Exploring the kynurenine pathway in mild traumatic brain injury: A longitudinal study.

A potential source of novel biomarkers for mTBI is the kynurenine pathway (KP), a metabolic pathway of tryptophan (Trp), that is up-regulated by neuroinflammation and stress. Considering that metabolites of the KP (kynurenines) are implicated in various neuropsychiatric diseases, exploration of this pathway could potentially bridge the gap between physiological and psychological factors in the recovery process after mTBI. This study, therefore, set out to characterize the KP after mTBI and to examine associations with long-term outcome. Patients were prospectively recruited at the emergency department (ED), and blood samples were obtained in the acute phase (<24 h; N = 256) and at 1-month follow-up (N = 146). A comparison group of healthy controls (HC; N = 32) was studied at both timepoints. Trp, kynurenines, and interleukin (IL)-6 and IL-10 were quantified in plasma. Clinical outcome was measured at six months post-injury. Trp, xanthurenic acid (XA), and picolinic acid (PA) were significantly reduced in patients with mTBI relative to HC, corrected for age and sex. For Trp (d = -0.57 vs. d = -0.29) and XA (d = -0.98 vs. d = -0.32), larger effects sizes were observed during the acute phase compared to one-month follow-up, while for PA (d = -0.49 vs. d = -0.52) effect sizes remained consistent. Findings for other kynurenines (e.g., kynurenine, kynurenic acid, and quinolinic acid) were non-significant after correction for multiple testing. Within the mTBI group, lower acute Trp levels were significantly related to incomplete functional recovery and higher depression scores at 6 months post-injury. No significant relationships were found for Trp, XA, and PA with IL-6 or IL-10 concentrations. In conclusion, our findings indicate that perturbations of the plasma KP in the hyperacute phase of mTBI and 1 month later are limited to the precursor Trp, and glutamate system modulating kynurenines XA and PA. Correlations between acute reductions of Trp and unfavorable outcomes may suggest a potential substrate for pharmacological intervention.

A cautionary tale on the effects of different covariance structures in linear mixed effects modeling of fMRI data.

With the steadily increasing abundance of longitudinal neuroimaging studies with large sample sizes and multiple repeated measures, questions arise regarding the appropriate modeling of variance and covariance. The current study examined the influence of standard classes of variance-covariance structures in linear mixed effects (LME) modeling of fMRI data from patients with pediatric mild traumatic brain injury (pmTBI; N = 181) and healthy controls (N = 162). During two visits, participants performed a cognitive control fMRI paradigm that compared congruent and incongruent stimuli. The hemodynamic response function was parsed into peak and late peak phases. Data were analyzed with a 4-way (GROUP×VISIT×CONGRUENCY×PHASE) LME using AFNI's 3dLME and compound symmetry (CS), autoregressive process of order 1 (AR1), and unstructured (UN) variance-covariance matrices. Voxel-wise results dramatically varied both within the cognitive control network (UN>CS for CONGRUENCY effect) and broader brain regions (CS>UN for GROUP:VISIT) depending on the variance-covariance matrix that was selected. Additional testing indicated that both model fit and estimated standard error were superior for the UN matrix, likely as a result of the modeling of individual terms. In summary, current findings suggest that the interpretation of results from complex designs is highly dependent on the selection of the variance-covariance structure using LME modeling.

Good Health-Related Quality of Life in Older Patients One Year after mTBI despite Incomplete Recovery: An Indication of the Disability Paradox?

Background: Older adults (OAs) with mild traumatic brain injury (OA-mTBI) are a growing population, but studies on long-term outcomes and quality of life are scarce. Our aim was to determine the health-related quality of life (HRQoL) in OA-mTBI one year after injury and to assess the early predictors of HRQoL. Methods: Data from a prospective follow-up study of 164 older (≥60 years) and 289 younger mTBI patients (<60 years) admitted to the emergency department were analyzed. Post-traumatic complaints, emotional distress and coping were evaluated 2 weeks post-injury using standardized questionnaires. At 12 months post-injury, HRQoL and functional recovery were determined with the abbreviated version of the World Health Organization Quality of Life scale and Glasgow Outcome Scale Extended (GOSE), respectively. Results: One year post-injury, 80% (n = 131) of the OA-mTBI rated their HRQoL as "good" or "very good", which was comparable to younger patients (79% (n = 226), p = 0.72). Incomplete recovery (GOSE <8) was present in 43% (n = 69) of OA-mTBI, with 67% (n = 46) reporting good HRQoL. Two weeks post-injury, fewer OA-mTBI had (≥2) post-traumatic complaints compared to younger patients (68% vs. 80%, p = 0.01). In the multivariable analyses, only depression-related symptoms (OR = 1.20 for each symptom, 95% CI = 1.01-1.34, p < 0.01) were predictors of poor HRQoL in OA-mTBI. Conclusions: Similar to younger patients, most OA-mTBI rated their HRQoL as good at one year after injury, although a considerable proportion showed incomplete recovery according to the GOSE, suggesting a disability paradox. Depression-related symptoms emerged as a significant predictor for poor HRQoL and can be identified as an early target for treatment after mTBI.

Abnormal Cerebrovascular Activity, Perfusion, and Glymphatic Clearance in Lewy Body Diseases.

Cerebrovascular activity is not only crucial to optimal cerebral perfusion, but also plays an important role in the glymphatic clearance of interstitial waste, including α-synuclein. This highlights a need to evaluate how cerebrovascular activity is altered in Lewy body diseases. This review begins by discussing how vascular risk factors and cardiovascular autonomic dysfunction may serve as upstream or direct influences on cerebrovascular activity. We then discuss how patients with Lewy body disease exhibit reduced and delayed cerebrovascular activity, hypoperfusion, and reductions in measures used to capture cerebrospinal fluid flow, suggestive of a reduced capacity for glymphatic clearance. Given the lack of an existing framework, we propose a model by which these processes may foster α-synuclein aggregation and neuroinflammation. Importantly, this review highlights several avenues for future research that may lead to treatments early in the disease course, prior to neurodegeneration. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Parkinson's disease cerebrovascular reactivity pattern: A feasibility study.

A mounting body of research points to cerebrovascular dysfunction as a fundamental element in the pathophysiology of Parkinson's disease (PD). In the current feasibility study, blood-oxygen-level-dependent (BOLD) MRI was used to measure cerebrovascular reactivity (CVR) in response to hypercapnia in 26 PD patients and 16 healthy controls (HC), and aimed to find a multivariate pattern specific to PD. Whole-brain maps of CVR amplitude (i.e., magnitude of response to CO2) and latency (i.e., time to reach maximum amplitude) were computed, which were further analyzed using scaled sub-profile model principal component analysis (SSM-PCA) with leave-one-out cross-validation. A meaningful pattern based on CVR latency was identified, which was named the PD CVR pattern (PD-CVRP). This pattern was characterized by relatively increased latency in basal ganglia, sensorimotor cortex, supplementary motor area, thalamus and visual cortex, as well as decreased latency in the cerebral white matter, relative to HC. There were no significant associations with clinical measures, though sample size may have limited our ability to detect significant associations. In summary, the PD-CVRP highlights the importance of cerebrovascular dysfunction in PD, and may be a potential biomarker for future clinical research and practice.

Cerebral autoregulation, spreading depolarization, and implications for targeted therapy in brain injury and ischemia.

Cerebral autoregulation is an intrinsic myogenic response of cerebral vasculature that allows for preservation of stable cerebral blood flow levels in response to changing systemic blood pressure. It is effective across a broad range of blood pressure levels through precapillary vasoconstriction and dilation. Autoregulation is difficult to directly measure and methods to indirectly ascertain cerebral autoregulation status inherently require certain assumptions. Patients with impaired cerebral autoregulation may be at risk of brain ischemia. One of the central mechanisms of ischemia in patients with metabolically compromised states is likely the triggering of spreading depolarization (SD) events and ultimately, terminal (or anoxic) depolarization. Cerebral autoregulation and SD are therefore linked when considering the risk of ischemia. In this scoping review, we will discuss the range of methods to measure cerebral autoregulation, their theoretical strengths and weaknesses, and the available clinical evidence to support their utility. We will then discuss the emerging link between impaired cerebral autoregulation and the occurrence of SD events. Such an approach offers the opportunity to better understand an individual patient's physiology and provide targeted treatments.

Identification of At-Risk Patients That Need More Intensive Treatment Following mTBI: Post-Hoc Insights From the UPFRONT-Study.

OBJECTIVE: To investigate which factors within an at-risk group make patients less likely to benefit from preventive treatment following mild traumatic brain injury (mTBI). SETTING: Inclusion in 3 level I trauma centers in the Netherlands. Data collection through surveys as outpatients. PARTICIPANTS: mTBI patients (18-66 years), reporting 3 or more complaints 2 weeks postinjury (at-risk status). Eighty-four patients included and randomized (39 patients cognitive behavioral therapy, 45 patients telephonic counseling). Eighty patients filled out the questionnaires 12 months postinjury. Post hoc analysis investigating 80 patients as 1 at-risk group receiving psychological treatment. DESIGN: Post hoc study of a randomized controlled trial (RCT). Binomial logistic regression performed determining which variables 2 weeks postinjury contributed strongly to unsuccessful return to work/study (RTW) and unfavorable outcome at 12 months. MAIN MEASURES: RTW and functional outcome as measured with the Glasgow Outcome Scale-Extended (GOSE) at 12 months postinjury. RESULTS: Out of 80 patients, 43 (53.8%) showed a favorable functional outcome at 12 months, and 56 (70%) patients had a full RTW. Patients with unfavorable outcome had a higher age and higher reports of anxiety, depression at 2 weeks and 12 months postinjury. Patients with an unsuccessful RTW had a higher age and higher reports of depression, and posttraumatic stress disorder at 2 weeks and 12 months postinjury. A logistic regression model for functional outcome (GOSE) was statistically significant (χ²7 = 40.30, P < .0001). Of 6 predictor variables, 3 were significant: anxiety, depression, and treatment condition. For RTW, logistic regression was also statistically significant (χ²7 = 19.15, P = .008), with only 1 out of 6 predictor variables (ie, age) being significant. CONCLUSION: Main findings comprise differences in demographic and psychological measures between patients with favorable and unfavorable outcomes and patients with RTW versus no RTW. Prediction models of outcome and RTW showed several psychological measures at 2 weeks greatly determining patients' likelihood benefitting from the preventive treatment. Results suggest that from the beginning there are some patients for whom a short preventive treatment is not sufficient. Selection and treatment of at-risk patients might be better based on psychological symptoms instead of posttraumatic complaints.

Validation of real-time fMRI neurofeedback procedure for cognitive training using counterbalanced active-sham study design.

Investigation of neural mechanisms of real-time functional MRI neurofeedback (rtfMRI-nf) training requires an efficient study control approach. A common rtfMRI-nf study design involves an experimental group, receiving active rtfMRI-nf, and a control group, provided with sham rtfMRI-nf. We report the first study in which rtfMRI-nf procedure is controlled through counterbalancing training runs with active and sham rtfMRI-nf for each participant. Healthy volunteers (n = 18) used rtfMRI-nf to upregulate fMRI activity of an individually defined target region in the left dorsolateral prefrontal cortex (DLPFC) while performing tasks that involved mental generation of a random numerical sequence and serial summation of numbers in the sequence. Sham rtfMRI-nf was provided based on fMRI activity of a different brain region, not involved in these tasks. The experimental procedure included two training runs with the active rtfMRI-nf and two runs with the sham rtfMRI-nf, in a randomized order. The participants achieved significantly higher fMRI activation of the left DLPFC target region during the active rtfMRI-nf conditions compared to the sham rtfMRI-nf conditions. fMRI functional connectivity of the left DLPFC target region with the nodes of the central executive network was significantly enhanced during the active rtfMRI-nf conditions relative to the sham conditions. fMRI connectivity of the target region with the nodes of the default mode network was similarly enhanced. fMRI connectivity changes between the active and sham conditions exhibited meaningful associations with individual performance measures on the Working Memory Multimodal Attention Task, the Approach-Avoidance Task, and the Trail Making Test. Our results demonstrate that the counterbalanced active-sham study design can be efficiently used to investigate mechanisms of active rtfMRI-nf in direct comparison to those of sham rtfMRI-nf. Further studies with larger group sizes are needed to confirm the reported findings and evaluate clinical utility of this study control approach.

Neurophysiological signatures of mild traumatic brain injury in the acute and subacute phase.

BACKGROUND: Mild traumatic brain injury (mTBI) affects 48 million people annually, with up to 30% experiencing long-term complaints such as fatigue, blurred vision, and poor concentration. Assessing neurophysiological features related to visual attention and outcome measures aids in understanding clinical symptoms and prognostication. METHODS: We recorded EEG and eye movements in mTBI patients during a computerized task performed in the acute (< 24 h, TBI-A) and subacute phase (4-6 weeks thereafter). We estimated the posterior dominant rhythm, reaction times (RTs), fixation duration, and event-related potentials (ERPs). Clinical outcome measures were assessed using the Head Injury Symptom Checklist (HISC) and the Extended Glasgow Outcome Scale (GOSE) at 6 months post-injury. Similar analyses were performed in an age-matched control group (measured once). Linear mixed effect modeling was used to examine group differences and temporal changes within the mTBI group. RESULTS: Twenty-nine patients were included in the acute phase, 30 in the subacute phase, and 19 controls. RTs and fixation duration were longer in mTBI patients compared to controls (p < 0.05), but not between TBI-A and TBI-S (p < 0.05). The frequency of the posterior dominant rhythm was significantly slower in TBI-A (0.6 Hz, p < 0.05) than TBI-S. ERP mean amplitude was significantly lower in mTBI patients than in controls. Neurophysiological features did not significantly relate to clinical outcome measures. CONCLUSION: mTBI patients demonstrate impaired processing speed and stimulus evaluation compared to controls, persisting up to 6 weeks after injury. Neurophysiological features in mTBI can assist in determining the extent and temporal progression of recovery.

Evaluation of Glial Fibrillary Acidic Protein and Ubiquitin C-Terminal Hydrolase-L1 Using a Rapid Point of Care Test for Predicting Head Computed Tomography Lesions After Mild Traumatic Brain Injury in a Dutch Multi-Center Cohort.

Mild traumatic brain injury (mTBI) is a common condition seen in emergency departments worldwide. Blood-based biomarkers glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase-L1 (UCH-L1) are recently U.S. Food and Drug Administration-approved for the prediction of intracranial lesions on head computed tomography (CT) scans in mTBI. We evaluated the diagnostic performance of GFAP and UCH-L1 in a Dutch cohort using the i-STAT TBI assay. In a multi-center observational study, we enrolled 253 mTBI patients. Head CT scans were scored using the Marshall classification system. Logistic regression models were used to assess the contribution of biomarkers and clinical parameters to diagnostic performance. Detection of UCH-L1 and GFAP resulted in a sensitivity of 97% and specificity of 19% for CT positivity in mTBI patients, along with a negative predictive value of 95% (88-100%) and a positive predictive value of 27% (21-33%). Combining biomarker testing with loss of consciousness and time to sample increased specificity to 46%. Combined testing of UCH-L1 and GFAP testing resulted in possibly more unnecessary CT scans compared with GFAP testing alone, with only limited increase in sensitivity. This study confirmed high sensitivity of GFAP and UCH-L1 for CT abnormalities in mTBI patients using the i-STAT TBI test. The results support the potential use of GFAP and UCH-L1 as tools for determining the indication for CT scanning in mTBI patients, possibly offering a cost- and time-effective approach to management of patients with mTBI. Prospective studies in larger cohorts are warranted to validate our findings.

Dynamic Functional Connectivity in Pediatric Mild Traumatic Brain Injury.

Resting-state fMRI can be used to identify recurrent oscillatory patterns of functional connectivity within the human brain, also known as dynamic brain states. Alterations in dynamic brain states are highly likely to occur following pediatric mild traumatic brain injury (pmTBI) due to the active developmental changes. The current study used resting-state fMRI to investigate dynamic brain states in 200 patients with pmTBI (ages 8-18 years, median = 14 years) at the subacute (∼1-week post-injury) and early chronic (∼ 4 months post-injury) stages, and in 179 age- and sex-matched healthy controls (HC). A k-means clustering analysis was applied to the dominant time-varying phase coherence patterns to obtain dynamic brain states. In addition, correlations between brain signals were computed as measures of static functional connectivity. Dynamic connectivity analyses showed that patients with pmTBI spend less time in a frontotemporal default mode/limbic brain state, with no evidence of change as a function of recovery post-injury. Consistent with models showing traumatic strain convergence in deep grey matter and midline regions, static interhemispheric connectivity was affected between the left and right precuneus and thalamus, and between the right supplementary motor area and contralateral cerebellum. Changes in static or dynamic connectivity were not related to symptom burden or injury severity measures, such as loss of consciousness and post-traumatic amnesia. In aggregate, our study shows that brain dynamics are altered up to 4 months after pmTBI, in brain areas that are known to be vulnerable to TBI. Future longitudinal studies are warranted to examine the significance of our findings in terms of long-term neurodevelopment.

Sex- and Age-Related Differences in Post-Concussive Symptom Reporting Among Children and Their Parents.

Pediatric mild traumatic brain injury (pmTBI) has received increased public attention over the past decade, especially for children who experience persistent post-concussive symptoms (PCS). Common methods for obtaining pediatric PCS rely on both self- and parental report, exhibit moderate test-retest reliability, and variable child-parent agreement, and may yield high false positives. The current study investigated the impact of age and biological sex on PCS reporting (Post-Concussion Symptom Inventory) in patients with pmTBI (n = 286) at retrospective, 1 week, 4 months, and 1 year post-injury time points, as well as reported symptoms in healthy controls (HC; n = 218) at equivalent assessment times. HC and their parents reported higher PCS for their retrospective rating relative to the other three other study visits. Child-parent agreement was highest for female adolescents, but only approached acceptable ranges (≥ 0.75) immediately post-injury. Poor-to-fair child/parental agreement was observed for most other study visits for pmTBI and at all visits for HC. Parents rated female adolescents as being more symptomatic than their male counterparts in spite of small (pmTBI) or no (HC) sex-related differences in self-reported ratings, suggestive of a potential cultural bias in parental ratings. Test-retest reliability for self-report was typically below acceptable ranges for both pmTBI and HC groups, with reliability decreasing for HC and increasing for pmTBI as a function of time between visits. Parental test-retest reliability was higher for females. Although continued research is needed, current results support the use of child self-report over parental ratings for estimating PCS burden. Results also highlight the perils of relying on symptom self-report for diagnostic and prognostic purposes.

Multifaceted neural and vascular pathologies after pediatric mild traumatic brain injury.

Dynamic changes in neurodevelopment and cognitive functioning occur during adolescence, including a switch from reactive to more proactive forms of cognitive control, including response inhibition. Pediatric mild traumatic brain injury (pmTBI) affects these cognitions immediately post-injury, but the role of vascular versus neural injury in cognitive dysfunction remains debated. This study consecutively recruited 214 sub-acute pmTBI (8-18 years) and age/sex-matched healthy controls (HC; N = 186), with high retention rates (>80%) at four months post-injury. Multimodal imaging (functional MRI during response inhibition, cerebral blood flow and cerebrovascular reactivity) assessed for pathologies within the neurovascular unit. Patients exhibited increased errors of commission and hypoactivation of motor circuitry during processing of probes. Evidence of increased/delayed cerebrovascular reactivity within motor circuitry during hypercapnia was present along with normal perfusion. Neither age-at-injury nor post-concussive symptom load were strongly associated with imaging abnormalities. Collectively, mild cognitive impairments and clinical symptoms may continue up to four months post-injury. Prolonged dysfunction within the neurovascular unit was observed during proactive response inhibition, with preliminary evidence that neural and pure vascular trauma are statistically independent. These findings suggest pmTBI is characterized by multifaceted pathologies during the sub-acute injury stage that persist several months post-injury.

An exploratory study on the association between blood-based biomarkers and subacute neurometabolic changes following mild traumatic brain injury.

BACKGROUND AND OBJECTIVES: Blood-based biomarkers and advanced neuroimaging modalities such as magnetic resonance spectroscopy (MRS) or diffusion tensor imaging (DTI) have enhanced our understanding of the pathophysiology of mild traumatic brain injury (mTBI). However, there is limited published data on how blood biomarkers relate to neuroimaging biomarkers post-mTBI. METHODS: To investigate this, 30 patients with mTBI and 21 healthy controls were enrolled. Data was collected at two timepoints postinjury: acute, < 24 h, (blood) and subacute, four-to-six weeks, (blood and imaging). Interleukin (IL) 6 and 10 (inflammation), free thiols (systemic oxidative stress) and neurofilament light (NF-L) (axonal injury) were quantified in plasma. The neurometabolites total N-acetyl aspartate (tNAA) (neuronal energetics), Myo-Inositol (Ins) and total Choline (tCh) (inflammation) and, Glutathione (GSH, oxidative stress) were quantified using MRS. RESULTS: Concentrations of IL-6 and IL-10 were significantly elevated in the acute phase post-mTBI, while NF-L was elevated only in the subacute phase. Total NAA was lowered in patients with mTBI, although this difference was only nominally significant (uncorrected P < 0.05). Within the patient group, acute IL-6 and subacute tNAA levels were negatively associated (r = - 0.46, uncorrected-P = 0.01), albeit not at a threshold corrected for multiple testing (corrected-P = 0.17). When age was added as a covariate a significant increase in correlation magnitude was observed (ρ = - 0.54, corrected-P = 0.03). CONCLUSION: This study demonstrates potential associations between the intensity of the inflammatory response in the acute phase post-mTBI and neurometabolic perturbations in the subacute phase. Future studies should assess the longitudinal dynamics of blood-based and imaging biomarkers after injury.

Dynamic phase-locking states and personality in sub-acute mild traumatic brain injury: An exploratory study.

Research has shown that maladaptive personality characteristics, such as Neuroticism, are associated with poor outcome after mild traumatic brain injury (mTBI). The current exploratory study investigated the neural underpinnings of this process using dynamic functional network connectivity (dFNC) analyses of resting-state (rs) fMRI, and diffusion MRI (dMRI). Twenty-seven mTBI patients and 21 healthy controls (HC) were included. After measuring the Big Five personality dimensions, principal component analysis (PCA) was used to obtain a superordinate factor representing emotional instability, consisting of high Neuroticism, moderate Openness, and low Extraversion, Agreeableness, and Conscientiousness. Persistent symptoms were measured using the head injury symptom checklist at six months post-injury; symptom severity (i.e., sum of all items) was used for further analyses. For patients, brain MRI was performed in the sub-acute phase (~1 month) post-injury. Following parcellation of rs-fMRI using independent component analysis, leading eigenvector dynamic analysis (LEiDA) was performed to compute dynamic phase-locking brain states. Main patterns of brain diffusion were computed using tract-based spatial statistics followed by PCA. No differences in phase-locking state measures were found between patients and HC. Regarding dMRI, a trend significant decrease in fractional anisotropy was found in patients relative to HC, particularly in the fornix, genu of the corpus callosum, anterior and posterior corona radiata. Visiting one specific phase-locking state was associated with lower symptom severity after mTBI. This state was characterized by two clearly delineated communities (each community consisting of areas with synchronized phases): one representing an executive/saliency system, with a strong contribution of the insulae and basal ganglia; the other representing the canonical default mode network. In patients who scored high on emotional instability, this relationship was even more pronounced. Dynamic phase-locking states were not related to findings on dMRI. Altogether, our results provide preliminary evidence for the coupling between personality and dFNC in the development of long-term symptoms after mTBI.

The impact of frontal lesions after mild to moderate traumatic brain injury on frontal network measures.

To investigate the impact of frontal macro-structural lesions on intrinsic network measures, we examined brain network function during resting-state fMRI in patients with frontal lesions in the subacute phase after mild to moderate traumatic brain injury. Additionally, network function was related to neuropsychological performances. 17 patients with frontal lesions, identified on admission CT after mild to moderate trauma, were compared to 30 traumatic brain injury patients without frontal lesions and 20 healthy controls. Three months post-injury, we acquired fMRI scans and neuropsychological assessments (measuring frontal executive functions and information processing speed). Using independent component analysis, the activity of and connectivity between network components (largely located in the prefrontal cortex) and relations with neuropsychological measures were examined and compared across groups. The analysis yielded five predominantly frontal components: anterior and posterior part of the default mode network, left and right frontoparietal network and salience network. No significant differences concerning fMRI measures were found across groups. However, the frontal lesions group performed significantly worse on neuropsychological tests than the other two groups. Additionally, the frontal lesions group showed a significant positive association of stronger default mode network-salience network connectivity with better executive performances. Our findings suggest that, on fMRI level, frontal network measures are not largely affected by frontal lesions following a mild to moderate traumatic brain injury. Yet, patients with damage to the frontal structures did show poorer executive abilities which might to some degree be related to altered frontal network connectivity between the default mode network and salience network.

Neural correlates of cognitive control deficits in pediatric mild traumatic brain injury.

There is a growing body of research showing that cerebral pathophysiological processes triggered by pediatric mild traumatic brain injury (pmTBI) may extend beyond the usual clinical recovery timeline. It is paramount to further unravel these processes, because the possible long-term cognitive effects resulting from ongoing secondary injury in the developing brain are not known. In the current fMRI study, neural processes related to cognitive control were studied in 181 patients with pmTBI at sub-acute (SA; ~1 week) and early chronic (EC; ~4 months) stages post-injury. Additionally, a group of 162 age- and sex-matched healthy controls (HC) were recruited at equivalent time points. Proactive (post-cue) and reactive (post-probe) cognitive control were examined using a multimodal attention fMRI paradigm for either congruent or incongruent stimuli. To study brain network function, the triple-network model was used, consisting of the executive and salience networks (collectively known as the cognitive control network), and the default mode network. Additionally, whole-brain voxel-wise analyses were performed. Decreased deactivation was found within the default mode network at the EC stage following pmTBI during both proactive and reactive control. Voxel-wise analyses revealed sub-acute hypoactivation of a frontal area of the cognitive control network (left pre-supplementary motor area) during proactive control, with a reversed effect at the EC stage after pmTBI. Similar effects were observed in areas outside of the triple-network during reactive control. Group differences in activation during proactive control were limited to the visual domain, whereas for reactive control findings were more pronounced during the attendance of auditory stimuli. No significant correlations were present between task-related activations and (persistent) post-concussive symptoms. In aggregate, current results show alterations in neural functioning during cognitive control in pmTBI up to 4 months post-injury, regardless of clinical recovery. We propose that subacute decreases in activity reflect a general state of hypo-excitability due to the injury, while early chronic hyperactivation represents a compensatory mechanism to prevent default mode interference and to retain cognitive control.

Increased brain age and relationships with blood-based biomarkers following concussion in younger populations.

OBJECTIVE: Brain age is increasingly being applied to the spectrum of brain injury to define neuropathological changes in conjunction with blood-based biomarkers. However, data from the acute/sub-acute stages of concussion are lacking, especially among younger cohorts. METHODS: Predicted brain age differences were independently calculated in large, prospectively recruited cohorts of pediatric concussion and matched healthy controls (total N = 446), as well as collegiate athletes with sport-related concussion and matched non-contact sport controls (total N = 184). Effects of repetitive head injury (i.e., exposure) were examined in a separate cohort of contact sport athletes (N = 82), as well as by quantifying concussion history through semi-structured interviews and years of contact sport participation. RESULTS: Findings of increased brain age during acute and sub-acute concussion were independently replicated across both cohorts, with stronger evidence of recovery for pediatric (4 months) relative to concussed athletes (6 months). Mixed evidence existed for effects of repetitive head injury, as brain age was increased in contact sport athletes, but was not associated with concussion history or years of contact sport exposure. There was no difference in brain age between concussed and contact sport athletes. Total tau decreased immediately (~ 1.5 days) post-concussion relative to the non-contact group, whereas pro-inflammatory markers were increased in both concussed and contact sport athletes. Anti-inflammatory markers were inversely related to brain age, whereas markers of axonal injury (neurofilament light) exhibited a trend positive association. CONCLUSION: Current and previous findings collectively suggest that the chronicity of brain age differences may be mediated by age at injury (adults > children), with preliminary findings suggesting that exposure to contact sports may also increase brain age.

Altered brain connectivity in hyperkinetic movement disorders: A review of resting-state fMRI.

BACKGROUND: Hyperkinetic movement disorders (HMD) manifest as abnormal and uncontrollable movements. Despite reported involvement of several neural circuits, exact connectivity profiles remain elusive. OBJECTIVES: Providing a comprehensive literature review of resting-state brain connectivity alterations using resting-state fMRI (rs-fMRI). We additionally discuss alterations from the perspective of brain networks, as well as correlations between connectivity and clinical measures. METHODS: A systematic review was performed according to PRISMA guidelines and searching PubMed until October 2022. Rs-fMRI studies addressing ataxia, chorea, dystonia, myoclonus, tics, tremor, and functional movement disorders (FMD) were included. The standardized mean difference was used to summarize findings per region in the Automated Anatomical Labeling atlas for each phenotype. Furthermore, the activation likelihood estimation meta-analytic method was used to analyze convergence of significant between-group differences per phenotype. Finally, we conducted hierarchical cluster analysis to provide additional insights into commonalities and differences across HMD phenotypes. RESULTS: Most articles concerned tremor (51), followed by dystonia (46), tics (19), chorea (12), myoclonus (11), FMD (11), and ataxia (8). Altered resting-state connectivity was found in several brain regions: in ataxia mainly cerebellar areas; for chorea, the caudate nucleus; for dystonia, sensorimotor and basal ganglia regions; for myoclonus, the thalamus and cingulate cortex; in tics, the basal ganglia, cerebellum, insula, and frontal cortex; for tremor, the cerebello-thalamo-cortical circuit; finally, in FMD, frontal, parietal, and cerebellar regions. Both decreased and increased connectivity were found for all HMD. Significant spatial convergence was found for dystonia, FMD, myoclonus, and tremor. Correlations between clinical measures and resting-state connectivity were frequently described. CONCLUSION: Key brain regions contributing to functional connectivity changes across HMD often overlap. Possible increases and decreases of functional connections of a specific region emphasize that HMD should be viewed as a network disorder. Despite the complex interplay of physiological and methodological factors, this review serves to gain insight in brain connectivity profiles across HMD phenotypes.

Multi-Site Mild Traumatic Brain Injury Classification with Machine Learning and Harmonization.

Traumatic brain injury (TBI) can drastically affect an individual's cognition, physical, emotional wellbeing, and behavior. Even patients with mild TBI (mTBI) may suffer from a variety of long-lasting symptoms, which motivates researchers to find better biomarkers. Machine learning algorithms have shown promising results in detecting mTBI from resting-state functional network connectivity (rsFNC) data. However, data collected at multiple sites introduces additional noise called site-effects, resulting in erroneous conclusions. Site errors are controlled through a process called harmonization, but its use in classifying neuroimaging data has been addressed lightly. With the ongoing need to improve mTBI detection, this study shows that harmonization should be integrated into the machine learning process when working with multi-site neuroimaging datasets.