = [0.0004, 0.039]). Florbetapir was not significantly associated with years of football exposure, cognition, or daily functioning. CONCLUSIONS: Cognitive impairment in former American football players is not associated with PET imaging of neuritic Aß plaque deposition. These findings are inconsistent with a neuropathological diagnosis of AD in individuals with substantial RHI exposure and have both clinical and medico-legal implications. TRIAL REGISTRATION: NCT02798185.

Investigation of brain iron in anorexia nervosa, a quantitative susceptibility mapping study.

BACKGROUND: Anorexia nervosa (AN) is a potentially fatal psychiatric condition, associated with structural brain changes such as gray matter volume loss. The pathophysiological mechanisms for these changes are not yet fully understood. Iron is a crucial element in the development and function of the brain. Considering the systemic alterations in iron homeostasis in AN, we hypothesized that brain iron would be altered as a possible factor associated with structural brain changes in AN. METHODS: In this study, we used quantitative susceptibility mapping (QSM) magnetic resonance imaging to investigate brain iron in current AN (c-AN) and weight-restored AN compared with healthy individuals. Whole-brain voxel wise comparison was used to probe areas with possible group differences. Further, the thalamus, caudate nucleus, putamen, nucleus accumbens, hippocampus, and amygdala were selected as the regions of interest (ROIs) for ROI-based comparison of mean QSM values. RESULTS: Whole-brain voxel-wise and ROI-based comparison of QSM did not reveal any differences between groups. Exploratory analyses revealed a correlation between higher regional QSM (higher iron) and lower body mass index, higher illness severity, longer illness duration, and younger age at onset in the c-AN group. CONCLUSIONS: This study did not find evidence of altered brain iron in AN compared to healthy individuals. However, the correlations between clinical variables and QSM suggest a link between brain iron and weight status or biological processes in AN, which warrants further investigation.

Adverse Outcome Following Mild Traumatic Brain Injury Is Associated with Microstructure Alterations at the Gray and White Matter Boundary.

The gray matter/white matter (GM/WM) boundary of the brain is vulnerable to shear strain associated with mild traumatic brain injury (mTBI). It is, however, unknown whether GM/WM microstructure is associated with long-term outcomes following mTBI. The diffusion and structural MRI data of 278 participants between 18 and 65 years of age with and without military background from the Department of Defense INTRuST study were analyzed. Fractional anisotropy (FA) was extracted at the GM/WM boundary across the brain and for each lobe. Additionally, two conventional analytic approaches were used: whole-brain deep WM FA (TBSS) and whole-brain cortical thickness (FreeSurfer). ANCOVAs were applied to assess differences between the mTBI cohort (n = 147) and the comparison cohort (n = 131). Associations between imaging features and post-concussive symptom severity, and functional and cognitive impairment were investigated using partial correlations while controlling for mental health comorbidities that are particularly common among military cohorts and were present in both the mTBI and comparison group. Findings revealed significantly lower whole-brain and lobe-specific GM/WM boundary FA (p < 0.011), and deep WM FA (p = 0.001) in the mTBI cohort. Whole-brain and lobe-specific GM/WM boundary FA was significantly negatively correlated with post-concussive symptoms (p < 0.039), functional (p < 0.016), and cognitive impairment (p < 0.049). Deep WM FA was associated with functional impairment (p = 0.002). Finally, no significant difference was observed in cortical thickness, nor between cortical thickness and outcome (p > 0.05). Findings from this study suggest that microstructural alterations at the GM/WM boundary may be sensitive markers of adverse long-term outcomes following mTBI.

Exploring the impact of hippocampal sclerosis on white matter tracts and memory in individuals with mesial temporal lobe epilepsy.

OBJECTIVE: To investigate how the presence/side of hippocampal sclerosis (HS) are related to the white matter structure of cingulum bundle (CB), arcuate fasciculus (AF), and inferior longitudinal fasciculus (ILF) in mesial temporal lobe epilepsy (MTLE). METHODS: We acquired diffusion-weighted magnetic resonance imaging (MRI) from 86 healthy and 71 individuals with MTLE (22 righ-HS; right-HS, 34 left-HS; left-HS, and 15 nonlesional MTLE). We utilized two-tensor tractography and fiber clustering to compare fractional anisotropy (FA) of each side/tract between groups. Additionally, we examined the association between FA and nonverbal (WMS-R) and verbal (WMS-R, RAVLT codification) memory performance for MTLE individuals. RESULTS: White matter abnormalities depended on the side and presence of HS. The left-HS demonstrated widespread abnormalities for all tracts, the right-HS showed lower FA for ipsilateral tracts and the nonlesional MTLE group did not differ from healthy individuals. Results indicate no differences in verbal/nonverbal memory performance between the groups, but trend-level associations between higher FA of visual memory and the left CB (r = 0.286, P = 0.018), verbal memory (RAVLT) and -left CB (r = 0.335, P = 0.005), -right CB (r = 0.286, P = 0.016), and -left AF (r = 0.287, P = 0.017). SIGNIFICANCE: Our results highlight that the presence and side of HS are crucial to understand the pathophysiology of MTLE. Specifically, left-sided HS seems to be related to widespread bilateral white matter abnormalities. Future longitudinal studies should focus on developing diagnostic and treatment strategies dependent on HS's presence/side.

Altered microstructure of the contralesional ventral premotor cortex and motor output after stroke.

Cortical thickness analyses have provided valuable insights into changes in cortical brain structure after stroke and their association with recovery. Across studies though, relationships between cortical structure and function show inconsistent results. Recent developments in diffusion-weighted imaging of the cortex have paved the way to uncover hidden aspects of stroke-related alterations in cortical microstructure, going beyond cortical thickness as a surrogate for cortical macrostructure. We re-analysed clinical and imaging data of 42 well-recovered chronic stroke patients from 2 independent cohorts (mean age 64 years, 4 left-handed, 71% male, 16 right-sided strokes) and 33 healthy controls of similar age and gender. Cortical fractional anisotropy and cortical thickness values were obtained for six key sensorimotor areas of the contralesional hemisphere. The regions included the primary motor cortex, dorsal and ventral premotor cortex, supplementary and pre-supplementary motor areas, and primary somatosensory cortex. Linear models were estimated for group comparisons between patients and controls and for correlations between cortical fractional anisotropy and cortical thickness and clinical scores. Compared with controls, stroke patients exhibited a reduction in fractional anisotropy in the contralesional ventral premotor cortex (P = 0.005). Fractional anisotropy of the other regions and cortical thickness did not show a comparable group difference. Higher fractional anisotropy of the ventral premotor cortex, but not cortical thickness, was positively associated with residual grip force in the stroke patients. These data provide novel evidence that the contralesional ventral premotor cortex might constitute a key sensorimotor area particularly susceptible to stroke-related alterations in cortical microstructure as measured by diffusion MRI and they suggest a link between these changes and residual motor output after stroke.

Development of the PSYCHS: Positive SYmptoms and Diagnostic Criteria for the CAARMS Harmonized with the SIPS.

Aim: To harmonize two ascertainment and severity rating instruments commonly used for the clinical high risk syndrome for psychosis (CHR-P): the Structured Interview for Psychosis-risk Syndromes (SIPS) and the Comprehensive Assessment of At-Risk Mental States (CAARMS). Methods: The initial workshop is described in the companion report from Addington et al. After the workshop, lead experts for each instrument continued harmonizing attenuated positive symptoms and criteria for psychosis and CHR-P through an intensive series of joint videoconferences. Results: Full harmonization was achieved for attenuated positive symptom ratings and psychosis criteria, and partial harmonization for CHR-P criteria. The semi-structured interview, named P ositive SY mptoms and Diagnostic Criteria for the C AARMS H armonized with the S IPS (PSYCHS), generates CHR-P criteria and severity scores for both CAARMS and SIPS. Conclusion: Using the PSYCHS for CHR-P ascertainment, conversion determination, and attenuated positive symptom severity rating will help in comparing findings across studies and in meta-analyses.

Characterization of the extracellular free water signal in schizophrenia using multi-site diffusion MRI harmonization.

Studies applying Free Water Imaging have consistently reported significant global increases in extracellular free water (FW) in populations of individuals with early psychosis. However, these published studies focused on homogenous clinical participant groups (e.g., only first episode or chronic), thereby limiting our understanding of the time course of free water elevations across illness stages. Moreover, the relationship between FW and duration of illness has yet to be directly tested. Leveraging our multi-site diffusion magnetic resonance imaging(dMRI) harmonization approach, we analyzed dMRI scans collected by 12 international sites from 441 healthy controls and 434 individuals diagnosed with schizophrenia-spectrum disorders at different illness stages and ages (15-58 years). We characterized the pattern of age-related FW changes by assessing whole brain white matter in individuals with schizophrenia and healthy controls. In individuals with schizophrenia, average whole brain FW was higher than in controls across all ages, with the greatest FW values observed from 15 to 23 years (effect size range = [0.70-0.87]). Following this peak, FW exhibited a monotonic decrease until reaching a minima at the age of 39 years. After 39 years, an attenuated monotonic increase in FW was observed, but with markedly smaller effect sizes when compared to younger patients (effect size range = [0.32-0.43]). Importantly, FW was found to be negatively associated with duration of illness in schizophrenia (p = 0.006), independent of the effects of other clinical and demographic data. In summary, our study finds in a large, age-diverse sample that participants with schizophrenia with a shorter duration of illness showed higher FW values compared to participants with more prolonged illness. Our findings provide further evidence that elevations in the FW are present in individuals with schizophrenia, with the greatest differences in the FW being observed in those at the early stages of the disorder, which might suggest acute extracellular processes.

Sleep Quality Disturbances Are Associated with White Matter Alterations in Veterans with Post-Traumatic Stress Disorder and Mild Traumatic Brain Injury.

Sleep disturbances are strongly associated with mild traumatic brain injury (mTBI) and post-traumatic stress disorder (PTSD). PTSD and mTBI have been linked to alterations in white matter (WM) microstructure, but whether poor sleep quality has a compounding effect on WM remains largely unknown. We evaluated sleep and diffusion magnetic resonance imaging (dMRI) data from 180 male post-9/11 veterans diagnosed with (1) PTSD (n = 38), (2) mTBI (n = 25), (3) comorbid PTSD+mTBI (n = 94), and (4) a control group with neither PTSD nor mTBI (n = 23). We compared sleep quality (Pittsburgh Sleep Quality Index, PSQI) between groups using ANCOVAs and calculated regression and mediation models to assess associations between PTSD, mTBI, sleep quality, and WM. Veterans with PTSD and comorbid PTSD+mTBI reported poorer sleep quality than those with mTBI or no history of PTSD or mTBI (p = 0.012 to <0.001). Poor sleep quality was associated with abnormal WM microstructure in veterans with comorbid PTSD+mTBI (p < 0.001). Most importantly, poor sleep quality fully mediated the association between greater PTSD symptom severity and impaired WM microstructure (p < 0.001). Our findings highlight the significant impact of sleep disturbances on brain health in veterans with PTSD+mTBI, calling for sleep-targeted interventions.

Current and Emerging Techniques in Neuroimaging of Sport-Related Concussion.

SUMMARY: Sport-related concussion (SRC) affects an estimated 1.6 to 3.8 million Americans each year. Sport-related concussion results from biomechanical forces to the head or neck that lead to a broad range of neurologic symptoms and impaired cognitive function. Although most individuals recover within weeks, some develop chronic symptoms. The heterogeneity of both the clinical presentation and the underlying brain injury profile make SRC a challenging condition. Adding to this challenge, there is also a lack of objective and reliable biomarkers to support diagnosis, to inform clinical decision making, and to monitor recovery after SRC. In this review, the authors provide an overview of advanced neuroimaging techniques that provide the sensitivity needed to capture subtle changes in brain structure, metabolism, function, and perfusion after SRC. This is followed by a discussion of emerging neuroimaging techniques, as well as current efforts of international research consortia committed to the study of SRC. Finally, the authors emphasize the need for advanced multimodal neuroimaging to develop objective biomarkers that will inform targeted treatment strategies after SRC.