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Background: Persistent posttraumatic symptoms (PPS) may manifest after a mild-moderate traumatic brain injury (mmTBI) even when standard brain imaging appears normal. Transcranial direct current stimulation (tDCS) represents a promising treatment that may ameliorate pathophysiological processes contributing to PPS.Objective/Hypothesis: We hypothesized that in a mmTBI population, active tDCS combined with training would result in greater improvement in executive functions and post-TBI cognitive symptoms and increased resting state connectivity of the stimulated region, i.e., left dorsolateral prefrontal cortex (DLPFC) compared to control tDCS.Methods: Thirty-four subjects with mmTBI underwent baseline assessments of demographics, symptoms, and cognitive function as well as resting state functional magnetic resonance imaging (rsfMRI) in a subset of patients (n = 24). Primary outcome measures included NIH EXAMINER composite scores, and the Neurobehavioral Symptom Inventory (NSI). All participants received 10 daily sessions of 30 min of executive function training coupled with active or control tDCS (2 mA, anode F3, cathode right deltoid). Imaging and assessments were re-obtained after the final training session, and assessments were repeated after 1 month. Mixed-models linear regression and repeated measures analyses of variance were calculated for main effects and interactions.Results: Both active and control groups demonstrated improvements in executive function (EXAMINER composite: p < 0.001) and posttraumatic symptoms (NSI cognitive: p = 0.01) from baseline to 1 month. Active anodal tDCS was associated with greater improvements in working memory reaction time compared to control (p = 0.007). Reaction time improvement correlated significantly with the degree of connectivity change between the right DLPFC and the left anterior insula (p = 0.02).Conclusion: Anodal tDCS improved reaction time on an online working memory task in a mmTBI population, and decreased connectivity between executive network and salience network nodes. These findings generate important hypotheses for the mechanism of recovery from PPS after mild-moderate TBI.

Abstract. Depression is a pervasive psychiatric problem following mild traumatic brain injury (mTBI). However, the onset and course of symptom expression following mTBI can differ from that of spontaneous episodes of depression. Here, we aimed to assess a physiological metric closely linked to depression: respiratory sinus arrhythmia (RSA), a measure of high frequency heart rate variability. RSA is reduced during depressive episodes, and higher resting RSA has been shown to predict future recovery from depression. In this study, we investigated if these patterns were observed throughout the typical timeframe of sub-acute mTBI recovery. Although RSA did not differ between mTBI ( n = 50) and control ( n = 27) groups, depressive symptoms were reliably correlated with RSA only in the mTBI group. This pattern was consistent 2 weeks, 2 months, and 4 months post-injury. Furthermore, resting RSA shortly following injury predicted the trajectory of depressive symptoms 2 months later. These findings generalize the connection between RSA and depression to a clinical population where depressive symptoms are common but often difficult to parse from other post-trauma consequences.

Delayed memory deficits are common for patients with mild traumatic brain injury (mTBI), according to a recent systematic review of meta-analyses (Karr et al., 2014). However, there has been little work to identify different cognitive processes that may be underpinning these delayed memory deficits for mTBI. Frontal cortex is important for delayed memory, and is implicated in the pathophysiology of mTBI; moreover, frontal lobes are typically considered the locus of executive abilities. To further explore these relationships, we sought to partly explain delayed memory deficits after mTBI by examining behavioral indicators of executive function. Results showed that sub-acute as well as chronic mTBI patients performed worse than controls on the delayed memory trial of the Hopkins Verbal Learning Test-Revised (Brandt & Benedict, 2001), recalling approximately 18% and 15% fewer words, respectively. Furthermore, worse delayed memory performance was associated with less use of the cognitive strategy of semantic clustering, and with lower scores for the executive function composite from a standardized neuropsychological battery (NIH EXAMINER; Kramer et al., 2014). In contrast, serial clustering, a memory organizational strategy thought to be less dependent on executive function, did not show strong relationships to clinical status or delayed memory performance. This exploratory work suggests novel hypotheses to be tested in future, confirmatory studies, including that general executive functions and/or semantic clustering will mediate delayed memory deficits following mTBI.

Objective: This study assessed the convergent validity of the NIHTB-CB in a sample of children and adolescents with CCM-1 and non-affected relatives. Method: Twenty-two participants with CCM-1 and 7 non-affected relatives completed the NIHTB-CB and traditional neuropsychological measures. The following domains were assessed: memory (NIHTB-CB Picture Sequencing Memory and Child and Adolescent Memory Profile- Screening Index), word reading (NIHTB-CB Oral Reading and Wide Range Achievement Test-4th Word Reading [WRAT-4 WR]), processing speed (NIHTB-CB Pattern Comparison and Symbol Digit Modalities Test), and attention/working memory (NIHTB-CB List Sorting and Digit Span). Results: The non-affected group scored higher than the CCM-1 group on WRAT-4 WR (t = 2.68, p = .02) and NIHTB-CB Oral Reading (t = 2.18, p = .05). The groups did not differ on the other measures (p > .05). Pearson’s correlations ranged from .45 for memory to .81 for word reading, demonstrating adequate construct validity for memory, processing speed, and attention/ working memory and good to very good for word reading. The NIHTB-CB was more likely to identify participants as impaired for memory (17.2% vs 6.9%) and processing speed (62.1% vs. 3.4%). The traditional attention/working memory measure was more likely to identify participants as impaired (27.6% vs 3.4%). Impairment rates were similar for the word reading measures. Conclusions: Of the domains considered, convergent validity was best established for word reading. Although correlations were adequate, rates of impairment differed for memory, processing speed, and attention/ working memory, suggesting that caution is warranted when comparing the NIHTB-CB to traditional measures in these areas.

Objective: CCM1 is a rare condition that confers risk for negative neurological sequelae, including hemorrhage, seizures, and chronic headache. This study examines cognitive and psychosocial functioning in pediatric patients with CCM1 and describes emerging clinical care guidelines. Method: Twenty-two children and adolescents with CCM-1 and 7 non-affected relatives participated in this cross-sectional pilot study. Cognitive testing and behavior and emotion questionnaires were completed. A subset of participants with CCM1 (n = 11) had repeat brain MRI (average 4.89 years between scans). Results: Patients with CCM1 and their non-affected relatives did not differ on the NIH Toolbox Fluid and Crystallized composites (p > 0.05). Processing speed also did not significantly differ, although both group means were below average normatively (NIH Toolbox Pattern Comparison T-score; CCM1 = 31.50 [12.02], non-affected relatives = 37.57 [14.58]). In the subgroup with repeat imaging, slower processing speed was associated with an increase in large lesions (p = 0.03) and with younger age at CCM1 diagnosis (p = 0.04). Self- and parent-reported internalizing problems and parent-reported externalizing problems did not differ between groups (p > 05). In the CCM1 group, patient-reported disengaged coping was associated with more internalizing problems (p = 0.03). Conclusions: Neuropsychological evaluation is an important component of long-term, multi-disciplinary care for pediatric patients with CCM1, particularly if lesions are progressive. The pilot sample was overall well-adjusted behaviorally and emotionally. The use of disengaged coping strategies was associated with more internalizing symptoms and coping may be a key modifiable risk factor in this population. Psychosocial monitoring may therefore be warranted.

Apathy is a common and impairing sequela of traumatic brain injury (TBI). Yet, little is known about the neural mechanisms determining in which patients apathy does or does not develop post-TBI. We aimed to elucidate the impact of TBI on motivational neural circuits and how this shapes apathy over the course of TBI recovery. Resting-state functional magnetic resonance imaging data were collected in patients with subacute mild TBI (n = 44), chronic mild-to-moderate TBI (n = 26), and nonbrain-injured control participants (CTRL; n = 28). We measured ventromedial prefrontal cortex (vmPFC) functional connectivity (FC) as a function of apathy, using an a priori vmPFC seed adopted from a motivated decision-making study in an independent TBI study cohort. Patients reported apathy using a well-validated tool for assaying apathy in TBI. The vmPFC-to-wholebrain FC was contrasted between groups, and we fit regression models with apathy predicting vmPFC FC. Subacute and chronic TBI caused increased apathy relative to CTRL, replicating previous work suggesting that apathy has an enduring impact in TBI. The vmPFC was functionally connected to the canonical default network, and this architecture did not differ between subacute TBI, chronic TBI, and CTRL groups. Critically, in TBI, increased apathy scores predicted decreased vmPFC-dorsal anterior cingulate cortex (dACC) FC. Last, we subdivided the TBI group based on patients above versus below the threshold for “clinically significant apathy,” finding that TBI patients with clinically significant apathy demonstrated comparable vmPFC-dACC FC to CTRLs, whereas TBI patients with subthreshold apathy scores demonstrated vmPFC-dACC hyperconnectivity relative to both CTRLs and patients with clinically significant apathy. Post-TBI vmPFC-dACC hyperconnectivity may represent an adaptive compensatory response, helping to maintain motivation and enabling resilience to the development of apathy after neurotrauma. Given the role of vmPFC-dACC circuits in value-based decision making, rehabilitation strategies designed to improve this ability may help to reduce apathy and improve functional outcomes in TBI.

Background: Persistent post-traumatic symptoms (PPS) after traumatic brain injury (TBI) can lead to significant chronic functional impairment. Pseudocontinuous arterial spin labeling (pCASL) has been used in multiple studies to explore changes in cerebral blood flow (CBF) that may result in acute and chronic TBI, and is a promising neuroimaging modality for assessing response to therapies. Methods: Twenty-four subjects with chronic mild-moderate TBI (mmTBI) were enrolled in a pilot study of 10 days of computerized executive function training combined with active or sham anodal transcranial direct current stimulation (tDCS) for treatment of cognitive PPS. Behavioral surveys, neuropsychological testing, and magnetic resonance imaging (MRI) with pCASL sequences to assess global and regional CBF were obtained before and after the training protocol. Results: Robust improvements in depression, anxiety, complex attention, and executive function were seen in both active and sham groups between the baseline and post-treatment visits. Global CBF decreased over time, with differences in regional CBF noted in the right inferior frontal gyrus (IFG). Active stimulation was associated with static or increased CBF in the right IFG, whereas sham was associated with reduced CBF. Neuropsychological performance and behavioral symptoms were not associated with changes in CBF. Discussion: The current study suggests a complex picture between mmTBI, cerebral perfusion, and recovery. Changes in CBF may result from physiologic effect of the intervention, compensatory neural mechanisms, or confounding factors. Limitations include a small sample size and heterogenous injury sample, but these findings suggest promising directions for future studies of cognitive training paradigms in mmTBI.

Mild traumatic brain injury (mTBI) can affect high-level executive functioning long after somatic symptoms resolve. We tested if simple EEG responses within an oddball paradigm could capture variance relevant to this clinical problem. The P3a and P3b components reflect bottom-up and top-down processes driving engagement with exogenous stimuli. Since these features are related to primitive decision abilities, abnormal amplitudes following mTBI may account for problems in the ability to exert executive control. Sub-acute (2 weeks) mTBI participants (N = 38) and healthy controls (N = 24) were assessed at an initial session as well as a two-month follow-up (sessions 1 and 2). We contrasted the initial assessment to a comparison group of participants with chronic symptomatology following brain injury (N = 23). There were no group differences in P3a or P3b amplitudes. Yet in the sub-acute mTBI group, higher symptomatology on the Frontal Systems Behavior scale (FrSBe), a questionnaire validated as measuring symptomatic distress related to frontal lobe injury, correlated with lower P3a in session 1. This relationship was replicated in session 2. These findings were distinct from chronic TBI participants, who instead expressed a relationship between increased FrSBe symptoms and a lower P3b component. In the sub-acute group, P3b amplitudes in the first session correlated with the degree of symptom change between sessions 1 and 2, above and beyond demographic predictors. Controls did not show any relationship between FrSBe symptoms and P3a or P3b. These findings identify symptom-specific alterations in neural systems that vary along the time course of post-concussive symptomatology.