Journal of neurotraumaPub Date : 2024-10-01Epub Date: 2024-06-27DOI: 10.1089/neu.2024.0027
Sandro M Krieg, Maximilian Schwendner, Leonie Kram, Haosu Zhang, Raimunde Liang, Chiara Negwer, Bernhard Meyer
{"title":"Transcranial Transmission Ultrasound for Reliable Noninvasive Exclusion of Intracranial Hypertension in Traumatic Brain Injury Patients: A Proof of Concept Study.","authors":"Sandro M Krieg, Maximilian Schwendner, Leonie Kram, Haosu Zhang, Raimunde Liang, Chiara Negwer, Bernhard Meyer","doi":"10.1089/neu.2024.0027","DOIUrl":"10.1089/neu.2024.0027","url":null,"abstract":"<p><p>For many years, noninvasive methods to measure intracranial pressure (ICP) have been unsuccessful. However, such methods are crucial for the assessment of patients with nonpenetrating traumatic brain injuries (TBIs) who are unconscious. In this study, we explored the use of transcranial transmission ultrasound (TTUS) to gather experimental data through brain pulsatility, assessing its effectiveness in detecting high ICP using machine learning analysis. We included patients with severe TBI under invasive ICP monitoring in our intensive care unit. During periods of both normal and elevated ICP, we simultaneously recorded ICP, arterial blood pressure, heart rate, and TTUS measurements. Our classification model was based on data from 9 patients, encompassing 387 instances of elevated ICP (>15 mmHg) and 345 instances of normal ICP (<10 mmHg), and validated through a leave-one-subject-out method. The study, conducted from October 2021 to October 2022, involved 25 patients with an average age of 61.6 ± 17.6 years, producing 279 datasets with an average ICP of 11.3 mmHg (1st quartile 6.1 mmHg; 3rd quartile 14.8 mmHg). The automated TTUS analysis effectively identified ICP values over 15 mmHg with 100% sensitivity and 47% specificity. It achieved a 100% negative predictive value and a 14% positive predictive value. This suggests that TTUS can accurately rule out high ICP above 15 mmHg in TBI patients, indicating patients who may need immediate imaging or intervention. These promising results, if confirmed and expanded in larger studies, could lead to the first reliable, noninvasive screening tool for detecting elevated ICP.</p>","PeriodicalId":16512,"journal":{"name":"Journal of neurotrauma","volume":" ","pages":"2298-2306"},"PeriodicalIF":3.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141236979","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Journal of neurotraumaPub Date : 2024-10-01Epub Date: 2024-07-13DOI: 10.1089/neu.2023.0550
Nathan E Cook, Alicia Kissinger-Knox, Ila A Iverson, Katie Stephenson, Marc A Norman, Amy A Hunter, Altaf Saadi, Grant L Iverson
{"title":"Social Determinants of Health and Health Equity in the Treatment and Rehabilitation of Sport-Related Concussion: A Content Analysis of Intervention Research and Call-To-Action.","authors":"Nathan E Cook, Alicia Kissinger-Knox, Ila A Iverson, Katie Stephenson, Marc A Norman, Amy A Hunter, Altaf Saadi, Grant L Iverson","doi":"10.1089/neu.2023.0550","DOIUrl":"10.1089/neu.2023.0550","url":null,"abstract":"<p><p>This review was designed to (1) determine the extent to which the clinical science on sport-related concussion treatment and rehabilitation has considered social determinants of health (SDoH) or health equity and (2) offer recommendations to enhance the incorporation of SDoH and health equity in concussion treatment research and clinical care. The Concussion in Sport Group consensus statement (2023) was informed by two systematic reviews examining prescribed rest or exercise following concussion and targeted interventions to facilitate concussion recovery. We examined 31 studies, including 2,698 participants, from those two reviews. Race (<i>k</i> = 6; 19.4%) and ethnicity (<i>k</i> = 4; 12.9%) of the study samples were usually not reported. Four studies examined ethnicity (i.e., Hispanic), exclusively as a demographic category. Five studies (16.1%) examined race as a demographic category. Three studies (9.7%) examined socioeconomic status (SES; measured as household income) as a demographic category/sample descriptor and one study (3.2%) examined SES in-depth, by testing whether the treatment and control groups differed by SES. Five studies examined an SDoH domain in a descriptive manner and four studies in an inferential/intentional manner. No study mentioned SDoH, health equity, or disparities by name. Many studies (61.3%) excluded participants based on demographic, sociocultural, or health factors, primarily due to language proficiency. The new consensus statement includes recommendations for concussion treatment and rehabilitation that rely on an evidence base that has not included SDoH or studies addressing health equity. Researchers are encouraged to design treatment and rehabilitation studies that focus specifically on underrepresented groups to determine if they have specific and unique treatment and rehabilitation needs, whether certain practical modifications to treatment protocols might be necessary, and whether completion rates and treatment adherence and response are similar.</p>","PeriodicalId":16512,"journal":{"name":"Journal of neurotrauma","volume":" ","pages":"2201-2218"},"PeriodicalIF":4.3,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11564856/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140957902","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Journal of neurotraumaPub Date : 2024-10-01Epub Date: 2024-04-05DOI: 10.1089/neu.2023.0543
Carrie Esopenko, Divya Jain, Shambhu Prasad Adhikari, Kristen Dams-O'Connor, Michael Ellis, Halina Lin Haag, Elizabeth S Hovenden, Finian Keleher, Inga K Koerte, Hannah M Lindsey, Amy D Marshall, Karen Mason, J Scott McNally, Deleene S Menefee, Tricia L Merkley, Emma N Read, Philine Rojcyk, Sandy R Shultz, Mujun Sun, Danielle Toccalino, Eve M Valera, Paul van Donkelaar, Cheryl Wellington, Elisabeth A Wilde
{"title":"Intimate Partner Violence-Related Brain Injury: Unmasking and Addressing the Gaps.","authors":"Carrie Esopenko, Divya Jain, Shambhu Prasad Adhikari, Kristen Dams-O'Connor, Michael Ellis, Halina Lin Haag, Elizabeth S Hovenden, Finian Keleher, Inga K Koerte, Hannah M Lindsey, Amy D Marshall, Karen Mason, J Scott McNally, Deleene S Menefee, Tricia L Merkley, Emma N Read, Philine Rojcyk, Sandy R Shultz, Mujun Sun, Danielle Toccalino, Eve M Valera, Paul van Donkelaar, Cheryl Wellington, Elisabeth A Wilde","doi":"10.1089/neu.2023.0543","DOIUrl":"10.1089/neu.2023.0543","url":null,"abstract":"<p><p>Intimate partner violence (IPV) is a significant, global public health concern. Women, individuals with historically underrepresented identities, and disabilities are at high risk for IPV and tend to experience severe injuries. There has been growing concern about the risk of exposure to IPV-related head trauma, resulting in IPV-related brain injury (IPV-BI), and its health consequences. Past work suggests that a significant proportion of women exposed to IPV experience IPV-BI, likely representing a distinct phenotype compared with BI of other etiologies. An IPV-BI often co-occurs with psychological trauma and mental health complaints, leading to unique issues related to identifying, prognosticating, and managing IPV-BI outcomes. The goal of this review is to identify important gaps in research and clinical practice in IPV-BI and suggest potential solutions to address them. We summarize IPV research in five key priority areas: (1) unique considerations for IPV-BI study design; (2) understanding non-fatal strangulation as a form of BI; (3) identifying objective biomarkers of IPV-BI; (4) consideration of the chronicity, cumulative and late effects of IPV-BI; and (5) BI as a risk factor for IPV engagement. Our review concludes with a call to action to help investigators develop ecologically valid research studies addressing the identified clinical-research knowledge gaps and strategies to improve care in individuals exposed to IPV-BI. By reducing the current gaps and answering these calls to action, we will approach IPV-BI in a trauma-informed manner, ultimately improving outcomes and quality of life for those impacted by IPV-BI.</p>","PeriodicalId":16512,"journal":{"name":"Journal of neurotrauma","volume":" ","pages":"2219-2237"},"PeriodicalIF":4.3,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11564844/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139697736","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jared A Rowland, Jennifer R Stapleton-Kotloski, Dwayne W Godwin, Craig A Hamilton, Sarah L Martindale
{"title":"The Functional Connectome and Long-Term Symptom Presentation Associated With Mild Traumatic Brain Injury and Blast Exposure in Combat Veterans.","authors":"Jared A Rowland, Jennifer R Stapleton-Kotloski, Dwayne W Godwin, Craig A Hamilton, Sarah L Martindale","doi":"10.1089/neu.2023.0315","DOIUrl":"10.1089/neu.2023.0315","url":null,"abstract":"<p><p>Mild traumatic brain injury (TBI) sustained in a deployment environment (deployment TBI) can be associated with increased severity of long-term symptom presentation, despite the general expectation of full recovery from a single mild TBI. The heterogeneity in the effects of deployment TBI on the brain can be difficult for a case-control design to capture. The functional connectome of the brain is an approach robust to heterogeneity that allows global measurement of effects using a common set of outcomes. The present study evaluates how differences in the functional connectome relate to remote symptom presentation following combat deployment and determines if deployment TBI, blast exposure, or post-traumatic stress disorder (PTSD) are associated with these neurological differences. Participants included 181 Iraq and Afghanistan combat-exposed Veterans, approximately 9.4 years since deployment. Structured clinical interviews provided diagnoses and characterizations of TBI, blast exposure, and PTSD. Self-report measures provided characterization of long-term symptoms (psychiatric, behavioral health, and quality of life). Resting-state magnetoencephalography was used to characterize the functional connectome of the brain individually for each participant. Linear regression identified factors contributing to symptom presentation including relevant covariates, connectome metrics, deployment TBI, blast exposure PTSD, and conditional relationships. Results identified unique contributions of aspects of the connectome to symptom presentation. Furthermore, several conditional relationships were identified, demonstrating that the connectome was related to outcomes in the presence of only deployment-related TBI (including blast-related TBI, primary blast TBI, and blast exposure). No conditional relationships were identified for PTSD; however, the main effect of PTSD on symptom presentation was significant for all models. These results demonstrate that the connectome captures aspects of brain function relevant to long-term symptom presentation, highlighting that deployment-related TBI influences symptom outcomes through a neurological pathway. These findings demonstrate that changes in the functional connectome associated with deployment-related TBI are relevant to symptom presentation over a decade past the injury event, providing a clear demonstration of a brain-based mechanism of influence.</p>","PeriodicalId":16512,"journal":{"name":"Journal of neurotrauma","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141988162","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Reid A Syrydiuk, Adrian J Boltz, Landon B Lempke, Jaclyn B Caccese, Thomas W McAllister, Michael A McCrea, Paul F Pasquina, Steven P Broglio
{"title":"SCAT Symptom Evolution in the Acute Concussion Phase: Findings from the NCAA-DoD CARE Consortium.","authors":"Reid A Syrydiuk, Adrian J Boltz, Landon B Lempke, Jaclyn B Caccese, Thomas W McAllister, Michael A McCrea, Paul F Pasquina, Steven P Broglio","doi":"10.1089/neu.2024.0243","DOIUrl":"10.1089/neu.2024.0243","url":null,"abstract":"<p><p>The Sport Concussion Assessment Tool (SCAT) is the most widely used tool following sport-related concussion (SRC). Initial SCAT symptom burden is a strong predictor of recovery in collegiate athletes; however, it is unknown if symptom presentation varies within the acute (<48 h) post-SRC phase. The purpose of this cohort study was to examine acute SRC symptom presentation among the National Collegiate Athletic Association (NCAA) athletes. Concussed NCAA varsity athletes (<i>n</i> = 1,780) from 30 universities across the United States, which participated in the Concussion Assessment, Research, and Education (CARE) Consortium, were included. Time of injury occurrence and SCAT administration data were recorded, from which time-to-SCAT (hours, continuous) was calculated. The main outcome was SCAT total symptom severity [(TSS), 0-126]. Multivariable negative binomial regression was used to examine the association between time (hours) since injury and TSS. Covariates included sex, previous concussion, sport contact level, amnesia/loss of consciousness, immediate reporting of injury, and injury situation. A random effect (person level) accounted for multiple assessments. TSS score ratios (SR) with associated 95% confidence intervals (CI) were provided. The SCAT was administered an average of 14 (25th-75th percentile: 1.2-24) hours post-SRC, and average TSS was 27.35 ± 21.28 across all participants. Time-to-SCAT was associated with a 1% decrease in TSS after adjusting for covariate effects (SR: 0.99, 95% CI: 0.99-0.99, <i>p</i> < 0.001). Overall, we observed a small, but significant decrease in TSS with each hour post-SRC. Assessing a concussed athlete once in the acute phase will likely provide a sufficient sense of their symptomatic well-being, as measures did not fluctuate dramatically. Future research should aim to examine how acute symptom evolution influences recovery metrics.</p>","PeriodicalId":16512,"journal":{"name":"Journal of neurotrauma","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142108278","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Marija Markicevic, Francesca Mandino, Takuya Toyonaga, Zhengxin Cai, Arman Fesharaki-Zadeh, Xilin Shen, Stephen M Strittmatter, Evelyn M R Lake
{"title":"Repetitive Mild Closed-Head Injury Induced Synapse Loss and Increased Local BOLD-fMRI Signal Homogeneity.","authors":"Marija Markicevic, Francesca Mandino, Takuya Toyonaga, Zhengxin Cai, Arman Fesharaki-Zadeh, Xilin Shen, Stephen M Strittmatter, Evelyn M R Lake","doi":"10.1089/neu.2024.0095","DOIUrl":"10.1089/neu.2024.0095","url":null,"abstract":"<p><p>Repeated mild head injuries due to sports, or domestic violence and military service are increasingly linked to debilitating symptoms in the long term. Although symptoms may take decades to manifest, potentially treatable neurobiological alterations must begin shortly after injury. Better means to diagnose and treat traumatic brain injuries requires an improved understanding of the mechanisms underlying progression and means through which they can be measured. Here, we employ a repetitive mild traumatic brain injury (rmTBI) and chronic variable stress mouse model to investigate emergent structural and functional brain abnormalities. Brain imaging is achieved with [<sup>18</sup>F]SynVesT-1 positron emission tomography, with the synaptic vesicle glycoprotein 2A ligand marking synapse density and BOLD (blood-oxygen-level-dependent) functional magnetic resonance imaging (fMRI). Animals were scanned six weeks after concluding rmTBI/Stress procedures. Injured mice showed widespread <i>decreases</i> in synaptic density coupled with an i<i>ncrease</i> in local BOLD-fMRI synchrony detected as regional homogeneity. Injury-affected regions with <i>higher</i> synapse density showed a <i>greater increase</i> in fMRI regional homogeneity. Taken together, these observations may reflect compensatory mechanisms following injury. Multimodal studies are needed to provide deeper insights into these observations.</p>","PeriodicalId":16512,"journal":{"name":"Journal of neurotrauma","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141878898","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Editorial commentary on NEU-2023-0576.R2, \"Acute Development of Traumatic Intracranial Aneurysms Following Civilian Gunshot Wounds to the Head\".","authors":"Rocco Armonda,Andrii Sirko","doi":"10.1089/neu.2024.0451","DOIUrl":"https://doi.org/10.1089/neu.2024.0451","url":null,"abstract":"","PeriodicalId":16512,"journal":{"name":"Journal of neurotrauma","volume":"27 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142266232","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
John D Corrigan,Flora McConnell Hammond,Angelle Sander,Kurt Kroenke
{"title":"Recognition of Traumatic Brain Injury as a Chronic Condition: A Commentary.","authors":"John D Corrigan,Flora McConnell Hammond,Angelle Sander,Kurt Kroenke","doi":"10.1089/neu.2024.0356","DOIUrl":"https://doi.org/10.1089/neu.2024.0356","url":null,"abstract":"Many clinicians believe that residual impairments due to traumatic brain injury (TBI) are static once initial recovery has plateaued. That is, the effcts of the injury are not expected to change significantly over the remainder of a person's life. This assumption has been called into question by several independent longitudinal studies showing that the long-term course of TBI may be better characterized as dynamic rather than static. Healthcare services that recognize brain injury as a chronic condition would encourage education on self-management to improve or protect health, as well as proactive healthcare that anticipates common co-morbidities. Those who have had a TBI would be encouraged to engage in lifestyles that optimize wellness. Almost all developed countries commit additional public health resources to addressing chronic conditions. In the United States, specific benefits are available from health insurance plans, particularly Medicare and Medicaid, for persons experiencing chronic health conditions. Potentially the most important benefit would derive from healthcare practitioners becoming aware of the dynamic nature of chronic brain injury and thus being more attentive to how their patients could be better served to optimize improvement and minimize decline. Recognition of TBI as a chronic condition would not only focus more resources on problems assoiciated with living with brain injury, but would enhance both the public's and professionals' awareness of how to optimize the health and well-being of persons living with the effects of TBI.","PeriodicalId":16512,"journal":{"name":"Journal of neurotrauma","volume":"50 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142266233","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Natasha L Wilkins,Daniel Medina Aguinaga,Robert Hoey,Jason Fell,Susan J Harkema,Charles H Hubscher
{"title":"Bladder responses to thoracolumbar epidural stimulation in female urethane-anesthetized rats with graded contusion spinal cord injuries.","authors":"Natasha L Wilkins,Daniel Medina Aguinaga,Robert Hoey,Jason Fell,Susan J Harkema,Charles H Hubscher","doi":"10.1089/neu.2024.0209","DOIUrl":"https://doi.org/10.1089/neu.2024.0209","url":null,"abstract":"Spinal cord epidural stimulation (scES) is a therapeutic option that promotes functional improvements in sensory, motor, and autonomic functions following spinal cord injury (SCI). Previous scES mapping studies targeting the lower urinary tract (LUT) in rats demonstrated functional response variability based upon lumbosacral level, parameters used, extent of injury (spinally intact versus chronic anatomically complete spinal transections), and sex. In the current study, female rats with clinically relevant graded incomplete T9 contusion injuries were mapped with scES at 60 days-post-injury at three spinal levels (T13, L3, L6) with a novel miniature 15-electrode array designed to deliver optimal specificity. The results obtained during bladder fill and void cycles conducted under urethane anesthesia indicate frequency dependent sub-motor threshold effects on LUT function with a single row of electrodes positioned across the full medio-lateral extent of the dorsal cord. The findings of improved storage and emptying, represented by significantly longer inter-contractile intervals with T13 scES and L3 scES and by a significantly increased estimated void efficiency with L6 scES, respectively, is consistent with previous studies using intact and chronic complete transected male and female rats. The data support the efficacy of selective spinal network stimulation to drive functionally relevant networks for storage versus emptying phases of the urinary cycle. The current findings further demonstrate the translational promise of scES for SCI individuals with LUT dysfunctions, regardless of injury severity.","PeriodicalId":16512,"journal":{"name":"Journal of neurotrauma","volume":"13 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142266237","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Savvina Prapiadou,Ernst Mayerhofer,Marios K Georgakis,Mart Kals,Farid Radmanesh,Saef Izzy,Sylvia Richardson,David O Okonkwo,Ava M Puccio,Nancy Temkin,Aarno Palotie,Samuli Ripatti,Ramon Diaz-Arrastia,Murray B Stein,Geoffrey T Manley,David Menon,Jonathan Rosand,Livia Parodi,Christopher D Anderson
{"title":"Exploring synaptic pathways in traumatic brain injury: a cross-phenotype genomics approach.","authors":"Savvina Prapiadou,Ernst Mayerhofer,Marios K Georgakis,Mart Kals,Farid Radmanesh,Saef Izzy,Sylvia Richardson,David O Okonkwo,Ava M Puccio,Nancy Temkin,Aarno Palotie,Samuli Ripatti,Ramon Diaz-Arrastia,Murray B Stein,Geoffrey T Manley,David Menon,Jonathan Rosand,Livia Parodi,Christopher D Anderson","doi":"10.1089/neu.2024.0153","DOIUrl":"https://doi.org/10.1089/neu.2024.0153","url":null,"abstract":"Traumatic brain injury (TBI), a global leading cause of mortality and disability, lacks effective treatments to enhance recovery. Synaptic remodeling has been postulated as one mechanism that influences outcomes after TBI. We sought to investigate whether common mechanisms affecting synapse maintenance are shared between TBI and other neuropsychiatric conditions using pathway enrichment tools and genome-wide genotype data, with the goal of highlighting novel treatment targets. We leveraged an integrative approach, combining data from Genome-Wide Association Studies (GWAS) with pathway and gene-set enrichment analyses. Literature review-based and Reactome database-driven approaches were combined to identify synapse-related pathways of interest in TBI outcome, and to assess for shared associations with conditions in which synapse-related pathobiological mechanisms have been implicated, including Alzheimer's disease (AD), schizophrenia (SCZ), major depressive disorder (MDD), post-traumatic stress disorder (PTSD), attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). Gene and pathway-level enrichment analyses were conducted using MAGMA and its extensions, e- and H-MAGMA, followed by Mendelian Randomization (MR) to investigate potential causal associations. Of the 98 pathways tested, 32 were significantly enriched in the included conditions. In TBI outcome, we identified significant enrichment in five pathways: \"Serotonin clearance from the synaptic cleft\" (p-value = 0.0001), \"Presynaptic nicotinic acetylcholine receptors\" (p-value = 0.0003), \"Postsynaptic nicotinic acetylcholine receptors\" (p-value = 0.0003), \"Highly sodium permeable postsynaptic acetylcholine nicotinic receptors\" (p-value = 0.0001), and \"Acetylcholine binding and downstream events\" pathways (p-value = 0.0003). These associations highlight potential involvement of the cholinergic and serotonergic systems in post-TBI recovery. Three of those pathways were shared between TBI and schizophrenia, suggesting possible pathophysiologic commonalities. In this study we utilize comparative and integrative genomic approaches across brain conditions that share synaptic mechanisms to explore the pathophysiology of TBI outcome. Our results implicate associations between TBI outcome and synaptic pathways as well as pathobiologic overlap with other neuropsychiatric diseases.","PeriodicalId":16512,"journal":{"name":"Journal of neurotrauma","volume":"76 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142266234","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}