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The role of the Met66 brain-derived neurotrophic factor allele in the recovery of executive functioning after combat-related traumatic brain injury.

ABSTRACT: Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, promotes survival and synaptic plasticity in the human brain. The Val66Met polymorphism of the BDNF gene interferes with intracellular trafficking, packaging, and regulated secretion of this neurotrophin. The human prefrontal cortex (PFC) shows lifelong neuroplastic adaption implicating the Val66Met BDNF polymorphism in the recovery of higher-order executive functions after traumatic brain injury (TBI). In this study, we examined the effect of this BDNF polymorphism on the recovery of executive functioning after TBI. We genotyped a sample of male Vietnam combat veterans consisting of a frontal lobe lesion group with focal penetrating head injuries and a non-head-injured control group for the Val66Met BDNF polymorphism. The Delis-Kaplan Executive Function System as a standardized psychometric battery was administrated to examine key domains of executive functions. The results revealed that the Met allele but not the hypothesized Val allele promotes recovery of executive functioning. Overall, the Met66 carriers in the lesion group performed as well as the Met66 carriers in the control group. The Met66 allele accounted for 6.2% of variance for executive functioning independently of other significant predictors including preinjury intelligence, left hemisphere volume loss, and dorsolateral PFC volume loss. The findings point to different mechanisms of the Val66Met BDNF gene in complex phenotypes under normal and pathological conditions. A better understanding of these mechanisms could be instrumental in the development and application of effective therapeutic strategies to facilitate recovery from TBI.

SUBMITTER: Krueger F

PROVIDER: S-EPMC3195417 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Deficits in executive control functions are some of the most common and disabling consequences of both military and civilian brain injury. However, effective interventions are scant. The goal of this study was to assess whether cognitive rehabilitation training that was successfully applied in chronic civilian brain injury would be effective for military veterans with traumatic brain injury (TBI). In a prior study, participants with chronic acquired brain injury significantly improved after training in Goal-Oriented Attentional Self-Regulation (GOALS) on measures of attention/executive function, functional task performance, and goal-directed control over neural processing on functional magnetic resonance imaging. The objective of this study was to assess effects of GOALS training in veterans with chronic TBI. A total of 33 veterans with chronic TBI and executive difficulties in their daily life completed either 5 weeks of manualized GOALS training or Brain-Health Education (BHE) matched by time and intensity. Evaluator-blinded assessments at baseline and post-training included neuropsychological and complex functional task performance and self-report measures of emotional regulation. After GOALS, but not BHE training, participants significantly improved from baseline on primary outcome measures of Overall Complex Attention/Executive Function composite neuropsychological performance score (F = 7.10, p = 0.01; partial η2 = 0.19), and on overall complex functional task performance (Goal Processing Scale Overall Performance; F = 6.92, p = 0.01, partial η2 = 0.20). Additionally, post-GOALS participants indicated significant improvement on emotional regulation self-report measures (Profile of Mood States Confusion Score; F = 6.05, p = 0.02, partialη2 = 0.20). Training in attentional self-regulation applied to participant-defined goals may improve cognitive functioning in veterans with chronic TBI. Attention regulation training may not only impact executive control functioning in real-world complex tasks, but also may improve emotional regulation and functioning. Implications for treatment of veterans with TBI are discussed.

Project description:ImportanceExecutive functions are critical for school and social success. Although these functions are adversely affected by pediatric traumatic brain injury (TBI), recovery patterns are not well established.ObjectiveTo examine 3-year trajectories of selected children's executive functions after TBI.Design, setting, and participantsThis prospective cohort study was conducted from January 22, 2013, to September 30, 2015, with 3-year follow-up at the level I pediatric trauma centers Primary Children's Hospital in Salt Lake City, Utah and Children's Memorial Hermann Hospital in Houston, Texas. Study participants included children aged 2 to 15 years with TBI or orthopedic injury (OI) who were treated at the participating hospitals. Children were consecutively recruited and stratified by injury severity and age group. A total of 625 children consented and completed a baseline survey; 559 (89%) children completed at least 1 follow-up and composed the analysis cohort. It was hypothesized that recovery would differ by injury severity, age at injury, and sex. Data analyses were performed from June to October 2019.Main outcomes and measuresGrowth curve models examined the pattern of change in the Emotional Control, Inhibit, Working Memory, and Plan-Organize subscales of the Behavior Rating Inventory of Executive Function (BRIEF) or BRIEF-Preschool. For all BRIEF subscales, higher scores indicate worse symptoms, and a score of 65 or greater represents clinical impairment.ResultsA total of 559 children (mean [SD] age, 8.6 [4.4] years; 356 boys [64%], 328 non-Hispanic White children [59%]) were included in the study: 155 (28%) children had mild TBI, 162 (29%) had complicated mild or moderate TBI, 90 (16%) had severe TBI, and 152 (27%) had OI. Growth curve trajectories varied by BRIEF subscale and injury severity. Overall, children with TBI did not return to their preinjury baseline, with a stepwise worsening of each outcome at 36 months by TBI severity compared with OI. Among children with severe TBI, trajectories accelerated fastest, indicating increased problems, from injury to 12 months for the Emotional Control (9.0 points; 95% CI, 6.0-11.9 points), Inhibit (3.6 points; 95% CI, 1.6-5.6 points), and Working Memory (7.0 points; 95% CI, 4.1-9.9 points) subscales. Their trajectories plateaued, with a secondary acceleration before 36 months for the Emotional Control and Working Memory subscales. Children with mild TBI had worse 36-month scores on all subscales except Inhibit compared with OI. Recovery patterns were similar for boys and girls.Conclusions and relevanceIn this longitudinal cohort study of children with TBI, trajectory analysis revealed that some children worsen after a recovery plateau, suggesting a need for longitudinal reassessment beyond 1 year postinjury.

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The role of the Met66 brain-derived neurotrophic factor allele in the recovery of executive functioning after combat-related traumatic brain injury.

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