Exosomal MicroRNA Differential Expression in Plasma of Young Adults with Chronic Mild Traumatic Brain Injury and Healthy Control

Chronic mild traumatic brain injury (mTBI) has long-term consequences, such as neurological disability, but its pathophysiological mechanism is unknown. Exosomal microRNAs (exomiRNAs) may be important mediators of molecular and cellular changes involved in persistent symptoms after mTBI. We profiled exosomal microRNAs (exomiRNAs) in plasma from young adults with or without a chronic mTBI to decipher the underlying mechanisms of its long-lasting symptoms after mTBI. We identified 25 significantly dysregulated exomiRNAs in the chronic mTBI group (n = 29, with 4.48 mean years since the last injury) compared to controls (n = 11). These miRNAs are associated with pathways of neurological disease, organismal injury and abnormalities, and psychological disease. Dysregulation of these plasma exomiRNAs in chronic mTBI may indicate that neuronal inflammation can last long after the injury and result in enduring and persistent post-injury symptoms. These findings are useful for diagnosing and treating chronic mTBIs.

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Outcomes after Complicated and Uncomplicated Mild Traumatic Brain Injury at Three-and Six-Months Post-Injury: Results from the CENTER-TBI Study

Journal of Clinical Medicine ◽

10.3390/jcm9051525 ◽

2020 ◽

Vol 9 (5) ◽

pp. 1525 ◽

Cited By ~ 1

Author(s):

Daphne C. Voormolen ◽

Marina Zeldovich ◽

Juanita A. Haagsma ◽

Suzanne Polinder ◽

Sarah Friedrich ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Functional Outcome ◽

Mild Traumatic Brain Injury ◽

Intracranial Injury ◽

Post Injury ◽

Long Term Outcome ◽

Sf 36 ◽

Disease Specific

The objective of this study was to provide a comprehensive examination of the relation of complicated and uncomplicated mild traumatic brain injury (mTBI) with multidimensional outcomes at three- and six-months after TBI. We analyzed data from the Collaborative European NeuroTrauma Effectiveness Research (CENTER-TBI) research project. Patients after mTBI (Glasgow Coma scale (GCS) score of 13–15) enrolled in the study were differentiated into two groups based on computed tomography (CT) findings: complicated mTBI (presence of any traumatic intracranial injury on first CT) and uncomplicated mTBI (absence of any traumatic intracranial injury on first CT). Multidimensional outcomes were assessed using seven instruments measuring generic and disease-specific health-related quality of life (HRQoL) (SF-36 and QOLIBRI), functional outcome (GOSE), and psycho-social domains including symptoms of post-traumatic stress disorder (PTSD) (PCL-5), depression (PHQ-9), and anxiety (GAD-7). Data were analyzed using a multivariate repeated measures approach (MANOVA-RM), which inspected mTBI groups at three- and six-months post injury. Patients after complicated mTBI had significantly lower GOSE scores, reported lower physical and mental component summary scores based on the SF-36 version 2, and showed significantly lower HRQoL measured by QOLIBRI compared to those after uncomplicated mTBI. There was no difference between mTBI groups when looking at psychological outcomes, however, a slight improvement in PTSD symptoms and depression was observed for the entire sample from three to six months. Patients after complicated mTBI reported lower generic and disease specific HRQoL and worse functional outcome compared to individuals after uncomplicated mTBI at three and six months. Both groups showed a tendency to improve from three to six months after TBI. The complicated mTBI group included more patients with an impaired long-term outcome than the uncomplicated group. Nevertheless, patients, clinicians, researchers, and decisions-makers in health care should take account of the short and long-term impact on outcome for patients after both uncomplicated and complicated mTBI.

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Long-term cognitive and emotional consequences of mild traumatic brain injury

Psychological Medicine ◽

10.1017/s0033291710001728 ◽

2010 ◽

Vol 41 (6) ◽

pp. 1197-1211 ◽

Cited By ~ 133

Author(s):

C. Konrad ◽

A. J. Geburek ◽

F. Rist ◽

H. Blumenroth ◽

B. Fischer ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Mild Traumatic Brain Injury ◽

Response Bias ◽

Negative Response ◽

Control Subjects ◽

Negative Response Bias ◽

Healthy Control ◽

Dsm Iv

BackgroundThe objective of this study was to investigate long-term cognitive and emotional sequelae of mild traumatic brain injury (mTBI), as previous research has remained inconclusive with respect to their prevalence and extent.MethodThirty-three individuals who had sustained mTBI on average 6 years prior to the study and 33 healthy control subjects were matched according to age, gender and education. Structural brain damage at time of testing was excluded by magnetic resonance imaging (MRI). A comprehensive neuropsychological test battery was conducted to assess learning, recall, working memory, attention and executive function. Psychiatric symptoms were assessed by the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I) and the Beck Depression Inventory (BDI). Possible negative response bias was ruled out by implementing the Word Memory Test (WMT).ResultsThe mTBI individuals had significant impairments in all cognitive domains compared to the healthy control subjects. Effect sizes of cognitive deficits were medium to large, and could not be accounted for by self-perceived deficits, depression, compensation claims or negative response bias. BDI scores were significantly higher in the patient group, and three patients fulfilled DSM-IV criteria for a mild episode of major depression.ConclusionsPrimarily, well-recovered individuals who had sustained a minor trauma more than half a decade ago continue to have long-term cognitive and emotional sequelae relevant for everyday social and professional life. mTBI may lead to a lasting disruption of neurofunctional circuits not detectable by standard structural MRI and needs to be taken seriously in clinical and forensic evaluations.

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Young adults’ perspectives on their psychosocial outcomes 16 years following childhood traumatic brain injury

Social Care and Neurodisability ◽

10.1108/scn-06-2013-0022 ◽

2014 ◽

Vol 5 (3) ◽

pp. 135-144 ◽

Cited By ~ 11

Author(s):

S. Rosema ◽

F. Muscara ◽

V. Anderson ◽

C. Godfrey ◽

S. Eren ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Young Adults ◽

Longitudinal Study ◽

Brain Injury ◽

Internalizing Symptoms ◽

Psychosocial Outcomes ◽

Psychological Problems ◽

Post Injury ◽

Content Type

Purpose – Childhood traumatic brain injury (CTBI) is one of the most common causes of mortality and disability in children and adolescents that impacts on neuropsychological, social and psychological development. A disruption of development in these areas often results in long-term problems with interpersonal relationships, participation in leisure and social activities and employment status. These social and psychological problems appear to persist longer in comparison to other functional consequences, although evidence is scarce. The purpose of this paper is to investigate social and psychological outcomes 15 years post-injury. Design/methodology/approach – In all, 36 participants post-CTBI (mean age 21.47 years, SD=2.74), 16 males) and 18 healthy controls (mean age 20.94 years, SD=2.21), 12 males) were recruited from a larger sample of a longitudinal study conducted at the Royal Children's Hospital, Melbourne, Australia. Information about social and psychological functioning was collected via questionnaires completed at 15 years post-injury. Findings – Results showed that post-CTBI, adolescents and young adults reported elevated risk of developing psychological problems following their transition into adulthood. CTBI survivors reported greatest problems on internalizing symptoms such as depression, anxiety and withdrawal. Social implications – Despite the reported psychological symptoms, the survivors of CTBI did not report more social problems than their peers. Further research is needed to identify long-term social and psychological problems so that optimal intervention may be provided. Originality/value – This is the first perspective longitudinal study investigating the young adults perspective of their long-term psychosocial outcomes following CTBI.

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A Live Video Mind-Body Treatment to Prevent Persistent Symptoms Following Mild Traumatic Brain Injury: Protocol for a Mixed Methods Study (Preprint)

10.2196/preprints.25746 ◽

2020 ◽

Author(s):

Jonathan Greenberg ◽

Tanya Singh ◽

Grant L Iverson ◽

Noah D Silverberg ◽

Eric A Macklin ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Young Adults ◽

Brain Injury ◽

Mild Traumatic Brain Injury ◽

Massachusetts General Hospital ◽

Controlled Trial ◽

Phase 1 ◽

Live Video ◽

Comorbid Anxiety ◽

Persistent Symptoms

BACKGROUND Every year, approximately 42 million people sustain a mild traumatic brain injury (mTBI, also known as concussion), with particularly high rates among college-aged individuals. A substantial proportion of these people (44%-64%) develop persistent symptoms that are challenging to treat, costly, and associated with significant disability. Anxiety has emerged as a risk factor for progression from acute to persistent mTBI symptoms. OBJECTIVE This study aims to develop, adapt, and establish the feasibility of the <i>Toolkit for Optimal Recovery after Concussions</i> (TOR-C), an innovative mind-body program aimed at preventing persistent symptoms among young adults with mTBI and comorbid anxiety. Here, we describe the proposed study design, methodology, measurement, and treatment manuals. METHODS In phase 1, we will conduct individual, live video qualitative interviews (up to n=20) with college-aged individuals with mTBI and comorbid anxiety to inform adaptation of the intervention and study procedures. In phase 2, an open pilot of the live video TOR-C (n=5) with exit interviews will be conducted to explore the initial feasibility, acceptability, and credibility of the program and to refine the study procedures. Phase 3 will involve conducting a feasibility randomized controlled trial (N=50) of the TOR-C versus a health education control (Health Enhancement for Concussions; HE-C), both delivered via live video, to establish feasibility of recruitment procedures (screening, eligibility, and enrollment) and data collection; feasibility, credibility, and acceptability of the live video TOR-C and HE-C (adherence, retention, fidelity, and satisfaction) following prespecified benchmarks; and a signal of improvement in outcomes. RESULTS Phase 1 of the study has been approved by the Massachusetts General Hospital Institutional Review Board. Study completion is anticipated by early 2025. CONCLUSIONS We will develop and test the first mind-body intervention focused on prevention of persistent symptoms following mTBI in young adults with comorbid anxiety problems. This will allow us to establish feasibility markers in postconcussive symptoms, anxiety, disability, and fear avoidance to inform a future efficacy trial of the TOR-C versus HE-C. INTERNATIONAL REGISTERED REPORT PRR1-10.2196/25746

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The Nature of Permanent Post-concussion Symptoms after Mild Traumatic Brain Injury

Brain Impairment ◽

10.1017/brimp.2013.17 ◽

2013 ◽

Vol 14 (2) ◽

pp. 235-242 ◽

Cited By ~ 8

Author(s):

Nigel S. King ◽

Simon Kirwilliam

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Mild Traumatic Brain Injury ◽

Post Injury ◽

Factors Affecting ◽

Wide Range ◽

Mean Time ◽

Poor Concentration ◽

Do So

Objective: Very few studies have examined permanent post-concussion symptoms (PCSs) after mild traumatic brain injury (MTBI). None have reported the nature of such symptoms. Our recent study was the first to report on a wide range of factors affecting PCSs in a representative sample of such patients. This paper presents the frequencies of the different PCSs experienced by this group and compares them with PCSs at earlier stages post injury.Method: One hundred consecutively referred patients to a Community Head Injury Service in Buckinghamshire, UK, for the treatment of long-term PCSs after MTBI were invited to participate in the original study. Those consenting to do so (n = 24, mean time post injury = 6.9 years) completed a Rivermead Post Concussion Symptoms Questionnaire. The frequency of the types of symptoms reported is presented. These are then contrasted with comparable PCS presentations at 7–10 days and 6 months post injury from two other studies.Results: Fatigue was reported by all long-term patients. Poor concentration, sleep disturbance, taking longer to think and irritability were the other most frequently endorsed permanent symptoms. The least reported were blurred/double vision, photophobia, nausea, headache and dizziness. A similar pattern was present in those at earlier stages post injury.Conclusions: The most common permanent PCSs may be those best conceptualised as the more cognitively and emotionally based symptoms, and the least common the more somatically based ones. There may be some consistency in the nature of PCSs reported over time.

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Saccadic Eye Movements in Mild Traumatic Brain Injury: A Pilot Study OPEN ACCESS

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques ◽

10.1017/s0317167100016279 ◽

2014 ◽

Vol 41 (1) ◽

pp. 58-65 ◽

Cited By ~ 15

Author(s):

Sarah J. Mullen ◽

Yeni H. Yücel ◽

Michael Cusimano ◽

Tom A. Schweizer ◽

Anton Oentoro ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Eye Movements ◽

Brain Injury ◽

Pilot Study ◽

Mild Traumatic Brain Injury ◽

Neuropsychological Testing ◽

Saccadic Eye Movements ◽

Post Injury ◽

Persistent Symptoms

Objective:To investigate whether repeat saccadic reaction time (SRT) measurements using a portable saccadometer is useful to monitor patients with mild traumatic brain injury (mTBI).Methods:Seven patients with newly-diagnosed mTBI and five agematched controls were prospectively recruited from an emergency Department. Saccadic eye movements, symptom self-reporting and neuropsychological tests were performed within one week of injury and again at follow-up three weeks post-injury. Control patients underwent saccade recordings at similar intervals.Results:Median saccade reaction times were significantly prolonged within one week post-injury in mTBI compared to controls. At follow-up assessment there was no significant between-groups difference. Changes in median SRT between the two assessments were not statistically significant. Four of the seven mTBI patients showed significantly increased SRT at follow-up; three of the mTBI patients and all controls showed no significant change. Among the three mTBI patients with persistent decreased SRT, two experienced loss of consciousness and reported the greatest symptoms, while the third was the only subject with significant decrease in neuropsychological testing scores at both assessments.Conclusion:In three of seven mTBI patients, saccadic eye movements remained delayed within three weeks post-injury. These three patients also showed persistent symptoms or no improvement on neuropsychological testing. This pilot study using a portable saccadometer suggests that comparing SRT from three weeks post-injury to that within one week of injury may be useful for early detection of a subpopulation at risk of persistent disability from mTBI. This finding suggests that further investigation in a large study population is warranted.

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Do Mild Traumatic Brain Injury Severity Sub-classification Systems Help to Identify People Who Go on to Experience Long-Term Symptoms?

Brain Impairment ◽

10.1017/brimp.2017.11 ◽

2017 ◽

Vol 19 (2) ◽

pp. 119-132

Author(s):

Alice Theadom ◽

Suzanne Barker-Collo ◽

Andrea Greenwood ◽

Priya Parmar ◽

Kelly Jones ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Mild Traumatic Brain Injury ◽

Classification System ◽

Injury Severity ◽

Contextual Factors ◽

Classification Systems ◽

Post Injury ◽

Mild Tbi

Objective: To identify the systems available to sub-classify mild traumatic brain injury (TBI) and to determine their utility in predicting 1-year outcome.Methods: A systematic review to identify mild-TBI sub-classification systems was conducted until March 2016. The identified systems were applied to a cohort ofN= 290 adults who had experienced a mild-TBI, and who had been assessed for post-concussion symptoms 1-year post injury. ANOVAs and regression models were used to determine whether each sub-classification system could distinguish between outcomes and to explore their contribution to explaining variance in post-concussion symptoms 1-year post injury.Results: Nineteen sub-classification systems for mild-TBI met the inclusion criteria for this review. The Saal (1991) classification system significantly differentiated the experience of post-concussion symptoms in our cohort 1-year post injury (F= 2.39,p= 0.05). However, the findings did not remain significant following correction for multiple comparisons and inclusion of socio-demographic and contextual factors in the regression model.Conclusions: Current sub-classification systems fail to explain much of the variance in post-concussion symptoms 1 year following mild-TBI. Further research is needed to identify the factors (including socio-demographic and contextual factors) to determine, who may be at risk of developing persistent post-concussion symptoms.

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EMDR Treatment for Persistent Post Concussion Symptoms Following Mild Traumatic Brain Injury: A Case Study

Journal of EMDR Practice and Research ◽

10.1891/emdr-d-21-00015 ◽

2021 ◽

pp. EMDR-D-21-00015

Author(s):

Phil S. Moore

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Mild Traumatic Brain Injury ◽

Road Traffic ◽

Behavioral Therapy ◽

Single Case ◽

Psychological Symptom ◽

Persistent Symptoms

The majority of people who experience mild Traumatic Brain Injury (mTBI) have a healthy recovery, where initial somatic, cognitive, psychological, and behavioral mTBI-related symptoms resolve naturally within hours or days. Unfortunately, a significant minority of people unfortunately develop persistent symptoms referred to as persistent Post Concussion Syndrome (pPCS), often causing severe long-term reduction in wellbeing and daily function. Psychological and neuropsychological treatments are typically limited to antidepressants, psycho-education on mTBI and pPCS, basic neuro-rehabilitative cognitive compensatory strategies, traditional Cognitive Behavioral Therapy, or no treatment at all. This paper discusses a single case study which demonstrates how Eye Movement Desensitization Reprocessing (EMDR) therapy might provide psychological improvement in clients who sustain mTBI who develop pPCS. The case example describes a 57-year-old man who sustained a mTBI from a serious road traffic collision as a pedestrian, and who developed pPCS. Treatment included nine, 1.5-hour EMDR sessions across a 5-month period (1st being an assessment). Measures of psychological symptom change and client feedback were taken at pretreatment, midtreatment, posttreatment, and aftertreatment had ceased to gauge long-term status. Measures were taken at 18-month follow-up and 4-year review (which followed litigation settlement). The novel viability for the application of EMDR for this client group is discussed.

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Prognostic Factors for Persistent Symptoms in Adults With Mild Traumatic Brain Injury: Protocol for an Overview of Systematic Reviews

10.21203/rs.3.rs-72770/v1 ◽

2020 ◽

Author(s):

Julien Déry ◽

Élaine De Guise ◽

Marie-Eve Lamontagne

Keyword(s):

Traumatic Brain Injury ◽

Prognostic Factors ◽

Brain Injury ◽

Mild Traumatic Brain Injury ◽

Systematic Reviews ◽

Clinical Decision Making ◽

Public Health Problem ◽

Persistent Symptoms ◽

Overview Of Systematic Reviews

Abstract Background: Mild traumatic brain injury (mTBI) is an increasing public health problem, and persistent symptoms following mTBI have several functional consequences. Understanding the prognosis of a condition is an important component of clinical decision-making and can help to guide prevention of long-term disabilities and to intervene with mTBI patients. Prognosis of chronic symptoms in mTBI has stimulated several empirical primary research papers and many systematic reviews. We aim to integrate these heterogenous factors into a model in order to have a better understanding of such prognostic factors on the development of chronic symptoms.Methods: We will conduct an overview of systematic reviews following steps described in the Cochrane Handbook. We will search for systematic reviews in databases using a search strategy to include articles that review evidence about prognosis of persistent symptoms after an mTBI in the adult population. Two reviewers will independently screen all references and then select eligible reviews based on eligibility criteria. Any disagreements will be discussed by the two reviewers and if consensus is not reached, we will consult a third reviewer. A data extraction grid will be used to extract relevant information. The risk of bias included will be rated using ROBIS tool. Data will be synthesized into a comprehensive conceptual map in order to have a better understanding of the predictor factors that could impact the recovery after mTBI.Discussion: Results will help multiple stakeholders, such as clinicians and rehabilitation program managers, to understand the prognosis of long-term consequences following an mTBI. It could guide stakeholders to recognize predisposing, precipitating, and perpetuating factors of their patients and to invest their time and resources on patients needing the most.Systematic review registration: PROSPERO CRD42020176676

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Trehalose Enhances Long-term Recovery in 18-month-old Mice by Increasing Autophagy after Traumatic Brain Injury

Innovation in Aging ◽

10.1093/geroni/igab046.3538 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. 994-995

Author(s):

Rodney Ritzel ◽

Yun Li ◽

Jordan Carter ◽

Niaz Khan ◽

Junyun He ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Therapeutic Strategy ◽

Enhanced Recovery ◽

Critical Role ◽

Post Injury ◽

Recovery Potential ◽

Underlying Mechanisms ◽

Microglial Response

Abstract Older patients with traumatic brain injury (TBI) have higher mortality and poorer long-term outlook compared to younger individuals. This may contribute to the assumption that aggressive management of geriatric TBI is futile. The present study examined the long-term recovery potential and underlying mechanisms associated with advanced age in male C57BL/6 mice using a controlled cortical impact model of TBI. Older (18 mos) mice had higher mortality compared to younger (10 wks) mice at 12 weeks post-injury. While aging alone had a profound impact on behavioral ability, the recovery slope in some, but not all, neurobehavioral tests was relatively similar between young and old injured mice. NanoString analysis identified several age- and injury-specific genes that were differentially expressed, including those involved with the complement, phagocytosis, and autophagy pathways. Flow cytometry demonstrated dysregulation of autophagic function in microglia with normal aging which was exacerbated after TBI. Given the critical role for autophagy in promoting the cellular degradation of cytoplasmic materials, we reasoned that treatment with the autophagic inducer, trehalose, may be a viable therapeutic strategy. Trehalose was administered in the drinking water (3%) starting at d1 post-injury up to 8 weeks. Older TBI mice treated with trehalose exhibited either delayed deficits or enhanced recovery in cognitive and motor tasks. Trehalose modified expression of autophagy markers and reprogrammed the microglial response to TBI. Our data indicate that microglia undergo chronic changes in autophagic regulation that are associated with poor outcome. Boosting autophagy may be a promising therapeutic strategy for older TBI patients.

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