Ann Guernon

Repetitive transcranial magnetic stimulation-associated neurobehavioral gains during coma recovery

BACKGROUND Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive method to induce changes in cortical neural excitability. This report presents findings from the first participant of a safety and efficacy study that examined a therapeutic rTMS protocol for persons with severe traumatic brain injury (TBI). OBJECTIVE The primary hypothesis was that there will be no adverse events related to the provision of a 6-week rTMS protocol for persons with severe TBI who remain, at best, in a minimally conscious state for longer than 3 months. The secondary hypothesis was that the rTMS protocol would induce significant neurobehavioral gains during treatment and that these gains would persist at 6-week follow-up. METHODS A 6-week rTMS protocol (30 sessions) was delivered to a 26-year-old man who remained in a vegetative state 287 days after severe TBI. Stimulation was directed over the right dorsolateral prefrontal cortex. Repeated safety measures, neurobehavioral assessments, clinical examinations, and evoked potentials (EP) were obtained at baseline, every fifth rTMS session (weekly), and at a 6-week follow-up. RESULTS There were no adverse events related to the provision of rTMS treatment. A trend toward significant (P = .066) neurobehavioral gains was temporally related to provision of rTMS. Left-sided brain stem auditory EP wave V latencies and waves I to V interpeak latencies improved along with neurobehavioral gains during provision of rTMS, suggesting that improved neural conduction in the pathway mediated the neurobehavioral improvements. CONCLUSIONS Repetitive TMS merits further investigation as a safe therapeutic intervention to alter neural activity, to modulate neural activity, and/or to facilitate recovery in persons with disordered consciousness subsequent to severe TBI.

A measure of neurobehavioral functioning after coma. Part II: Clinical and scientific implementation

This is a longitudinal validation study that is Part II of a two-part series. Part I focuses on the methods used to construct the neurobehavioral measure derived from the Disorders of Consciousness Scale (DOCS) as well as the evidence of reliability and validity. Part II illustrates, through a series of selected case reports, the clinical use of repeated DOCS measures to enhance and complement medical rehabilitation management. The use of repeated DOCS measures in scientific investigations of mechanisms of injury is also described. Participants included patients at rehabilitation hospitals who were 18 years of age and older and unconscious after severe brain injury. Medical decision making regarding short-term effects of pharmacological intervention was augmented and improved through the examination of individual neurobehavioral recovery patterns. We identified medications to treat secondary medical complications and successfully determined effective dosage, presumably improving prognosis for recovery. We facilitated and enhanced development and refinement of individualized rehabilitation programs. Two investigations of treatment effectiveness during coma recovery and examination of the relationship between behavioral changes and neural adaptation are also described. By systematically tracking and mapping individual patterns of neurobehavioral recovery, we show that medical and rehabilitation management after coma can be enhanced. In addition, we also show that by examining the relationship between the DOCS neurobehavioral measure with mechanistic indicators of neurological recovery such as functional magnetic resonance imaging, scientific investigations of treatment and rehabilitation effectiveness can be enhanced.

Medical Comorbidities in Disorders of Consciousness Patients and Their Association With Functional Outcomes

OBJECTIVE To identify, for patients in states of seriously impaired consciousness, comorbid conditions present during inpatient rehabilitation and their association with function at 1 year. DESIGN Abstracted data from a prospective cross-sectional observational study with data collection occurring January 1996 through December 2007. SETTING Four inpatient rehabilitation facilities in metropolitan areas. PARTICIPANTS The study sample of 68 participants is abstracted from a database of 157 patients remaining in states of seriously impaired consciousness for at least 28 days. INTERVENTIONS Not applicable. MAIN OUTCOME MEASURE One-year cognitive, motor, and total FIM score. RESULTS The most common medical complications during inpatient rehabilitation for the study sample are active seizures (46%), spasticity (57%), urinary tract infections (47%), and hydrocephalus with and without shunt (38%). Presence of ≥3 medical complications during inpatient rehabilitation, controlling for injury severity, is significantly (P<.05) associated with poorer total FIM and FIM motor scores 1 year after injury. The presence of hydrocephalus with and without shunt (r=-.20, -.21, -.18; P ≤.15), active seizures (r=-.31, -.22, -.42), spasticity (r=-.38, -.28, -.40), and urinary tract infections (r=-.25, -.24, -.26) were significantly (P<.10) associated with total FIM, FIM cognitive, and FIM motor scores, respectively. CONCLUSIONS Reported findings indicate that persons in states of seriously impaired consciousness with higher numbers of medical complications during inpatient rehabilitation are more likely to have lower functional levels 1-year postinjury. The findings indicate that persons with ≥3 medical complications during inpatient rehabilitation are at a higher risk for poorer functional outcomes at 1 year. It is, therefore, prudent to evaluate these patients for indications of these complications during inpatient rehabilitation.

Placebo-Controlled Trial of Familiar Auditory Sensory Training for Acute Severe Traumatic Brain Injury: A Preliminary Report

Background. Sensory stimulation is often provided to persons incurring severe traumatic brain injury (TBI), but therapeutic effects are unclear. Objective. This preliminary study investigated neurobehavioral and neurophysiological effects related to sensory stimulation on global neurobehavioral functioning, arousal, and awareness. Methods. A double-blind randomized placebo-controlled trial where 15 participants in states of disordered consciousness (DOC), an average of 70 days after TBI, were provided either the Familiar Auditory Sensory Training (FAST) or Placebo of silence. Global neurobehavioral functioning was measured with the Disorders of Consciousness Scale (DOCS). Arousal and awareness were measured with the Coma-Near-Coma (CNC) scale. Neurophysiological effect was measured using functional magnetic resonance imaging (fMRI). Results. FAST (n = 8) and Placebo (n = 7) groups each showed neurobehavioral improvement. Mean DOCS change (FAST = 13.5, SD = 8.2; Placebo = 18.9, SD = 15.6) was not different, but FAST patients had significantly (P = .049; 95% confidence interval [CI] = −1.51, −.005) more CNC gains (FAST = 1.01, SD = 0.60; Placebo = 0.25, SD = 0.70). Mixed-effects models confirm CNC findings (P = .002). Treatment effect, based on CNC, is large (d = 1.88, 95% CI = 0.77, 3.00). Number needed to treat is 2. FAST patients had more fMRI activation in language regions and whole brain (P values <.05) resembling healthy controls’ activation. Conclusions. For persons with DOC 29 to 170 days after TBI, FAST resulted in CNC gains and increased neural responsivity to vocal stimuli in language regions. Clinicians should consider providing the FAST to support patient engagement in neurorehabilitation.

Predictive Value of the Disorders of Consciousness Scale (DOCS)

To examine the predictive validity of measures of neurobehavioral change derived from the Disorders of Consciousness Scale (DOCS) for predicting return to consciousness 4, 8, and 12 months after severe brain injury (BI).

Establishing a prognosis for functional outcome during coma recovery

Primary objective: One of the most challenging tasks for clinicians caring for survivors of severe brain injury (BI) is establishing a prognosis, for long-term functional outcome, while the patient is unconscious. The objective of this article is to report findings regarding the prediction of functional outcomes 1-year after severe BI using data available when the patient is unconscious. Research design: Longitudinal prognostication study. Methods and procedures: Persons unconscious after severe BI who present to inpatient (IP) rehabilitation hospitals in the Midwestern US are enrolled in an ongoing study. Each subject is followed for 1-year and the final outcome interview includes ∼70 questions; 32 of these questions are from the Craig Handicap Assessment and Reporting Technique (CHART). A sample of 63 persons was abstracted from the study database to examine the predictability of 42 independent variables and 16 dichotomous outcomes. Main outcomes and results: Twelve of the 16 dichotomous outcomes were found to be significantly predictable (p < 0.05). These involve activity, participation, environment and quality of life outcomes. Ten predictors were found to be significant (p < 0.05): aetiology (Closed Head Injury vs. Other BI), presence of urinary tract infection (UTI), seizure, hypertension during IP rehabilitation, veteran benefit eligibility, health insurance, marital status at injury, whether or not recovery of consciousness occurred within 1 year, the number of days between injury and admission to acute rehabilitation and the average length of IP rehabilitation stay. Eight of the 10 variables are available early after injury or when the patient is unconscious.

Psychometric Properties of the Disorders of Consciousness Scale

OBJECTIVE To provide evidence for psychometric properties of the Disorders of Consciousness Scale (DOCS). DESIGN Prospective observational cohort. SETTINGS Seven rehabilitation facilities. PARTICIPANTS Patients (N=174) with severe brain injury. INTERVENTIONS Not applicable. MAIN OUTCOME MEASURE DOCS RESULTS Initial analyses suggested eliminating 6 items to maximize psychometrics, resulting in the DOCS-25. The 25 items form a unidimensional hierarchy, rating scale categories are ordered, there are no misfitting items, and differential item functioning was not found according to sex, type of brain injury, veteran status, and days from onset. Person separation reliability (.91) indicates that the DOCS-25 is appropriate for individual patient measurement. Items are well targeted to the sample, with the difference between mean person and item calibrations less than 1 logit. DOCS-25 Rasch measures result in a 62% gain in relative precision over total raw scores. Internal consistency is very good (Cronbach α=.86); interrater agreement is excellent (intracIass correlation coefficient=.90) for both the DOCS-25 and the sensory subscales. The DOCS-25 total measure, but not subscale measures, correlates with the Glasgow Coma Scale and the Coma/Near-Coma Scales and distinguishes significantly between vegetative and minimally conscious states, indicating concurrent validity. CONCLUSIONS The DOCS-25 is psychometrically strong. It has excellent measurement precision and captures a broad range of patient function, which is critical for capturing recovery of consciousness. The sensory subscales are clinically informative but should not be reported as separate measures. The Keyform synthesizes clinical observations to visualize response patterns with potential for informing clinical decision-making. Future studies should determine sensitivity to change, examine issues of rater severity, and explore the usefulness of the Keyform in clinical practice.

Predicting levels of independence with expressing needs and ideas 1 year after severe brain injury

PURPOSE/OBJECTIVE Severe brain injury (BI) is a catastrophic event often evolving into a complex chronic and severely disabling condition making activity participation possible only with sustained caregiving. One aspect of building sustainable caregiving is early provision of information about expected outcomes germane to patients and their caregivers. An analysis was conducted to determine whether 2 levels of independence with expressing needs and ideas 1-year after severe BI could be predicted using variables available early after injury. METHOD The authors examined a subsample (n = 79) of participants of an outcome study who received repeated neurobehavioral evaluations with the Disorders of Consciousness Scale (DOCS) and who were assessed 1 year after injury with the Functional Independence Measures (FIM). Explanatory variables included DOCS measures, patient characteristics, coexisting conditions, and interventions. The outcome is measured with the FIM Expression item. Optimal data analysis was used to construct multivariate classification tree models. RESULTS The 2nd (p = .004) DOCS visual measure and seizure (p = .004) entered the final model providing 79% accuracy in classifying more or less independence with expressing needs and ideas at 1 year. The model will correctly identify 78% of future severe BI survivors who will have more independence and 82% of persons who will have less independence. CONCLUSIONS For persons incurring severe BI, it is possible to predict, early after injury, more and less independence with expressing needs and ideas 1-year after injury. This evidence is 1 contribution to a larger body of evidence needed to enable early caregiver education about recovery expectations in terms of patient functioning relative to caregiving needs, which in turn will help build sustainable caregiving for this population.

Preliminary framework for familiar auditory sensory training (FAST) provided during coma recovery

Since there remains a need to examine the nature of the neural effect and therapeutic efficacy/effectiveness of sensory stimulation provided to persons in states of seriously impaired consciousness, a passive sensory stimulation intervention, referred to as the Familiar Auditory Sensory Training (FAST) protocol, was developed for examination in an ongoing, double-blind, randomized clinical trial (RCT). The FAST protocol is described in this article according to the preliminary framework, which is a synthesis of knowledge regarding principles of plasticity and capabilities of the human brain to automatically and covertly process sensory input. Feasibility issues considered during the development of the intervention are also described. To enable replication of this intervention, we describe procedures to create the intervention and lessons learned regarding the creation process. The potential effect of the intervention is illustrated using functional brain imaging of nondisabled subjects. This illustration also demonstrates the relevance of the rationale for designing the FAST protocol. To put the intervention within the context of the scientific development process, the article culminates with a description of the study design for the ongoing RCT examining the efficacy of the FAST protocol.

RTMS safety for two subjects with disordered consciousness after traumatic brain injury.

Since our initial publication regarding provision of a repetitive transcranial magnetic stimulation (rTMS) protocol to a patient in the vegetative state (VS) [1e3] eight months after traumatic brain injury (TBI) [4], there remains limited rTMS safety data for this population. Therefore, we report safety data for twomore patients who received this same rTMS protocol [4]. The study was conducted with an FDA investigational device exemption (IDE #G040195) and IRB-approved informed consent was obtained. Patient #1, a 54-year-old male was in VS when he was enrolled 188 days after incurring a TBI. At injury, his Glasgow Coma Scale (GCS) [5] score was 6. He had diffuse axonal injury involving the splenium, dorsolateral midbrain and upper pons. Although he never had a documented seizure, he was placed on prophylactic levetiracetam (500 mg BID). Study eligibility criteria included being both seizure free and off anti-epileptic medications, but baseline electroencephalography (EEG) studies showed no epileptiform activity. The FDA, therefore, approved subject enrollment contingent upon provision of levetiracetam during rTMS. Patient #2, a 32-year-old male was enrolled nine years after incurring a TBI. His GCS score at injury was 6 and he required emergent right craniectomy with evacuation of subdural hematoma and repeat surgery two days later for epidural hematoma evacuation. He required implantation of a left ventriculoperitoneal (VP) shunt with a programmable Strata II valve (Medtronic Neurological, Minneapolis, MN). During the sixmonths prior to enrollment no clinical seizures were documented. At enrollment, head CT showed multicystic encephalomalacia of almost the entire right cerebral hemisphere and most of the basal ganglia as well as hypoattenuation in the anterior frontal lobe and dilatation of third and lateral ventricles. During study procedures, provided in an acute research unit, patients did not receive central nervous system stimulants. Patient safety was monitored in accordance with a data safety monitoring plan (DSMP) specifying how 15 indicators, previously described [4], are monitored for change using a five-point scale where higher numbers indicate more deleterious change. Weekly structural MRIs and daily pre/post rTMS EEGs were compared to baseline EEG. While it was unlikely that rTMS would dislodge a VP valve [6], we added shunt monitoring indicators to the DSMP due to risk for alteration of valve pressure which was checked and reset (as needed) following each rTMS session and each MRI. Skull x-rays were used to monitor for gross shunt movement.