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1.
Proc Natl Acad Sci U S A ; 121(19): e2313568121, 2024 May 07.
Article in English | MEDLINE | ID: mdl-38648470

ABSTRACT

United States (US) Special Operations Forces (SOF) are frequently exposed to explosive blasts in training and combat, but the effects of repeated blast exposure (RBE) on SOF brain health are incompletely understood. Furthermore, there is no diagnostic test to detect brain injury from RBE. As a result, SOF personnel may experience cognitive, physical, and psychological symptoms for which the cause is never identified, and they may return to training or combat during a period of brain vulnerability. In 30 active-duty US SOF, we assessed the relationship between cumulative blast exposure and cognitive performance, psychological health, physical symptoms, blood proteomics, and neuroimaging measures (Connectome structural and diffusion MRI, 7 Tesla functional MRI, [11C]PBR28 translocator protein [TSPO] positron emission tomography [PET]-MRI, and [18F]MK6240 tau PET-MRI), adjusting for age, combat exposure, and blunt head trauma. Higher blast exposure was associated with increased cortical thickness in the left rostral anterior cingulate cortex (rACC), a finding that remained significant after multiple comparison correction. In uncorrected analyses, higher blast exposure was associated with worse health-related quality of life, decreased functional connectivity in the executive control network, decreased TSPO signal in the right rACC, and increased cortical thickness in the right rACC, right insula, and right medial orbitofrontal cortex-nodes of the executive control, salience, and default mode networks. These observations suggest that the rACC may be susceptible to blast overpressure and that a multimodal, network-based diagnostic approach has the potential to detect brain injury associated with RBE in active-duty SOF.


Subject(s)
Blast Injuries , Military Personnel , Humans , Blast Injuries/diagnostic imaging , Adult , Male , United States , Magnetic Resonance Imaging , Female , Positron-Emission Tomography , Cognition/physiology , Brain/diagnostic imaging , Brain/metabolism , Young Adult
2.
Ann Neurol ; 94(6): 1008-1023, 2023 12.
Article in English | MEDLINE | ID: mdl-37470289

ABSTRACT

OBJECTIVE: It is not currently possible to predict long-term functional dependency in patients with disorders of consciousness (DoC) after traumatic brain injury (TBI). Our objective was to fit and externally validate a prediction model for 1-year dependency in patients with DoC ≥ 2 weeks after TBI. METHODS: We included adults with TBI enrolled in TBI Model Systems (TBI-MS) or Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) studies who were not following commands at rehabilitation admission or 2 weeks post-injury, respectively. We fit a logistic regression model in TBI-MS and validated it in TRACK-TBI. The primary outcome was death or dependency at 1 year post-injury, defined using the Disability Rating Scale. RESULTS: In the TBI-MS Discovery Sample, 1,960 participants (mean age 40 [18] years, 76% male, 68% white) met inclusion criteria, and 406 (27%) were dependent 1 year post-injury. In a TBI-MS held out cohort, the dependency prediction model's area under the receiver operating characteristic curve was 0.79 (95% CI 0.74-0.85), positive predictive value was 53% and negative predictive value was 86%. In the TRACK-TBI external validation (n = 124, age 40 [16] years, 77% male, 81% white), the area under the receiver operating characteristic curve was 0.66 (0.53, 0.79), equivalent to the standard IMPACTcore + CT score (p = 0.8). INTERPRETATION: We developed a 1-year dependency prediction model using the largest existing cohort of patients with DoC after TBI. The sensitivity and negative predictive values were greater than specificity and positive predictive values. Accuracy was diminished in an external sample, but equivalent to the IMPACT model. Further research is needed to improve dependency prediction in patients with DoC after TBI. ANN NEUROL 2023;94:1008-1023.


Subject(s)
Brain Injuries, Traumatic , Brain Injuries , Adult , Humans , Male , Female , Consciousness Disorders/diagnosis , Consciousness Disorders/etiology , Brain Injuries, Traumatic/complications , Brain Injuries/rehabilitation , Predictive Value of Tests , Functional Status , Prognosis
3.
Ann Neurol ; 94(5): 919-924, 2023 11.
Article in English | MEDLINE | ID: mdl-37488068

ABSTRACT

We developed and validated an abbreviated version of the Coma Recovery Scale-Revised (CRS-R), the CRS-R For Accelerated Standardized Testing (CRSR-FAST), to detect conscious awareness in patients with severe traumatic brain injury in the intensive care unit. In 45 consecutively enrolled patients, CRSR-FAST administration time was approximately one-third of the full-length CRS-R (mean [SD] 6.5 [3.3] vs 20.1 [7.2] minutes, p < 0.0001). Concurrent validity (simple kappa 0.68), test-retest (Mak's ρ = 0.76), and interrater (Mak's ρ = 0.91) reliability were substantial. Sensitivity, specificity, and accuracy for detecting consciousness were 81%, 89%, and 84%, respectively. The CRSR-FAST facilitates serial assessment of consciousness, which is essential for diagnostic and prognostic accuracy. ANN NEUROL 2023;94:919-924.


Subject(s)
Coma , Consciousness , Humans , Coma/diagnosis , Reproducibility of Results , Feasibility Studies , Recovery of Function , Intensive Care Units , Consciousness Disorders/diagnosis
4.
Neurocrit Care ; 40(3): 865-878, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38243150

ABSTRACT

The advent of neurotechnologies including advanced functional magnetic resonance imaging and electroencephalography to detect states of awareness not detectable by traditional bedside neurobehavioral techniques (i.e., covert consciousness) promises to transform neuroscience research and clinical practice for patients with brain injury. As these interventions progress from research tools into actionable, guideline-endorsed clinical tests, ethical guidance for clinicians on how to responsibly communicate the sensitive results they yield is crucial yet remains underdeveloped. Drawing on insights from empirical and theoretical neuroethics research and our clinical experience with advanced neurotechnologies to detect consciousness in behaviorally unresponsive patients, we critically evaluate ethical promises and perils associated with disclosing the results of clinical covert consciousness assessments and describe a semistructured approach to responsible data sharing to mitigate potential risks.


Subject(s)
Consciousness , Electroencephalography , Humans , Disclosure/ethics , Brain Injuries , Persistent Vegetative State/diagnosis , Consciousness Disorders/diagnosis
5.
J Head Trauma Rehabil ; 38(4): 351-357, 2023.
Article in English | MEDLINE | ID: mdl-36854104

ABSTRACT

Functional magnetic resonance imaging (fMRI) now promises to improve diagnostic and prognostic accuracy for patients with disorders of consciousness, and accordingly has been endorsed by professional society guidelines, including those of the American Academy of Neurology, American College of Rehabilitation Medicine, National Institute on Disability, Independent Living, and Rehabilitation Research, and the European Academy of Neurology. Despite multiple professional society endorsements of fMRI in evaluating patients with disorders of consciousness following severe brain injury, insurers have yet to issue clear guidance regarding coverage of fMRI for this indication. Lack of insurer coverage may be a rate-limiting barrier to accessing this technique, which could uncover essential diagnostic and prognostic information for patients and their families. The emerging clinical and ethical case for harmonized insurer recognition and reimbursement of fMRI for vulnerable persons following severe brain injury with disorders of consciousness is explained and critically evaluated.


Subject(s)
Brain Injuries , Insurance Carriers , Humans , Consciousness Disorders , Rehabilitation Research , Magnetic Resonance Imaging , Consciousness , Brain Injuries/diagnostic imaging
6.
J Head Trauma Rehabil ; 38(3): E186-E194, 2023.
Article in English | MEDLINE | ID: mdl-36730991

ABSTRACT

OBJECTIVE: The goal of this study is to describe national trends in inpatient rehabilitation facility (IRF) discharges for the most severely disabled cohort of patients with traumatic brain injury (TBI). METHODS: Data from the Uniform Data System for Medical Rehabilitation for patients discharged from an IRF between January 1, 2002, and December 31, 2017, with a diagnosis of TBI and an admission Functional Independence Measure of 18, the lowest possible score, were obtained and analyzed. RESULTS: Of the 252 112 patients with TBI discharged during the study period, 10 098 met the study criteria. From 2002 to 2017, the number of patients with an IRF admission Functional Independence Measure of 18 following TBI discharged from IRFs annually decreased from 649 to 488, modeled by a negative regression (coefficient = -2.97; P = .001), and the mean age (SD) increased from 43.0 (21.0) to 53.7 (21.3) years (coefficient = 0.70; P < .001). During the study period, the number of patients with the most severe disability on admission to IRF who were discharged annually as a proportion of total patients with TBI decreased from 5.5% to 2.5% (odds ratio = 0.95; P < .001) and their mean length of stay decreased from 41.5 (36.2) to 29.3 (24.9) days (coefficient = -0.83; P < .001]. CONCLUSION: The number and proportion of patients with the most severe disability on IRF admission following TBI who are discharged from IRFs is decreasing over time. This may represent a combination of primary prevention, early mortality due to withdrawal of life-sustaining treatment, alternative discharge dispositions, or changes in admitting and reimbursement practices. Furthermore, there has been a decrease in the duration of IRF level care for these individuals, which could ultimately lead to poorer functional outcomes, particularly given the importance of specialized rehabilitative care in this population.


Subject(s)
Brain Injuries, Traumatic , Disabled Persons , Humans , Inpatients , Rehabilitation Centers , Recovery of Function , Length of Stay , Patient Discharge , Retrospective Studies , Treatment Outcome
7.
Neurocrit Care ; 38(3): 584-590, 2023 06.
Article in English | MEDLINE | ID: mdl-37029315

ABSTRACT

Early reemergence of consciousness predicts long-term functional recovery for patients with severe brain injury. However, tools to reliably detect consciousness in the intensive care unit are lacking. Transcranial magnetic stimulation electroencephalography has the potential to detect consciousness in the intensive care unit, predict recovery, and prevent premature withdrawal of life-sustaining therapy.


Subject(s)
Consciousness , Transcranial Magnetic Stimulation , Humans , Consciousness/physiology , Electroencephalography , Intensive Care Units , Consciousness Disorders/diagnosis , Consciousness Disorders/therapy
8.
Neurocrit Care ; 2023 Sep 19.
Article in English | MEDLINE | ID: mdl-37726548

ABSTRACT

BACKGROUND: The recent publication of practice guidelines for management of patients with disorders of consciousness (DoC) in the United States and Europe was a major step forward in improving the accuracy and consistency of terminology, diagnostic criteria, and prognostication in this population. There remains a pressing need for a more precise brain injury classification system that combines clinical semiology with neuroimaging, electrophysiologic, and other biomarker data. To address this need, the National Institute of Neurological Disorders and Stroke launched the Common Data Elements (CDEs) initiative to facilitate systematic collection of high-quality research data in studies involving patients with neurological disease. The Neurocritical Care Society's Curing Coma Campaign expanded this effort in 2018 to develop CDEs for DoC. Herein, we present CDE recommendations for behavioral phenotyping of patients with DoC. METHODS: The Behavioral Phenotyping Workgroup used a preestablished, five-step process to identify and select candidate CDEs that included review of existing National Institute of Neurological Disorders and Stroke CDEs, nomination and systematic vetting of new CDEs, CDE classification, iterative review, and approval of panel recommendations and development of corresponding case review forms. RESULTS: We identified a slate of existing and newly proposed basic, supplemental, and exploratory CDEs that can be used for behavioral phenotyping of adult and pediatric patients with DoC. CONCLUSIONS: The proposed behavioral phenotyping CDEs will assist with international harmonization of DoC studies and allow for more precise characterization of study cohorts, favorably impacting observational studies and clinical trials aimed at improving outcome in this population.

9.
Semin Neurol ; 42(3): 249-258, 2022 06.
Article in English | MEDLINE | ID: mdl-36100225

ABSTRACT

Severe brain injury is associated with a period of impaired level of consciousness that can last from days to months and results in chronic impairment. Systematic assessment of level of function in patients with disorders of consciousness (DoC) is critical for diagnosis, prognostication, and evaluation of treatment efficacy. Approximately 40% of patients who are thought to be unconscious based on clinical bedside behavioral assessment demonstrate some signs of consciousness on standardized behavioral assessment. This finding, in addition to a growing body of literature demonstrating the advantages of standardized behavioral assessment of DoC, has led multiple professional societies and clinical guidelines to recommend standardized assessment over routine clinical evaluation of consciousness. Nevertheless, even standardized assessment is susceptible to biases and misdiagnosis, and examiners should consider factors, such as fluctuating arousal and aphasia, that may confound evaluation. We review approaches to behavioral assessment of consciousness, recent clinical guideline recommendations for use of specific measures to evaluate patients with DoC, and strategies for mitigating common biases that may confound the examination.


Subject(s)
Consciousness Disorders , Consciousness , Consciousness Disorders/therapy , Humans
10.
Brain ; 144(11): 3291-3310, 2021 12 16.
Article in English | MEDLINE | ID: mdl-34347037

ABSTRACT

Neuroethical questions raised by recent advances in the diagnosis and treatment of disorders of consciousness are rapidly expanding, increasingly relevant and yet underexplored. The aim of this thematic review is to provide a clinically applicable framework for understanding the current taxonomy of disorders of consciousness and to propose an approach to identifying and critically evaluating actionable neuroethical issues that are frequently encountered in research and clinical care for this vulnerable population. Increased awareness of these issues and clarity about opportunities for optimizing ethically responsible care in this domain are especially timely given recent surges in critically ill patients with prolonged disorders of consciousness associated with coronavirus disease 2019 around the world. We begin with an overview of the field of neuroethics: what it is, its history and evolution in the context of biomedical ethics at large. We then explore nomenclature used in disorders of consciousness, covering categories proposed by the American Academy of Neurology, the American Congress of Rehabilitation Medicine and the National Institute on Disability, Independent Living and Rehabilitation Research, including definitions of terms such as coma, the vegetative state, unresponsive wakefulness syndrome, minimally conscious state, covert consciousness and the confusional state. We discuss why these definitions matter, and why there has been such evolution in this nosology over the years, from Jennett and Plum in 1972 to the Multi-Society Task Force in 1994, the Aspen Working Group in 2002 and the 2018 American and 2020 European Disorders of Consciousness guidelines. We then move to a discussion of clinical aspects of disorders of consciousness, the natural history of recovery and ethical issues that arise within the context of caring for people with disorders of consciousness. We conclude with a discussion of key challenges associated with assessing residual consciousness in disorders of consciousness, potential solutions and future directions, including integration of crucial disability rights perspectives.


Subject(s)
Bioethical Issues , Consciousness Disorders/classification , Neurology/ethics , COVID-19 , Consciousness Disorders/diagnosis , Humans , SARS-CoV-2
11.
Arch Phys Med Rehabil ; 103(9): 1870-1873, 2022 09.
Article in English | MEDLINE | ID: mdl-35398046

ABSTRACT

OBJECTIVE: To determine whether consistent command-following (CCF) should be added to the diagnostic criteria for emergence from the minimally conscious state (eMCS). DESIGN: Retrospective cohort study. SETTING: Inpatient rehabilitation hospital. PARTICIPANTS: Patients (N=214) with acquired brain injury resulting in disorders of consciousness (DoC) admitted to a specialized rehabilitation program. MAIN OUTCOME MEASURES: Difference between time to recovery of CCF and time to recovery of functional object use (FOU) or functional communication (FC), the 2 existing criteria for eMCS as measured by the Coma Recovery Scale-Revised (CRS-R). RESULTS: Of 214 patients (median age, 53 years [interquartile range {IQR}, 34-66 years], male: 134 [62.6%], traumatic etiology: 115 [53.7%], admission CRS-R total score: 10 [IQR, 7-13]) admitted to rehabilitation without CCF, FOU, or FC, 162 (75.7%) recovered CCF and FOU or FC during the 8-week observation period. On average, recovery of CCF, FOU, and FC was observed within 1 day of one another, approximately 46 days (IQR, 38.25-58 days) post injury. One hundred and sixteen patients (71.6%) recovered FOU or FC prior to or at the same time as CCF. CONCLUSIONS: In patients recovering from DoC, CCF reemerges around the same time as FOU and FC. This finding may reflect the shared dependency of these behaviors on cognitive processes (eg, language comprehension, attention, motor control) that are essential for effective interpersonal interaction and social participation. Our results support the addition of CCF to the existing diagnostic criteria for eMCS, but further validation in an independent sample should be conducted.


Subject(s)
Consciousness Disorders , Persistent Vegetative State , Adult , Aged , Coma , Consciousness Disorders/rehabilitation , Humans , Male , Middle Aged , Persistent Vegetative State/rehabilitation , Recovery of Function , Retrospective Studies
12.
Neurocrit Care ; 37(1): 47-59, 2022 08.
Article in English | MEDLINE | ID: mdl-35141860

ABSTRACT

BACKGROUND: Although coma is commonly encountered in critical care, worldwide variability exists in diagnosis and management practices. We aimed to assess variability in coma definitions, etiologies, treatment strategies, and attitudes toward prognosis. METHODS: As part of the Neurocritical Care Society Curing Coma Campaign, between September 2020 and January 2021, we conducted an anonymous, international, cross-sectional global survey of health care professionals caring for patients with coma and disorders of consciousness in the acute, subacute, or chronic setting. Survey responses were solicited by sequential emails distributed by international neuroscience societies and social media. Fleiss κ values were calculated to assess agreement among respondents. RESULTS: The survey was completed by 258 health care professionals from 41 countries. Respondents predominantly were physicians (n = 213, 83%), were from the United States (n = 141, 55%), and represented academic centers (n = 231, 90%). Among eight predefined items, respondents identified the following cardinal features, in various combinations, that must be present to define coma: absence of wakefulness (81%, κ = 0.764); Glasgow Coma Score (GCS) ≤ 8 (64%, κ = 0.588); failure to respond purposefully to visual, verbal, or tactile stimuli (60%, κ = 0.552); and inability to follow commands (58%, κ = 0.529). Reported etiologies of coma encountered included medically induced coma (24%), traumatic brain injury (24%), intracerebral hemorrhage (21%), and cardiac arrest/hypoxic-ischemic encephalopathy (11%). The most common clinical assessment tools used for coma included the GCS (94%) and neurological examination (78%). Sixty-six percent of respondents routinely performed sedation interruption, in the absence of contraindications, for clinical coma assessments in the intensive care unit. Advanced neurological assessment techniques in comatose patients included quantitative electroencephalography (EEG)/connectivity analysis (16%), functional magnetic resonance imaging (7%), single-photon emission computerized tomography (6%), positron emission tomography (4%), invasive EEG (4%), and cerebral microdialysis (4%). The most commonly used neurostimulants included amantadine (51%), modafinil (37%), and methylphenidate (28%). The leading determinants for prognostication included etiology of coma, neurological examination findings, and neuroimaging. Fewer than 20% of respondents reported routine follow-up of coma survivors after hospital discharge; however, 86% indicated interest in future research initiatives that include postdischarge outcomes at six (85%) and 12 months (65%). CONCLUSIONS: There is wide heterogeneity among health care professionals regarding the clinical definition of coma and limited routine use of advanced coma assessment techniques in acute care settings. Coma management practices vary across sites, and mechanisms for coordinated and sustained follow-up after acute treatment are inconsistent. There is an urgent need for the development of evidence-based guidelines and a collaborative, coordinated approach to advance both the science and the practice of coma management globally.


Subject(s)
Aftercare , Coma , Coma/diagnosis , Coma/epidemiology , Coma/etiology , Cross-Sectional Studies , Glasgow Coma Scale , Humans , Patient Discharge , Surveys and Questionnaires
13.
Ann Neurol ; 88(4): 851-854, 2020 10.
Article in English | MEDLINE | ID: mdl-32613682

ABSTRACT

Many patients with severe coronavirus disease 2019 (COVID-19) remain unresponsive after surviving critical illness. Although several structural brain abnormalities have been described, their impact on brain function and implications for prognosis are unknown. Functional neuroimaging, which has prognostic significance, has yet to be explored in this population. Here we describe a patient with severe COVID-19 who, despite prolonged unresponsiveness and structural brain abnormalities, demonstrated intact functional network connectivity, and weeks later recovered the ability to follow commands. When prognosticating for survivors of severe COVID-19, clinicians should consider that brain networks may remain functionally intact despite structural injury and prolonged unresponsiveness. ANN NEUROL 2020;88:851-854.


Subject(s)
Brain/diagnostic imaging , Coma/diagnostic imaging , Coronavirus Infections/physiopathology , Persistent Vegetative State/diagnostic imaging , Pneumonia, Viral/physiopathology , Recovery of Function , Betacoronavirus , Brain/physiopathology , COVID-19 , Coma/physiopathology , Coronavirus Infections/therapy , Electroencephalography , Functional Neuroimaging , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Neural Pathways , Pandemics , Persistent Vegetative State/physiopathology , Pneumonia, Viral/therapy , Prognosis , Renal Insufficiency/physiopathology , Respiration, Artificial , Respiratory Distress Syndrome/physiopathology , Respiratory Distress Syndrome/therapy , SARS-CoV-2 , Shock/physiopathology
14.
Brain Inj ; 35(12-13): 1552-1562, 2021 11 10.
Article in English | MEDLINE | ID: mdl-34546806

ABSTRACT

PRIMARY OBJECTIVE: We hypothesized that, in patients with acute severe traumatic brain injury (TBI) who recover basic language function, speech-evoked blood-oxygen-level-dependent (BOLD) functional MRI (fMRI) responses within the canonical language network increase over the first 6 months post-injury. RESEARCH DESIGN: We conducted a prospective, longitudinal fMRI pilot study of adults with acute severe TBI admitted to the intensive care unit. We also enrolled age- and sex-matched healthy subjects. METHODS AND PROCEDURES: We evaluated BOLD signal in bilateral superior temporal gyrus (STG) and inferior frontal gyrus (IFG) regions of interest acutely and approximately 6 months post-injury. Given evidence that regions outside the canonical language network contribute to language processing, we also performed exploratory whole-brain analyses. MAIN OUTCOMES AND RESULTS: Of the 16 patients enrolled, eight returned for follow-up fMRI, all of whom recovered basic language function. We observed speech-evoked longitudinal BOLD increases in the left STG, but not in the right STG, right IFG, or left IFG. Whole-brain analysis revealed increases in the right supramarginal and middle temporal gyri but no differences between patients and healthy subjects (n = 16). CONCLUSION: This pilot study suggests that, in patients with severe TBI who recover llanguage function, speech-evoked responses in bihemispheric language-processing cortex reemerge by 6 months post-injury.


Subject(s)
Brain Injuries, Traumatic , Language , Adult , Brain/diagnostic imaging , Brain Injuries, Traumatic/diagnostic imaging , Brain Mapping , Humans , Magnetic Resonance Imaging , Pilot Projects , Prospective Studies
15.
Arch Phys Med Rehabil ; 101(11): 2041-2050, 2020 11.
Article in English | MEDLINE | ID: mdl-32738198

ABSTRACT

In response to the need to better define the natural history of emerging consciousness after traumatic brain injury and to better describe the characteristics of the condition commonly labeled posttraumatic amnesia, a case definition and diagnostic criteria for the posttraumatic confusional state (PTCS) were developed. This project was completed by the Confusion Workgroup of the American Congress of Rehabilitation Medicine Brain Injury Interdisciplinary Special Interest group. The case definition was informed by an exhaustive literature review and expert opinion of workgroup members from multiple disciplines. The workgroup reviewed 2466 abstracts and extracted evidence from 44 articles. Consensus was reached through teleconferences, face-to-face meetings, and 3 rounds of modified Delphi voting. The case definition provides detailed description of PTCS (1) core neurobehavioral features, (2) associated neurobehavioral features, (3) functional implications, (4) exclusion criteria, (5) lower boundary, and (6) criteria for emergence. Core neurobehavioral features include disturbances of attention, orientation, and memory as well as excessive fluctuation. Associated neurobehavioral features include emotional and behavioral disturbances, sleep-wake cycle disturbance, delusions, perceptual disturbances, and confabulation. The lower boundary distinguishes PTCS from the minimally conscious state, while upper boundary is marked by significant improvement in the 4 core and 5 associated features. Key research goals are establishment of cutoffs on assessment instruments and determination of levels of behavioral function that distinguish persons in PTCS from those who have emerged to the period of continued recovery.


Subject(s)
Brain Injuries, Traumatic/psychology , Confusion/diagnosis , Consciousness Disorders/diagnosis , Mental Status and Dementia Tests/standards , Confusion/psychology , Consciousness Disorders/psychology , Consensus , Delphi Technique , Humans
16.
Neurocrit Care ; 33(2): 449-457, 2020 10.
Article in English | MEDLINE | ID: mdl-31900883

ABSTRACT

BACKGROUND/OBJECTIVE: Behavioral examinations may fail to detect language function in patients with severe traumatic brain injury (TBI) due to confounds such as having an endotracheal tube. We investigated whether resting and stimulus-evoked electroencephalography (EEG) methods detect the presence of language function in patients with severe TBI. METHODS: Four EEG measures were assessed: (1) resting background (applying Forgacs' criteria), (2) reactivity to speech, (3) background and reactivity (applying Synek's criteria); and (4) an automated support vector machine (classifier for speech versus rest). Cohen's kappa measured agreement between the four EEG measures and evidence of language function on a behavioral coma recovery scale-revised (CRS-R) and composite (CRS-R or functional MRI) reference standard. Sensitivity and specificity of each EEG measure were calculated against the reference standards. RESULTS: We enrolled 17 adult patients with severe TBI (mean ± SD age 27.0 ± 7.0 years; median [range] 11.5 [2-1173] days post-injury) and 16 healthy subjects (age 28.5 ± 7.8 years). The classifier, followed by Forgacs' criteria for resting background, demonstrated the highest agreement with the behavioral reference standard. Only Synek's criteria for background and reactivity showed significant agreement with the composite reference standard. The classifier and resting background showed balanced sensitivity and specificity for behavioral (sensitivity = 84.6% and 80.8%; specificity = 57.1% for both) and composite reference standards (sensitivity = 79.3% and 75.9%, specificity = 50% for both). CONCLUSIONS: Methods applying an automated classifier, resting background, or resting background with reactivity may identify severe TBI patients with preserved language function. Automated classifier methods may enable unbiased and efficient assessment of larger populations or serial timepoints, while qualitative visual methods may be practical in community settings.


Subject(s)
Consciousness , Language , Adult , Coma/diagnosis , Coma/etiology , Consciousness Disorders/diagnosis , Consciousness Disorders/etiology , Electroencephalography , Humans , Persistent Vegetative State
17.
Neurocrit Care ; 33(2): 364-375, 2020 10.
Article in English | MEDLINE | ID: mdl-32794142

ABSTRACT

There are currently no therapies proven to promote early recovery of consciousness in patients with severe brain injuries in the intensive care unit (ICU). For patients whose families face time-sensitive, life-or-death decisions, treatments that promote recovery of consciousness are needed to reduce the likelihood of premature withdrawal of life-sustaining therapy, facilitate autonomous self-expression, and increase access to rehabilitative care. Here, we present the Connectome-based Clinical Trial Platform (CCTP), a new paradigm for developing and testing targeted therapies that promote early recovery of consciousness in the ICU. We report the protocol for STIMPACT (Stimulant Therapy Targeted to Individualized Connectivity Maps to Promote ReACTivation of Consciousness), a CCTP-based trial in which intravenous methylphenidate will be used for targeted stimulation of dopaminergic circuits within the subcortical ascending arousal network (ClinicalTrials.gov NCT03814356). The scientific premise of the CCTP and the STIMPACT trial is that personalized brain network mapping in the ICU can identify patients whose connectomes are amenable to neuromodulation. Phase 1 of the STIMPACT trial is an open-label, safety and dose-finding study in 22 patients with disorders of consciousness caused by acute severe traumatic brain injury. Patients in Phase 1 will receive escalating daily doses (0.5-2.0 mg/kg) of intravenous methylphenidate over a 4-day period and will undergo resting-state functional magnetic resonance imaging and electroencephalography to evaluate the drug's pharmacodynamic properties. The primary outcome measure for Phase 1 relates to safety: the number of drug-related adverse events at each dose. Secondary outcome measures pertain to pharmacokinetics and pharmacodynamics: (1) time to maximal serum concentration; (2) serum half-life; (3) effect of the highest tolerated dose on resting-state functional MRI biomarkers of connectivity; and (4) effect of each dose on EEG biomarkers of cerebral cortical function. Predetermined safety and pharmacodynamic criteria must be fulfilled in Phase 1 to proceed to Phase 2A. Pharmacokinetic data from Phase 1 will also inform the study design of Phase 2A, where we will test the hypothesis that personalized connectome maps predict therapeutic responses to intravenous methylphenidate. Likewise, findings from Phase 2A will inform the design of Phase 2B, where we plan to enroll patients based on their personalized connectome maps. By selecting patients for clinical trials based on a principled, mechanistic assessment of their neuroanatomic potential for a therapeutic response, the CCTP paradigm and the STIMPACT trial have the potential to transform the therapeutic landscape in the ICU and improve outcomes for patients with severe brain injuries.


Subject(s)
Brain Injuries, Traumatic , Brain Injuries , Connectome , Consciousness , Humans , Intensive Care Units , Treatment Outcome
18.
J Int Neuropsychol Soc ; 25(3): 302-313, 2019 03.
Article in English | MEDLINE | ID: mdl-30681046

ABSTRACT

OBJECTIVES: Individuals with moderate-severe traumatic brain injury (TBI) experience a transitory state of impaired consciousness and confusion often called posttraumatic confusional state (PTCS). This study examined the neuropsychological profile of PTCS. METHODS: Neuropsychometric profiles of 349 individuals in the TBI Model Systems National Database were examined 4 weeks post-TBI (±2 weeks). The PTCS group was subdivided into Low (n=46) and High Performing PTCS (n=45) via median split on an orientation/amnesia measure, and compared to participants who had emerged from PTCS (n=258). Neuropsychological patterns were examined using multivariate analyses of variance and mixed model analyses of covariance. RESULTS: All groups were globally impaired, but severity differed across groups (F(40,506)=3.44; p<.001; ŋp 2 =.206). Rate of forgetting (memory consolidation) was impaired in all groups, but failed to differentiate them (F(4,684)=0.46; p=.762). In contrast, executive memory control was significantly more impaired in PTCS groups than the emerged group: Intrusion errors: F(2,343)=8.78; p<.001; ŋ p 2=.049; False positive recognition errors: F(2,343)=3.70; p<.05; ŋp 2=.021. However, non-memory executive control and other executive memory processes did not differentiate those in versus emerged from PTCS. CONCLUSIONS: Executive memory control deficits in the context of globally impaired cognition characterize PTCS. This pattern differentiates individuals in and emerged from PTCS during the acute recovery period following TBI. (JINS, 2019, 25, 302-313).


Subject(s)
Amnesia/physiopathology , Brain Injuries, Traumatic/physiopathology , Cognitive Dysfunction/physiopathology , Executive Function/physiology , Memory Consolidation/physiology , Mental Recall/physiology , Recognition, Psychology/physiology , Adolescent , Adult , Aged , Aged, 80 and over , Amnesia/etiology , Brain Concussion/complications , Brain Concussion/physiopathology , Brain Injuries, Traumatic/complications , Cognitive Dysfunction/etiology , Female , Follow-Up Studies , Humans , Male , Middle Aged , Young Adult
19.
Brain Inj ; 33(5): 610-617, 2019.
Article in English | MEDLINE | ID: mdl-30663426

ABSTRACT

OBJECTIVE: To study the predictive relationship among persons with traumatic brain injury (TBI) between an objective indicator of injury severity (the adapted Marshall computed tomography [CT] classification scheme) and clinical indicators of injury severity in the acute phase, functional outcomes at inpatient rehabilitation discharge, and functional and participation outcomes at 1 year after injury, including death. PARTICIPANTS: The sample involved 4895 individuals who received inpatient rehabilitation following acute hospitalization for TBI and were enrolled in the Traumatic Brain Injury Model Systems National Database between 1989 and 2014. DESIGN: Head CT variables for each person were fit into adapted Marshall CT classification categories I through IV. MAIN MEASURES: Prediction models were developed to determine the amount of variability explained by the CT classification categories compared with commonly used predictors, including a clinical indicator of injury severity. RESULTS: The adapted Marshall classification categories aided only in the prediction of craniotomy or craniectomy during acute hospitalization, otherwise making no meaningful contribution to variance in the multivariable models predicting outcomes at any time point after injury. CONCLUSION: Results suggest that head CT findings classified in this manner do not inform clinical discussions related to functional prognosis or rehabilitation planning after TBI. ABBREVIATIONS: CT: computed tomography; DRS: disability rating scale; EGOS: extended Glasgow outcome scale; FIM: functional independence measure; NDB: National Data Base; PTA: posttraumatic amnesia; RLOS: rehabilitation length of stay; SPOS: semipartial omega squared statistic; TBI: traumatic brain injury; TBIMS: Traumatic Brain Injury Model Systems.


Subject(s)
Brain Injuries, Traumatic/diagnostic imaging , Brain/diagnostic imaging , Disability Evaluation , Adult , Age Factors , Aged , Brain Injuries, Traumatic/rehabilitation , Female , Glasgow Outcome Scale , Humans , Injury Severity Score , Male , Middle Aged , Neuroimaging , Predictive Value of Tests , Prognosis , Recovery of Function , Tomography, X-Ray Computed , Young Adult
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