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.

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.

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.

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.

Diffusion magnetic resonance spectroscopy captures microglial reactivity related to gut-derived systemic lipopolysaccharide: A preliminary study.

Neuroinflammation is a key component underlying multiple neurological disorders, yet non-invasive and cost-effective assessment of in vivo neuroinflammatory processes in the central nervous system remains challenging. Diffusion weighted magnetic resonance spectroscopy (dMRS) has shown promise in addressing these challenges by measuring diffusivity properties of different neurometabolites, which can reflect cell-specific morphologies. Prior work has demonstrated dMRS utility in capturing microglial reactivity in the context of lipopolysaccharide (LPS) challenges and serious neurological disorders, detected as changes of microglial metabolite diffusivity properties. However, the extent to which such dMRS metrics are capable of detecting subtler and more nuanced levels of neuroinflammation in populations without overt neuropathology is unknown. Here we examined the relationship between intrinsic, gut-derived levels of systemic LPS and dMRS-based apparent diffusion coefficients (ADC) of choline, creatine, and N-acetylaspartate (NAA) in two brain regions: the thalamus and the corona radiata. Higher plasma LPS concentrations were significantly associated with increased ADC of choline and NAA in the thalamic region, with no such relationships observed in the corona radiata for any of the metabolites examined. As such, dMRS may have the sensitivity to measure microglial reactivity across populations with highly variable levels of neuroinflammation, and holds promising potential for widespread applications in both research and clinical settings.

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.

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 (χ² 7 = 40.30, P < .0001). Of 6 predictor variables, 3 were significant: anxiety, depression, and treatment condition. For RTW, logistic regression was also statistically significant (χ² 7 = 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.

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.

White matter microstructure of the neural emotion regulation circuitry in mild traumatic brain injury.

Emotion regulation is related to recovery after mild traumatic brain injury (mTBI). This longitudinal tractography study examined white matter tracts subserving emotion regulation across the spectrum of mTBI, with a focus on persistent symptoms. Four groups were examined: (a) symptomatic (n = 33) and (b) asymptomatic (n = 20) patients with uncomplicated mTBI (i.e., no lesions on computed tomography [CT]), (c) patients with CT-lesions in the frontal areas (n = 14), and (d) healthy controls (HC) (n = 20). Diffusion and conventional MRI were performed approximately 1- and 3-months post-injury. Whole-brain deterministic tractography followed by region of interest analyses was used to identify forceps minor (FM), uncinate fasciculus (UF), and cingulum bundle as tracts of interest. An adjusted version of the ExploreDTI Atlas Based Tractography method was used to obtain reliable tracts for every subject. Mean fractional anisotropy (FA), mean, radial and axial diffusivity (MD, RD, AD), and number of streamlines were studied per tract. Linear mixed models showed lower FA, and higher MD, and RD of the right UF in asymptomatic patients with uncomplicated mTBI relative to symptomatic patients and HC. Diffusion alterations were most pronounced in the group with frontal lesions on CT, particularly in the FM and UF; these effects increased over time. Within the group of patients with uncomplicated mTBI, there were no associations of diffusion measures with the number of symptoms nor with lesions on conventional MRI. In conclusion, mTBI can cause microstructural changes in emotion regulation tracts, however, no explanation was found for the presence of symptoms.

Trajectories of Fatigue, Psychological Distress, and Coping Styles After Mild Traumatic Brain Injury: A 6-Month Prospective Cohort Study.

OBJECTIVE: To analyze fatigue after mild traumatic brain injury (TBI) with latent class growth analysis (LCGA) to determine distinct recovery trajectories and investigate influencing factors, including emotional distress and coping styles. DESIGN: An observational cohort study design with validated questionnaires assessing fatigue, anxiety, depression, posttraumatic stress, and coping at 2 weeks and 3 and 6 months postinjury. SETTING: Three level 1 trauma centers. PARTICIPANTS: Patients with mild TBI (N=456). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Fatigue was measured with the fatigue severity subscale of the Checklist Individual Strength, including 8 items (sum score, 8-56). Subsequently, 3 clinical categories were created: high (score, 40-56), moderate (score, 26-38), and low (score, 8-25). RESULTS: From the entire mild TBI group, 4 patient clusters with distinct patterns for fatigue, emotional distress, and coping styles were found with LCGA. Clusters 1 and 2 showed favorable recovery from fatigue over time, with low emotional distress and the predominant use of active coping in cluster 1 (30%) and low emotional distress and decreasing passive coping in cluster 2 (25%). Clusters 3 and 4 showed unfavorable recovery, with persistent high fatigue and increasing passive coping together with low emotional distress in cluster 3 (27%) and high emotional distress in cluster 4 (18%). Patients with adverse trajectories were more often women and more often experiencing sleep disturbances and pain. CONCLUSIONS: The prognosis for recovery from posttraumatic fatigue is favorable for 55% of mild TBI patients. Patients at risk for chronic fatigue can be signaled in the acute phase postinjury based on the presence of high fatigue, high passive coping, and, for a subgroup of patients, high emotional distress. LCGA proved to be a highly valuable and multipurpose statistical method to map distinct courses of disease-related processes over time.

Coping with stress before and after mild traumatic brain injury: a pilot hair cortisol study.

Background: Cortisol is a crucial hormone for adaptation to challenging and stressful situations. Hair cortisol measurement is used to determine chronic stress; the growth rate of hair allows to determine averaged cortisol levels for a longer period. Objective: Pre- and post-injury measures of hair cortisol were compared in patients with mild traumatic brain injury (mTBI), and related to their coping styles.Methods: For 46 patients with mTBI, 3 cm scalp hair samples were collected 4-6 weeks post-injury, resulting in two 1 cm segments, pre- and post-injury. Hair samples were also collected for 11 healthy controls. Hair cortisol was quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Complaints, anxiety, depression and coping style were measured two weeks post-injury and long term (six-twelve months), added with measures for post-traumatic stress and functional outcome.Results: There were no differences between patients' pre- and post-injury cortisol levels, nor between cortisol levels of patients and controls. However, pre- and post-injury cortisol levels of patients were negatively correlated with both passive and an avoidant coping style.Conclusions: Our findings suggest that mTBI has no separate impact on chronic long-term cortisol levels, possibility indicating that variability in cortisol levels reflects individuals' premorbid characteristics determining coping with stress in general.

Functional outcome is tied to dynamic brain states after mild to moderate traumatic brain injury.

The current study set out to investigate the dynamic functional connectome in relation to long-term recovery after mild to moderate traumatic brain injury (TBI). Longitudinal resting-state functional MRI data were collected (at 1 and 3 months postinjury) from a prospectively enrolled cohort consisting of 68 patients with TBI (92% mild TBI) and 20 healthy subjects. Patients underwent a neuropsychological assessment at 3 months postinjury. Outcome was measured using the Glasgow Outcome Scale Extended (GOS-E) at 6 months postinjury. The 57 patients who completed the GOS-E were classified as recovered completely (GOS-E = 8; n = 37) or incompletely (GOS-E < 8; n = 20). Neuropsychological test scores were similar for all groups. Patients with incomplete recovery spent less time in a segregated brain state compared to recovered patients during the second visit. Also, these patients moved less frequently from one meta-state to another as compared to healthy controls and recovered patients. Furthermore, incomplete recovery was associated with disruptions in cyclic state transition patterns, called attractors, during both visits. This study demonstrates that poor long-term functional recovery is associated with alterations in dynamics between brain networks, which becomes more marked as a function of time. These results could be related to psychological processes rather than injury-effects, which is an interesting area for further work. Another natural progression of the current study is to examine whether these dynamic measures can be used to monitor treatment effects.

Early Predictors for Long-Term Functional Outcome After Mild Traumatic Brain Injury in Frail Elderly Patients.

OBJECTIVE: To identify the effect of frailty and early postinjury measures on the long-term outcome after mild traumatic brain injury in elderly patients. SETTING: Patients admitted to 3 Dutch hospitals designated as level 1 trauma centers. PARTICIPANTS: The elderly (≥60 years) with mild traumatic brain injury (N = 161). DESIGN: A prospective observational cohort study. MAIN MEASURES: Posttraumatic complaints and the Hospital Anxiety and Depression Scale determined 2 weeks postinjury; the Glasgow Outcome Scale Extended and Groningen frailty indicator determined 1 to 3 years postinjury. RESULTS: A total of 102 nonfrail (63%) and 59 frail elderly (37%) patients, mean age of 70.8 (6.3) years were included. Most patients (54%; 72% nonfrail and 24% frail) recovered completely 1 to 3 years postinjury. Two weeks postinjury, 81% had posttraumatic complaints (83% frail and 80% nonfrail elderly), and 30% showed emotional distress (50% frail and 20% nonfrail). Frailty (odds ratio, 2.1; 95% confidence interval, 1.59-2.77) and presence of early complaints (odds ratio, 1.13; 95% confidence interval, 1.01-1.27) (Nagelkerke R = 46%) were found to predict long-term outcome, whereas age was not a significant predictor. CONCLUSION: The frail elderly had worse long-term outcome, and early complaints were found to be a stronger predictor of unfavorable outcome than age. Understanding the implications of frailty on outcome could help clinicians recognize patients at risk of a poor outcome and allocate care more efficiently.

Risk factors and outcomes associated with post-traumatic headache after mild traumatic brain injury.

OBJECTIVES: To determine the prevalence and potential risk factors of acute and chronic post-traumatic headache (PTH) in patients with mild to moderate traumatic brain injury (TBI) in a prospective longitudinal observational multicentre study. Acute PTH (aPTH) is defined by new or worsening of pre-existing headache occurring within 7 days after trauma, whereas chronic PTH (cPTH) is defined as persisting aPTH >3 months after trauma. An additional goal was to study the impact of aPTH and cPTH in terms of return to work (RTW), anxiety and depression. METHODS: This was a prospective observational study conducted between January 2013 and February 2014 in three trauma centres in the Netherlands. Patients aged 16 years and older with a GCS score of 9-15 on admission to the ED, with loss of consciousness and/or amnesia were prospectively enrolled. Follow-up questionnaires were completed at 2 weeks and 3 months after injury with the Head Injury Symptom Checklist, the Hospital Anxiety and Depression Scale and RTW scale. RESULTS: In total, 628 patients were enrolled in the study, 469 completed the 2-week questionnaire (75%) at 2 weeks and 409 (65%) at 3 months. At 2 weeks, 238 (51%) had developed aPTH and at 3 months 95 (23%) had developed cPTH. Female gender, younger age, headache immediately at the ED and CT scan abnormalities increased the risk for aPTH. Risk factors for cPTH were female gender and headache at the ED. Patients with cPTH were less likely to have returned to work than those without cPTH (35% vs 14%, P=0.001). Patients with aPTH and cPTH more often report anxiety (20% and 28%, P=0.001) and depression (19% and 28%, P=0.001) after trauma in comparison with the group without PTH (10% anxiety and 8% depression). CONCLUSIONS: PTH is an important health problem with a significant impact on long-term outcome of TBI patients. Several risk factors were identified, which can aid in early identification of subjects at risk for PTH.

Brain network dysregulation, emotion, and complaints after mild traumatic brain injury.

OBJECTIVES: To assess the role of brain networks in emotion regulation and post-traumatic complaints in the sub-acute phase after non-complicated mild traumatic brain injury (mTBI). EXPERIMENTAL DESIGN: Fifty-four patients with mTBI (34 with and 20 without complaints) and 20 healthy controls (group-matched for age, sex, education, and handedness) were included. Resting-state fMRI was performed at four weeks post-injury. Static and dynamic functional connectivity were studied within and between the default mode, executive (frontoparietal and bilateral frontal network), and salience network. The hospital anxiety and depression scale (HADS) was used to measure anxiety (HADS-A) and depression (HADS-D). PRINCIPAL OBSERVATIONS: Regarding within-network functional connectivity, none of the selected brain networks were different between groups. Regarding between-network interactions, patients with complaints exhibited lower functional connectivity between the bilateral frontal and salience network compared to patients without complaints. In the total patient group, higher HADS-D scores were related to lower functional connectivity between the bilateral frontal network and both the right frontoparietal and salience network, and to higher connectivity between the right frontoparietal and salience network. Furthermore, whereas higher HADS-D scores were associated with lower connectivity within the parietal midline areas of the bilateral frontal network, higher HADS-A scores were related to lower connectivity within medial prefrontal areas of the bilateral frontal network. CONCLUSIONS: Functional interactions of the executive and salience networks were related to emotion regulation and complaints after mTBI, with a key role for the bilateral frontal network. These findings may have implications for future studies on the effect of psychological interventions.

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.

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.

White matter abnormalities in aneurysmal and angiographically negative subarachnoid hemorrhage: A diffusion kurtosis imaging study.

OBJECTIVE: Aneurysmal subarachnoid hemorrhage (aSAH) and angiographically negative subarachnoid hemorrhage (anSAH) cause an abrupt rise in intracranial pressure, resulting in shearing forces, causing damage to the white matter tracts. This study aims to investigate whole-brain white matter abnormalities with diffusion kurtosis imaging (DKI) after both aSAH and anSAH and explores whether these abnormalities are associated with impaired cognitive functioning. METHODS: Five months post-ictus, 34 patients with aSAH, 24 patients with anSAH and 17 healthy controls (HC) underwent DKI MRI scanning and neuropsychological assessment (measuring verbal memory, psychomotor speed, executive control, and social cognition). Differences in DKI measures (fractional anisotropy, mean diffusivity, axial diffusivity [AD], radial diffusivity, and mean kurtosis) were examined using tract-based spatial statistics. Significant voxel masks were then correlated with neuropsychological scores. RESULTS: All DKI measures differed significantly between patients with aSAH and HC, but no significant differences were found between patients with anSAH and HC. Although the two SAH groups did not differ significantly on all DKI parameters, effect sizes indicated that the anSAH group might be more similar to HC. Cognitive impairments were found for both SAH groups relative to HC. No significant associations were found between these impairments and white matter abnormalities in the aSAH group, but lower psychomotor speed scores were associated with higher AD values (r = -0.41, p = 0.04) in patients with anSAH. CONCLUSIONS: Patients with aSAH showed significant white matter diffusion abnormalities, while the anSAH group, despite cognitive deficits, did not. However, there were no significant differences between the SAH groups, and no correlations between DKI metrics and cognitive measures, except for one test on psychomotor speed in the anSAH group. Overall, this study suggests that while anSAH may not be as severe as aSAH, it is still not a benign condition. Further research with larger anSAH cohorts is necessary to gain a more precise understanding of white matter injuries, particularly regarding their prevalence.

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.