Neuroimaging-based classification of PTSD using data-driven computational approaches: A multisite big data study from the ENIGMA-PGC PTSD consortium.

BACKGROUND: Recent advances in data-driven computational approaches have been helpful in devising tools to objectively diagnose psychiatric disorders. However, current machine learning studies limited to small homogeneous samples, different methodologies, and different imaging collection protocols, limit the ability to directly compare and generalize their results. Here we aimed to classify individuals with PTSD versus controls and assess the generalizability using a large heterogeneous brain datasets from the ENIGMA-PGC PTSD Working group. METHODS: We analyzed brain MRI data from 3,477 structural-MRI; 2,495 resting state-fMRI; and 1,952 diffusion-MRI. First, we identified the brain features that best distinguish individuals with PTSD from controls using traditional machine learning methods. Second, we assessed the utility of the denoising variational autoencoder (DVAE) and evaluated its classification performance. Third, we assessed the generalizability and reproducibility of both models using leave-one-site-out cross-validation procedure for each modality. RESULTS: We found lower performance in classifying PTSD vs. controls with data from over 20 sites (60 % test AUC for s-MRI, 59 % for rs-fMRI and 56 % for d-MRI), as compared to other studies run on single-site data. The performance increased when classifying PTSD from HC without trauma history in each modality (75 % AUC). The classification performance remained intact when applying the DVAE framework, which reduced the number of features. Finally, we found that the DVAE framework achieved better generalization to unseen datasets compared with the traditional machine learning frameworks, albeit performance was slightly above chance. CONCLUSION: These results have the potential to provide a baseline classification performance for PTSD when using large scale neuroimaging datasets. Our findings show that the control group used can heavily affect classification performance. The DVAE framework provided better generalizability for the multi-site data. This may be more significant in clinical practice since the neuroimaging-based diagnostic DVAE classification models are much less site-specific, rendering them more generalizable.

Left anterior supramarginal gyrus activity during tool use action observation after extensive tool use training.

The advanced use of complex tools is considered a primary characteristic of human evolution and technological advancement. However, questions remain regarding whether humans possess unique underlying brain networks that support advanced tool-using abilities. Specifically, previous studies have demonstrated the presence of a structurally and functionally unique region in the left anterior supramarginal gyrus (aSMG), that is consistently active during tool use action observation. This region has been proposed as a primary hub for integrating semantic and technical information to form action plans with tools. However, it is still largely unknown how tool use motor learning affects left aSMG activation or connectivity with other brain regions. To address this, participants with little experience using chopsticks observed an experimenter using chopsticks to perform a novel task while undergoing two functional magnetic resonance imaging (fMRI) scans. Between the scans, participants underwent four weeks of behavioral training where they learned to use chopsticks and achieve proficiency in the observed task. Results demonstrated a significant change in effective connectivity between the left aSMG and the left anterior intraparietal sulcus (aIPS), a region involved in object affordances and planning grasping actions. These findings suggest that during unfamiliar tool use, the left aSMG integrates semantic and technical information to communicate with regions involved with grasp selection, such as the aIPS. This communication then allows appropriate grasps to be planned based on the physical properties of the objects involved and their potential interactions.

Sensorimotor control of object manipulation following middle cerebral artery (MCA) stroke.

Methods for assessing the loss of hand function post-stroke examine limited aspects of motor performance and are not sensitive to subtle changes that can cause deficits in everyday object manipulation tasks. Efficiently lifting an object entails a prediction of required forces based on intrinsic features of the object (sensorimotor integration), short-term updates in the forces required to lift objects that are poorly predicted (sensorimotor memory), as well as the ability to modulate distal fingertip forces, which are not measured by existing assessment tools used in clinics for both diagnostic and rehabilitative purposes. The presented research examined these three components of skilled object manipulation in 60 chronic, unilateral middle cerebral artery stroke participants. Performance was compared to age-matched control participants, and linear regressions were used to predict performance based on clinical scores. Most post-stroke participants performed below control levels in at least one of the tasks. Post-stroke participants presented with combinations of deficits in each of the tasks performed, regardless of the hemisphere damaged by the stroke. Surprisingly, the ability to modulate distal forces was impaired in those patients with damage ipsilateral (right hemisphere) to the hand being used. Sensorimotor integration was also impaired in patients with right hemisphere damage, though they performed at control levels in later lifts, whereas left-hemisphere-damaged patients did not. Lastly, during a task requiring sensorimotor memory, neither patient group performed outside of control ranges on initial lifts, with patients with right hemisphere damage showing impaired performance in later lifts suggesting they were unable to learn the mapping novel mapping of color and mass of the objects. The presented research demonstrates unilateral MCA stroke patients can have deficits in one or more components required for the successful manipulation of hand-held objects and that skillful object lifting requires intact bilateral systems. Further, this information may be used in future studies to aid efforts that target rehabilitation regimens to a stroke survivor's specific pattern of deficits.

Methylation of genes and regulation of inflammatory processes on emotional response in young adults with alcoholic parents.

Many Americans are adult children of an alcoholic parent (ACoA), which can confer an increased risk of trauma and hazardous alcohol use, as well as heritable and environmental genetic influence. Psychological health and related neural activity can be influenced by inflammation responses, but it is not clear how these factors interact regarding risk or resilience to hazardous alcohol use. The goals of this study were to better understand the relationships between current alcohol use and inflammation, how these are modified by single nucleotide polymorphisms (SNPs) and/or epigenetic modifications of inflammation-associated genes; and how these alter neural reactivity to emotionally-salient stimuli. To do so, ACoA participants were dichotomized as resilient (not engaged in hazardous alcohol use) or vulnerable (currently engaged in hazardous alcohol use). Measures of blood-oxygen-level-dependent (BOLD) activity within regions of interest (ROIs), SNPs and DNA methylation of specific inflammation regulatory genes, and biological markers of inflammation were compared between these groups. Vulnerable ACoAs exhibited higher plasma C-reactive protein (CRP) and greater BOLD activity in the right hippocampus and ventral anterior cingulate cortex in response to emotional cues as well as reduced methylation of CRP and glucocorticoid-related genes. Path analysis revealed significant relationships between alcohol use, SNPs, DNA methylation of inflammatory-related genes, CRP levels, and BOLD activity to emotional stimuli. Taken together, these findings suggest a complex association related to hazardous alcohol use in ACoAs that may predict current inflammation and neural reactivity to emotional stimuli. A better understanding of these associations could direct the future of individual treatment options.

Chronic Stroke Sensorimotor Impairment Is Related to Smaller Hippocampal Volumes: An ENIGMA Analysis.

Background Persistent sensorimotor impairments after stroke can negatively impact quality of life. The hippocampus is vulnerable to poststroke secondary degeneration and is involved in sensorimotor behavior but has not been widely studied within the context of poststroke upper-limb sensorimotor impairment. We investigated associations between non-lesioned hippocampal volume and upper limb sensorimotor impairment in people with chronic stroke, hypothesizing that smaller ipsilesional hippocampal volumes would be associated with greater sensorimotor impairment. Methods and Results Cross-sectional T1-weighted magnetic resonance images of the brain were pooled from 357 participants with chronic stroke from 18 research cohorts of the ENIGMA (Enhancing NeuoImaging Genetics through Meta-Analysis) Stroke Recovery Working Group. Sensorimotor impairment was estimated from the FMA-UE (Fugl-Meyer Assessment of Upper Extremity). Robust mixed-effects linear models were used to test associations between poststroke sensorimotor impairment and hippocampal volumes (ipsilesional and contralesional separately; Bonferroni-corrected, P<0.025), controlling for age, sex, lesion volume, and lesioned hemisphere. In exploratory analyses, we tested for a sensorimotor impairment and sex interaction and relationships between lesion volume, sensorimotor damage, and hippocampal volume. Greater sensorimotor impairment was significantly associated with ipsilesional (P=0.005; ß=0.16) but not contralesional (P=0.96; ß=0.003) hippocampal volume, independent of lesion volume and other covariates (P=0.001; ß=0.26). Women showed progressively worsening sensorimotor impairment with smaller ipsilesional (P=0.008; ß=-0.26) and contralesional (P=0.006; ß=-0.27) hippocampal volumes compared with men. Hippocampal volume was associated with lesion size (P<0.001; ß=-0.21) and extent of sensorimotor damage (P=0.003; ß=-0.15). Conclusions The present study identifies novel associations between chronic poststroke sensorimotor impairment and ipsilesional hippocampal volume that are not caused by lesion size and may be stronger in women.

The ENIGMA Stroke Recovery Working Group: Big data neuroimaging to study brain-behavior relationships after stroke.

The goal of the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Stroke Recovery working group is to understand brain and behavior relationships using well-powered meta- and mega-analytic approaches. ENIGMA Stroke Recovery has data from over 2,100 stroke patients collected across 39 research studies and 10 countries around the world, comprising the largest multisite retrospective stroke data collaboration to date. This article outlines the efforts taken by the ENIGMA Stroke Recovery working group to develop neuroinformatics protocols and methods to manage multisite stroke brain magnetic resonance imaging, behavioral and demographics data. Specifically, the processes for scalable data intake and preprocessing, multisite data harmonization, and large-scale stroke lesion analysis are described, and challenges unique to this type of big data collaboration in stroke research are discussed. Finally, future directions and limitations, as well as recommendations for improved data harmonization through prospective data collection and data management, are provided.

Assessment of brain age in posttraumatic stress disorder: Findings from the ENIGMA PTSD and brain age working groups.

BACKGROUND: Posttraumatic stress disorder (PTSD) is associated with markers of accelerated aging. Estimates of brain age, compared to chronological age, may clarify the effects of PTSD on the brain and may inform treatment approaches targeting the neurobiology of aging in the context of PTSD. METHOD: Adult subjects (N = 2229; 56.2% male) aged 18-69 years (mean = 35.6, SD = 11.0) from 21 ENIGMA-PGC PTSD sites underwent T1-weighted brain structural magnetic resonance imaging, and PTSD assessment (PTSD+, n = 884). Previously trained voxel-wise (brainageR) and region-of-interest (BARACUS and PHOTON) machine learning pipelines were compared in a subset of control subjects (n = 386). Linear mixed effects models were conducted in the full sample (those with and without PTSD) to examine the effect of PTSD on brain predicted age difference (brain PAD; brain age - chronological age) controlling for chronological age, sex, and scan site. RESULTS: BrainageR most accurately predicted brain age in a subset (n = 386) of controls (brainageR: ICC = 0.71, R = 0.72, MAE = 5.68; PHOTON: ICC = 0.61, R = 0.62, MAE = 6.37; BARACUS: ICC = 0.47, R = 0.64, MAE = 8.80). Using brainageR, a three-way interaction revealed that young males with PTSD exhibited higher brain PAD relative to male controls in young and old age groups; old males with PTSD exhibited lower brain PAD compared to male controls of all ages. DISCUSSION: Differential impact of PTSD on brain PAD in younger versus older males may indicate a critical window when PTSD impacts brain aging, followed by age-related brain changes that are consonant with individuals without PTSD. Future longitudinal research is warranted to understand how PTSD impacts brain aging across the lifespan.

Smaller spared subcortical nuclei are associated with worse post-stroke sensorimotor outcomes in 28 cohorts worldwide.

Up to two-thirds of stroke survivors experience persistent sensorimotor impairments. Recovery relies on the integrity of spared brain areas to compensate for damaged tissue. Deep grey matter structures play a critical role in the control and regulation of sensorimotor circuits. The goal of this work is to identify associations between volumes of spared subcortical nuclei and sensorimotor behaviour at different timepoints after stroke. We pooled high-resolution T1-weighted MRI brain scans and behavioural data in 828 individuals with unilateral stroke from 28 cohorts worldwide. Cross-sectional analyses using linear mixed-effects models related post-stroke sensorimotor behaviour to non-lesioned subcortical volumes (Bonferroni-corrected, P < 0.004). We tested subacute (≤90 days) and chronic (≥180 days) stroke subgroups separately, with exploratory analyses in early stroke (≤21 days) and across all time. Sub-analyses in chronic stroke were also performed based on class of sensorimotor deficits (impairment, activity limitations) and side of lesioned hemisphere. Worse sensorimotor behaviour was associated with a smaller ipsilesional thalamic volume in both early (n = 179; d = 0.68) and subacute (n = 274, d = 0.46) stroke. In chronic stroke (n = 404), worse sensorimotor behaviour was associated with smaller ipsilesional putamen (d = 0.52) and nucleus accumbens (d = 0.39) volumes, and a larger ipsilesional lateral ventricle (d = -0.42). Worse chronic sensorimotor impairment specifically (measured by the Fugl-Meyer Assessment; n = 256) was associated with smaller ipsilesional putamen (d = 0.72) and larger lateral ventricle (d = -0.41) volumes, while several measures of activity limitations (n = 116) showed no significant relationships. In the full cohort across all time (n = 828), sensorimotor behaviour was associated with the volumes of the ipsilesional nucleus accumbens (d = 0.23), putamen (d = 0.33), thalamus (d = 0.33) and lateral ventricle (d = -0.23). We demonstrate significant relationships between post-stroke sensorimotor behaviour and reduced volumes of deep grey matter structures that were spared by stroke, which differ by time and class of sensorimotor measure. These findings provide additional insight into how different cortico-thalamo-striatal circuits support post-stroke sensorimotor outcomes.

Cortical volume abnormalities in posttraumatic stress disorder: an ENIGMA-psychiatric genomics consortium PTSD workgroup mega-analysis.

Studies of posttraumatic stress disorder (PTSD) report volume abnormalities in multiple regions of the cerebral cortex. However, findings for many regions, particularly regions outside commonly studied emotion-related prefrontal, insular, and limbic regions, are inconsistent and tentative. Also, few studies address the possibility that PTSD abnormalities may be confounded by comorbid depression. A mega-analysis investigating all cortical regions in a large sample of PTSD and control subjects can potentially provide new insight into these issues. Given this perspective, our group aggregated regional volumes data of 68 cortical regions across both hemispheres from 1379 PTSD patients to 2192 controls without PTSD after data were processed by 32 international laboratories using ENIGMA standardized procedures. We examined whether regional cortical volumes were different in PTSD vs. controls, were associated with posttraumatic stress symptom (PTSS) severity, or were affected by comorbid depression. Volumes of left and right lateral orbitofrontal gyri (LOFG), left superior temporal gyrus, and right insular, lingual and superior parietal gyri were significantly smaller, on average, in PTSD patients than controls (standardized coefficients = -0.111 to -0.068, FDR corrected P values < 0.039) and were significantly negatively correlated with PTSS severity. After adjusting for depression symptoms, the PTSD findings in left and right LOFG remained significant. These findings indicate that cortical volumes in PTSD patients are smaller in prefrontal regulatory regions, as well as in broader emotion and sensory processing cortical regions.

Neural and psychological characteristics of college students with alcoholic parents differ depending on current alcohol use.

A significant proportion of college students are adult children of an alcoholic parent (ACoA), which can confer greater risk of depression, poor self-esteem, alcohol and drug problems, and greater levels of college attrition. However, some ACoA are resilient to these negative outcomes. The goal of this study was to better understand the psychobiological factors that distinguish resilient and vulnerable college-aged ACoAs. To do so, scholastic performance and psychological health were measured in ACoA college students not engaged in hazardous alcohol use (resilient) and those currently engaged in hazardous alcohol use (vulnerable). Neural activity (as measured by functional magnetic resonance imaging) in response to performing working memory and emotion-based tasks were assessed. Furthermore, the frequency of polymorphisms in candidate genes associated with substance use, risk taking and stress reactivity were compared between the two ACoA groups. College ACoAs currently engaged in hazardous alcohol use reported more anxiety, depression and posttraumatic stress symptoms, and increased risky nicotine and marijuana use as compared to ACoAs resistant to problem alcohol use. ACoA college students with current problem alcohol showed greater activity of the middle frontal gyrus and reduced activation of the posterior cingulate in response to visual working memory and emotional processing tasks, which may relate to increased anxiety and problem alcohol and drug behaviors. Furthermore, polymorphisms of cholinergic receptor and the serotonin transporter genes also appear to contribute a role in problem alcohol use in ACoAs. Overall, findings point to several important psychobiological variables that distinguish ACoAs based on their current alcohol use that may be used in the future for early intervention.

Resource forecasting: Differential effects of glucose taste and ingestion on delay discounting and self-control.

We tested a novel hypothesis that glucose taste acts as a signal for resource acquisition, motivating preference for immediate rewards while actual glucose ingestion prompts resource conservation, promoting future-orientated self-regulation. In Study 1, participants were engaged in a delay-discounting task and a grip-control task before and after a beverage intervention (glucose drink, water drink, or glucose mouth-rinse). Glucose ingestion decreased delay discounting, making larger-and-later rewards more attractive. In contrast, glucose rinse increased delay discounting. Water ingestion had none of the effects. In the grip-control task, only glucose ingestion improved the performance. Study 2 using fMRI revealed that glucose rinse and glucose ingestion resulted in distinct brain activational patterns. Compared to glucose rinse, glucose ingestion deactivated a few brain regions (e.g., the anterior cingulate gyrus and inferior frontal gyrus) that are previously shown to be more active when making more difficult intertemporal choices, suggesting that glucose ingestion eases the process of making intertemporal choice. In sum, our behavioral and neuroimaging findings together suggest a dual signaling role of glucose sensation and ingestion in regulating delay discounting and self-control.

Getting a handle on virtual tools: An examination of the neuronal activity associated with virtual tool use.

Tool use is associated with three visual streams-dorso-dorsal, ventro-dorsal, and ventral visual streams. These streams are involved in processing online motor planning, action semantics, and tool semantics features, respectively. Little is known about the way in which the brain represents virtual tools. To directly assess this question, a virtual tool paradigm was created that provided the ability to manipulate tool components in isolation of one another. During functional magnetic resonance imaging (fMRI), adult participants performed a series of virtual tool manipulation tasks in which vision and movement kinematics of the tool were manipulated. Reaction time and hand movement direction were monitored while the tasks were performed. Functional imaging revealed that activity within all three visual streams was present, in a similar pattern to what would be expected with physical tool use. However, a previously unreported network of right-hemisphere activity was found including right inferior parietal lobule, middle and superior temporal gyri and supramarginal gyrus - regions well known to be associated with tool processing within the left hemisphere. These results provide evidence that both virtual and physical tools are processed within the same brain regions, though virtual tools recruit bilateral tool processing regions to a greater extent than physical tools.