Aim: This study investigates the application of Integrated Information Theory (IIT) and Phi values, derived from resting-state fMRI, to predict long-term outcomes in post-anoxic patients with prolonged Disorders of Consciousness (pDoC), including vegetative state (VS) and minimally conscious state (MCS).

Methods: We retrospectively analyzed data from 18 anoxic pDoC patients, extracted from two datasets: Dataset A (n=6; mean age 57 ± 21.5 years; 2 females, all VS) and Dataset B (n=12; mean age 45 ± 13.5 years; 7 females, 9 VS). Dataset A patients were scanned using a 3T Siemens Biograph mMR tomograph at IRCCS SDN, Naples, while Dataset B patients were scanned on a GE MR 3T HDXt scanner at IDC-Hermitage, Naples. Healthy controls (n=24; aged 20-64) were scanned at St. Joseph’s Hospital, London, Ontario, using the same Siemens Biograph mMR scanner and protocols as Dataset A. Patients were followed for up to 12 months post-injury. Resting-state fMRI data were preprocessed using standard toolboxes (SPM12, FSL), and time series were extracted from the five most representative regions of interest (ROIs) within 11 Resting-State Networks (RSNs). Transition Probability Matrices (TPMs) were constructed, and Phi values were calculated using the PyPhi package, with validation through temporal and spatial permutation tests.

Results: Phi values across all RSNs were significantly higher in the control group compared to pDoC patients (p<0.001). Patients with positive outcomes (n=4; 2 VS to MCS minus; 2 MCS minus to MCS plus) in Dataset B had higher Phi values than both negative outcome groups (B+ vs B-: p<0.001; B+ vs A-: p=0.04). Dataset A's negative outcome group exhibited higher Phi values than Dataset B's negative group (p=0.01). In network-specific analyses, controls showed significantly higher Phi values in four RSNs (cingulo-parietal, cingulo-opercular, ventral attention, visual). The retrosplenial temporal network demonstrated higher Phi values in controls and B+ compared to both negative outcome groups. Permutation tests validated that Phi values from RSNs were consistently higher than those from randomized regions.

Conclusions: Phi values derived from rs-fMRI hold promise as potential prognostic markers for assessing outcomes in post-anoxic pDoC patients. These results suggest that IIT may provide valuable insights into the neural mechanisms underlying recovery in pDoC, though further validation is required for clinical application.

Background: There is an established link between repetitive mild traumatic brain injury (mTBI) and risk of neurodegenerative disease (e.g., dementia) in older adulthood. Data from our lab suggest that young adults with repetitive mTBI recruit compensatory neural resources to support behavioral performance, which – importantly – is also observed in aging. Because aging is the strongest risk factor for dementia, we theorized that neural mechanisms, like compensatory recruitment, are triggered by repetitive mTBI and reflect accelerated neurocognitive aging and may underlie risk for neurodegenerative disease. To continue testing this theory, we developed a protocol to elicit additional neural mechanisms linked to aging. Specifically, we predicted that young adults with repetitive mTBI would show signs of Hemispheric Asymmetry Reduction in Older Adults (HAROLD). This model states that older adults recruit bilateral prefrontal cortices (PFC) to support task performance while young adults leverage unilateral recruitment. Thus, we expected that young adults with repetitive mTBI, compared to never-injured controls, would require bilateral PFC recruitment to support equivalent motor task performance.

Methods: Our protocol includes a lower extremity (LE) and upper extremity (UE) subtask and is administered with simultaneous, portable functional near infrared spectroscopy (fNIRS). Each subtask has single motor and dual tasks; here, we will describe single motor tasks. Tasks include overground walking (LE) and throwing/catching a ball (UE), which generates gait speed and number of catches. FNIRS optodes measure from bilateral motor cortices, due to task demands, and bilateral PFC for hypothesis testing. Standardized fNIRS preprocessing steps are completed with raw data.

Results: As data collection is ongoing, we completed an interim analysis from 9 young adults with mTBI (Mean Age= 20.75; 3 males) and 6 never-injured controls (Mean Age= 20.71; 2 males) using between-subject t-tests for behavioral outcomes, within-subject contrasts (single motor vs. rest) to quantify task-dependent PFC activity, and between-group contrasts to compare bilateral PFC activity. As predicted, groups had equivalent motor performance in gait speed (p= .622) and catches (p= .634). However, within-subject contrasts revealed differences aligning with HAROLD-related hypotheses. Control participants had significant task-dependent activity in right PFC during both LE (p< .001) and UE (p< .001) single motor tasks, but not in left PFC (p values> .05). In contrast, mTBI participants had significant task-dependent activity in both right PFC and left PFC during LE and UE single motor tasks (all p values< .001). Between-subject analyses confirmed that the mTBI group had bilateral PFC activation, as the mTBI group had significantly more left PFC activity than controls (who had no significant activity) during both LE (p< .001, µ2= .996) and UE (p< .001, µ2= .997) single motor tasks.

Methods: Our hypotheses were confirmed and may provide additional evidence of accelerated neurocognitive aging in young adults with repetitive mTBI.

Background: The last decade has led to considerable change in our approach towards concussion management. No longer is it thought that rest-is-best after a concussion. Instead, it is now thought that exercise-is-medicine for concussion, with dozens of studies (and meta-analyses of them) showing that sub-maximal aerobic exercise can reduce concussion symptoms or time to symptom resolution. However, we do not know how the exercise being prescribed, post-concussion, impacts the brain with respect to functional activity in these patients. The goal of this study was to perform the first investigation of the effects of a single bout of sub-maximal aerobic exercise on resting state functional brain activity in children with concussion.

Methods: Prospective cohort study of children with their first concussion (and no prior neurological history) within the first four-weeks of injury, and age- and sex-matched controls. The study took place over two visits. Visit 1 involved performing sub-maximal aerobic exercise per the Buffalo Concussion Treadmill Test. Visit 2 involved a baseline functional MRI (fMRI), 10-minutes of treadmill exercise at an intensity calibrated to the results of the Visit 1 exercise test, and a follow-up resting state fMRI, allowing us to assess within-subject and between-group differences in brain activity pre-post exercise.

Results: Currently, recruitment is ongoing, and the data presented here are preliminary and based on 6 children with concussion (4 males, aged 14.8 ± 2.1) and 5 healthy controls (2 males, aged 14.2 ± 2.3). Thus far, using a seed-based approach (with a seed placed in the posterior cingulate cortex, a key anatomical region of the default mode network) we found that there were no pre-post exercise changes in fMRI activity in the healthy controls (threshold, t=2.771, p=0.005). In contrast, in children with concussion, we observed multiple regions of hypoconnectivity following exercise (including the inferior parietal lobule and post-central gyrus). At a group-level analysis, similar hypoconnectivity was observed in the concussion group vs. healthy controls following treadmill exercise.

Discussion: These initial findings suggest that there may be a differential fMRI response to exercise in children with concussion in comparison to their healthy peers. Our initial findings are similar to those reported in adults with mild traumatic brain injury. In completing our study and performing final analyses, important insight may be gained into the impact of exercise on outcomes beyond symptoms, potentially raising the question of how to optimize exercise to promote both symptoms and brain health.

Background: Long-COVID is a heterogeneous disorder with common symptoms including fatigue, anosmia, and brain fog, however, the pathophysiology of long-COVID and long-COVID symptoms is unclear. This study aimed to compare long-COVID patients and individuals who recovered normally from COVID-19 on markers of white matter diffusivity in the brain and scores on objective cognitive testing.

Methods: Long-COVID participants were defined as those who experienced COVID-19 symptoms for more than 60 days post-infection (n=56). Normal recovery participants were those who recovered from COVID-19 within 60 days of infection (n=35). Self-reported information regarding physical and mental health, and COVID-19 illness was collected. The National Institute of Health Toolbox Cognition Battery was administered. Participants underwent magnetic resonance imaging (MRI) with diffusion tensor imaging (DTI). The DTI metrics (fractional anisotropy, axial diffusivity, mean diffusivity, radial diffusivity) were compared using tract-based spatial statistics to perform a whole-brain voxel-wise analysis, controlling for age and sex. Cognitive performance between long-COVID and normal recovery groups was compared using the NIH Toolbox Age-Adjusted Fluid Cognition Scores, covarying for Age-Adjusted Crystallized Cognition Scores and years of education. False discovery rate correction was applied for multiple comparisons.

Results: There were no group differences in age, sex, or history of neurovascular risk factors. The long-COVID group had significantly (p<0.05) lower mean diffusivity than the normal recovery group across multiple white matter regions, including the corticospinal tract, corona radiata, corpus callosum, superior and inferior fronto-occiptal fasciculus, and posterior and anterior thalamic radiation. However, the effect sizes of these differences were small (all 𝛽<|0.3|) and there were no significant differences in the other DTI metrics. Fluid cognition composite scores did not differ significantly between the long-COVID and normal recovery groups (p=0.28, β=-0.22 [-0.6, 0.2]). We additionally compared the subgroup of long-COVID patients experiencing ongoing cognitive symptoms (n=20) to our normal recovery group. The long-COVID patients had lower mean diffusivity than the normal recovery group (p<0.05), but there was no group difference for the Fluid cognitive composite scores (p=0.80, β=-0.1 [-0.6, 0.5]).

Conclusions: We report lower mean diffusivity in long-COVID compared to normal recovery. These findings may represent subtle areas of pathology such as gliosis but considering the small effect sizes and the non-specific nature of the diffusion indices, it is difficult to make pathological inference. Although long-COVID patients frequently reported neuropsychiatric symptoms, there were no significant differences in objective cognitive performance between long-COVID and normal recovery or between long-COVID patients with ongoing cognitive symptoms and normal recovery.

Traumatic brain injury (TBI) is a leading cause of long-term disability, affecting millions of individuals each year. Survivors often face a wide range of cognitive, emotional, and physical challenges with highly variable recovery trajectories. This variability is influenced by several factors, including location and extent of brain damage, pre-existing health conditions, age, and intensity of rehabilitation efforts. Unpredictability of recovery poses a significant challenge to clinicians seeking to provide personalized rehabilitation plans. Reliable biomarkers, both neuroimaging-based and biochemical, that can predict recovery outcomes would allow for more accurate treatment planning, leading to better patient outcomes.

Purpose: The study explored how baseline neuroimaging and blood biomarkers relate to cognitive recovery in patients with TBI.

Methods: Sixteen participants with moderate to severe TBI were enrolled from hospital settings. Blood samples were collected at enrollment and analyzed for Brain-Derived Neurotrophic Factor (BDNF), Interferon Gamma (IFN-γ), Interleukin-6 (IL-6), Interleukin-8 (IL-8), Tumor Necrosis Factor Alpha (TNF-α), Interleukin-10 (IL-10), and C-Reactive Protein (CRP). Neuroimaging data were acquired using Magnetic Resonance Imaging (MRI) with diffusion tensor imaging (DTI) to assess white matter tract integrity and grey matter volume, using a region of interest (ROI) approach defined by the John Hopkins University (JHU) white matter and Harvard-Oxford cortical atlases. Cognitive function was measured using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), Disability Rating Scale (DRS), and Montreal Cognitive Assessment (MoCA), with evaluations conducted at study enrollment and six-month follow-up. Spearman Rank Order Correlation (JASP) was used for statistical analysis.

Results: Initial white matter integrity, as measured by fractional anisotropy (FA), was significantly correlated with changes in cognitive scores. FA in the genu (rs = 0.937, p = 0.002) and splenium of the corpus callosum (rs = 0.955, p < 0.001) was strongly correlated with changes in RBANS - Attention scores. FA in the fornix was correlated with changes in RBANS - Total (rs = 0.928, p = 0.008), while FA in the left tapetum showed a correlation with changes in RBANS - Visuospatial scores (rs = 0.964, p < 0.001). Additionally, grey matter volume in the right temporal fusiform cortex was correlated with changes in RBANS - Attention scores (rs = 0.975, p = 0.005). Blood biomarkers did not show significant associations with cognitive changes; however, small sample size and variability in blood draw times limit our ability to make definitive inferences.

Conclusions: White matter integrity and grey matter volume within temporal and interhemispheric regions appear to be valuable markers for predicting cognitive recovery in TBI patients. These findings support the use of neuroimaging data to guide personalized rehabilitation strategies in TBI recovery. Further research with larger samples is necessary to confirm results and refine the prognostic value of these markers in clinical practice.

Objectives: The purpose of this study was to assess the relationship between insulin-like growth factor 1 (IGF-1) level and symptom severity following traumatic brain injury (TBI) in adolescents. Specifically, the study evaluates whether IGF-1 levels correlate with post-injury symptom severity, depression, and anxiety.

Design: This retrospective observational study included adolescents aged 13-17 years (n=52) with mild TBI (mTBI, n=30) or moderate-to-severe TBI (msTBI, n=22) based on Glasgow Coma Scale scores. Participants were 3-12 months post-TBI and had available IGF-1 values along with complete Rivermead Post Concussion Symptoms Questionnaire (RPQ-13), Generalized Anxiety Disorder-7 (GAD-7), and Patient Health Questionnaire-9 (PHQ-9) responses. Age and gender were standardized using IGF-1 z-scores. Demographic and clinical characteristics including age, sex, BMI, race, mechanism of injury, psychiatric history, time to clinic presentation and lab draw were compared between the mTBI and msTBI groups using either Fisher’s Exact Test or the Median Two-Sample Test. Outcome measures included intergroup comparison of RPQ-13, PHQ-9, and GAD-7 scores, which were then correlated to IGF-1 z-scores using Kendall’s Tau analysis.

Results: Data showed that the msTBI group mean age was one year younger than those with mTBI (p=0.0179). Differences between participant BMI, sex distribution, race, mechanism of injury, psychiatric history, time to clinic presentation, or time to lab draw were nonsignificant between mTBI and msTBI. Median post-injury RPQ-13 and GAD-7 scores were significantly higher in the msTBI group compared to mTBI (p=0.0472 and p=0.0085, respectively), while PHQ-9 scores approached but did not reach significance (p=0.0762).Kendall’s Tau analysis demonstrated significant negative correlations between IGF-1 z-scores and RPQ-13, PHQ-9, and GAD-7 scores. IGF-1 z-scores were strongly and negatively correlated with RPQ-13 scores in both mild (tau=-0.65,p<0.0001) and moderate-to-severe (tau=-0.85,p<0.0001) TBI groups, suggesting that higher IGF-1 levels were associated with lower post-injury symptom severity. Similarly, a negative correlation was observed between IGF-1 z-score and GAD-7 score in both mild (tau=-0.30,p=0.0302) and moderate-to-severe (tau=-0.39,p=0.0144) TBI. In contrast, only the msTBI group demonstrated a significant negative correlation between IGF-1 z-score and PHQ-9 score (tau=-0.82,p<0.0001), while the mild TBI group did not reach statistical significance (tau=-0.14,p=0.3104).

Conclusions: In this study, the msTBI group had higher RPQ-13 and GAD-7 scores, suggesting that in adolescents, brain injury severity may affect the degree of post-injury symptom severity and anxiety experienced as compared to those with mTBI. Results further suggest that a low IGF-1 level post-injury correlates to greater degree of post-injury symptom severity and anxiety in both mTBI and msTBI. Only the msTBI group showed a similar strong and negative correlation between IGF-1 z-score and degree of post-injury depression. This study presents compelling support for IGF-1 as a potential biomarker in adolescent TBI, particularly for post-injury symptom severity and neuropsychiatric impact, though additional investigation is needed.

Introduction: Most adults recover from a concussion within 4 weeks of injury, however, up to 30% experience symptoms beyond 1 month, termed persistent post-concussive symptoms (PPCS). Predicting recovery after concussion remains a high-priority research area, and currently, there is no accurate, quantitative prediction tool for concussion recovery in adults. Multiple fluid biomarkers of central nervous system injury have demonstrated potential as prognostic biomarkers for recovery following concussion. Specifically, glial fibrillary acidic protein (GFAP), a marker of astroglial reactivity, and Neurofilament light (NfL), a marker of axonal damage, are promising biomarkers in the brain injury literature. The primary objective of this pilot study was to evaluate the utility of plasma GFAP and NfL measured acutely post-concussion in relationship to PPCS at 4 weeks post-injury. The secondary objective was to compare plasma concentrations of GFAP and NfL in adults with concussion to matched musculoskeletal injury (MSK) controls.

Methods: Adults (18-65 years) with physician-diagnosed concussion (ACRM 2023 definition) and age- and sex-matched MSK controls were recruited from the Foothills Medical Centre Emergency Department (ED; Calgary, Alberta). Blood samples were collected in the ED at the initial visit (0-2 days post-injury). Plasma NfL and GFAP were analyzed using Meso Scale Diagnostics S-Plex Neurology Panel 1 Cat# K15639 assay (Rockville, Maryland, US). Participants with concussion were followed up to 4 weeks post-injury at which time they were categorized as recovered or experiencing PPCS (≥ 3 symptoms on the Post-Concussion Symptom Checklist and/or < 95% subjective recovery). Mann-Whitney U-tests were used to compare plasma protein levels between groups. Spearman Rank correlations were used to examine the relationship between initial plasma levels of GFAP and NfL and days to recovery.

Results: This preliminary sample included 20 participants (10 concussion [39.1±13.0 years, 0.4±0.5 days post-injury]; 10 MSK [38.8±13.3 years, 0.3±0.5 days post-injury], 50% female). There were no differences in initial post-injury GFAP (U=32.0, p=0.190) or NfL (U=36.0, p=0.315) levels between adults with concussion and MSK controls. At 4 weeks post-injury, 3 participants with concussion had recovered, 4 had PPCS, and 3 were lost to follow-up. Plasma NfL levels were significantly higher in those with PPCS than those who recovered by 4 weeks post-injury and significantly correlated with days to recovery (r=0.829, p=0.042). Plasma GFAP did not differ by recovery groups at 4 weeks post-injury (U=5.0, p=0.724) or correlate to days to recovery (r=-0.371, p=0.468).

Conclusions: This preliminary analysis found acute plasma NfL levels were higher in concussed participants who developed PPCS than those who recovered by 4 weeks and correlated to time to symptom recovery, suggesting that NfL might have potential as a prognostic biomarker of PPCS in adults. Further research with a larger sample size is necessary to validate these results.

Annually, an estimated 2.8 million individuals in the United States seek care at emergency departments (ED) for traumatic brain injuries (TBI), costing approximately $40 billion. Mild traumatic brain injury (otherwise known as concussion), accounts for 80% of all TBIs. Researchers and clinicians have noted the co-occurrence of TBI and alcohol use, estimated in up to 50% of the cases. When co-occurring, TBI and alcohol present a non-linear aggregated effect that is expected to result in increased systematic inflammation, an altered gut microbiome, and worse health outcomes (e.g., increased risk for suicide). Indeed, health-based studies on the impact of pre-injury alcohol use on mild TBIs have been mixed, which suggests that other factors may be of importance in terms of distal health outcomes, including biological responses. In this study, longitudinal sampling was conducted from ED patients with post-acute mild TBI. Samples included the fecal microbiome within 48 hours of admission (baseline) and at monthly intervals for up to 12 months in 23 participants for 167 total fecal samples (mean >7 samples per participant). Plasma was collected at baseline for all participants and at 12 months for a subset of 11 participants and analyzed for changes in inflammatory markers (i.e., C-reactive protein, interleukin (IL)-1β, IL-6, CXCL8, tumor necrosis factor). Data regarding psychological histories/symptoms were obtained at baseline and each month of participation. Preliminary analysis was conducted based on results from the Structured Clinical Interview for DSM-5 of current alcohol use disorder (AUD) with 9 positive and 14 negative participants. Overall, we observed a reduction of IL-6 across all participants from initial injury to 12 months. Participants with AUD, as compared to those without, had significantly lower number of unique bacteria (e.g. lower alpha-diversity) and an altered fecal microbial community (e.g., different beta-diversity). Specifically, over the year post injury, alcohol use at the time of injury was one of the most significant predictors of a divergent gut microbiome. While not significant, participants with current AUD had a higher relative abundance of Bacteroides and a lower abundance of anti-inflammatory bacteria Akkermansia and Faecalibacterium. Preliminary analysis of the oral microbiome is on-going oral microbiome with initial results similar to differences observed in the fecal analysis, indicating a potential change in multiple microbial locations. It is expected that findings will contribute to knowledge regarding the biological mechanisms between microbiome post-injury and symptoms of depression and anxiety among those with and without a history of alcohol use.
(This research was funded by the State of Colorado, MINDSOURCE Brain Injury Network)

Objective: Symptom-limited exercise intolerance is a physiological sign of sport-related concussion (SRC) that may be caused by limited oxygen consumption in exercising muscle or by aerobic deconditioning. The autonomic nervous system (ANS) modulates cerebral and systemic hemodynamic responses to aerobic exercise. During concussive injury, rotational forces may be applied to the upper cervical spine, potentially damaging functional ANS centers within the brainstem, leading to an uncoupling of the connections between the central ANS, the arterial baroreceptors, and the heart. Hence, this study examined cardiopulmonary function during cycle ergometer exercise in concussed adolescent athletes within 10 days of SRC.

Methods: Concussed participants (n = 26, 15.4±1.1 years, 54% male, mean 7.3±1.8 days from injury) and healthy controls (n = 24, 15.8±1.6 years, 58% male) completed the Buffalo Concussion Bike Test (BCBT). Blood pressure (BP), heart rate (HR), stroke volume (SV), cardiac output (CO), respiratory rate (RR), minute ventilation (MV), oxygen consumption (VO2), and end-tidal CO2 (EtCO2) were collected at rest and continuously during exercise. Participant demographics and resting physiological parameters were compared at baseline using independent samples t-tests and χ2 tests. Mixed model linear regressions were used to compare groups within the first five stages of the BCBT.

Results: Concussed and control participants did not differ in demographics except that concussed participants reported a higher number of previous concussions (p< 0.001). Concussed participants exercised for 16.24±5.6 minutes, had symptom exacerbation by the tenth minute and reported higher perceived exertion throughout exercise versus controls. Controls exercised for 25.08±7.0 minutes without symptom exacerbation. There were no differences in resting cardiopulmonary measures between groups. Concussed participants had higher MV during exercise, and their BP plateaued at lower values.

Conclusion: Our data did not find evidence of aerobic deconditioning in patients with SRC. Our results suggest that attenuated autonomic control of cardiac function is the primary cause of exercise intolerance in adolescent athletes after SRC. These results should be considered in future research on concussion physiology and therapeutic approaches to improve outcomes.