Accelerated Aging after Traumatic Brain Injury: An ENIGMA Multi-Cohort Mega-Analysis.

OBJECTIVE: The long-term consequences of traumatic brain injury (TBI) on brain structure remain uncertain. Given evidence that a single significant brain injury event increases the risk of dementia, brain-age estimation could provide a novel and efficient indexing of the long-term consequences of TBI. Brain-age procedures use predictive modeling to calculate brain-age scores for an individual using structural magnetic resonance imaging (MRI) data. Complicated mild, moderate, and severe TBI (cmsTBI) is associated with a higher predicted age difference (PAD), but the progression of PAD over time remains unclear. We sought to examine whether PAD increases as a function of time since injury (TSI) and if injury severity and sex interacted to influence this progression. METHODS: Through the ENIGMA Adult Moderate and Severe (AMS)-TBI working group, we examine the largest TBI sample to date (n = 343), along with controls, for a total sample size of n = 540, to replicate and extend prior findings in the study of TBI brain age. Cross-sectional T1w-MRI data were aggregated across 7 cohorts, and brain age was established using a similar brain age algorithm to prior work in TBI. RESULTS: Findings show that PAD widens with longer TSI, and there was evidence for differences between sexes in PAD, with men showing more advanced brain age. We did not find strong evidence supporting a link between PAD and cognitive performance. INTERPRETATION: This work provides evidence that changes in brain structure after cmsTBI are dynamic, with an initial period of change, followed by relative stability in brain morphometry, eventually leading to further changes in the decades after a single cmsTBI. ANN NEUROL 2024;96:365-377.

Rate of abnormalities in quantitative MR neuroimaging of persons with chronic traumatic brain injury.

BACKGROUND: Mild traumatic brain injury (mTBI) can result in lasting brain damage that is often too subtle to detect by qualitative visual inspection on conventional MR imaging. Although a number of FDA-cleared MR neuroimaging tools have demonstrated changes associated with mTBI, they are still under-utilized in clinical practice. METHODS: We investigated a group of 65 individuals with predominantly mTBI (60 mTBI, 48 due to motor-vehicle collision, mean age 47 ± 13 years, 27 men and 38 women) with MR neuroimaging performed in a median of 37 months post-injury. We evaluated abnormalities in brain volumetry including analysis of left-right asymmetry by quantitative volumetric analysis, cerebral perfusion by pseudo-continuous arterial spin labeling (PCASL), white matter microstructure by diffusion tensor imaging (DTI), and neurometabolites via magnetic resonance spectroscopy (MRS). RESULTS: All participants demonstrated atrophy in at least one lobar structure or increased lateral ventricular volume. The globus pallidi and cerebellar grey matter were most likely to demonstrate atrophy and asymmetry. Perfusion imaging revealed significant reductions of cerebral blood flow in both occipital and right frontoparietal regions. Diffusion abnormalities were relatively less common though a subset analysis of participants with higher resolution DTI demonstrated additional abnormalities. All participants showed abnormal levels on at least one brain metabolite, most commonly in choline and N-acetylaspartate. CONCLUSION: We demonstrate the presence of coup-contrecoup perfusion injury patterns, widespread atrophy, regional brain volume asymmetry, and metabolic aberrations as sensitive markers of chronic mTBI sequelae. Our findings expand the historic focus on quantitative imaging of mTBI with DTI by highlighting the complementary importance of volumetry, arterial spin labeling perfusion and magnetic resonance spectroscopy neurometabolite analyses in the evaluation of chronic mTBI.

Traumatic brain injury and post-traumatic stress disorder are not associated with Alzheimer's disease pathology measured with biomarkers.

INTRODUCTION: Epidemiological studies report an association between traumatic brain injury (TBI) and post-traumatic stress disorder (PTSD) and clinically diagnosed Alzheimer's disease (AD). We examined the association between TBI/PTSD and biomarker-defined AD. METHODS: We identified 289 non-demented veterans with TBI and/or PTSD and controls who underwent clinical evaluation, cerebrospinal fluid (CSF) collection, magnetic resonance imaging (MRI), amyloid beta (Aß) and tau positron emission tomography, and apolipoprotein E testing. Participants were followed for up to 5.2 years. RESULTS: Exposure groups (TBI, PTSD, and TBI + PTSD) had higher prevalence of mild cognitive impairment (MCI: P < .0001) and worse Mini-Mental State Examination scores (PTSD: P = .008; TBI & PTSD: P = .009) than controls. There were no significant differences in other cognitive scores, MRI volumes, Aß or tau accumulation, or in most longitudinal measures. DISCUSSION: TBI and/or PTSD were not associated with elevated AD biomarkers. The poorer cognitive status of exposed veterans may be due to other comorbid pathologies.

Cortical lesions causing loss of consciousness are anticorrelated with the dorsal brainstem.

Brain lesions can provide unique insight into the neuroanatomical substrate of human consciousness. For example, brainstem lesions causing coma map to a specific region of the tegmentum. Whether specific lesion locations outside the brainstem are associated with loss of consciousness (LOC) remains unclear. Here, we investigate the topography of cortical lesions causing prolonged LOC (N = 16), transient LOC (N = 91), or no LOC (N = 64). Using standard voxel lesion symptom mapping, no focus of brain damage was associated with LOC. Next, we computed the network of brain regions functionally connected to each lesion location using a large normative connectome dataset (N = 1,000). This technique, termed lesion network mapping, can test whether lesions causing LOC map to a connected brain circuit rather than one brain region. Connectivity between cortical lesion locations and an a priori coma-specific region of brainstem tegmentum was an independent predictor of LOC (B = 1.2, p = .004). Connectivity to the dorsal brainstem was the only predictor of LOC in a whole-brain voxel-wise analysis. This relationship was driven by anticorrelation (negative correlation) between lesion locations and the dorsal brainstem. The map of regions anticorrelated to the dorsal brainstem thus defines a distributed brain circuit that, when damaged, is most likely to cause LOC. This circuit showed a slight posterior predominance and had peaks in the bilateral claustrum. Our results suggest that cortical lesions causing LOC map to a connected brain circuit, linking cortical lesions that disrupt consciousness to brainstem sites that maintain arousal.

Traumatic Brain Injury Severity, Comorbidity, Social Support, Family Functioning, and Community Reintegration Among Veterans of the Afghanistan and Iraq Wars.

OBJECTIVE: To examine the association between traumatic brain injury (TBI) severity; social, family, and community reintegration outcomes; and return to work status among post-9/11 veterans in Department of Veterans Affairs (VA) care. DESIGN: Retrospective observational cohort study. SETTING: Mail/online survey fielded to a national sample of veterans. PARTICIPANTS: Sample of post-9/11 veterans with at least 3 years of VA care stratified according to TBI severity and comorbidities who completed and returned surveys (N=2023). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Deployment Risk and Resilience Inventory-2 family functioning and social support subscales; Military to Civilian Questionnaire; and employment status. RESULTS: Bivariate analyses revealed that veterans with every classification of TBI severity reported significantly more difficulty on social, family, and community reintegration outcomes than those with no TBI. In the fully adjusted model, veterans with unclassified and moderate/severe TBI reported significantly more difficulty with community reintegration and were less likely to be employed relative to those with no TBI; those with unclassified TBI also reported significantly more difficulty with family functioning. Veterans with mild TBI also reported significantly more difficulty with community reintegration. CONCLUSIONS: This study provides insight into long-term outcomes associated with TBI in post-9/11 veterans and suggests that exposure to TBI has a negative effect on social and family functioning, community reintegration, and return to work even after controlling for comorbidity, deployment experiences, and sociodemographic characteristics. Additional research is required to explicate what appears to be complex interactions among TBI severity, psychosocial well-being, combat exposures, and socioeconomic resources in this population.

Assessing the dysexecutive syndrome in dementia.

OBJECTIVE: We compared performance on tests of dysexecutive behaviour (DB) and executive function (EF) in patients with behavioural variant frontotemporal dementia (bvFTD), primary progressive aphasia (PPA) and corticobasal syndrome (CBS). METHODS: Patients diagnosed with bvFTD (n=124), PPA (n=34) and CBS (n=85) were recruited. EF was measured with the Delis-Kaplan Executive Function System (DKEFS: performance based), and DB was measured with the Frontal Systems Behavior Scale (FrSBe: caregiver-report based). Confirmatory factor analysis characterised the relationship between EF and DB, binary logistic regression evaluated the incremental diagnostic utility of the measures and neuroimaging data from 110 patients identified neural correlates. RESULTS: EF was lowest and DB was highest in bvFTD participants. EF and DB were distinct but related (r=-0.48). Measures correctly classified 89% of bvFTD from CBS patients and 93% of bvFTD from PPA patients-30% and 13% above base rates (59%, 80%), respectively. All modalities were useful in identifying CBS and PPA, whereas DB alone was useful for identifying bvFTD. EF was uniquely associated with caudal left dorsolateral prefrontal and lateral temporo-parietal cortices. DB was uniquely associated with the cingulate (R>L), right subcallosal and right anterior frontal cortex. EF and DB were associated with the rostral dorsolateral prefrontal cortex bilaterally. CONCLUSIONS: EF and DB measures displayed criterion and construct validity, had incremental utility at low DB levels (CBS and PPA) and were associated with overlapping and distinct neural correlates. EF and DB procedures can conjointly provide useful diagnostic and descriptive information in identifying and ruling out the dysexecutive syndrome.

Lesion mapping of social problem solving.

Accumulating neuroscience evidence indicates that human intelligence is supported by a distributed network of frontal and parietal regions that enable complex, goal-directed behaviour. However, the contributions of this network to social aspects of intellectual function remain to be well characterized. Here, we report a human lesion study (n = 144) that investigates the neural bases of social problem solving (measured by the Everyday Problem Solving Inventory) and examine the degree to which individual differences in performance are predicted by a broad spectrum of psychological variables, including psychometric intelligence (measured by the Wechsler Adult Intelligence Scale), emotional intelligence (measured by the Mayer, Salovey, Caruso Emotional Intelligence Test), and personality traits (measured by the Neuroticism-Extraversion-Openness Personality Inventory). Scores for each variable were obtained, followed by voxel-based lesion-symptom mapping. Stepwise regression analyses revealed that working memory, processing speed, and emotional intelligence predict individual differences in everyday problem solving. A targeted analysis of specific everyday problem solving domains (involving friends, home management, consumerism, work, information management, and family) revealed psychological variables that selectively contribute to each. Lesion mapping results indicated that social problem solving, psychometric intelligence, and emotional intelligence are supported by a shared network of frontal, temporal, and parietal regions, including white matter association tracts that bind these areas into a coordinated system. The results support an integrative framework for understanding social intelligence and make specific recommendations for the application of the Everyday Problem Solving Inventory to the study of social problem solving in health and disease.

The prevalence of epilepsy and association with traumatic brain injury in veterans of the Afghanistan and Iraq wars.

OBJECTIVE: To examine the association of epilepsy with traumatic brain injury (TBI) in Afghanistan and Iraq (Operation Enduring Freedom [OEF]/Operation Iraqi Freedom [OIF]) Veterans. DESIGN: Cross-sectional observational study. PARTICIPANTS: A total 256 284 OEF/OIF Veterans who received inpatient and outpatient care in the Veterans Health Administration in fiscal years 2009-2010. MAIN OUTCOME MEASURES: We used algorithms developed for use with International Classification of Diseases, Ninth Revision, Clinical Modification, codes to identify epilepsy, TBI (penetrating TBI [pTBI]/other TBI), and other risk factors for epilepsy (eg, stroke). TBI and other risk factors were identified prior to the index date (first date of seizure or October 1, 2009) for primary analyses. RESULTS: Epilepsy prevalence was 10.6 per 1000 (N = 2719) in fiscal year 2010; age-adjusted prevalence was 6.1. Of 37 718 individuals with a diagnosis of TBI, 29 297 Veterans had a diagnosis of TBI prior to the index date. Statistically significant associations were found between epilepsy and prior TBI diagnosis (pTBI: adjusted odds ratio = 18.77 [95% confidence interval, 9.21-38.23]; other TBI: adjusted odds ratio = 1.64 [1.43-1.89]). CONCLUSIONS: Among OEF/OIF Veterans, epilepsy was associated with previous TBI diagnosis, with pTBI having the strongest association. Because war-related epilepsy in Vietnam War Veterans with TBI continued 35 years postwar, a detailed, prospective study is needed to understand the relationship between epilepsy and TBI severity in OEF/OIF Veterans.

Aggression, DRD1 polymorphism, and lesion location in penetrating traumatic brain injury.

OBJECTIVE: This study evaluated whether structural brain lesions modulate the relationship between pathological aggression and the dopaminergic system in traumatic brain injury (TBI). While converging evidence suggests that different areas of the prefrontal cortex modulate dopaminergic activity, to date no evidence exists of a modulation of endogenous dopaminergic tone by lesion localization in penetrating TBI (pTBI). METHODS: This study included 141 male Caucasian veterans who suffered penetrating pTBI during their service in Vietnam and 29 healthy male Caucasian Vietnam veterans. Participants were genotyped for 3 functional single nucleotide polymorphisms (SNPs): dopamine receptor D1 (DRD1) rs686, dopamine receptor D2 (DRD2) rs4648317, and catechol-O-methyltransferase (COMT) Val158Met. Patients underwent brain CT scans and were divided into medial prefrontal cortex, lateral prefrontal cortex, and posterior cortex lesion groups. Long-term aggression levels were evaluated with the agitation/aggression subscale of the Neuropsychiatric Inventory. RESULTS: Our data showed that carriers of more transcriptionally active DRD1 alleles compared to noncarriers demonstrated greater aggression levels due to medial prefrontal cortex lesions but reduced aggression levels due to lateral prefrontal cortex lesions independently of DRD2 rs4648317 or COMT Val158Met genotypes. CONCLUSIONS: Our results suggest that the relationship between pTBI-related aggression and the dopaminergic system is modulated by lesion location. Potentially lesion location could represent an easy-to-use, widely available, para-clinical marker to help in the development of an individualized therapeutic approach to pTBI-related pathological aggression.

Causal network localization of brain stimulation targets for trait anxiety.

Transcranial magnetic stimulation (TMS) and deep brain stimulation (DBS) can treat some neuropsychiatric disorders, but there is no consensus approach for identifying new targets. We localized causal circuit-based targets for anxiety that converged across multiple natural experiments. Lesions (n=451) and TMS sites (n=111) that modify anxiety mapped to a common normative brain circuit (r=0.68, p=0.01). In an independent dataset (n=300), individualized TMS site connectivity to this circuit predicted anxiety change (p=0.02). Subthalamic DBS sites overlapping the circuit caused more anxiety (n=74, p=0.006), thus demonstrating a network-level effect, as the circuit was derived without any subthalamic sites. The circuit was specific to trait versus state anxiety in datasets that measured both (p=0.003). Broadly, this illustrates a pathway for discovering novel circuit-based targets across neuropsychiatric disorders.

Brain lesions disrupting addiction map to a common human brain circuit.

Drug addiction is a public health crisis for which new treatments are urgently needed. In rare cases, regional brain damage can lead to addiction remission. These cases may be used to identify therapeutic targets for neuromodulation. We analyzed two cohorts of patients addicted to smoking at the time of focal brain damage (cohort 1 n = 67; cohort 2 n = 62). Lesion locations were mapped to a brain atlas and the brain network functionally connected to each lesion location was computed using human connectome data (n = 1,000). Associations with addiction remission were identified. Generalizability was assessed using an independent cohort of patients with focal brain damage and alcohol addiction risk scores (n = 186). Specificity was assessed through comparison to 37 other neuropsychological variables. Lesions disrupting smoking addiction occurred in many different brain locations but were characterized by a specific pattern of brain connectivity. This pattern involved positive connectivity to the dorsal cingulate, lateral prefrontal cortex, and insula and negative connectivity to the medial prefrontal and temporal cortex. This circuit was reproducible across independent lesion cohorts, associated with reduced alcohol addiction risk, and specific to addiction metrics. Hubs that best matched the connectivity profile for addiction remission were the paracingulate gyrus, left frontal operculum, and medial fronto-polar cortex. We conclude that brain lesions disrupting addiction map to a specific human brain circuit and that hubs in this circuit provide testable targets for therapeutic neuromodulation.

Brain stimulation and brain lesions converge on common causal circuits in neuropsychiatric disease.

Damage to specific brain circuits can cause specific neuropsychiatric symptoms. Therapeutic stimulation to these same circuits may modulate these symptoms. To determine whether these circuits converge, we studied depression severity after brain lesions (n = 461, five datasets), transcranial magnetic stimulation (n = 151, four datasets) and deep brain stimulation (n = 101, five datasets). Lesions and stimulation sites most associated with depression severity were connected to a similar brain circuit across all 14 datasets (P < 0.001). Circuits derived from lesions, deep brain stimulation and transcranial magnetic stimulation were similar (P < 0.0005), as were circuits derived from patients with major depression versus other diagnoses (P < 0.001). Connectivity to this circuit predicted out-of-sample antidepressant efficacy of transcranial magnetic stimulation and deep brain stimulation sites (P < 0.0001). In an independent analysis, 29 lesions and 95 stimulation sites converged on a distinct circuit for motor symptoms of Parkinson's disease (P < 0.05). We conclude that lesions, transcranial magnetic stimulation and DBS converge on common brain circuitry that may represent improved neurostimulation targets for depression and other disorders.

C9orf72, age at onset, and ancestry help discriminate behavioral from language variants in FTLD cohorts.

OBJECTIVE: We sought to characterize C9orf72 expansions in relation to genetic ancestry and age at onset (AAO) and to use these measures to discriminate the behavioral from the language variant syndrome in a large pan-European cohort of frontotemporal lobar degeneration (FTLD) cases. METHODS: We evaluated expansions frequency in the entire cohort (n = 1,396; behavioral variant frontotemporal dementia [bvFTD] [n = 800], primary progressive aphasia [PPA] [n = 495], and FTLD-motor neuron disease [MND] [n = 101]). We then focused on the bvFTD and PPA cases and tested for association between expansion status, syndromes, genetic ancestry, and AAO applying statistical tests comprising Fisher exact tests, analysis of variance with Tukey post hoc tests, and logistic and nonlinear mixed-effects model regressions. RESULTS: We found C9orf72 pathogenic expansions in 4% of all cases (56/1,396). Expansion carriers differently distributed across syndromes: 12/101 FTLD-MND (11.9%), 40/800 bvFTD (5%), and 4/495 PPA (0.8%). While addressing population substructure through principal components analysis (PCA), we defined 2 patients groups with Central/Northern (n = 873) and Southern European (n = 523) ancestry. The proportion of expansion carriers was significantly higher in bvFTD compared to PPA (5% vs 0.8% [p = 2.17 × 10-5; odds ratio (OR) 6.4; confidence interval (CI) 2.31-24.99]), as well as in individuals with Central/Northern European compared to Southern European ancestry (4.4% vs 1.8% [p = 1.1 × 10-2; OR 2.5; CI 1.17-5.99]). Pathogenic expansions and Central/Northern European ancestry independently and inversely correlated with AAO. Our prediction model (based on expansions status, genetic ancestry, and AAO) predicted a diagnosis of bvFTD with 64% accuracy. CONCLUSIONS: Our results indicate correlation between pathogenic C9orf72 expansions, AAO, PCA-based Central/Northern European ancestry, and a diagnosis of bvFTD, implying complex genetic risk architectures differently underpinning the behavioral and language variant syndromes.

A Family's Affair: Caring for Veterans with Penetrating Traumatic Brain Injury.

Approximately 1.1 million family members are primary caregivers to post 9/11 veterans. These military caregivers assume a role that requires a long-term commitment that may affect their own health status; however, the impact on health among military caregivers is underestimated and underrepresented. As part of a larger retrospective cohort study that aimed to assess the health-related outcomes of post 9/11 veterans with penetrating traumatic brain injury (pTBI), we examined the health impact of caregiving on caregivers. Caregivers (n = 66) of veterans with pTBI completed a survey that captured the veterans' and their own health-related outcomes. Surveys included veteran and caregiver sociodemographics, caregiver role, tasks, burden, and caregiver-reported measures of veterans' health and quality of life. The participants were spouses (58%) and parents (32%) providing full-time assistance for more than 5 yr (74%). In their caregiver role, they provided assistance with activities of daily living and emotional/social support. Forty-eight percent of these caregivers met the definition of experiencing clinically significant burden. Veterans with pTBI had other comorbidities (e.g., depression, cognitive dysfunction, and anger), which were associated with caregiver burden. The findings further confirm the impact of caregiving on health status of caregivers, specifically when assisting veterans with pTBI.

Injured Brains and Adaptive Networks: The Benefits and Costs of Hyperconnectivity.

A common finding in human functional brain-imaging studies is that damage to neural systems paradoxically results in enhanced functional connectivity between network regions, a phenomenon commonly referred to as 'hyperconnectivity'. Here, we describe the various ways that hyperconnectivity operates to benefit a neural network following injury while simultaneously negotiating the trade-off between metabolic cost and communication efficiency. Hyperconnectivity may be optimally expressed by increasing connections through the most central and metabolically efficient regions (i.e., hubs). While adaptive in the short term, we propose that chronic hyperconnectivity may leave network hubs vulnerable to secondary pathological processes over the life span due to chronically elevated metabolic stress. We conclude by offering novel, testable hypotheses for advancing our understanding of the role of hyperconnectivity in systems-level brain plasticity in neurological disorders.