COMT Val158Met and BDNF Val66Met Single-Nucleotide Polymorphisms Are Not Associated With Emotional Distress One Year After Moderate-Severe Traumatic Brain Injury.

Emotional distress is a common, but poorly addressed, feature of moderate-severe traumatic brain injury (TBI). Previously identified sociodemographic, psychological, and injury-related factors account for only a small proportion of the variability in emotional distress post-TBI. Genetic factors may help to further understand emotional distress in this population. The catechol-O-methyltransferase (COMT) Val158 and brain-derived neurotrophic factor (BDNF) 66Met single-nucleotide polymorphisms (SNPs) have been identified as possible contributory factors to outcomes after TBI. We investigated whether the COMT Val158 and BDNF 66Met SNPs were associated with emotional distress 1 year after moderate-severe TBI, and whether these associations were moderated by age, sex, and TBI severity (as measured by the duration of post-traumatic amnesia [PTA]). Moderate-severe TBI survivors (COMT, n = 391; BDNF, n = 311) provided saliva samples after admission to a TBI rehabilitation hospital. At a follow-up interview ∼1 year after injury, participants completed a self-report measure of emotional distress (Hospital Anxiety and Depression Scale; HADS). Multiple linear regression models were constructed for each SNP to predict total scores on the HADS. Neither COMT Val158 nor BDNF 66Met carriage status (carrier vs. non-carrier) significantly predicted emotional distress (COMT, p = 0.49; BDNF, p = 0.66). Interactions of SNP × age (COMT, p = 0.90; BDNF, p = 0.93), SNP × sex (COMT, p = 0.09; BDNF, p = 0.60), SNP × injury severity (COMT, p = 0.53; BDNF, p = 0.87), and SNP × sex × age (COMT, p = 0.08; BDNF, p = 0.76) were also non-significant. Our null findings suggest that COMT Val158 and BDNF 66Met SNPs do not aid the prediction of emotional distress 1 year after moderate-severe TBI, neither in isolation nor in interaction with age, sex and injury severity. The reporting of null findings such as ours is important to avoid publication bias and prompt researchers to consider the challenges of single-gene candidate studies in understanding post-TBI outcomes. Analyses in larger samples that incorporate multiple genetic factors and their relevant moderating factors may provide a greater understanding of the role of genetics in post-TBI emotional distress.

Network analysis of anxiety and depressive symptoms one year after traumatic brain injury.

We used network analysis to explore interrelationships between anxiety and depressive symptoms after traumatic brain injury (TBI). At one year post-injury, 882 adult civilians who received inpatient rehabilitation for moderate-severe TBI self-reported anxiety and depressive symptoms (Hospital Anxiety and Depression Scale). The severity of TBI was characterized acutely by the duration of post-traumatic amnesia (PTA), and TBI-related functional disability was rated by an examiner at one year post-injury using a structured interview (Glasgow Outcome Scale - Extended). We estimated two cross-sectional, partial correlation networks. In the first network, anxiety and depressive symptoms were densely interconnected yet formed three distinct, data-driven communities: Hyperarousal, Depression, and General Distress. Worrying thoughts and having difficulty relaxing were amongst the most central symptoms, showing strong connections with other symptoms within and between communities. In the second network, TBI severity was directly negatively associated with hyperarousal symptoms but indirectly positively associated with depressive symptoms via greater functional disability. The results highlight the potential utility of simultaneous, transdiagnostic assessment and treatment of anxiety and depressive symptoms after moderate-severe TBI. Worrying thoughts, having difficulty relaxing, and the experience of disability may be important targets for treatment, although future studies examining symptom dynamics within individuals and over time are required.

Bifactor analysis of the Hospital Anxiety and Depression Scale (HADS) in individuals with traumatic brain injury.

Anxiety and depression symptoms are commonly experienced after traumatic brain injury (TBI). However, studies validating measures of anxiety and depression for this population are scarce. Using novel indices derived from symmetrical bifactor modeling, we evaluated whether the Hospital Anxiety and Depression Scale (HADS) reliably differentiated anxiety and depression in 874 adults with moderate-severe TBI. The results showed that there was a dominant general distress factor accounting for 84% of the systematic variance in HADS total scores. The specific anxiety and depression factors accounted for little residual variance in the respective subscale scores (12% and 20%, respectively), and overall, minimal bias was found in using the HADS as a unidimensional measure. Further, in a subsample of 184 participants, the HADS subscales did not clearly discriminate between formal anxiety and depressive disorders diagnosed via clinical interview. Results were consistent when accounting for degree of disability, non-English speaking background, and time post-injury. In conclusion, variance in HADS scores after TBI predominately reflects a single underlying latent variable. Clinicians and researchers should exercise caution in interpreting the individual HADS subscales and instead consider using the total score as a more valid, transdiagnostic measure of general distress in individuals with TBI.

Ten-Year Cohort Study of Emotional Distress Trajectories After Moderate-Severe Traumatic Brain Injury.

OBJECTIVE: To characterize trajectories of emotional distress across the first decade after moderate-severe traumatic brain injury (TBI) and explore relations with personal and injury-related factors. DESIGN: Cohort study with follow-ups at 1, 2, 3, 5, and 10 years post-injury. SETTING: Community. PARTICIPANTS: Participants were sampled from a larger longitudinal study of 4300 individuals recruited from consecutive inpatient TBI admissions to a rehabilitation hospital between 1985 and 2021 (N=4300). We analyzed data from 596 unique individuals (13.86% of total dataset; 70.81% male; Mage=40.11 years, SDage=17.49 years; 7.59% non-English-speaking background) with moderate-severe TBI who had complete data on all personal and injury-related variables (collected on admission) and emotional data at 3 or more time-points. There were 464 participants at the 1-year post-injury time-point, 485 at 2 years, 454 at 3 years, 450 at 5 years, and 248 at 10 years. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: The Hospital Anxiety and Depression Scale (HADS). RESULTS: Visualization of the individual HADS symptoms (line graph) showed that the most highly endorsed symptoms at each time-point were feeling slowed down and restlessness. On average, each symptom reduced across the first decade post-TBI, with an overall mild level of emotional distress at 10 years. However, visualization of participants' individual trajectories based on the HADS total score (Sankey diagram) revealed significant heterogeneity. Using latent class analysis, we identified 5 distinct trajectory types based on the HADS total score: "Gradual Improving" (38.93%), "Resilience" (36.41%), "Gradual Worsening" (10.40%), and 2 non-linear trajectories of "Worsening-Remitting" (8.22%) and "Improving-Relapsing" (6.04%). Middle age at injury, lower Glasgow Coma Scale score, comorbid spinal and limb injuries, and receipt of pre-injury mental health treatment predicted earlier and/or worsening post-injury emotional distress. CONCLUSIONS: Emotional distress across the first decade after moderate-severe TBI is dynamic, heterogeneous, and often chronic, underscoring a need for ongoing monitoring and responsive treatment.

Interaction between APOE ɛ4 and Age Is Associated with Emotional Distress One Year after Moderate-Severe Traumatic Brain Injury.

Emotional distress is common following moderate-severe traumatic brain injury (TBI) and is associated with poorer post-injury outcomes. Previously investigated sociodemographic, psychological, and injury-related factors account for only a small proportion of variance in post-TBI emotional distress, highlighting a need to consider other factors such as genetic factors. The apolipoprotein E gene (APOE) has been commonly studied in the TBI literature, with the ɛ4 allele linked to worse neuronal repair and recovery. Few studies have investigated the potential relationship between APOE ɛ4 and emotional distress after moderate-severe TBI, and results have been varied. We examined whether APOE ɛ4 was associated with emotional distress 1 year following moderate-severe TBI, and whether this relationship was moderated by age, sex, and TBI severity (as indexed by the duration of post-traumatic amnesia [PTA]). Moderate-severe TBI survivors provided saliva samples following inpatient admission to a TBI rehabilitation hospital. They completed a self-report measure of emotional distress, the Hospital Anxiety and Depression Scale (HADS), at a follow-up interview ∼1 year post-injury. Complete genetic and follow-up data were available for 441 moderate-severe TBI survivors (mean age = 39.42 years; 75% male). We constructed a linear regression model that included APOE ɛ4 carriage status (carrier vs. non-carrier) and interactions with age, sex, and TBI severity (APOE × age, APOE × sex, APOE × age × sex, and APOE × PTA duration) to predict total score on the HADS, while covarying for the main effects of age, sex, PTA duration, and previous head injury. There was a significant main effect of APOE ɛ4, whereby ɛ4 carriers reported less emotional distress than non-carriers (p = 0.04). However, we also found a significant interaction with age such that APOE ɛ4 carriers reported increasingly greater emotional distress with older age compared with non-carriers (p = 0.01). A sensitivity analysis (n = 306) suggested that the APOE × age interaction, and main effects of age and previous head injury, were not unique to individuals with pre-injury mental health problems (n = 136). However, the main effect of APOE ɛ4 was no longer significant when individuals with pre-injury mental health problems were removed. Our findings highlight the importance of considering moderation of genetic associations, suggesting that APOE ɛ4 may be a risk factor for emotional distress specifically among older survivors of moderate-severe TBI. If these findings can be independently replicated, APOE ɛ4 carriage status, interpreted in the context of age, could be incorporated into risk prediction models of emotional distress after moderate-severe TBI, enhancing targeted early detection and intervention efforts.

Moderators of gene-outcome associations following traumatic brain injury.

The field of genomics is the principal avenue in the ongoing development of precision/personalised medicine for a variety of health conditions. However, relating genes to outcomes is notoriously complex, especially when considering that other variables can change, or moderate, gene-outcome associations. Here, we comprehensively discuss moderation of gene-outcome associations in the context of traumatic brain injury (TBI), a common, chronically debilitating, and costly neurological condition that is under complex polygenic influence. We focus our narrative review on single nucleotide polymorphisms (SNPs) of three of the most studied genes (apolipoprotein E, brain-derived neurotrophic factor, and catechol-O-methyltransferase) and on three demographic variables believed to moderate associations between these SNPs and TBI outcomes (age, biological sex, and ethnicity). We speculate on the mechanisms which may underlie these moderating effects, drawing widely from biomolecular and behavioural research (n = 175 scientific reports) within the TBI population (n = 72) and other neurological, healthy, ageing, and psychiatric populations (n = 103). We conclude with methodological recommendations for improved exploration of moderators in future genetics research in TBI and other populations.