A multimodality intervention to improve musculoskeletal health, function, metabolism, and well-being in spinal cord injury: study protocol for the FIT-SCI randomized controlled trial.

BACKGROUND: A spinal cord injury (SCI) is a devastating, life-changing event that has profoundly deleterious effects on an individual's health and well-being. Dysregulation of neuromuscular, cardiometabolic, and endocrine organ systems following an SCI contribute to excess morbidity, mortality and a poor quality of life. As no effective treatments currently exist for SCI, the development of novel strategies to improve the functional and health status of individuals living with SCI are much needed. To address this knowledge gap, the current study will determine whether a Home-Based Multimodality Functional Recovery and Metabolic Health Enhancement Program that consists of functional electrical stimulation of the lower extremity during leg cycling (FES-LC) plus arm ergometry (AE) administered using behavioral motivational strategies, and testosterone therapy, is more efficacious than FES-LC plus AE and placebo in improving aerobic capacity, musculoskeletal health, function, metabolism, and wellbeing in SCI. METHODS: This single-site, randomized, placebo-controlled, parallel group trial will enroll 88 community-dwelling men and women, 19 to 70 years of age, with cervical and thoracic level of SCI, ASIA Impairment Scale grade: A, B, C, or D, 6 months or later after an SCI. Participants randomized to the multimodality intervention will undergo 16 weeks of home-based FES-LC and AE training plus testosterone undecanoate. Testosterone undecanoate injections will be administered by study staff in clinic or by a visiting nurse in the participant's home. The control group will receive 16 weeks of home-based FES-LC and AE exercise plus placebo injections. The primary outcome of this trial is peak aerobic capacity, measured during an incremental exercise testing protocol. Secondary outcomes include whole body and regional lean and adipose tissue mass; muscle strength and power; insulin sensitivity, lipids, and inflammatory markers; SCI functional index and wellbeing (mood, anxiety, pain, life satisfaction and depressive symptoms); and safety. DISCUSSION: We anticipate that a multimodality intervention that simultaneously addresses multiple physiological impairments in SCI will result in increased aerobic capacity and greater improvements in other musculoskeletal, metabolic, functional and patient-reported outcomes compared to the control intervention. The findings of this study will have important implications for improving the care of people living with an SCI. TRIAL REGISTRATION: ClinicalTrials.gov :  ( NCT03576001 ). Prospectively registered: July 3, 2018.

Association between intraoperative non-depolarising neuromuscular blocking agent dose and 30-day readmission after abdominal surgery.

BACKGROUND: We hypothesised that intraoperative non-depolarising neuromuscular blocking agent (NMBA) dose is associated with 30-day hospital readmission. METHODS: Data from 13,122 adult patients who underwent abdominal surgery under general anaesthesia at a tertiary care hospital were analysed by multivariable regression, to examine the effects of intraoperatively administered NMBA dose on 30-day readmission (primary endpoint), hospital length of stay, and hospital costs. RESULTS: Clinicians used cisatracurium (mean dose [SD] 0.19 mg kg-1 [0.12]), rocuronium (0.83 mg kg-1 [0.53]) and vecuronium (0.14 mg kg-1 [0.07]). Intraoperative administration of NMBAs was dose-dependently associated with higher risk of 30-day hospital readmission (adjusted odds ratio 1.89 [95% Confidence Interval (CI) 1.26-2.84] for 5th quintile vs 1st quintile; P for trend: P<0.001), prolonged hospital length of stay (adjusted incidence rate ratio [aIRR] 1.20 [95% CI 1.11-1.29]; P for trend: P<0.001) and increased hospital costs (aIRR 1.18 [95% CI 1.13-1.24]; P for trend: P<0.001). Admission type (same-day vs inpatient surgery) significantly modified the risk (interaction term: aOR 1.31 [95% CI 1.05-1.63], P=0.02), and the adjusted odds of readmission in patients undergoing ambulatory surgical procedures who received high-dose NMBAs vs low-dose NMBAs amounted to 2.61 [95% CI 1.11-6.17], P for trend: P<0.001. Total intraoperative neostigmine dose increased the risk of 30-day readmission (aOR 1.04 [1.0-1.08], P=0.048). CONCLUSIONS: In a retrospective analysis, high doses of NMBAs given during abdominal surgery was associated with an increased risk of 30-day readmission, particularly in patients undergoing ambulatory surgery.

Inter-site and inter-scanner diffusion MRI data harmonization.

We propose a novel method to harmonize diffusion MRI data acquired from multiple sites and scanners, which is imperative for joint analysis of the data to significantly increase sample size and statistical power of neuroimaging studies. Our method incorporates the following main novelties: i) we take into account the scanner-dependent spatial variability of the diffusion signal in different parts of the brain; ii) our method is independent of compartmental modeling of diffusion (e.g., tensor, and intra/extra cellular compartments) and the acquired signal itself is corrected for scanner related differences; and iii) inter-subject variability as measured by the coefficient of variation is maintained at each site. We represent the signal in a basis of spherical harmonics and compute several rotation invariant spherical harmonic features to estimate a region and tissue specific linear mapping between the signal from different sites (and scanners). We validate our method on diffusion data acquired from seven different sites (including two GE, three Philips, and two Siemens scanners) on a group of age-matched healthy subjects. Since the extracted rotation invariant spherical harmonic features depend on the accuracy of the brain parcellation provided by Freesurfer, we propose a feature based refinement of the original parcellation such that it better characterizes the anatomy and provides robust linear mappings to harmonize the dMRI data. We demonstrate the efficacy of our method by statistically comparing diffusion measures such as fractional anisotropy, mean diffusivity and generalized fractional anisotropy across multiple sites before and after data harmonization. We also show results using tract-based spatial statistics before and after harmonization for independent validation of the proposed methodology. Our experimental results demonstrate that, for nearly identical acquisition protocol across sites, scanner-specific differences can be accurately removed using the proposed method.

Controlled cortical impact injury affects dopaminergic transmission in the rat striatum.

The therapeutic benefits of dopamine (DA) agonists after traumatic brain injury (TBI) imply a role for DA systems in mediating functional deficits post-TBI. We investigated how experimental TBI affects striatal dopamine systems using fast scan cyclic voltammetry (FSCV), western blot, and d-amphetamine-induced rotational behavior. Adult male Sprague-Dawley rats were injured by a controlled cortical impact (CCI) delivered unilaterally to the parietal cortex, or were naïve controls. Amphetamine-induced rotational behavior was assessed 10 days post-CCI. Fourteen days post-CCI, animals were anesthetized and underwent FSCV with bilateral striatal carbon fiber microelectrode placement and stimulating electrode placement in the medial forebrain bundle (MFB). Evoked DA overflow was assessed in the striatum as the MFB was electrically stimulated at 60 Hz for 10 s. In 23% of injured animals, but no naïve animals, rotation was observed with amphetamine administration. Compared with naïves, striatal evoked DA overflow was lower for injured animals in the striatum ipsilateral to injury (p < 0.05). Injured animals exhibited a decrease in V(max) (52% of naïve, p < 0.05) for DA clearance in the hemisphere ipsilateral to injury compared with naïves. Dopamine transporter (DAT) expression was proportionally decreased in the striatum ipsilateral to injury compared with naïve animals (60% of naïve, p < 0.05), despite no injury-related changes in vesicular monoamine transporter or D2 receptor expression (DRD2) in this region. Collectively, these data appear to confirm that the clinical efficacy of dopamine agonists in the treatment of TBI may be related to disruptions in the activity of subcortical dopamine systems.

Gender and environmental effects on regional brain-derived neurotrophic factor expression after experimental traumatic brain injury.

Alterations in brain-derived neurotrophic factor expression have been reported in multiple brain regions acutely after traumatic brain injury, however neither injury nor post-injury environmental enrichment has been shown to affect hippocampal brain-derived neurotrophic factor gene expression in male rats chronically post-injury. Studies have demonstrated hormone-related neuroprotection for female rats after traumatic brain injury, and estrogen and exercise both influence brain-derived neurotrophic factor levels. Despite recent studies suggesting that exposure post-traumatic brain injury to environmental enrichment improves cognitive recovery in male rats, we have shown that environmental enrichment mediated improvements with spatial learning are gender specific and only positively affect males. Therefore the purpose of this study was to evaluate the effect of gender and environmental enrichment on chronic post-injury cortical and hippocampal brain-derived neurotrophic factor protein expression. Sprague-Dawley male and cycling female rats were placed into environmental enrichment or standard housing after controlled cortical impact or sham surgery. Four weeks post-surgery, hippocampal and frontal cortex brain-derived neurotrophic factor expression were examined using Western blot. Results revealed significant increases in brain-derived neurotrophic factor expression in the frontal cortex ipsilateral to injury for males (P=0.03). Environmental enrichment did not augment this effect. Neither environmental enrichment nor injury significantly affected cortical brain-derived neurotrophic factor expression for females. In the hippocampus ipsilateral to injury brain-derived neurotrophic factor expression for both males and females was half (49% and 51% respectively) of that observed in shams housed in the standard environment. For injured males, there was a trend in this region for environmental enrichment to restore brain-derived neurotrophic factor levels to sham values. However, there were robust increases in hippocampal brain-derived neurotrophic factor expression ipsilateral to the injury for injured females in environmental enrichment compared with both sham and injured females placed in standard housing (P

The minimally conscious state: definition and diagnostic criteria.

OBJECTIVE: To establish consensus recommendations among health care specialties for defining and establishing diagnostic criteria for the minimally conscious state (MCS). BACKGROUND: There is a subgroup of patients with severe alteration in consciousness who do not meet diagnostic criteria for coma or the vegetative state (VS). These patients demonstrate inconsistent but discernible evidence of consciousness. It is important to distinguish patients in MCS from those in coma and VS because preliminary findings suggest that there are meaningful differences in outcome. METHODS: An evidence-based literature review of disorders of consciousness was completed to define MCS, develop diagnostic criteria for entry into MCS, and identify markers for emergence to higher levels of cognitive function. RESULTS: There were insufficient data to establish evidence-based guidelines for diagnosis, prognosis, and management of MCS. Therefore, a consensus-based case definition with behaviorally referenced diagnostic criteria was formulated to facilitate future empirical investigation. CONCLUSIONS: MCS is characterized by inconsistent but clearly discernible behavioral evidence of consciousness and can be distinguished from coma and VS by documenting the presence of specific behavioral features not found in either of these conditions. Patients may evolve to MCS from coma or VS after acute brain injury. MCS may also result from degenerative or congenital nervous system disorders. This condition is often transient but may also exist as a permanent outcome. Defining MCS should promote further research on its epidemiology, neuropathology, natural history, and management.

Phenol and alcohol blocks for the treatment of spasticity.

The role of neurolytic agents in the treatment of tone disorders is not new. Exploration of their use, however, has been limited, and few studies address use in select populations. In practice use of phenol and alcohol blocks requires considerable experience and skill. This article will focus on mechanism of action, rationale for use, technique of administration, and potential side-effects.

Long-term recovery course after traumatic brain injury: a comparison of the functional independence measure and disability rating scale.

OBJECTIVES: To study group changes over time after traumatic brain injury (TBI). DESIGN: Prospective cohort. SETTING AND PARTICIPANTS: TBI Model System Database with 1160 subjects using cohort with complete data. MAIN OUTCOME MEASURES: Functional Independence Measure (FIM) and Disability Rating Scale (DRS) at rehabilitation discharge and annually after injury. RESULTS: Statistically significant differences existed between FIM-total, FIM-Motor, FIM-Cognitive subscales, and DRS at rehabilitation discharge and year 1. Comparisons of year-to-year intervals, years 1 and 3, 1 and 5, and 3 and 5, revealed no statistically significant differences except between years 1 and 3 and 1 and 5 with DRS, and years 1 and 5 with FIM. Including only those more dependent at year 1 revealed statistically significant differences between years 1 and 2 and 1 and 5 on FIM-Cognitive and DRS, but not the FIM-Motor. The proportion of change for FIM and DRS items from year 1 to years 2 and 5 revealed DRS Level of Functioning and Employability items accounted for most DRS change, whereas FIM change was more spread across its components. CONCLUSIONS: DRS is more sensitive to changes during a shorter time period than FIM and seems to be more appropriate for detecting long-term deficits. However, research studies aimed at detecting meaningful changes year to year after TBI may need to use other tools or consider changes among individuals instead of group changes. DRS Level of Function and Employability Items represent complex functions expected to recover later than the more basic DRS items. Sole use of these two DRS items might provide an efficient means of measuring long-term recovery when resources are limited, whereas expansion of these two items might allow greater sensitivity and detail.

Safety and feasibility of craniectomy with duraplasty as the initial surgical intervention for severe traumatic brain injury.

BACKGROUND: Decompressive craniectomy has historically served as a salvage procedure to control intracranial pressure after severe traumatic brain injury. We assessed the safety and feasibility of performing craniectomy as the initial surgical intervention. METHODS: Of 29 consecutive patients undergoing emergent decompression for severe traumatic brain injury with horizontal midline shift greater than explained by a removable hematoma, 17 had traditional craniotomy with or without brain resection and 12 underwent craniectomy. RESULTS: The craniectomy group had lower Glasgow Coma Scale scores at surgery (median, 4 vs. 7; p = 0.04) and more severe radiographic injuries (using specific measures). Mortality, Glasgow Outcome Scale scores, Functional Independence Measures, and length of stay in both the acute care setting and the rehabilitation phase were similar between the surgical groups. CONCLUSION: Despite more severe injury severity, patients undergoing initial craniectomy had outcomes similar to those undergoing traditional surgery. A randomized evaluation of the effect of early craniectomy on outcome is warranted.

Factors associated with balance deficits on admission to rehabilitation after traumatic brain injury: a multicenter analysis.

OBJECTIVE: To evaluate how demographics, measures of injury severity, and acute care complications relate to sitting and standing balance in patients with traumatic brain injury (TBI). DESIGN: Multicenter analysis of consecutive admissions to designated TBI Model Systems of Care (TBIMS). SETTING: Ten National Institute for Disability and Rehabilitation Research TBI Model System centers for coordinated acute and rehabilitation care. PARTICIPANTS: 908 adults with TBI were included in the study. MAIN OUTCOME MEASURES: Sitting and standing balance were assessed within 72 hours of admission to inpatient rehabilitation. RESULTS: Age less than 50 years had a significant association with normal sitting and standing balance (P =.001 and.05, respectively). Measures of severity of traumatic brain injury, including admission Glasgow Coma Score, length of posttraumatic amnesia (PTA), length of coma, and acute care length of stay were each significantly related to impaired sitting and standing balance ratings (P <.01). Initial abnormalities in pupillary response had a significant relationship with impairment of sitting (P =.009) but not standing balance. Incidence of respiratory failure, pneumonia, soft tissue infections, and urinary tract infections were all related to impaired sitting balance (P <.01). Presence of intracranial hemorrhages did not have a significant relationship with either sitting or standing balance. Intracranial compression had a significant relationship with standing (P =.05) but not sitting balance. A discriminant function analysis, which included neuroradiological findings, injury severity, and medical complications, could not accurately predict impaired balance ratings. CONCLUSIONS: This study demonstrated that rehabilitation admission balance ratings have a significant relationship with age, multiple measures of severity, and acute care medical complications after TBI. Prospective studies are indicated to evaluate the role balance at rehabilitation admission plays in the functional prognosis of patients with TBI.

Insomnia screening in postacute traumatic brain injury: utility and validity of the Pittsburgh Sleep Quality Index.

OBJECTIVE: To assess insomnia in a rehabilitation population, the authors examined the utility and validity of the Pittsburgh Sleep Quality Index (PSQI). The assessment of insomnia is relevant to the treatment of traumatic brain injury at the postacute level and routine screening for insomnia may be enhanced by the availability of a standardized, conveniently used, self-report sleep questionnaire. DESIGN: The authors prospectively studied 91 consecutive patients with traumatic brain injury who were admitted to an outpatient neurorehabilitation program. Besides administering the PSQI, Beck Depression Inventory, Epworth Sleepiness Scale, and Multidimensional Pain Inventory, sleep diary and interview data were obtained and used to divide subjects into insomnia and noninsomnia groups according to the criteria established by the Diagnostic and Statistical Manual of Mental Disorders, ed 4. RESULTS: Sensitivity and specificity rates to the clinical diagnosis of insomnia were 93% and 100%, respectively, for a PSQI Global Score of >8, and 83% and 100% for a diagnosis of insomnia based exclusively on PSQI-derived sleep variable data. Sleep diary data provided concurrent validity for PSQI estimates of sleep-onset latency, sleep duration, and sleep efficiency. The Beck Depression Inventory, Epworth Sleepiness Scale, and Multidimensional Pain Inventory established concurrent validity for individual PSQI items pertaining to mood, hypersomnia, and pain disturbance. CONCLUSION: The PSQI was demonstrated to be a valid and useful screening tool for assessing insomnia among postacute patients with traumatic brain injury.

Verbal recall and recognition following traumatic brain injury: a [0-15]-water positron emission tomography study.

Although several studies exist which have examined static functional neuroimaging following traumatic brain injury (TBI), controlled cognitive activation studies of episodic memory in this population have not been published. The present investigation studied verbal recall using [O-15]-water positron emission tomography (PET) in 5 individuals who sustained severe TBI (M GCS=6.8; M years post-injury=3.18), and 4 non-injured control participants. Statistical image analysis demonstrated changes in frontoparietal regional cerebral blood flow (rCBF) in both groups, but there were interesting differences between groups and across conditions. Frontal lobe rCBF changes in TBI patients were reduced during free recall but enhanced during recognition, when compared to controls. Changes in cerebellar rCBF were observed in the control group during free recall, but not in the TBI sample. In both groups, bifrontal rCBF increases were noted on recognition tasks. The present findings provide evidence of alterations in specific substrates involved in verbal recall following brain injury.

Penetrating head injury: a prospective study of outcomes.

The purpose of our study was to describe the outcomes of persons with penetrating brain injury resulting from a gunshot wound to the head. It is a prospective study of 442 patients admitted with gunshot wounds to the head over a 7 year period to our University Trauma Center Emergency Department, an urban trauma center and an inpatient rehabilitation hospital with a specialized brain injury unit. Measures and factors described include initial Glasgow Coma Scale score, Revised Trauma Score, the Disability Rating Scale, Functional Independence Measure, levels of cognitive functioning, patient demographics, length of stay, hospital charges, and discharge disposition. Initially 36% of patients expired in or were dead upon arrival to the Emergency Department; 64% of patients survived to be admitted for inpatient care. Of those admitted, 41% expired within the first 48 h of admission. Fifty-two percent of those admitted had severe injuries, 7% moderate injuries, and 42% had mild head injuries. Sixty-two percent of the survivors were discharged from acute care to private residences. The remaining 38% were discharged to programs providing varying levels of care depending upon their level of functioning and care needs. Patients sustaining severe injuries following gunshot wound(s) to the head have high early mortality. Survivors able to participate in an inpatient rehabilitation program have good potential for functional improvement.

Severe penetrating head injury: a study of outcomes.

OBJECTIVE: To determine and describe the demographics and functional outcomes of persons who require inpatient rehabilitation for severe penetrating head injury resulting from a gunshot wound to the head. DESIGN: Data were collected prospectively from the time of admission to acute care through discharge from inpatient rehabilitation. SETTING: Two sites: an urban, level I, acute care, trauma center and an inpatient rehabilitation hospital with a specialized brain injury unit. PARTICIPANTS: Twenty-seven persons with severe penetrating head injury. MAIN OUTCOME MEASURES: The FIM instrument, the Disability Rating Scale (DRS), and the length of stay (LOS). RESULTS: Demographic data showed our population to be similar to other groups of persons at high risk for violent injury. Eighty-five percent of the subjects were men with a mean age of 34 years. The majority were African American (93%), reflective of our general patient population. Average acute care LOS was 31 days and average rehabilitation LOS was 44 days. Average FIM gain was 40.2 and, on average, DRS scores improved 7.6 points from rehabilitation admission to discharge. All study participants made enough progress to be discharged to private residences. CONCLUSION: Although the mortality rate is high among patients with penetrating head injury, those who survive to receive inpatient rehabilitation can achieve functional improvement.

Factors associated with insomnia among post-acute traumatic brain injury survivors.

This study investigated the relationships between insomnia and select demographic, injury and psychosocial variables in post-acute, traumatic brain injury. Clinical assessment of sleep and mood was undertaken via objective measures and a diagnostic interview among 91 consecutive brain injury admissions to an outpatient neurorehabilitation clinic. No associations between insomnia and gender, education, age, and time since injury were found. A logistic regression model of insomnia prediction based upon the Beck Depression Inventory (BDI), self-reported pain disturbance, litigation and Glasgow Coma Score (GCS) correctly classified 87% of the sample with respect to the presence or absence of insomnia; however, depression and injury severity were the only variables that made a significant unique contribution to the prediction of insomnia. It is concluded that among post-acute traumatic brain injury patients, insomnia is linked with both the presence of depression and a history of milder brain injuries. This suggests that the determinants of insomnia may differ from the acute to the post-acute phase, with neurological factors playing a primary role early in the recovery process and psychosocial factors ascending later. Therefore, assessment and treatment of insomnia must give careful attention to the larger psychosocial context in which the sleep disorder emerges, particularly to role of emotional disturbance.

The hippocampus: anatomy, pathophysiology, and regenerative capacity.

Cognitive deficits following insults to the central nervous system-particularly those involving the hippocampus and related structures-are often persistent and severely debilitating. Progress has been made in establishing the role of the hippocampus in integrating information in the formation of memory necessary for subsequent recollection of information. The present article will review anatomic, physiological, and functional aspects of the hippocampus in reference to learning and memory. Both animal and human hippocampal pathophysiological processes will be explored. Adaptive and maladaptive central nervous system responses will be reviewed, with a special emphasis on neurogenesis. Ideally, physiological and cellular compensatory responses ought to parallel clinical observation. However, this association is not clearly established. Finally, the current understanding of neuromodulatory mechanisms (although quite preliminary) will also be discussed.