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Cognitive impairment is common in veterans with histories of traumatic brain injury (TBI). Cholinergic deficits have been hypothesized as contributors to this impairment. We report the effects of cholinesterase inhibitor rivastigmine transdermal patch treatment in veterans with TBI and post-traumatic memory impairment. Our objective was to evaluate the efficacy and safety of a 9.5 mg/24 h (10 cm

Objective: As part of an initiative led by the Brain Injury Special Interest Group Mild Traumatic Brain Injury (TBI) Task Force of the American Congress of Rehabilitation Medicine (ACRM) to update the 1993 ACRM definition of mild TBI, the present study aimed to characterize current expert opinion on diagnostic considerations. Design: Cross-sectional web-based survey. Setting: Not applicable. Participants: An international, interdisciplinary group of clinician-scientists (N=31) with expertise in mild TBI completed the survey by invitation between May and July 2019 (100% completion rate). Interventions: Not applicable. Main Outcome Measures: Ratings of agreement with statements related to the diagnosis of mild TBI and ratings of the importance of various clinical signs, symptoms, test findings, and contextual factors for increasing the likelihood that the individual sustained a mild TBI, on a scale ranging from 1 (“not at all important”) to 10 (“extremely important”). Results: Men (n=25; 81%) and Americans (n=21; 68%) were over-represented in the sample. The survey revealed areas of expert agreement (eg, acute symptoms are diagnostically useful) and disagreement (eg, whether mild TBI with abnormal structural neuroimaging should be considered the same diagnostic entity as “concussion”). Observable signs were generally rated as more diagnostically important than subjective symptoms (Wilcoxon signed ranks test, Z=3.77; P

In response to the need to better define the natural history of emerging consciousness after traumatic brain injury and to better describe the characteristics of the condition commonly labeled posttraumatic amnesia, a case definition and diagnostic criteria for the posttraumatic confusional state (PTCS) were developed. This project was completed by the Confusion Workgroup of the American Congress of Rehabilitation Medicine Brain Injury Interdisciplinary Special Interest group. The case definition was informed by an exhaustive literature review and expert opinion of workgroup members from multiple disciplines. The workgroup reviewed 2466 abstracts and extracted evidence from 44 articles. Consensus was reached through teleconferences, face-to-face meetings, and 3 rounds of modified Delphi voting. The case definition provides detailed description of PTCS (1) core neurobehavioral features, (2) associated neurobehavioral features, (3) functional implications, (4) exclusion criteria, (5) lower boundary, and (6) criteria for emergence. Core neurobehavioral features include disturbances of attention, orientation, and memory as well as excessive fluctuation. Associated neurobehavioral features include emotional and behavioral disturbances, sleep-wake cycle disturbance, delusions, perceptual disturbances, and confabulation. The lower boundary distinguishes PTCS from the minimally conscious state, while upper boundary is marked by significant improvement in the 4 core and 5 associated features. Key research goals are establishment of cutoffs on assessment instruments and determination of levels of behavioral function that distinguish persons in PTCS from those who have emerged to the period of continued recovery.

Psychological distress is common in persons with traumatic brain injury (TBI) but treatments remain underdeveloped. This randomized controlled trial of Acceptance and Commitment Therapy (ACT) was designed to address this gap. Ninety-three persons with medically-documented complicated mild to severe TBI, normal-to-mildly impaired memory, and clinically significant psychological distress in the chronic phase of recovery were randomized to receive eight weeks of ACT (manualized with adaptations to address TBI-related cognitive impairments) or a single session of needs assessment, brief counseling/education, and referral. The ACT group showed significantly greater reduction of psychological distress (Brief Symptom Inventory 18) and demonstrated improvements in psychological flexibility and commitment to action (Acceptance and Action Questionnaire-II (AAQ-II) scores). The number of treatment responders (post-treatment BSI 18 GSI T scores

Introduction Cannabis products, including cannabidiol (CBD) and tetrahydrocannabinol (THC), are increasingly easy to procure and use across the United States. The 2018 National Survey on Drug Use and Health (NSDUH) reported a past-month cannabis use rate of 8.6% among adults 26 years of age or older in the U.S. general population. Cannabis use is commonly reported by U.S. Military Veterans with histories of mild traumatic brain injury (mTBI) receiving services at the Marcus Institute for Brain Health (MIBH), a specialty interdisciplinary clinic serving this population. The aims of this study are to describe the frequency and characteristics of cannabis product use among Veterans evaluated at MIBH and to compare the rate of cannabis use in this group to that in the general and Veteran populations reported in the 2018 NSDUH. Materials and Methods Study data were collected as part of MIBH clinical assessments between January 2018 and December 2019, which included the evaluation of the current use of cannabis products. Affirmative cannabis use responses were clarified with inquiries about the frequency of use, method of administration, product ingredients (i.e., THC and/or CBD), and reason(s) for use. Results Among 163 MIBH patients (92.6% male), 72 (44.2%) endorsed cannabis product use during the month preceding the clinical assessment. Cannabis users were significantly younger than nonusers. The frequency of past-month cannabis use was significantly greater than that reported in the comparably aged NSDUH survey general and Veteran populations (44.2% vs. 8.6% and 44.2% vs. 7.7%, respectively, both P Conclusions Self-reported cannabis use is significantly higher in the MIBH population than in similarly aged individuals in the general population and significantly more frequent among younger than older members of this cohort. Self-reported reasons for cannabis use in this cohort included mTBI-associated neuropsychiatric symptoms, sleep disturbances, and pain for which standard treatments (both pharmacologic and nonpharmacologic) provided insufficient relief and/or produced treatment-limiting adverse events. However, cannabis use did not provide sufficient improvement in those symptoms to obviate the need for further evaluation and treatment of those problems at MIBH or to replace, in part or in whole, standard medications and other treatments for those problems. Further study of cannabis use, including standardized individual cannabinoid (i.e., THC and CBD) and whole-plant cannabis preparations, in this and similar cohorts is needed to more fully understand the drivers, benefits, risks, and safety of cannabis use in this and in similar Veteran populations, as well as the potential pharmacological and/or nonpharmacological therapeutic alternatives to cannabis use.

The habenula is a small midbrain structure that is important for brain signaling and learning from negative events. Thus, the habenula is strongly connected to both the reward system and motor regions. Increasing evidence suggests a role for the habenula in the etiology of psychiatric disorders, including mood and substance use disorders. However, no studies to date have investigated habenular resting-state functional connectivity (rsFC) in suicide-related behaviors (SB). The authors enrolled 123 individuals with major depressive disorder (MDD) or bipolar disorder and a history of suicide-related behaviors (SB+), 74 individuals with MDD or bipolar disorder and a history of suicidal ideation but no history of SB (SB-), and 75 healthy control subjects (HC). A seed-based approach was used to identify regions showing different rsFC with the habenula followed by region of interest to region of interest post hoc comparisons. Compared with both the SB- and HC groups, the SB+ group showed higher connectivity between the left habenula and the left parahippocampal gyrus, the right amygdala, and the right precentral and postcentral gyri. Patients with mood disorders displayed higher rsFC between the left habenula and left middle temporal gyrus, the left angular gyrus, and the left posterior cingulate cortex, as well as lower rsFC between the right habenula and the left thalamus, when compared with HCs. These findings suggest that the habenula is involved in the neural circuitry of suicide. The higher habenular rsFC found in the SB+ group may mediate a dysfunction in the mechanism that links the habenula with motor activity and contextual associative processing.

Aims: The overarching goal of this project was to establish a group comprised of a variety of TBI stakeholders for the purpose of: (1) determining facilitators and barriers in management of neuropsychiatric symptoms after TBI; (2) identifying strategies for maintaining a TBI PCOR network; (3) enumerating research topics related to TBI neuropsychiatry; and (4) highlighting policy changes related to TBI neuropsychiatry.Methods: Twenty-nine TBI stakeholders participated in focus group discussions. Qualitative analyses were conducted both manually and using Dedoose software.Results: Participant-identified barriers included stigma associated with experiencing neuropsychiatric symptoms and poor insurance coverage. Facilitators included treatment focused on education of neuropsychiatric symptoms after TBI and having a comprehensive caregiver plan. Best strategies for maintaining TBI PCOR network included having a well-defined project, continued regular meetings, and on-going education of network members. Pertinent research topics included TBI and aging, factors influencing outcomes after TBI, substance use disorders related to TBI, and effectiveness of telemental health services. Needed policy changes included making TBI neuropsychiatry education accessible to stakeholders and improving accessibility of TBI neuropsychiatric care.Conclusion: TBI stakeholders identified several facilitators of care for neuropsychiatric symptoms after TBI and suggested research topics and best practices for conducting PCOR in this area.

Background Prior studies on the effects of lithium on limbic and subcortical gray matter volumes are mixed. It is possible that discrepant findings may be explained by the duration of lithium exposure. We investigated this issue in individuals with type I bipolar disorder (BP-I). Methods Limbic and subcortical gray matter volume was measured using FreeSurfer in 60 subjects: 15 with BP-I without prior lithium exposure [no-exposure group (NE)]; 15 with BP-I and lithium exposure 24 months [long-exposure group (LE)]; and 15 healthy controls (HC). Results No differences in limbic and subcortical gray matter volumes were found between LE and HC. Hippocampal and amygdalar volumes were larger bilaterally in both LE and HC when compared to NE. Amygdalar volumes were larger bilaterally in SE when compared to NE but did not differ from LE. Hippocampal volumes were smaller bilaterally in SE when compared to LE and HC but did not differ from NE. No between-group differences on subcortical gray matter or other limbic structure volumes were observed. Limitations Cross-sectional design and concurrent treatment with other medications limit attribution of between-group differences to lithium exposure alone. Conclusions The effect of lithium exposure on limbic and subcortical gray matter volumes appears to be time-dependent and relatively specific to the hippocampus and the amygdala, with short-term effects on the amygdala and long-term effects on both structures. These results support the clinical importance of long-term lithium treatment in BP-I.

To investigate the factor structure of the Everyday Memory Questionnaire (EMQ) in persons with traumatic brain injury (TBI).This was a secondary analysis of baseline data from two clinical trials targeting memory impairment after TBI. Participants were 169 persons with complicated mild, moderate, or severe TBI at an average of 41 months post-injury. They completed the EMQ via clinical interview. Exploratory factor analysis was conducted using a three-factor principal axis factoring estimation method with a polychoric correlation matrix and oblique rotation.The three factors accounted for 49.2% of the variance, with moderate correlations observed among the factors. The three factors appeared to represent general everyday memory (prospective and episodic), conversational memory, and spatial or action memory. The three factors added significantly to the variance in age-corrected objective learning test scores predicted by injury severity, education, and sex.The three factors of the EMQ are consistent with the heterogeneity of memory impairments observed after TBI. The factor scores may be used to target treatments for impaired memory and to evaluate their effectiveness.

Background We studied emotional information processing in youth with pediatric bipolar disorder (pBD) using the late positive potential (LPP), assessing automatic allocation of attentional resources to emotionally salient stimuli, and the occipital P1, assessing early sensory processing. Methods Participants were 20 youth with pBD and 26 healthy controls (HC). Participants passively viewed faces with a fearful, neutral or happy expressions. Group differences were tested with general linear models. P1 was included to examine modulating effects on LPP. We calculated Bayes factor (BF) values to express strength of evidence for choosing one hypothesis over another. Results A significant emotion by group interaction for LPP amplitude was associated with a larger amplitude for happy faces for pBD than HC (F[1,40] = 6.04, p = .018); this was not modulated by P1 amplitude or latency. P1 amplitude did not differ between groups, although P1 peaked earlier for HC (F[1,40] = 5.45, p = .025). BF for LPP was 2.93, suggesting moderate evidence favoring H1. BF for P1 latency of 14.58 suggests strong evidence favoring H1. Limitations Inclusion of children and adolescents prohibited careful control for neurodevelopmental effects. Conclusions Larger LPP amplitude for happy faces without change in P1 suggests enhanced automatic allocation of attentional resources to positive information in pBD. Delayed P1 latency in pBD suggests slower early processing of emotional information.

To study the predictive relationship among persons with traumatic brain injury (TBI) between an objective indicator of injury severity (the adapted Marshall computed tomography [CT] classification scheme) and clinical indicators of injury severity in the acute phase, functional outcomes at inpatient rehabilitation discharge, and functional and participation outcomes at 1 year after injury, including death.The sample involved 4895 individuals who received inpatient rehabilitation following acute hospitalization for TBI and were enrolled in the Traumatic Brain Injury Model Systems National Database between 1989 and 2014.Head CT variables for each person were fit into adapted Marshall CT classification categories I through IV.Prediction models were developed to determine the amount of variability explained by the CT classification categories compared with commonly used predictors, including a clinical indicator of injury severity.The adapted Marshall classification categories aided only in the prediction of craniotomy or craniectomy during acute hospitalization, otherwise making no meaningful contribution to variance in the multivariable models predicting outcomes at any time point after injury.Results suggest that head CT findings classified in this manner do not inform clinical discussions related to functional prognosis or rehabilitation planning after TBI.CT: computed tomography; DRS: disability rating scale; EGOS: extended Glasgow outcome scale; FIM: functional independence measure; NDB: National Data Base; PTA: posttraumatic amnesia; RLOS: rehabilitation length of stay; SPOS: semipartial omega squared statistic; TBI: traumatic brain injury; TBIMS: Traumatic Brain Injury Model Systems.

Background Alterations in hippocampal structure and function are present in bipolar disorder (BD). Childhood trauma is associated with risk for BD, and the several subfields of the hippocampus are differentially sensitive to the effects of stressors of the sort associated with risk for BD. The current study therefore sought to test the hypothesis that childhood trauma may be differentially associated with abnormal hippocampal subfield volumes in BD. Methods 104 participants with BD type I (BD-I, n = 56) or BD type II (BD-II, n = 48) and 81 healthy controls (HC) underwent high-resolution structural magnetic resonance neuroimaging. Hippocampal subfield volumes were determined using FreeSurfer. Childhood trauma was assessed with the Childhood Trauma Questionnaire (CTQ). Results There were significant effects of diagnosis on intracranial volume corrected hippocampal subfield volumes bilaterally as well as a significant interaction between diagnosis and childhood trauma. Hippocampal volumes did not differ between the BD-I and BD-II subgroups but hippocampal volumes were smaller in both groups when compared to HC. There was a significant effect of childhood trauma on bilateral presubiculum volume as well as significant interactions between diagnosis and childhood trauma on bilateral CA1, presubiculum and subiculum volumes, the direction of which differed between individuals with BD (larger) and HC (smaller). Limitations Recall bias may influence the reliability of the retrospective assessment of childhood trauma experiences. Conclusions Childhood trauma demonstrates differential effects on hippocampal subfield volumes of BD and HC, particularly in hippocampal subfields involved in emotion regulation.

Few studies have assessed the long-term functional outcomes of patients with a disorder of consciousness due to traumatic brain injury (TBI). This study examined functional status during the first 10 years after TBI among a cohort with disorders of consciousness (i.e., coma, vegetative state, minimally conscious state). The study sample included 110 individuals with TBI who were unable to follow commands prior to inpatient rehabilitation and for whom follow-up data were available at 1, 2, 5, and 10 years post-injury. The sample was subdivided into those who demonstrated command-following early (before 28 days post-injury) versus late (≥ 28 days post-injury or never). Functional Independence Measure (FIM) at 1, 2, 5, and 10 years following TBI was used to measure functional outcomes. Measureable functional recovery occurred throughout the 10-year period, with more than two thirds of the sample achieving independence in mobility and self-care, and about one quarter achieving independent cognitive function by 10 years. Following commands prior to 28 days was associated with greater functional independence at all outcome time-points. Multi-trajectory modeling of recovery of three FIM subscales (self-care, mobility, cognition) revealed four distinct prognostic groups with different temporal patterns of change on these subscales. More than half the sample achieved near-maximal recovery by 1 year post-injury, while the later command-following subgroups recovered over longer periods of time. Significant late functional decline was not observed in this cohort. Among a cohort of patients unable to follow commands at the time of inpatient rehabilitation, a substantial proportion achieved functional independence in self-care, mobility, and cognition. The proportion of participants achieving functional independence increased between 5 and 10 years post-injury. These findings suggest that individuals with disorders of consciousness may benefit from ongoing functional monitoring and updated care plans for at least the first decade after TBI.

Repeated traumatic brain injuries (rmTBI) are frequently associated with debilitating neuropsychiatric conditions such as cognitive impairment, mood disorders, and post-traumatic stress disorder. We tested the hypothesis that repeated mild traumatic brain injury impairs spatial memory and enhances anxiety-like behaviour.We used a between groups design using single (smTBI) or repeated (rmTBI) controlled cranial closed skull impacts to mice, compared to a control group.We assessed the effects of smTBI and rmTBI using measures of motor performance (Rotarod Test [RT]), anxiety-like behaviour (Elevated Plus Maze [EPM] and Open Field [OF] tests), and spatial memory (Morris Water Maze [MWM]) within 12 days of the final injury. In separate groups of mice, astrocytosis and microglial activation were assessed 24 hours after the final injury using GFAP and IBA-1 immunohistochemistry.RmTBI impaired spatial memory in the MWM and increased anxiety-like behaviour in the EPM and OFT. In addition, rmTBI elevated GFAP and IBA-1 immunohistochemistry throughout the mouse brain. RmTBI produced astrocytosis and microglial activation, and elicited impaired spatial memory and anxiety-like behaviour.rmTBI produces acute cognitive and anxiety-like disturbances associated with inflammatory changes in brain regions involved in spatial memory and anxiety.

Psychosis is a common and functionally disruptive symptom of many psychiatric, neurodevelopmental, neurologic, and medical conditions and an important target of evaluation and treatment in neurologic and psychiatric practice. The purpose of this review is to define psychosis, communicate recent changes to the classification of and criteria for primary psychotic disorders described in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), and summarize current evidence-based approaches to the evaluation and management of primary and secondary psychoses.The DSM-5 classification of and criteria for primary psychotic disorders emphasize that these conditions occur along a spectrum, with schizoid (personality) disorder and schizophrenia defining its mild and severe ends, respectively. Psychosis is also identified as only one of several dimensions of neuropsychiatric disturbance in these disorders, with others encompassing abnormal psychomotor behaviors, negative symptoms, cognitive impairments, and emotional disturbances. This dimensional approach regards hallucinations and delusions as arising from neural systems subserving perception and information processing, thereby aligning the neurobiological framework used to describe and study such symptoms in primary psychotic disorders with those used to study psychosis associated with other neurologic conditions.This article provides practicing neurologists with updates on current approaches to the diagnosis, evaluation, and treatment of primary and secondary psychoses.

The purpose of this multicenter, prospective, randomized, placebo-controlled study was to evaluate and compare the efficacy of two cognitive rehabilitation interventions (Memory and Attention Adaptation Training (MAAT) and Attention Builders Training (ABT)), with and without pharmacological enhancement (ie, with methylphenidate (MPH) or placebo), for treating persistent cognitive problems after traumatic brain injury (TBI). Adults with a history of TBI at least 4 months before study enrollment with either objective cognitive deficits or subjective cognitive complaints were randomized to receive MPH or placebo and MAAT or ABT, yielding four treatment combinations: MAAT/MPH (N=17), ABT/MPH (N=19), MAAT/placebo (N=17), and ABT/placebo (N=18). Assessments were conducted pre-treatment (baseline) and after 6 weeks of treatment (post treatment). Outcome measures included scores on neuropsychological measures and subjective rating scales. Statistical analyses used linear regression models to predict post-treatment scores for each outcome variable by treatment type, adjusting for relevant covariates. Statistically significant (PABT/placebo), nonverbal learning (MAAT/MPH>MAAT/placebo and MAAT/MPH>ABT/MPH), and auditory working memory and divided attention (MAAT/MPH>ABT/MPH). These results suggest that combined treatment with metacognitive rehabilitation (MAAT) and pharmacotherapy (MPH) can improve aspects of attention, episodic and working memory, and executive functioning after TBI.

Objective Distinguishing depressive episodes due to bipolar disorder (BD) or major depressive disorder (MDD) solely on clinical grounds is challenging. We aimed at comparing resting-state functional connectivity (rsFC) of regions subserving emotional regulation in similarly depressed BD and MDD. Method We enrolled 76 in-patients (BD, n = 36; MDD, n = 40) and 40 healthy controls (HC). A seed-based approach was used to identify regions showing different rsFC with the insula and the amygdala. Insular and amygdalar parcellations were then performed along with diagnostic accuracy of the main findings. Results Lower rsFC between the left insula and the left mid-dorsolateral prefrontal cortex and between bilateral insula and right frontopolar prefrontal cortex (FPPFC) was observed in BD compared to MDD and HC. These results were driven by the dorsal anterior and posterior insula (PI). Lower rsFC between the right amygdala and the left anterior hippocampus was observed in MDD compared to BD and HC. These results were driven by the centromedial and laterobasal amygdala. Left PI/right FPPC rsFC showed 78% accuracy differentiating BD and MDD. Conclusion rsFC of amygdala and insula distinguished between depressed BD and MDD. The observed differences suggest the possibility of differential pathophysiological mechanisms of emotional dysfunction in bipolar and unipolar depression.

In this article, we will examine the epidemiology and risk factors for the development of the most common mood disorders observed in the aftermath of TBI: depressive disorders and bipolar spectrum disorders. We will describe the classification approach and diagnostic criteria proposed in the fifth edition of the Diagnostic and Statistical Manual for Mental Disorders (DSM-V). We will also examine the differential diagnosis of post-TBI mood disorders and describe the mainstay of the evaluation process. Finally, we will place a special emphasis on the analysis of the different therapeutic options and provide guidelines for the appropriate management of these conditions.

Emotional and behavioral dyscontrol are relatively common neuropsychiatric sequelae of traumatic brain injury and present substantial challenges to recovery and community participation. Among the most problematic and functionally disruptive of these types of behaviors are pathologic laughing and crying, affective lability, irritability, disinhibition, and aggression. Managing these problems effectively requires an understanding of their phenomenology, epidemiology, and clinical evaluation. This article reviews these issues and provides clinicians with brief and practical suggestions for the management of emotional and behavioral dyscontrol.

Recent scientific reports and popular press describing chronic traumatic encephalopathy (CTE) collectively link this condition to a broad array of neuropsychiatric symptoms, including extremely rare and multi-determined behaviors such as murder-suicide. These reports are difficult to reconcile with several decades of research on the science of traumatic brain injury (TBI) and its consequences, especially the natural history and prognosis of mild TBI. This article attempts to reconcile these sources by reviewing the state of the science on CTE, with particular attention to case definitions and neuropathological criteria for this diagnosis. The evidence for links between TBI, CTE, and catastrophic clinical events is explored, and the complexity of attributing rare frequency behavioral events to CTE is highlighted. The clinical and medicolegal implications of the best available evidence are discussed, concluding with a cautionary note against prematurely generalizing current findings on CTE to entire populations of persons with, or at risk for, concussion exposures.