About

Akiva S. Cohen, PhD, is a Research Professor of Anesthesiology and Critical Care at the University of Pennsylvania's Perelman School of Medicine and an Assistant Investigator at the Joseph Stokes, Jr. Research Institute at Children's Hospital of Philadelphia. He is a member of the Institute of Neurological Sciences at the University of Pennsylvania. His research focuses on the fundamental cellular and molecular mechanisms underlying cognitive impairments associated with traumatic brain injury, with a primary concern for alterations in neuronal excitability within the limbic system of the brain, which plays a key role in higher cognitive functions such as learning and memory. Dr. Cohen's work incorporates a variety of techniques including intracellular and extracellular recording, whole-cell patch-clamp recording, immunocytochemistry, biochemistry, and calcium fluorescence, among others. His studies aim to understand injury-induced alterations in neuronal circuits and synaptic function, with the goal of elucidating mechanisms that cause injury-induced cognitive deficits. His research also explores potential therapeutic approaches to ameliorate cognitive dysfunction in patients with traumatic brain injury, contributing valuable insights into the cellular and molecular changes following brain injury.

Research topics

• Internal medicine
• Medicine
• Chemistry
• Psychiatry
• Psychology
• Surgery
• Neuroscience

Selected publications

• Mild Traumatic Brain Injury Impairs Fear Extinction and Network Excitability in the Infralimbic Cortex

  Journal of Neurotrauma · 2025-05-22 · 1 citations

  articleSenior author

  Traumatic brain injury (TBI) is a leading cause of morbidity and disability, with mild TBI (concussions) representing over 80% of cases. Although often considered benign, mild TBI is associated with persistent neuropsychiatric conditions, including post-traumatic stress disorder, anxiety, and depression. A hallmark of these conditions is impaired fear extinction (FE), the process by which learned fear responses are inhibited in safe contexts. This dysfunction contributes to maladaptive fear expression and is linked to altered neurocircuitry, particularly in the infralimbic cortex (IL), a key region in FE. Despite extensive evidence of impaired FE in patients with mild TBI and animal models, the specific mechanisms underlying this deficit remain poorly understood. This study aimed to address this gap by combining cued-FE behavior, local field potential recordings, and whole-cell patch-clamp techniques to investigate how mild TBI affects IL network activity and excitability in a mouse model of TBI. Our results demonstrate that mild lateral fluid percussion injury significantly impairs FE memory, as evidenced by an elevated cued-fear response during extinction testing 10 days post-injury. Field potential recordings revealed decreased activation of the IL network in both layers II/III and V, which was consistent with the observed behavioral deficits. Further analysis of synaptic physiology revealed an imbalance in excitatory and inhibitory neurotransmission (E/I imbalance) in the IL, characterized by reduced excitatory input and enhanced inhibitory input to neurons in both layers. Moreover, intrinsic excitability was altered in IL neurons after mild TBI. This study provides novel insights into how mild TBI disrupts the neurocircuitry underlying FE, specifically by suppressing IL excitability. These results highlight the importance of understanding the mechanistic disruptions in IL activity for developing therapeutic strategies to address fear-based disorders in patients with mild TBI.

  PublisherDOI

• SmART-TBI: A fully remote protocol for a randomized placebo-controlled double-blinded clinical trial for a dietary supplement to improve sleep in Veterans

  medRxiv · 2025-02-25

  preprintOpen access

  glutamate/GABA synthesis in the CNS, restored normal sleep-wake patterns and improved cognitive function in rodents. Our recent pilot work in humans showed preliminary feasibility/acceptability and limited efficacy for BCAAs to improve sleep in Veterans with TBI. However, these pilot data were limited in sample size, treatment dosages/duration, and therefore unable to establish efficacy or provide insight into dosing/duration parameters. The present study, SmART-TBI (supplementation with amino acid rehabilitative therapy in TBI: NCT04603443), represents a fully powered, placebo-controlled, double-masked randomized clinical trial (target n=120). Covariate adaptive randomization controlling for age, sex, TBI recency, pain, depression, and PTSD, allocated participants 1:1:1:1 to four groups comprising 3 BCAA doses ('high' 30g b.i.d.; 'medium' 20g b.i.d.; and 'low' 10g b.i.d.) and one placebo-control (rice protein, 10g b.i.d.). Outcome measures were assessed following a 2-week baseline period; after 4 weeks, 8 weeks, and 12 weeks of intervention; and after 4 weeks and 12 weeks post-intervention. Primary outcomes were feasibility and acceptability of the protocol. Exploratory outcomes included preliminary efficacy in improving sleep, assessed via a combination of actigraphy, mattress-sensors, sleep diaries (all analyzed daily), as well as pre- and post-BCAA overnight polysomnography for sleep staging, cognition, and quality of life measures. Results indicated high feasibility and acceptability of this fully remote protocol among Veterans with TBI.

  PublisherOA PDFDOI

• 1290 Amino Acid Supplementation Improves Sleep in Older Adults with Traumatic Brain Injury at Risk for Neurodegeneration

  SLEEP · 2025-05-01

  articleOpen access

  Abstract Introduction Older adults with a history of traumatic brain injury (TBI) are more likely to experience chronic sleep disturbances and cognitive impairments, elevating their risk of future neurodegeneration. Interventions to mitigate sleep and cognitive disturbances are critically needed. Our prior preclinical work demonstrated dietary supplementation with branched chain amino acids (BCAA: leucine, isoleucine, and valine), precursors to de novo glutamate production, restore orexin/hypocretin neuron function, sleep-wake regulation, and memory in rodent models of TBI. The present study aims to translate this potential therapeutic approach to humans with a history of TBI. Methods Veterans with TBI (n=157) were recruited (135 eligible, 115 enrolled, with 106 allocated 1:1:1:1), in this double-blind, placebo-controlled randomized clinical trial comparing dietary BCAA supplementation at three dosages (high: 60g/day, medium: 40g/day, and low: 20g/day) with placebo (rice protein, 60g/day) for 12-weeks. Primary outcomes included feasibility/acceptability metrics, sleep (self-report, wrist-based actigraphy, overnight polysomnography) and neuropsychological testing, which were collected at baseline and 4-, 8-, and 12-weeks of intervention. Follow-up questionnaire-based assessments were collected at 4 and 12-weeks post-intervention. Results Of the 106 Veterans allocated/randomized, 49 have completed data collection (13 high, 8 medium, 14 low, and 14 placebo), 29 have withdrawn, and 57 are presently active. This interim analysis considers only the 78 who have completed or withdrawn (i.e., 65% of the 120 target sample). We demonstrate overall retention of 63%, with most attrition by week 4 (15.7%; no difference across study arms). Protocol compliance was 95% for full adherence to intervention (5-7 days/week), and ~98% reported being very to extremely satisfied, with most complaints attributed to gastrointestinal discomfort. In the high dose group, pre vs. post BCAA supplementation showed improved self-reported sleep (insomnia severity index scores, 13.6±2.8 to 8.9±2.9, p< 0.05) and actigraphy measures: total sleep time (6:23±1:04 vs. 7:04±1:08 hh:mm, p< 0.05), sleep onset latency (19.5±16.1 vs. 6.0±9.1 minutes, p< 0.05), and wake-after-sleep onset (65.7±26.0 vs. 47.8±23.1 minutes, p< 0.05). Conclusion Dietary BCAA supplementation is a feasible and acceptable home-based intervention to improve sleep in older adults with a history of TBI. Ongoing work will yield effectiveness data related cognitive function, BCAA dosing and treatment duration. Support (if any) VA-BLRD-IK2-BX002712, VA-RRD-IK2RX002947, VA-CSRD-MRA-#I01-X002022

  PublisherOA PDFDOI

• Fool's gold standard? Immunoperoxidase staining with the mouse monoclonal antibody (Clone 22C11) for detecting axonal pathology after traumatic brain injury

  Frontiers in Neuroscience · 2025-06-02

  articleOpen accessSenior author

  Traumatic brain injury (TBI) is a leading cause of morbidity and mortality in the United States (Coronado et al., 2011). Pathology and functional deficits resulting from TBI vary with the mechanical insults, but a common characteristic in the experimental as well as clinical realm is diffuse axonal injury (DAI). DAI is typically inferred from hemorrhages and axonal damage in white matter tracts detected with hematoxylin and eosin (H&E) staining and Palmgren silver impregnation (Adams et al., 1982(Adams et al., , 1989)). Furthermore, DAI can be confirmed with electron microscopy (Mierzwa et al., 2015;Ziogas and Koliatsos 2018), tractography (Hayes et al., 2016;Nolan et al., 2021), NeuroSilver staining (Koliatsos et al., 2011;Xiong et al., 2023Xiong et al., , 2024) ) and transgenic labeling (Hånell et al., 2015;Xiong et al., 2023).It is hypothesized that disrupted transport in injured axons results in an accumulation of amyloid precursor protein (APP) at the sites of rupture. Using immunoperoxidase staining with a mouse monoclonal antibody (Clone 22C11) against the N-Terminus of APP, Gentleman et al (1993Gentleman et al ( , 1995) ) first demonstrated varicosities in white matter from TBI patients and interpreted them as axonal swellings. These 22C11-positive varicosities can be detected as early as 3 hours after TBI (Gentleman et al., 1993(Gentleman et al., , 1995;;Sherriff et al., 1994a, b;Graham et al., 2004;Reichard et al., 2005;Hortobágyi et al., 2007;Johnson et al., 2013Johnson et al., , 2016;;Koch et al., 2020) and remain identifiable for months or even years after the initial insult (Chen et al., 2009;Johnson et al., 2013). Based on its wide application for more than three decades, immunoperoxidase staining with 22C11 is regarded as the "Gold Standard" for detecting axonal pathology after TBI (Johnson et al., 2013(Johnson et al., , 2016)).However, the accumulation of APP in axons has never been unequivocally confirmed. Here, we summarize existing evidence that questions the specificity of 22C11 for APP and the validity of immunoperoxidase staining to reveal axonal pathology after TBI. We then provide an alternate interpretation of the observed varicosities and recommend a strategy for the accurate determination of TBI-induced neuropathology.APP is a protein that is widely expressed in the brain (Del Turco et al., 2016;Xiong et al., 2023) and plays an important role in a variety of physiological functions (Hick et al., 2015;Muller et al., 2017). Antibodies specific to APP should therefore produce immunohistochemical staining patterns consistent with the expression of the protein in healthy i.e., non-injured brains. However, previous studies demonstrated negative staining with 22C11 in brains from control patients (See Johnson et al., 2013 for a review). Moreover, 22C11-stained varicosities were typically identified with an immunoperoxidase protocol, which makes it impossible to determine if these varicosities co-localize with any specific axonal marker (Gentleman et al., 1993(Gentleman et al., , 1995;;Sherriff et al., 1994a, b;Graham et al., 2004;Reichard et al., 2005;Hortobágyi et al., 2007;Johnson et al., 2013;Koch et al., 2020). A single group (Johnson et al., 2016) did attempt double immunofluorescent staining using 22C11 and the axonal marker spectrin N-terminal fragment (SNTF). However, using a porcine model of mild TBI as well as tissue from severe brain injured humans resulted in inconsistent results; thereby, failing to provide conclusive evidence for the claimed axonal identity of 22C11-positive varicosities. In addition, while varicosities are reliably reproduced in immunoperoxidase staining, they are not visible after immunofluorescent staining with 22C11 (Xiong et al., 2023). Lastly and most importantly, 22C11 produces a similar staining pattern in wild-type and APP knockout mice (Guo et al., 2012;Del Turco et al., 2016;Xiong et al., 2023), and stains out astrocytes (Chauvet et al., 1997;Young et al., 1999;Yasuoka et al., 2004;Xiong et al., 2023). Together, these observations indicate that 1) 22C11 does not specifically recognize APP, 2) an unknown protein this antibody actually binds is present on astrocytes but not necessarily in axons and 3) the varicosities observed with immunoperoxidase method after TBI are a product of the interaction of the reagents with the altered or newly expressed chemical components after TBI. Therefore, 22C11 is not the best or ideal marker for axonal damage after TBI.What then are the varicosities reliably observed with immunoperoxidase staining? Careful comparison of immunoperoxidase to immunofluorescent staining suggests that avidin binding to endogenous biotin may be the source of the varicose signals. As illustrated in Fig. 1, immunofluorescent staining (Fig. 1. A) of the primary antibody (22C11 or Y188, a validated specific antibody against the C-Terminus of APP) is accomplished with a fluorophore (FP)conjugated secondary antibody (2°) that is species-specific for the primary antibody. Conversely, immunoperoxidase staining (Fig. 1. B) is performed using a biotinylated (or biotin-conjugated; B) secondary antibody that is also species-specific for the primary antibody, resulting in specific staining. Unlike FP-conjugated secondary antibodies that are readily visible under a light microscope, biotinylated secondaries can only be visualized after avidin binding via ABC incubation and an enzymatic reaction for horseradish peroxide (HRP) that is contained in the ABC staining kit. Avidin (A)in the ABC kit can also bind to endogenous biotin (Vitamin B7, a coenzyme for 5 carboxylases; Zempleni et al., 2009) in the tissue and generates a spurious (or nonspecific) signal.The interference from endogenous biotin to immunoperoxidase staining has been demonstrated for more than two decades (Bhattacharjee et al., 1997;McKay et al., 2004). However, it has been overlooked in the practice of ABC-mediated immunoperoxidase staining with 22C11 (Gentleman et al., 1993(Gentleman et al., , 1995;;Sherriff et al., 1994a, b;Graham et al., 2004;Reichard et al., 2005;Hortobágyi et al., 2007;Johnson et al., 2013Johnson et al., , 2016;;Koch et al., 2020). Unlike avidin that is not present in mammals, biotin can be up taken from foods and is widely distributed in the brain (Wood and Warnke, 1981;Wang and Pevsner, 1999;McKay et al., 2008). Biotin is enriched in oligodendrocytes, the predominant cells in white matter tracts (LeVine and Macklin, 1988;McKay et al., 2004) and is also present in astrocytes (Xiong et al., 2023(Xiong et al., , 2024)). To determine whether endogenous biotin in these glial cells is the underlying source of the observed varicosities, we directly stained healthy brains with HRP-conjugated avidin (HRP-Avidin) and demonstrated fibrous astrocytes and varicosity-like oligodendrocytes in white matter tracts (Xiong et al., 2023(Xiong et al., , 2024)). Significantly, we found dramatically increased HRP-Avidin staining in injured mice, suggesting an upregulation in endogenous biotin after TBI (Xiong et al., 2023). Given that injury results in astrogliosis (Smith et al., 2015;Shahim et al., 2017) and oligodendrogliosis (Flygt et al., 2016), the varicosities observed with immunoperoxidase staining are therefore most likely due to avidin binding to endogenous biotin in activated glial cells.Additional support for avidin binding to endogenous biotin as the source of the varicosities comes from the extraordinarily high dilution of the primary antibody 22C11 in immuonperoxidase staining in tissue from TBI patients. While some researchers diluted 22C11 at 1:100-200 (Ryu et al., 2014;Xiong et al., 2023Xiong et al., , 2024) ) as recommended by the manufacturer (Millipore-Sigma), others used this primary antibody at a concentration as high as 1:80,000 or even 1:130,000 (Johnson et al., 2016;Koch et al., 2020). Highly diluted primary antibodies produce very weak signals that are easily masked and overshadowed by spurious staining. Therefore, it is highly likely that the varicosities in white matter tracts observed after TBI and widely considered to be a symbol of DAI, actually originated from reactive astrocytes and oligodendrocytes.Then, what is the most accurate method to determine axonal damage after TBI? Using C-Terminal antibodies specific for APP (including Y188), it has been demonstrated that axonal damage does indeed result in the accumulation of APP. However, the axonal staining is not in the form of varicosities but in blebs i.e., the proximal ends of the truncated axons adjacent to the parent neuronal cell bodies within or near gray matter (Stone et al., 2000;Singleton et al., 2002;Wang et al., 2011;Xiong et al., 2023Xiong et al., , 2024)). Using transgenic mice, we have verified co-localization of these Y188-positive blebs with fluorescent tags (Xiong et al., 2023). We also observed varicositylike punctate staining in white matter tracts with Y188 (Xiong et al., 2023). However, these Y188stained puncta do not co-localize with damaged axons in transgenic mice after TBI, suggesting that they are not derived from axons, but likely to be originated from oligodendrocytes that express APP (Palacios et al., 1992;Skaper et al., 2009;Xiong et al., 2023). Therefore, C-Terminal antibodies are still useful biomarkers for axonal blebs (or truncation) after TBI, with the caveat that white matter oligodendrocytes are stained in a varicosity-like pattern. It needs to be stated that these C-Terminal antibodies have been tested only in rodents for detecting axonal blebs in gray matter and puncta in white matter after TBI. They should also be applicable for TBI patient samples, as the amino acid sequence of APP is identical between rodents and humans.While DAI in white matter tracts is prominent after TBI, TBI-induced pathology should not be confined to DAI. Neuronal cell body damage, dendritic deformation and Wallerian degeneration (of axons) have all been demonstrated by staining with Fluoro-Jade dyes (Yang, et al., 2015(Yang, et al., , 2020;;Xiong et al., 2023Xiong et al., , 2024) ) and/or the NeuroSilver kit (Koliatsos et al., 2011;Xiong et al., 2023Xiong et al., , 2024)). These two major makers, together with C-Terminal antibodies for APP (such as Y188) can detect different pathological structures that emerge at different time windows after TBI. We therefore recommend that a combination of different biomarkers should be adopted and different time points need to be checked when assessing neuropathology after TBI (Xiong et al. 2024).In conclusion, 22C11 is not specific for APP and the varicosities in white matter tracts observed after immunoperoxidase staining may not represent axonal damages, but reactive glial cells. A combination of biomarkers revealing different stages of the injury will provide the most accurate and comprehensive pathology after TBI. microscope. An unknow antigen (Ag) in astrocytes can be specifically recognized by 22C11, and APP in oligodendrocytes by Y188. B: Immunoperoxidase staining is performed using biotinylated secondary antibodies that needs further incubation with the ABC kit before an enzymatic reaction for the horseradish peroxidase (HRP) contained in the staining kit. Avidin (A) in the kit will bind to biotin (B) that is conjugated to the secondary antibodies, resulting in specific immunostaining. Avidin can also bind to endogenous biotin (B) that is present in astrocytes and oligodendrocytes.Therefore, both glial groups can be coincidently stained by the ABC kit. Astro, astrocyte; Olig, oligodendrocyte.

  PublisherOA PDFDOI

• Effects of Traumatic Brain Injury on the Orexin/Hypocretin System

  Neurotrauma Reports · 2025-01-01 · 1 citations

  reviewOpen accessSenior authorCorresponding

  Traumatic Brain Injuries (TBIs) are known to cause a myriad of symptoms in patients. One common symptom after injury is sleep disruptions. One neuropeptide system has been studied repeatedly as a potential cause of sleep disruptions after TBI- the orexin/hypocretin system. Orexin promotes wakefulness and arousal while disrupting the orexin system causes increased sleepiness and narcolepsy. Studies of TBI in human and animal subjects have shown that TBI affects the orexin system. This review serves as an overview of how TBI affects the orexin/hypocretin system, including structural and functional changes to the neurons after injury. This review is the first to include studies that examine how TBI affects orexin/hypocretin receptors. This review also examines how sex is accounted for in the studies of the orexin system after TBI.

  PublisherDOI

• Microglia depletion improves hippocampal circuit function after mild traumatic brain injury in male mice

  Brain Behavior and Immunity · 2025-11-12 · 3 citations

  articleOpen accessSenior author
  PublisherOA PDFDOI

• Neonatal microglia replacement in mice modulates seizure severity in adulthood

  Molecular Therapy · 2025-08-26 · 2 citations

  articleOpen access
  PublisherOA PDFDOI

• SmART-TBI: a fully remote protocol for a placebo-controlled double-masked randomized clinical trial for a dietary supplement to improve sleep in veterans

  SLEEP Advances · 2025-12-09

  articleOpen access

  Abstract Traumatic brain injury (TBI) is associated with sleep disturbances and cognitive impairment, with limited effective therapeutic strategies. Our previous work showed dietary supplementation with branched chain amino acids (BCAAs; isoleucine, leucine, valine), the primary substrate for de novo glutamate/GABA synthesis in the CNS, restored normal sleep–wake patterns and improved cognitive function in rodents. Our recent pilot work in humans showed preliminary feasibility/acceptability and limited efficacy for BCAAs to improve sleep in Veterans with TBI. However, these pilot data were limited in sample size, treatment dosages/duration, and therefore unable to establish efficacy or provide insight into dosing/duration parameters. The present study, SmART-TBI (supplementation with amino acid rehabilitative therapy in TBI: NCT04603443), represents a placebo-controlled, double-masked randomized clinical trial (target n = 120). Covariate adaptive randomization controlling for age, sex, TBI recency, pain, depression, and PTSD, allocated participants 1:1:1:1 to four groups comprising 3 BCAA doses b.i.d. (“high” 30 g; “medium” 20 g; and “low” 10 g) and one placebo-control (rice protein, 10 g b.i.d.). Outcomes were assessed following a 2-week baseline period; after 4 weeks, 8 weeks, and 12 weeks of intervention; and after 4 weeks and 12 weeks post-intervention. The primary outcomes are overall feasibility/acceptability metrics, and secondarily, preliminary efficacy for BCAAs to improve subjective sleep as assessed by the Insomnia Severity Index. Additional sleep measures were obtained for future analyses using a combination of actigraphy, mattress-sensors, sleep diaries, as well as pre-/post-BCAA overnight polysomnography. Additional exploratory outcomes included sweat-based biomarkers. Analyses of primary outcome measures indicated high feasibility and acceptability for this fully protocol. Statement of Significance This is the first large-scale double-masked, placebo-controlled randomized clinical trial for dietary BCAA supplementation in Veterans with TBI. Moreover, this study protocol describes the specific aspects of success in implementing this study in a fully remote capacity, enabling potentially nationwide reach of participants. We demonstrated strong success in achieving the primary outcomes of high feasibility and acceptability, and also demonstrated strong preliminary efficacy for the intervention to improve self-reported sleep with BCAA supplementation.

  PublisherDOI

• Cannabinoid Receptor Agonist Affects Murine Contextual Fear Conditioned Memory after Mild Traumatic Brain Injury

  Medical Research Archives · 2025-01-01

  articleOpen accessSenior author

  Mild traumatic brain injuries are common and can lead to memory deficits, partly due to hippocampal dysfunction. Mild traumatic brain injury causes a decrease in network excitability in area CA1 of the hippocampus. We have previously demonstrated that applying the cannabinoid receptor agonist WIN55,212-2 to injured brain slices, restores action potential firing to levels not significantly different than action potentials recorded in slices from uninjured (sham) animals. Here, we evaluated whether WIN55,212-2 also improves hippocampal-dependent memory in vivo using a contextual fear conditioning paradigm. Mice subjected to lateral fluid percussion injury were treated with WIN55,212-2 at doses of 0.75, 0.25, or 0.1mg/kg. Memory is thought to consist of three components: encoding (conditioning), consolidation, and retrieval (testing). At 0.75mg/kg and 0.25mg/kg, all mice froze significantly more than control mice indicating that mouse locomotion was affected at those doses. At concentrations of 0.1mg/kg we observed that injured and sham mice showed no significant differences in freezing rate compared to control sham mice but froze significantly more than injured controls. When administered at 0.1mg/kg only on conditioning days, we saw a similar effect as when injected on both conditioning and testing days. These results suggest that WIN55,212-2 at 0.1 mg/kg primarily aids memory encoding rather than retrieval. Overall, the study demonstrates that at the 0.1mg/kg dose, WIN55,212-2 can restore hippocampal-dependent memory function in lateral fluid percussion injury mice, providing insights into the potential therapeutic role of cannabinoid receptor agonists in mitigating memory deficits following mild traumatic brain injury.

  PublisherOA PDFDOI

• Head Injury Treatment With Healthy and Advanced Dietary Supplements: A Pilot Randomized Controlled Trial of the Tolerability, Safety, and Efficacy of Branched Chain Amino Acids in the Treatment of Concussion in Adolescents and Young Adults

  Journal of Neurotrauma · 2024-03-12 · 17 citations

  articleOpen accessSenior author

  Concussion is a common injury in the adolescent and young adult populations. Although branched chain amino acid (BCAA) supplementation has shown improvements in neurocognitive and sleep function in pre-clinical animal models of mild-to-moderate traumatic brain injury (TBI), to date, no studies have been performed evaluating the efficacy of BCAAs in concussed adolescents and young adults. The goal of this pilot trial was to determine the efficacy, tolerability, and safety of varied doses of oral BCAA supplementation in a group of concussed adolescents and young adults. The study was conducted as a pilot, double-blind, randomized controlled trial of participants ages 11–34 presenting with concussion to outpatient clinics (sports medicine and primary care), urgent care, and emergency departments of a tertiary care pediatric children's hospital and an urban tertiary care adult hospital, between June 24, 2014 and December 5, 2020. Participants were randomized to one of five study arms (placebo and 15 g, 30 g, 45 g, and 54 g BCAA treatment daily) and followed for 21 days after enrollment. Outcome measures included daily computerized neurocognitive tests (processing speed, the a priori primary outcome; and attention, visual learning, and working memory), symptom score, physical and cognitive activity, sleep/wake alterations, treatment compliance, and adverse events. In total, 42 participants were randomized, 38 of whom provided analyzable data. We found no difference in our primary outcome of processing speed between the arms; however, there was a significant reduction in total symptom score (decrease of 4.4 points on a 0–54 scale for every 500 g of study drug consumed, p value for trend = 0.0036, [uncorrected]) and return to physical activity (increase of 0.503 points on a 0–5 scale for every 500 g of study drug consumed, p value for trend = 0.005 [uncorrected]). There were no serious adverse events. Eight of 38 participants reported a mild (not interfering with daily activity) or moderate (limitation of daily activity) adverse event; there were no differences in adverse events by arm, with only two reported mild adverse events (both gastrointestinal) in the highest (45 g and 54 g) BCAA arms. Although limited by slow enrollment, small sample size, and missing data, this study provides the first demonstration of efficacy, as well as safety and tolerability, of BCAAs in concussed adolescents and young adults; specifically, a dose-response effect in reducing concussion symptoms and a return to baseline physical activity in those treated with higher total doses of BCAAs. These findings provide important preliminary data to inform a larger trial of BCAA therapy to expedite concussion recovery.

  PublisherOA PDFDOI

Recent grants

• NIH Grant R01NS045975

  NIH · $1.6M · 2008

• Injury-Induced Alterations in Limbic Functional Circuity

  NIH · $4.3M · 2003–2024

• Restoring Normal Output After Traumatic Brain Injury

  NIH · $462k · 2016–2018

• Dietary reversal of cognitive impairment after traumatic brain injury

  NIH · $1.9M · 2010–2017

• NIH Grant R01HD059288

  NIH · $1.6M · 2014

Frequent coauthors

• Guoxiang Xiong

  Children's Hospital of Philadelphia

  48 shared

• Noam A. Cohen

  Philadelphia VA Medical Center

  44 shared

• Jaclynn A. Elkind

  Children's Hospital of Philadelphia

  36 shared

• Brian N. Johnson

  Children's Hospital of Philadelphia

  27 shared

• Douglas A. Coulter

  26 shared

• Hannah Metheny

  Children's Hospital of Philadelphia

  22 shared

• Miranda M. Lim

  Portland VA Medical Center

  18 shared

• Elizabeth Schwarzbach

  University of Tübingen

  16 shared

Labs

• Akiva S. Cohen LabPI

Education

• B.S., Microbiology

  University of Maryland College Park

  1985

• M.S., Zoology

  University of Maryland College Park

  1989

• Ph.D., Biophysics

  University of Maryland School of Medicine

  1994