Using latent profile analysis, Brett
et al. (
15- Brett B.L.
- Kramer M.D.
- Whyte J.
- McCrea M.A.
- Stein M.B.
- Giacino J.T.
- et al.
Latent profile analysis of neuropsychiatric symptoms and cognitive function of adults 2 weeks after traumatic brain injury: Findings from the TRACK-TBI study.
) recently showed that 1757 participants with TBI (mild to severe) could be classified into clinically distinct phenotypes based on emotional and cognitive functioning at 2 weeks postinjury assessed using 12 different tests included in the National Institutes of Health–endorsed common data elements. Latent profile analysis is a mixture modeling method that assumes the presence of underlying, unmeasured phenotypes (subgroups of participants) that can be identified from distinct patterns of observed variables (here, symptom and cognitive performance measures). These acute TBI phenotypes strongly predicted 6-month postinjury outcomes across functional, clinical, and quality-of-life domains using standard tests different from those used to define the phenotypes. A 4-group solution included 2 distinct profiles that differentiated patients experiencing postinjury neuropsychiatric distress (ND) (
n = 350) from patients exhibiting emotional resilience (ER) (
n = 419). Another 2 profiles were characterized by cognitive difficulties (
n = 368 patients) versus cognitive resilience (
n = 620 patients). The ER group stood out as having the best prognosis for functional, clinical, and quality-of-life outcomes at 6 months following injury, while the ND group had the worst prognosis.
Diffusion tensor imaging (DTI) has been widely applied to characterize white matter (WM) pathology in mTBI because of its sensitivity to diffuse axonal injury (DAI) (
18- Bazarian J.J.
- Zhong J.
- Blyth B.
- Zhu T.
- Kavcic V.
- Peterson D.
Diffusion tensor imaging detects clinically important axonal damage after mild traumatic brain injury: A pilot study.
,
19- Lipton M.L.
- Gulko E.
- Zimmerman M.E.
- Friedman B.W.
- Kim M.
- Gellella E.
- et al.
Diffusion-tensor imaging implicates prefrontal axonal injury in executive function impairment following very mild traumatic brain injury.
,
20Diffusion tensor imaging of mild traumatic brain injury.
,
21- Singh M.
- Jeong J.
- Hwang D.
- Sungkarat W.
- Gruen P.
Novel diffusion tensor imaging methodology to detect and quantify injured regions and affected brain pathways in traumatic brain injury.
,
22- Palacios E.M.
- Yuh E.L.
- Mac Donald C.L.
- Bourla I.
- Wren-Jarvis J.
- Sun X.
- et al.
Diffusion tensor imaging reveals elevated diffusivity of white matter microstructure that is independently associated with long-term outcome after mild traumatic brain injury: A TRACK-TBI study.
). Using DTI, Schmidt
et al. (
23- Schmidt A.T.
- Lindsey H.M.
- Dennis E.
- Wilde E.A.
- Biekman B.D.
- Chu Z.D.
- et al.
Diffusion tensor imaging correlates of resilience following adolescent traumatic brain injury.
) recently found that resilience-promoting factors (e.g., community support, close interpersonal relationships) were associated with intact WM microstructural integrity in a small adolescent sample of TBI of all severities (
23- Schmidt A.T.
- Lindsey H.M.
- Dennis E.
- Wilde E.A.
- Biekman B.D.
- Chu Z.D.
- et al.
Diffusion tensor imaging correlates of resilience following adolescent traumatic brain injury.
). Other studies indicate that WM microstructure correlates with resilience in adolescents (
24- Galinowski A.
- Miranda R.
- Lemaitre H.
- Martinot M.L.P.
- Artiges E.
- Vulser H.
- et al.
Resilience and corpus callosum microstructure in adolescence.
,
25- Burt K.B.
- Whelan R.
- Conrod P.J.
- Banaschewski T.
- Barker G.J.
- Bokde A.L.
- et al.
Structural brain correlates of adolescent resilience.
). WM structural network efficiency derived from diffusion magnetic resonance imaging (MRI) predicts resilience to cognitive decline in adults at risk for Alzheimer’s disease (
26- Fischer F.U.
- Wolf D.
- Tüscher O.
- Fellgiebel A.
Alzheimer’s Disease Neuroimaging Initiative
Structural network efficiency predicts resilience to cognitive decline in elderly at risk for Alzheimer’s disease.
). Conversely, reduced integrity of WM tracts has been observed in individuals with psychiatric diagnoses or higher levels of psychiatric symptoms (
27- Podwalski P.
- Szczygiel K.
- Tyburski E.
- Sagan L.
- Misiak B.
- Samochowiec J.
Magnetic resonance diffusion tensor imaging in psychiatry: A narrative review of its potential role in diagnosis.
). Taken together, WM microstructure represents a promising biological marker to elucidate emotional resilience versus neuropsychiatric distress following mTBI.
Discussion
This prospective, natural history study of patients with mTBI is the first, to our knowledge, to interrogate neural pathways of resilience associated with distinct neuropsychiatric phenotypes following injury. WM microstructural differences between ER and ND phenotypes of mTBI were clearly identified at 2 weeks after injury and became larger and more widespread at 6 months. DTI revealed lower WM AD and therefore possibly reduced microstructural integrity in ND patients compared with their ER counterparts. This difference increased from 2 to 13 major WM tracts during the first 6 months after injury, indicating that greater neuropsychiatric distress interacts with injury-related processes to confer worse biological responses to mTBI, whereas greater emotional resilience may serve as a protective factor, both early and especially later during mTBI recovery. These findings support the novel phenotypic classification of Brett
et al. (
15- Brett B.L.
- Kramer M.D.
- Whyte J.
- McCrea M.A.
- Stein M.B.
- Giacino J.T.
- et al.
Latent profile analysis of neuropsychiatric symptoms and cognitive function of adults 2 weeks after traumatic brain injury: Findings from the TRACK-TBI study.
), with a striking group difference in 6-month outcomes. Whereas the majority of the ER group identified early after injury had little or no long-term disability or symptoms, the majority of the ND group had poor long-term outcomes. This cannot be explained by differences in standard clinical and CT measures of injury severity, all of which indicated more severe TBI in the ER group rather than the ND group (
Table S1). This implies that emotional resilience is a major determinant of recovery after mTBI or that yet-to-be-determined (likely noninjury) factors drive long-term emotional and neurobiological outcomes. Given the high prevalence of mTBI worldwide, elucidating the neuroscientific underpinnings of resilience and leveraging this knowledge to improve diagnosis and treatment of patients with mTBI should be a major focus of research, especially if these neural mechanisms are also shared with other neurological and psychiatric disorders.
The evident association between mTBI phenotypes and WM integrity implicates particular neurobiological mechanisms and may prove useful as diagnostic, prognostic, and/or predictive biomarkers for clinical trials and patient management. The ER and ND phenotypes contrast along multiple psychiatric symptom dimensions following TBI, including internalizing factors (depression, anxiety, and fear) and somatic factors (sleep problems, physical difficulty, and pain) (
40- Nelson L.D.
- Kramer M.D.
- Joyner K.J.
- Patrick C.J.
- Stein M.B.
- Temkin N.
- et al.
Relationship between transdiagnostic dimensions of psychopathology and traumatic brain injury (TBI): A TRACK-TBI study.
). Distinct patterns of WM changes associated with these symptoms may contribute to the feature segregation between phenotypes. Axonal damage of tracts related to emotional functions may predict neuropsychiatric manifestations after TBI. Aldossary
et al. (
41- Aldossary N.M.
- Kotb M.A.
- Kamal A.M.
Predictive value of early MRI findings on neurocognitive and psychiatric outcomes in patients with severe traumatic brain injury.
) showed that patients with severe TBI and DAI were more likely to exhibit personality changes, aggression, and MDD, implicating emotional regulation neurotransmitter circuits of the frontal and anterior temporal lobes. We found greater reduction of diffusivity in superior fronto-occipital fasciculus, superior longitudinal fasciculus, uncinate fasciculus, and fornix, corroborating the hypothesized disrupted neurotransmitter circuits.
In the broader neurosciences, studies have linked limbic and neocortical association tracts with internalizing mental illness. The fornix and cingulum are associated with emotional dysfunction in bipolar disorder (
42- Kurumaji A.
- Itasaka M.
- Uezato A.
- Takiguchi K.
- Jitoku D.
- Hobo M.
- Nishikawa T.
A distinctive abnormality of diffusion tensor imaging parameters in the fornix of patients with bipolar II disorder.
). Decreased uncinate fasciculus integrity was found in MDD (
43- Zheng K.Z.
- Wang H.N.
- Liu J.
- Xi Y.B.
- Li L.
- Zhang X.
- et al.
Incapacity to control emotion in major depression may arise from disrupted white matter integrity and OFC-amygdala inhibition.
). Jenkins
et al. (
44- Jenkins L.M.
- Barba A.
- Campbell M.
- Lamar M.
- Shankman S.A.
- Leow A.D.
- et al.
Shared white matter alterations across emotional disorders: A voxel-based meta-analysis of fractional anisotropy.
) studied shared WM microstructural abnormalities of patients across various emotion disorders using DTI and found reduced FA in uncinate fasciculus and superior longitudinal fasciculus. This is germane to the current study, as the classification of ER and ND was based on a transdiagnostic approach comprising various dimensions of internalizing and somatic psychiatric symptoms. We observed significantly lower AD in fornix, uncinate fasciculus, and superior longitudinal fasciculus in ND patients versus ER patients, concordant with previous findings, and lower AD in the ND group in other neocortical association tracts, including external capsule, superior fronto-occipital fasciculus, and sagittal stratum, by 6 months after injury.
Compromised WM microstructure of commissural and projection tracts might also correlate with emotional deficits. Jenkins
et al. (
44- Jenkins L.M.
- Barba A.
- Campbell M.
- Lamar M.
- Shankman S.A.
- Leow A.D.
- et al.
Shared white matter alterations across emotional disorders: A voxel-based meta-analysis of fractional anisotropy.
) reported reduced FA in the genu of corpus callosum, anterior thalamic radiation, and superior corona radiata. Corpus callosum and anterior limb of internal capsule has lower FA in patients with MDD relative to control subjects (
45- Chen G.
- Guo Y.
- Zhu H.
- Kuang W.
- Bi F.
- Ai H.
- et al.
Intrinsic disruption of white matter microarchitecture in first-episode, drug-naive major depressive disorder: A voxel-based meta-analysis of diffusion tensor imaging.
). We observed cross-sectional and/or longitudinal differences of AD in the ND group versus the ER group in the anterior limb of internal capsule, but also in many more tracts at 6 months after injury. Interestingly, posterior fibers of the posterior corona radiata, posterior thalamic radiation, and sagittal stratum in ER patients trended toward an increased AD over time, suggesting possible recovery of axonal integrity.
Damage to the cerebellum might be important for the deleterious effects of mTBI, as it is sensitive to timing and has been postulated as the hub within the network for attentional prediction (
46The predictive brain state: Timing deficiency in traumatic brain injury?.
,
47- Gatti D.
- Rinaldi L.
- Ferreri L.
- Vecchi T.
The human cerebellum as a hub of the predictive brain.
). AD of the cerebellar peduncles was reduced in both collegiate athletes and emergency department patients with mTBI compared with control subjects (
48- Mallott J.M.
- Palacios E.M.
- Maruta J.
- Ghajar J.
- Mukherjee P.
Disrupted white matter microstructure of the cerebellar peduncles in scholastic athletes after concussion.
). In the current study, AD of the superior cerebellar peduncle was reduced in the ND group versus the ER group at both time points. Both cerebral and cerebellar peduncles (cerebral peduncle and inferior cerebellar peduncle) showed reduction of AD over time in the ND group, but not the ER group. Therefore, microstructural plasticity of cerebellar input and output WM pathways via its peduncles, which is vital for maintaining precise spike timing (
49A new mechanism of nervous system plasticity: Activity-dependent myelination.
,
50- Fields R.D.
- Woo D.H.
- Basser P.J.
Glial regulation of the neuronal connectome through local and long-distant communication.
,
51- Sampaio-Baptista C.
- Johansen-Berg H.
White matter plasticity in the adult brain.
), may be an important mechanism of mTBI resilience in addition to causing postconcussive symptoms when damaged. Hence, individuals with greater preinjury microstructural integrity of the cerebellar peduncles might tolerate the same severity of injury with fewer symptoms and less disability than individuals without this advantage.
These neurobiological correlates of ER versus ND are dynamic over time, leading to different potential interpretations at 2 weeks versus 6 months after injury. Higher AD at 2 weeks after injury may indicate that ER patients had less severe injury to axonal density and less disruption of axonal orientation coherence relative to ND patients. Higher AD 6 months later may indicate that the ER patients had recovered better and/or that the ND patients had more WM degeneration. However, a high AD does not necessarily mean better WM microstructural integrity in the ER patients at 2 weeks. Acute neural deformation edema can also have a transient effect on local AD, which may explain the finding by Brett
et al. (
15- Brett B.L.
- Kramer M.D.
- Whyte J.
- McCrea M.A.
- Stein M.B.
- Giacino J.T.
- et al.
Latent profile analysis of neuropsychiatric symptoms and cognitive function of adults 2 weeks after traumatic brain injury: Findings from the TRACK-TBI study.
) that the latent profiles did not intuitively cohere with TBI severity scores. They found that lower admission Glasgow Coma Scale scores (
<13) were observed more commonly in ER patients (7.9%) than ND patients (5.5%), indicating that ER patients tended to have greater injury severity. The ND group had a higher percentage of women than the ER group; however, sex differences cannot explain the different WM AD changes between the ER and ND groups across the two time points. Interestingly, differences of longitudinal AD changes between the ER and ND groups were evident in the ROI analysis, but not in the voxelwise analysis, likely because voxelwise analysis has more stringent multiple comparison corrections and thus lower statistical power.
Resilience can exist before TBI as a premorbid host factor. A minority of patients in the ER and ND groups reported preinjury psychiatric problems, which were only slightly more common in the ND group. McCauley
et al. (
52- McCauley S.R.
- Wilde E.A.
- Miller E.R.
- Frisby M.L.
- Garza H.M.
- Varghese R.
- et al.
Preinjury resilience and mood as predictors of early outcome following mild traumatic brain injury.
) evaluated preinjury clinical/functional resilience in patients with mTBI post hoc by using the Connor-Davidson Resilience Scale based on the patients’ memory of their functioning a month before the injury. These authors observed that preinjury resilience and preinjury depressed mood predicted postinjury outcomes. Another study of post-TBI resilience using the Connor-Davidson Resilience Scale found that premorbid host factors (e.g., minority group membership, preinjury substance abuse, and higher levels of anxiety and disability) were related to reduced resilience during the first year after injury (
53- Marwitz J.H.
- Sima A.P.
- Kreutzer J.S.
- Dreer L.E.
- Bergquist T.F.
- Zafonte R.
- et al.
Longitudinal examination of resilience after traumatic brain injury: A traumatic brain injury model systems study.
). TBI patients with MDD are more likely to have a history of mood and anxiety disorders than TBI patients without depression, linking lower resilience to emotional deficits after TBI (
54- Jorge R.E.
- Robinson R.G.
- Moser D.
- Tateno A.
- Crespo-Facorro B.
- Arndt S.
Major depression following traumatic brain injury.
). Premorbid somatization symptoms influence clinical recovery after sport-related concussion (
55- Nelson L.D.
- Tarima S.
- LaRoche A.A.
- Hammeke T.A.
- Barr W.B.
- Guskiewicz K.
- et al.
Preinjury somatization symptoms contribute to clinical recovery after sport-related concussion.
). Manic symptoms after TBI were more frequent in patients with a positive family history of bipolar disorder, suggesting that neuropsychiatric risk factors existed before injury (
56- Ahmed S.
- Venigalla H.
- Mekala H.M.
- Dar S.
- Hassan M.
- Ayub S.
Traumatic brain injury and neuropsychiatric complications.
). An earlier study also showed a strong relationship between severe mental illness after TBI and family histories of schizophrenia or bipolar disorder (
57- Malaspina D.
- Goetz R.R.
- Friedman J.H.
- Kaufmann C.A.
- Faraone S.V.
- Tsuang M.
- et al.
Traumatic brain injury and schizophrenia in members of schizophrenia and bipolar disorder pedigrees.
).
Alternatively, resilience after TBI may develop in response to injury. Schmidt
et al. (
23- Schmidt A.T.
- Lindsey H.M.
- Dennis E.
- Wilde E.A.
- Biekman B.D.
- Chu Z.D.
- et al.
Diffusion tensor imaging correlates of resilience following adolescent traumatic brain injury.
) suggested that the protective effects of resilience in adolescent patients with TBI may be a result of less disrupted WM tracts combined with quality of support from family and caregivers. Accordingly, resilience may be responsive and not just innate, although a positive correlation may exist between preinjury resilience and superior family/caregiver environments that can further enhance resilience after injury. Task-oriented coping and perceived social support, but not premorbid intelligence, predicted high resilience on the Connor-Davidson Resilience Scale after TBI (
58- Hanks R.A.
- Rapport L.J.
- Waldron Perrine B.
- Millis S.R.
Correlates of resilience in the first 5 years after traumatic brain injury.
).
As premorbid resilience cannot be ascertained in most TBI study designs, our study is unable to distinguish between altered microstructural WM integrity due to DAI and that due to resilience. The conventional explanation for the group differences (
Figure 1A) is that more severe DAI accounts for the lower WM integrity at 2 weeks in the ND group and that continued Wallerian axonal degeneration produces the widening gap between ND and ER groups at 6 months. However, there is no clinical evidence for greater DAI in the ND group; rather, the ER group trended toward higher proportions of loss of consciousness, posttraumatic amnesia, and acute intracranial injury on CT, which are all factors associated with greater injury severity. The alternative explanation (
Figure 1B) is that differences in preinjury resilience account for the differences in DTI metrics at 2 weeks and that persistent adaptive behaviors among the ER group, in contrast to maladaptive behaviors among the ND group, explain the relatively preserved WM microstructure of ER patients by 6 months after injury, similar to that of the uninjured control subjects, in contrast to the deteriorating WM integrity of the ND patients. This view is consistent with the finding of higher educational levels in the ER group. Rates of premorbid psychopathology did not differ between ER and ND groups, indicating that this construct is not simply due to preexisting neuropsychiatric history. Furthermore, the greatest variations in WM microstructure between the two groups were in tracts implicated in resilience and neuropsychiatric function, as opposed to the more uniform and diffuse group differences that would be postulated by the DAI hypothesis. However, there are likely interactions between DAI and preinjury resilience during the recovery from mTBI, as DAI can affect WM tracts required for clinical/functional resilience, and, in turn, resilience can promote adaptive responses to injury that might potentially prevent further WM degeneration induced by DAI. This latter interaction is supported by the 1-year follow-up DTI data from a recent pilot study of resilience-promoting factors in adolescents with complicated mild, moderate, and severe TBI (
23- Schmidt A.T.
- Lindsey H.M.
- Dennis E.
- Wilde E.A.
- Biekman B.D.
- Chu Z.D.
- et al.
Diffusion tensor imaging correlates of resilience following adolescent traumatic brain injury.
).
Given the enlarging differences in WM microstructure between ER and ND over time, improving post-TBI intervention is urgent, demanding clear identification of modifiable factors. Patients with mTBI presenting to the emergency department frequently receive limited education and follow-up care (
59- Seabury S.A.
- Gaudette É
- Goldman D.P.
- Markowitz A.J.
- Brooks J.
- McCrea M.A.
- et al.
Assessment of follow-up care after emergency department presentation for mild traumatic brain injury and concussion: Results from the TRACK-TBI study.
). Variation in TBI clinical care practices conceivably contributes to resilient versus adverse clinical and neurobiological outcomes. Advancing mTBI biological and phenotypic classification is critical to better precision medicine treatment approaches, as more precisely and accurately characterizing population heterogeneity will help ensure that interventions are tailored to the unique needs and preferences of individual patients (
30- Nelson L.D.
- Temkin N.R.
- Dikmen S.
- Barber J.
- Giacino J.T.
- Yuh E.
- et al.
Recovery after mild traumatic brain injury in patients presenting to US Level I trauma centers: A Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) study.
,
60- Manley G.T.
- Mac Donald C.L.
- Markowitz A.J.
- Stephenson D.
- Robbins A.
- Gardner R.C.
- et al.
The Traumatic Brain Injury Endpoints Development (TED) initiative: Progress on a public-private regulatory collaboration to accelerate diagnosis and treatment of traumatic brain injury.
,
61- Bowman K.
- Matney C.
- Berwick D.M.
Improving traumatic brain injury care and research: A report from the National Academies of Sciences, Engineering, and Medicine.
). Incorporating neuroscience-informed resilience theory and positive psychology into TBI rehabilitation promises to improve long-term quality of life (
62- Rabinowitz A.R.
- Arnett P.A.
Positive psychology perspective on traumatic brain injury recovery and rehabilitation.
,
63- Howe E.I.
- Langlo K.P.S.
- Terjesen H.C.A.
- Røe C.
- Schanke A.K.
- Søberg H.L.
- et al.
Combined cognitive and vocational interventions after mild to moderate traumatic brain injury: Study protocol for a randomized controlled trial.
,
64- Maas A.I.
- Menon D.K.
- Adelson P.D.
- Andelic N.
- Bell M.J.
- Belli A.
- et al.
Traumatic brain injury: Integrated approaches to improve prevention, clinical care, and research.
,
65- Savulich G.
- Menon D.K.
- Stamatakis E.A.
- Pickard J.D.
- Sahakian B.J.
Personalised treatments for traumatic brain injury: Cognitive, emotional and motivational targets.
). Patients’ perception of the injury might lead to differentiated neuropsychiatric outcomes (
3Long-term neuropsychiatric disorders after traumatic brain injury.
). Postinjury social and environmental challenges also have psychological impacts. For example, a patient and family may be unable to work to their full capacity following injury, which consequently stretches their financial resources (
66- Gaudette É
- Seabury S.A.
- Temkin N.
- Barber J.
- DiGiorgio A.M.
- Markowitz A.J.
- et al.
Employment and economic outcomes of mild traumatic brain injury patients presenting to US Level 1 trauma centers: A TRACK-TBI Study.
). Professional guidance should be integrated into rehabilitation to support coping with all these stressors (
67- Mikolić A.
- Polinder S.
- Helmrich I.R.R.
- Haagsma J.A.
- Cnossen M.C.
Treatment for posttraumatic stress disorder in patients with a history of traumatic brain injury: A systematic review.
).
Limitations and Future Directions
To control for all potential confounding factors (genetics, sex, education, lifestyles, socioeconomics) would have required a larger sample size. More studies would help to determine the effect of these different demographic characteristics. DTI data from 2 time points were inadequate to quantify the effect of acute edema on AD. Future studies incorporating earlier imaging time points as well as more advanced diffusion models (e.g., neurite orientation dispersion and density imaging) would help elucidate these acute effects of TBI.
Tract-based spatial statistics has limited anatomical specificity due to its reliance on FA and neglecting orientation information in the diffusion tensor (
68- Bach M.
- Laun F.B.
- Leemans A.
- Tax C.M.
- Biessels G.J.
- Stieltjes B.
- Maier-Hein K.H.
Methodological considerations on tract-based spatial statistics (TBSS).
). Also, the impact of heterogeneity in image acquisition on the results (e.g., due to scanner types) might have been reduced by advanced harmonization methods.
Regarding interpretation of the results, the reported effect sizes are not large enough to predict the outcomes of individual patients. Also, the present analyses cannot determine if particular neuropsychiatric factors (e.g., sleep, depression, anxiety, fear, sleep problems, physical difficulty, pain) were predominantly associated with AD to inform treatment recommendations. These limitations should inspire future hypothesis-driven investigations with more advanced diffusion MRI acquisition and analysis methodology.
Acknowledgments and Disclosures
This work was supported by the National Institute of Neurological Disorders and Stroke (Grant No. R01 NS110856 [to LDN]) and National Institute on Aging (Grant No. K23 AG073528-01 [to BLB]). The TRACK-TBI study is sponsored by the National Institutes of Health, National Institute of Neurological Disorders and Stroke (Grant No. U01 NS086090), U.S. Department of Defense (Grant No. W81XWH-14-2-0176), Abbott Laboratories, and One Mind. Abbott Laboratories is supported by the U.S. Army Medical Research and Development Command.
This paper is in memory of our coauthor Dr. Harvey S. Levin, who was a pioneer in the application of neuroimaging and neuropsychology to the study of mTBI, including the role of resilience in mTBI patient outcomes. Regarding International Committee of Medical Journal Editors authorship criteria, we note that, due to his illness, Dr. Levin was not able to approve the final submitted version of this manuscript.
ELY has a patent for United States Patent and Trademark Office No. 62/269,778 pending. GTM received grants from the National Institute of Neurological Disorders and Stroke during the conduct of the study; research funding from the U.S. Department of Energy, grants from the Department of Defense, research funding from Abbott Laboratories, grants from the National Football League Scientific Advisory Board, and research funding from One Mind outside the submitted work; in addition, GTM had a patent for Interpretation and Quantification of Emergency Features on Head Computed Tomography issued. He served for 2 seasons as an unaffiliated neurologic consultant for home games of the Oakland Raiders; he was compensated $1500 per game for 6 games during the 2017 season but received no compensation for this work during the 2018 season. MBS received personal fees from Aptinyx, Bionomics, Janssen, and Neurocrine as well as personal fees and stock options from Oxeia Biopharmaceuticals outside the submitted work. RD-A received personal fees and research funding from Neural Analytics, Inc., and travel reimbursement from Brain Box Solutions, Inc., outside the submitted work. DG received personal fees from Amgen, Avanir Pharmaceuticals, Acadia Pharmaceuticals, Aspen Health Strategy Group, and Celgene outside the submitted work. NK received personal fees from Portola outside the submitted work. PM received grants from GE Healthcare and nonfinancial support from the General Electric–National Football League Head Health Initiative outside the submitted work; in addition, PM had a patent for United States Patent and Trademark Office No. 62/269,778 pending. JR received personal fees from Boehringer Ingelheim and New Beta Innovations outside the submitted work. RDZ received royalties from Oakstone Publishing for an educational CD (Physical Medicine and Rehabilitation: A Comprehensive Review) and Demos Medical Publishing for serving as coeditor of Brain Injury Medicine. RDZ serves or served on the scientific advisory boards of Myomo, Oxeia Biopharma, Biodirection, and Elminda. He also evaluates patients in the Massachusetts General Hospital Brain and Body–TRUST Program, which is funded by the National Football League Players Association. RDZ served on the National Football League Players Association Mackey White Health and Safety Committee. None of these funding organizations influenced the scientific content of this paper. All other authors report no biomedical financial interests or potential conflicts of interest.
Article info
Publication history
Published online: September 20, 2022
Accepted:
August 31,
2022
Received in revised form:
August 12,
2022
Received:
May 10,
2022
Publication stage
In Press Journal Pre-ProofFootnotes
The TRACK-TBI consortium: Adam R. Ferguson, Geoffrey T. Manley, Amy J. Markowitz, Pratik Mukherjee, Sabrina R. Taylor, John K. Yue, Esther L. Yuh (University of California, San Francisco); Ruchira Jha (Barrow Neurological Institute); Shankar Gopinath, Claudia S. Robertson (Baylor College of Medicine); Joseph T. Giacino (Harvard University Spaulding Rehabilitation Center); Michael A. McCrea, Lindsay D. Nelson (Medical College of Wisconsin); Ramon Diaz-Arrastia (Hospital of the University of Pennsylvania); Sonia Jain, Murray B. Stein (University of California, San Diego); Laura B. Ngwenya (University of Cincinnati UC Gardner Neuroscience Institute); Neeraj Badjatia, Rao Gullapalli (University of Maryland Medical Center); Frederick K. Korley (University of Michigan); David O. Okonkwo, Ava M. Puccio (University of Pittsburgh Medical Center Brain Trauma Research Center); David Schnyer (University of Texas at Austin); Christopher Madden (UT Southwestern Medical Center); Ramesh Grandhi (University of Utah); C. Dirk Keene, Christine Mac Donald, Nancy Temkin (University of Washington); Randall Merchant (Virginia Commonwealth University Medical Center).
Copyright
© 2022 Published by Elsevier Inc on behalf of Society of Biological Psychiatry.