Harm J. van der Horn

Brain Networks Subserving Emotion Regulation and Adaptation after Mild Traumatic Brain Injury

The majority of patients with traumatic brain injury (TBI) sustain a mild injury (mTBI). One out of 4 patients experiences persistent complaints, despite their often normal neuropsychological test results and the absence of structural brain damage on conventional neuroimaging. Susceptibility to develop persistent complaints is thought to be affected by interindividual differences in adaptation, which can also be influenced by preinjury psychological factors. Coping is a key construct of adaptation and refers to strategies to deal with new situations and serious life events. An important element of coping is the ability to regulate emotions and stress. The prefrontal cortex is a crucial area in this regulation process, given that it exerts a top-down influence on the amygdala and other subcortical structures involved in emotion processing. However, little is known about the role of the prefrontal cortex and associated brain networks in emotion regulation and adaptation post-mTBI. Especially, the influence of prefrontal dysfunction on development of persistent postconcussive complaints is poorly understood. In this article, we aim to integrate findings from functional and structural MRI studies on this topic. Alterations within the default mode, executive and salience network have been found in relation to complaints post-mTBI. Dysfunction of the medial prefrontal cortex may impair network dynamics for emotion regulation and adaptation post-mTBI, resulting in persistent post-concussive complaints.

Postconcussive Complaints, Anxiety, and Depression Related to Vocational Outcome in Minor to Severe Traumatic Brain Injury

OBJECTIVES To investigate the relation of postconcussive complaints, anxiety, and depression with vocational outcome in patients with traumatic brain injury (TBI) of various severities and to assess sex differences. DESIGN A prospective cross-sectional cohort study. SETTING Level I trauma center. PARTICIPANTS Adults (N=242) with TBI of various severity. INTERVENTIONS Not applicable. MAIN OUTCOME MEASURES Extended Glasgow Outcome Scale, return to work (RTW), Head Injury Symptom Checklist, and Hospital Anxiety and Depression Scale. RESULTS In 67% of the patients, complaints were present; 22% were anxious, and 18% were depressed. The frequency of complaints increased significantly with injury severity, in contrast to anxiety and depression. Frequencies of patients with anxiety and depression (9% and 5%) were lower with complete RTW than with incomplete RTW (42% and 37%; P<.001). Patients with minor TBI with complaints were more anxious (50% vs 27%; P<.05) and depressed (46% vs 23%; P<.05) compared with patients with other severity categories and patients with incomplete RTW (67% vs 36% and 60% vs 30%, respectively). A higher percentage of women with minor TBI were depressed (45% vs 13%; P=.01) and had incomplete RTW (50% vs 18%; P<.05) compared with men. Multiple regression analysis showed that injury severity, complaints, anxiety, and depression were all predictive of RTW (explained variance 45%). In all severity categories, anxiety and depression were predictive of RTW, complaints, and sex only for minor TBI. CONCLUSIONS Anxiety and depression are related to vocational outcome after TBI, with a different profile in the minor TBI category, partly due to sex differences.

Early predictors of outcome after mild traumatic brain injury (UPFRONT): an observational cohort study

BACKGROUND Mild traumatic brain injury (mTBI) accounts for most cases of TBI, and many patients show incomplete long-term functional recovery. We aimed to create a prognostic model for functional outcome by combining demographics, injury severity, and psychological factors to identify patients at risk for incomplete recovery at 6 months. In particular, we investigated additional indicators of emotional distress and coping style at 2 weeks above early predictors measured at the emergency department. METHODS The UPFRONT study was an observational cohort study done at the emergency departments of three level-1 trauma centres in the Netherlands, which included patients with mTBI, defined by a Glasgow Coma Scale score of 13-15 and either post-traumatic amnesia lasting less than 24 h or loss of consciousness for less than 30 min. Emergency department predictors were measured either on admission with mTBI-comprising injury severity (GCS score, post-traumatic amnesia, and CT abnormalities), demographics (age, gender, educational level, pre-injury mental health, and previous brain injury), and physical conditions (alcohol use on the day of injury, neck pain, headache, nausea, dizziness)-or at 2 weeks, when we obtained data on mood (Hospital Anxiety and Depression Scale), emotional distress (Impact of Event Scale), coping (Utrecht Coping List), and post-traumatic complaints. The functional outcome was recovery, assessed at 6 months after injury with the Glasgow Outcome Scale Extended (GOSE). We dichotomised recovery into complete (GOSE=8) and incomplete (GOSE≤7) recovery. We used logistic regression analyses to assess the predictive value of patient information collected at the time of admission to an emergency department (eg, demographics, injury severity) alone, and combined with predictors of outcome collected at 2 weeks after injury (eg, emotional distress and coping). FINDINGS Between Jan 25, 2013, and Jan 6, 2015, data from 910 patients with mTBI were collected 2 weeks after injury; the final date for 6-month follow-up was July 6, 2015. Of these patients, 764 (84%) had post-traumatic complaints and 414 (45%) showed emotional distress. At 6 months after injury, outcome data were available for 671 patients; complete recovery (GOSE=8) was observed in 373 (56%) patients and incomplete recovery (GOSE ≤7) in 298 (44%) patients. Logistic regression analyses identified several predictors for 6-month outcome, including education and age, with a clear surplus value of indicators of emotional distress and coping obtained at 2 weeks (area under the curve [AUC]=0·79, optimism 0·02; Nagelkerke R2=0·32, optimism 0·05) than only emergency department predictors at the time of admission (AUC=0·72, optimism 0·03; Nagelkerke R2=0·19, optimism 0·05). INTERPRETATION Psychological factors (ie, emotional distress and maladaptive coping experienced early after injury) in combination with pre-injury mental health problems, education, and age are important predictors for recovery at 6 months following mTBI. These findings provide targets for early interventions to improve outcome in a subgroup of patients at risk of incomplete recovery from mTBI, and warrant validation. FUNDING Dutch Brain Foundation.

Patients “At Risk” of Suffering from Persistent Complaints after Mild Traumatic Brain Injury: The Role of Coping, Mood Disorders, and Post-Traumatic Stress

Although most patients recover fully following mild traumatic brain injury (mTBI), a minority (15-25%) of all patients develop persistent post-traumatic complaints (PTC) that interfere with the resumption of previous activities. An early identification of patients who are at risk for PTC is currently performed by measuring the number of complaints in the acute phase. However, only part of this group will actually develop persisting complaints, stressing the need for studies on additional risk factors. This study aimed to compare this group of patients with many complaints with patients with few and no complaints to identify potential additional discriminating characteristics and to evaluate which of these factors have the most predictive value for being at risk. We evaluated coping style, presence of psychiatric history, injury characteristics, mood-related symptoms, and post-traumatic stress. We included 820 patients (Glasgow Coma Scale [GCS] score 13-15) admitted to three level-1 trauma centers as part of the UPFRONT-study. At 2 weeks after injury, 60% reported three or more complaints (PTC-high), 25% reported few complaints (PTC-low), and 15% reported no complaints (PTC-zero). Results showed that PTC-high consisted of more females (78% vs. 73% and 52%, p < 0.001), were more likely to have a psychiatric history (7% vs. 2% and 5%), and had a higher number of reported depression (22% vs. 6% and 3%, p < 0.001), anxiety (25% vs. 7% and 5%), and post-traumatic stress (37% vs. 27% and 19%, p < 0.001) than the PTC-low and PTC-zero groups. We conclude that in addition to reported complaints, psychological factors such as coping style, depression, anxiety, and post-traumatic stress symptoms had the highest predictive value and should be taken into account in the identification of at-risk patients for future treatment studies.

Acute alcohol intoxication in patients with mild traumatic brain injury : Characteristics, recovery, and outcome

A substantial number of patients (30% to 50%) sustains a mild traumatic brain injury (mTBI) while they are under the influence of alcohol. An acute alcohol intoxication (AAI) at the time of injury has been subject of research in severe TBI, but little is known about the relation between AAI and mTBI. This study aimed to describe the characteristics of this intoxicated subgroup and evaluate recovery and outcome in comparison to sober mTBI patients. We included 528 mTBI patients (Glasgow Coma Scale [GCS] score 13-15) admitted to two Level 1 trauma centers as part of a prospective follow-up study. We compared clinical characteristics, demographics, and injury mechanism between groups. Post-concussive complaints, mood disorders, and post-traumatic stress-related complaints were assessed at 2 weeks post-injury, and outcome at 6 months with the Glasgow Outcome Scale Extended (GOSE). Thirty-three percent of the mTBI patients were intoxicated. Results showed that the intoxicated group was younger (36 vs. 40 years; p = 0.001) and were more frequently of male gender (78% vs. 60%; p < .001). The groups also differed in injury related characteristics, with intoxicated patients more frequently sustaining falls or violence-related injuries. The intoxicated group was assessed with a lower GCS score and had a higher hospital admission rate. However, at 2 weeks post-injury, intoxicated patients reported less complaints than the non-alcohol group and showed a better recovery at 6 months (average GOSE scores 7 vs. 7.3; p = 0.030). We conclude that AAI in mTBI represents a characteristically different group, which has implications for prevention measures, as well as the course of recovery.

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

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).

Executive Functioning in Relation to Coping in Mild Versus Moderate-Severe Traumatic Brain Injury

Objective: To examine associations between executive functioning (EF) and coping styles, separately for mild and moderate-severe traumatic brain injury (TBI) in the chronic phase postinjury. Method: Patients with mild (n = 47) and moderate-severe TBI (n = 59) were included, in addition to healthy controls (HCs; n = 51). Assessment consisted of EF tests (Trail Making Test, Zoo Map Test, Controlled Oral Word Association Test) and questionnaires examining EF (Dysexecutive Questionnaire) and coping styles (Utrecht Coping List). Results: Moderate-severe TBI patients showed significant more EF deficits, lower active coping and higher passive coping than mild TBI patients and HCs, whereas mild TBI patients did not differ from HCs. In the moderate-severe TBI group, a higher number of self-reported EF problems was related to lower levels of active coping, r = −.43, p < .01 and higher levels of passive coping, r = .58, p < .001, with proxy-reports relating to lower levels of active coping, r = −.33, p < .05. For mild TBI, a higher amount of self-reported EF problems was related to lower levels of active coping, r = −.38, p < .05 and higher levels of passive coping, r = .55, p < .001, with proxy-reports relating to higher levels of passive coping, r = .39, p < .05. Except for mental flexibility, EF performances were not associated with coping. Conclusions: This study shows strong associations between reported EF problems in daily life and coping styles. For moderate-severe TBI, proxy-reports may reflect EF impairments that complicate active problem-solving. However, reported EF problems by mild and moderate-severe TBI patients are also likely to reflect a psychological distress related to the way patients are inclined to deal with stressing situations that put a demand on their executive abilities.

Altered Wiring of the Human Structural Connectome in Adults with Mild Traumatic Brain Injury

In this study, structural connectivity after mild traumatic brain injury (mTBI) was examined from a network perspective, with a particular focus on post-traumatic complaints. Fifty-three patients with and without self-reported complaints at 2 weeks after uncomplicated mTBI were included, in addition to 20 matched healthy controls. Diffusion weighted imaging was performed at 4 weeks post-injury, and neuropsychological tests measuring processing speed and verbal memory were administered at 3 months post-injury to determine cognitive outcome. Structural connectivity was investigated using whole brain tractography and subsequent graph theory analysis. In patients with mTBI, eigenvector centrality within the left temporal pole was lower than in healthy controls. In patients without complaints, global and mean local efficiency were lower than in patients with complaints, although no differences were found between either subgroup and the group of healthy controls. Neuropsychological test scores were similar for patients with mTBI and healthy controls. However, patients with complaints showed higher processing speed than patients without complaints. Within the total mTBI group, a trend was found toward a correlation between lower network clustering and higher processing speed. Additionally, significant correlations were found between higher betweenness centrality values of language areas and lower verbal memory scores in patients with mTBI. In conclusion, our findings may indicate that global graph measures of the structural connectome are associated with pre- and/or non-injury-related factors that determine the susceptibility to developing (persistent) complaints after mTBI. Further, correlations between graph measures and neuropsychological test scores could suggest early compensatory mechanisms to maintain adequate cognitive performance.

Diagnosing Sporadic Creutzfeldt-Jakob Disease in a Patient with a Suspected Status Epilepticus in the Intensive Care Unit

Objective. Several tests are available in the diagnostics of sporadic Creutzfeldt-Jakob disease (sCJD); however, none of these is conclusive. We review the values of these tests, from an intensive care unit (ICU) perspective. Methods. Case report and review of the literature. Results. A 53-year-old woman initially presenting with psychiatric symptoms developed myoclonus and was admitted 1 month later to the ICU with a suspected nonconvulsive status epilepticus and respiratory insufficiency, probably due to extensive antiepileptic drug therapy. Typical MRI and EEG findings and a positive 14-3-3 protein led to the diagnosis of sCJD. All treatments were terminated, and autopsy confirmed sCJD. Conclusions. Clinical signs combined with MRI, EEG, and 14-3-3 and/or tau protein determination might be sufficient to diagnose or exclude sCJD and may therefore prevent the application of unnecessary diagnostic tests.

Graph Analysis of Functional Brain Networks in Patients with Mild Traumatic Brain Injury

Mild traumatic brain injury (mTBI) is one of the most common neurological disorders worldwide. Posttraumatic complaints are frequently reported, interfering with outcome. However, a consistent neural substrate has not yet been found. We used graph analysis to further unravel the complex interactions between functional brain networks, complaints, anxiety and depression in the sub-acute stage after mTBI. This study included 54 patients with uncomplicated mTBI and 20 matched healthy controls. Posttraumatic complaints, anxiety and depression were measured at two weeks post-injury. Patients were selected based on presence (n = 34) or absence (n = 20) of complaints. Resting-state fMRI scans were made approximately four weeks post-injury. High order independent component analysis resulted in 89 neural components that were included in subsequent graph analyses. No differences in graph measures were found between patients with mTBI and healthy controls. Regarding the two patient subgroups, degree, strength, local efficiency and eigenvector centrality of the bilateral posterior cingulate/precuneus and bilateral parahippocampal gyrus were higher, and eigenvector centrality of the frontal pole/ bilateral middle & superior frontal gyrus was lower in patients with complaints compared to patients without complaints. In patients with mTBI, higher degree, strength and eigenvector centrality of default mode network components were related to higher depression scores, and higher degree and eigenvector centrality of executive network components were related to lower depression scores. In patients without complaints, one extra module was found compared to patients with complaints and healthy controls, consisting of the cingulate areas. In conclusion, this research extends the knowledge of functional network connectivity after mTBI. Specifically, our results suggest that an imbalance in the function of the default mode- and executive network plays a central role in the interaction between emotion regulation and the persistence of posttraumatic complaints.