Growth Hormone Alters Brain Morphometry, Connectivity, and Behavior in Subjects with Fatigue after Mild Traumatic Brain Injury.

Pituitary dysfunction with reduced growth hormone (GH) secretion is common in patients following traumatic brain injury (TBI), and these patients often develop chronic symptoms including fatigue and altered cognition. We examined 18 subjects with a history of mild TBI, fatigue, and insufficient GH secretion. Subjects received GH replacement in a year-long, double-blind, placebo-controlled, crossover study, and were assessed for changes in physical performance, body composition, resting energy expenditure, fatigue, sleep, mood, and neuropsychological status. Additionally, magnetic resonance imaging (MRI) was used to assess changes in brain structure and resting state functional connectivity. GH replacement resulted in decreased fatigue, sleep disturbance, and anxiety, as well as increased resting energy expenditure, improved body composition, and altered perception of submaximal effort when performing exercise testing. Associated brain changes included increased frontal cortical thickness and gray matter volume and resting state connectivity changes in regions associated with somatosensory networks. GH replacement altered brain morphology and connectivity and reduced fatigue and related symptoms in mild TBI patients. Additional studies are needed to understand the mechanisms causing TBI-related fatigue and symptom relief with GH replacement.

Functional Changes after Recombinant Human Growth Hormone Replacement in Patients with Chronic Traumatic Brain Injury and Abnormal Growth Hormone Secretion.

We explored the effects of recombinant human growth hormone (rhGH) replacement on physical and cognitive functioning in subjects with a moderate-to-severe traumatic brain injury (TBI) with abnormal growth hormone (GH) secretion. Fifteen individuals who sustained a TBI at least 12 months prior to study enrollment were identified as having abnormal GH secretion by glucagon stimulation testing (maximum GH response less than 8 ng/mL). Peak cardiorespiratory capacity, body composition, and muscle force testing were assessed at baseline and one year after rhGH replacement. Additionally, standardized neuropsychological tests that assess memory, processing speed, and cognitive flexibility, as well as self-report inventories related to depression and fatigue, were administered at baseline and 1 year after rhGH replacement. Comparison tests were performed with proper post hoc analyses. All analyses were carried out at α < 0.05. Peak O2 consumption, peak oxygen pulse (estimate of cardiac stroke volume), and peak ventilation all significantly increased (p < 0.05). Maximal isometric and isokinetic force production were not altered. Skeletal muscle fatigue did not change but the perceptual rating of fatigue was reduced by ∼25% (p = 0.06). Cognitive performance did not change significantly over time, whereas self-reported symptoms related to depression and fatigue significantly improved. The observed changes suggest that rhGH replacement has a positive impact on cardiorespiratory fitness and a positive impact on perceptual fatigue in survivors of TBI with altered GH secretion.

Post-traumatic hypopituitarism and fatigue.

Post-traumatic hypopituitarism (PTH) associated with chronic cognitive, psychiatric, and/or behavioural sequelae is common following moderate to severe traumatic brain injury (TBI). More specifically, due to a cascade of hormonal deficiencies secondary to PTH, individuals with TBI may experience debilitating fatigue that can negatively impact functional recovery, as it can limit participation in brain injury rehabilitation services and lead to an increase in maladaptive lifestyle practices. While the mechanisms underlying fatigue and TBI are not entirely understood, the current review will address the specific anatomy and physiology of the pituitary gland, as well as the association between pituitary dysfunction and fatigue in individuals with TBI.

Psychiatric Disease and Post-Acute Traumatic Brain Injury.

Psychiatric disorders are common following traumatic brain injury (TBI) and can include depression, anxiety, and psychosis, as well as other maladaptive behaviors and personality changes. The epidemiologic data of psychiatric disorders post-TBI vary widely, although the incidence and prevalence rates typically are higher than in the general population. Although the experience of psychiatric symptoms may be temporary and may resolve in the acute period, many patients with TBI can experience psychopathology that is persistent or that develops in the post-acute period. Long-term psychiatric disorder, along with cognitive and physical sequelae and greater risk for substance use disorders, can pose a number of life-long challenges for patients and their caregivers, as they can interfere with participation in rehabilitation as well as limit functional independence in the community. The current review of the literature considers the common psychiatric problems affecting individuals with TBI in the post-acute period, including personality changes, psychosis, executive dysfunction, depression, anxiety, and substance misuse. Although treatment considerations (pharmacological and nonpharmacological) are referred to, an extensive description of such protocols is beyond the scope of the current review. The impact of persistent psychiatric symptoms on perceived caregiver burden and distress is also discussed.

Neuropsychological and physiological correlates of fatigue following traumatic brain injury.

BACKGROUND: Fatigue is a common and debilitating phenomenon experienced by individuals with traumatic brain injury (TBI) that can negatively influence rate and extent of functional recovery by reducing participation in brain injury rehabilitation services and increasing maladaptive lifestyle practices. The underlying mechanisms of TBI-related fatigue are not entirely understood and focused research on symptom reduction or prevention is limited. REVIEW: The current review of the literature suggests that the aetiology of TBI-related fatigue can be viewed as a multifactorial and complex model impacting physiological systems (i.e. endocrine, skeletal muscle and cardiorespiratory) that can be directly or indirectly influenced by neuropsychological correlates including cognitive and psychological impairment. Distinguishing central from peripheral fatigue is helpful in this regard. Potential therapeutic strategies and pharmacological agents to help alleviate fatigue in this patient population are discussed.

Naming Test of the Neuropsychological Assessment Battery: reliability and validity in a sample of patients with acquired brain injury.

The current study assessed the internal consistency, alternate forms reliability, and convergent/divergent validity of the Naming Test of the Neuropsychological Assessment Battery (NAB) in patients with acquired brain injury. Fifty-nine patients were administered the NAB Naming Test (forms 1 and 2) and the Boston Naming Test (BNT), as well as other tests of neuropsychological functioning. Forms 1 and 2 of the NAB Naming Test demonstrated adequate internal consistency and alternate forms reliability. The NAB Naming Test was significantly associated with scores from the BNT, as well as scores from tests that assess visuospatial skills, semantic fluency, and verbal memory. The divergent validity of the NAB Naming Test was demonstrated by non-significant associations with tests of attention and processing speed. BNT scores correlated significantly with the educational level and estimated premorbid intelligence but not age, whereas the NAB Naming Test scores only correlated significantly with estimated premorbid intelligence. The current study provides independent validation supporting the utility of the NAB Naming Test for patients with acquired brain injury.

Ecological validity of the screening module and the Daily Living tests of the Neuropsychological Assessment Battery using the Mayo-Portland Adaptability Inventory-4 in postacute brain injury rehabilitation.

PURPOSE: The assessment of ecological validity of neuropsychological measures is an area of growing interest, particularly in the postacute brain injury rehabilitation (PABIR) setting, as there is an increasing demand for clinicians to address functional and real-world outcomes. In the current study, we assessed the predictive value of the Screening module and the Daily Living tests of the Neuropsychological Assessment Battery (NAB) using clinician ratings from the Mayo-Portland Adaptability Inventory-4 (MPAI-4) in patients with moderate to severe traumatic brain injury. METHOD: Forty-seven individuals were each administered the NAB Screening module (NAB-SM) and the NAB Daily Living (NAB-DL) tests following admission to a residential PABIR program. MPAI-4 ratings were also obtained at admission. Linear regression analysis was used to examine the association between these functional and neuropsychological assessment measures. RESULTS: We replicated prior work (Temple at al., 2009) and expanded evidence for the ecological validity of the NAB-SM. Furthermore, our findings support the ecological validity of the NAB-DL Bill Payment, Judgment, and Map Reading tests with regards to functional skills and real-world activities. CONCLUSIONS: The current study supports prior work from our lab assessing the predictive value of the NAB-SM, as well as provides evidence for the ecological validity for select NAB-DL tests in patients with moderate to severe traumatic brain injury admitted to a residential PABIR program.

Balint's syndrome and post-acute brain injury rehabilitation: a case report.

BACKGROUND: Balint's syndrome includes the clinical symptom triad of simultagnosia, ocular apraxia and optic ataxia. These symptoms, in combination, are rare and can be quite debilitating as they impact visuospatial skills, visual scanning and attentional mechanisms. CASE STUDY: The literature addressing rehabilitation of individuals with Balint's syndrome is sparse. The current case report describes the outcome of a 58-year old male who presented with Balint's syndrome secondary to severe traumatic brain injury and following completion of a comprehensive post-acute brain injury rehabilitation programme. The patient was 4-months post-injury onset upon admission and received 6 months of rehabilitation services as an inpatient. The patient's comprehensive rehabilitation programme involved a 3-pronged approach including the implementation of (a) compensatory strategies, (b) remediation exercises and (c) transfer of learned skills in multiple environments and situations with implementation of psychoeducation and psychotherapy. Comprehensive neuropsychological and occupational therapy evaluations were performed at admission and at discharge in order to monitor cognitive, affective, neurological and functional change over time. CONCLUSIONS: Neuropsychological test improvements were noted on tasks that assess visuospatial functioning, although most gains were noted for functional and physical abilities.

Serum IGF-1 concentrations in a sample of patients with traumatic brain injury as a diagnostic marker of growth hormone secretory response to glucagon stimulation testing.

OBJECTIVE: The diagnosis of growth hormone deficiency (GHD) in adults is established through growth hormone (GH) stimulation testing, which is often complex, expensive, time-consuming and may be associated with adverse side effects. The decision to perform GH provocative testing is influenced by clinical findings, medical history and biochemical evidence. We report in this study our experience using the glucagon stimulation test (GST) in assessing GHD in adult patients with traumatic brain injury (TBI) as it relates to baseline serum insulin-like growth factor-1 (IGF-1) concentrations. DESIGN: A receiver operating characteristic (ROC) curve analysis was performed to determine the optimal IGF-1 cut-off for diagnosis of GHD at different potential diagnostic GST cut-off values (<3, <5, & <10 µg/l). PATIENTS: One hundred and thirty-eight patients (98 men and 40 women) with a documented history of moderate to severe TBI were assessed for GHD using serum IGF-1 concentrations and the GST. MEASUREMENTS: IGF-1 values were compared with peak GH values obtained following the GST. RESULTS: An IGF-1 cut-off value of 175 µg/l minimized the misclassification of GHD patients and GH-sufficient patients and provided a sensitivity of 83% and specificity of 40%, as well as a negative predictive power of 90% considering a criterion for peak GH response of <3 µg/l. CONCLUSIONS: Our current findings are consistent with previous work assessing peak GH response using the insulin tolerance test (ITT) in a non-TBI sample, suggesting that diagnostic accuracy may be optimized if the GST is used when obtained serum IGF-1 concentrations are below 175 µg/l. While the decision to perform provocative testing to assess GHD in adult patients should be based on the clinician's clinical impression, the findings from this retrospective study can provide useful clinical information and serve as a guide.

Neuropsychological Assessment Battery (NAB): Performance in a sample of patients with moderate-to-severe traumatic brain injury.

The Neuropsychological Assessment Battery (NAB; Stern & White, 2003) is a comprehensive test battery that assesses five cognitive domains (Attention, Language, Memory, Spatial, and Executive Functions). The purpose of the current descriptive study was to present data on the index and primary test scores from the five main NAB cognitive modules in a sample of patients with moderate-to-severe traumatic brain injury (TBI) admitted to a residential postacute rehabilitation program. Twenty patients were administered all five main NAB modules upon recommendation from the NAB Screening module. The sample performed significantly worse than normal on tests that assess selective and divided attention, psychomotor speed, verbal memory, and cognitive flexibility. The largest proportion of patients performing below an established impairment cutoff (10th percentile) occurred on the Numbers and Letters, List Learning, Story Learning, Daily Living Memory, and Categories Tests. Significant performance decrements were not observed on any indices or tests from the Language or Spatial cognitive domain modules. The pattern of performance on the NAB demonstrated by the current sample is consistent with the neuropsychological profile observed in postacute patients with moderate-to-severe TBI without focal deficits (e.g., aphasia), demonstrating its relative sensitivity in this patient population. A comparison between the current study sample and a related clinical sample from the NAB standardization data is discussed.

Effect of growth hormone replacement therapy on cognition after traumatic brain injury.

Traumatic brain injury (TBI) is a major public health issue, and yet medical science has little to offer for the persistent symptoms that prevent many of these individuals from fully re-entering society. Post-traumatic hypopituitarism, and specifically growth hormone deficiency (GHD), has been found in a large percentage of individuals with chronic moderate to severe TBI. Presently, there are no published treatment studies of hormone replacement in this population. In this study, 83 subjects with chronic TBI were screened for hypopituitarism. Forty-two subjects were found to have either GHD or GH insufficiency (GHI), of which 23 agreed to be randomized to either a year of GH replacement or placebo. All subjects completed the study with no untoward side effects from treatment. A battery of neuropsychological tests and functional measures were administered before and after treatment. Improvement was seen on the following tests: Dominant Hand Finger Tapping Test, Wechsler Adult Intelligence Scale III-Information Processing Speed Index, California Verbal Learning Test II, and the Wisconsin Card Sorting Test (executive functioning). The findings of this pilot study provide preliminary evidence suggesting that some of the cognitive impairments observed in persons who are GHD/GHI after TBI may be partially reversible with appropriate GH replacement therapy.

Changes in supervision needs following participation in a residential post-acute brain injury rehabilitation programme.

OBJECTIVE: Supervision needs typically increase following moderate-to-severe traumatic brain injury (TBI). Research assessing the impact of TBI residential rehabilitation programmes on supervision needs is limited. RESEARCH DESIGN: Prospective cross-sectional study. METHODS AND PROCEDURES: Ninety-four participants with moderate-to-severe TBI admitted to a post-acute brain injury rehabilitation programme (PABIR) were administered the supervision rating scale (SRS) at admission and at 1 month post-discharge. To account for spontaneous neurological recovery, patients were separated into those who were less than 1 year (L1Y, n = 55) or greater than 1 year (G1Y, n = 39) post-injury. EXPERIMENTAL INTERVENTION: None. MAIN OUTCOMES AND RESULTS: A mixed factorial design yielded a significant interaction (F(1, 92) = 18.2; p < 0.0001) with post-hoc results revealing that the L1Y group improved more dramatically in terms of supervision needs than the G1Y group. Using reliable change methodologies, 52.7% of the L1Y demonstrated decreasing scores on the SRS vs 20.5% of the G1Y group. CONCLUSIONS: Decreases in supervision needs following PABIR can be found, even after accounting for the impact of spontaneous neurological recovery both at the group and individual level.

Reliability and validity of the Neuropsychological Assessment Battery-Screening Module (NAB-SM) in a sample of patients with moderate-to-severe acquired brain injury.

The Screening module from the Neuropsychological Assessment Battery (NAB-SM; Stern & White, 2003) is a comprehensive cognitive screening measure that assesses five domains (Attention, Language, Memory, Spatial, and Executive Functions). The construct validity of the NAB-SM in comparison to established neuropsychological (NP) measures in individuals with moderate-to-severe brain injury has yet to be investigated. Participants were 42 individuals with acquired brain injury admitted to a post-acute residential rehabilitation program. The NAB-SM cognitive domain index scores demonstrated weak internal consistency, whereas internal consistency for the NAB-SM total index score was satisfactory. In demonstrating construct validity, the NAB-SM cognitive domain index scores and individual subtest scores maintained several significant relationships with other NP tests that shared test structure and content or not. These relationships were limited or absent for the NAB-SM Executive Functions subtests and the NAB-SM Shape Learning subtest. Our findings provide preliminary support for the reliability and validity of the NAB-SM in a sample of patients with moderate-to-severe brain injury.

Effect of recombinant growth hormone replacement in a growth hormone deficient subject recovering from mild traumatic brain injury: A case report.

OBJECTIVE: To assess the effects of growth hormone (GH) replacement in an individual who sustained mild traumatic brain injury (mTBI) as an adult and was found to have GH deficiency by glucagon stimulation testing. PARTICIPANT: A 43-year old woman who sustained a mild TBI at age 37 years. She was 6.8 years post-injury when she began supplementation. INTERVENTION: Recombinant human GH (rhGH) subcutaneously per day for 1 year. MAIN OUTCOME MEASURES: Single fibre muscle function was evaluated from muscle biopsies. Body composition, muscle strength and peak aerobic capacity were also measured. In addition, neuropsychological tests of memory, processing speed and motor dexterity and speed, as well as a self-report depression inventory were administered. All assessments were performed at baseline and after 6 and 12 months of rhGH replacement therapy. RESULTS: Single muscle fibre changes were greatest at 6 months. Body composition showed continuous improvement. Muscle strength improved for knee extension. Peak oxygen consumption increased at 6 months and total work and ventilatory equivalents continued to improve at 12 months. Significant improvements in neuropsychological test performance were not found, with the exception of performance on a test of motor dexterity and speed. CONCLUSION: rhGH replacement in a subject with GH deficiency after mild TBI improves muscle force production, body composition and aerobic capacity. Reliable improvements on tests of cognition were not found in this subject.

Ecological validity of the neuropsychological assessment battery screening module in post-acute brain injury rehabilitation.

PRIMARY OBJECTIVE: To assess the ecological validity of the Screening Module of the Neuropsychological Assessment Battery (NAB-SM) using the Functional Independence Measure (FIM). METHOD: Seventy individuals with moderate-to-severe traumatic brain injury at a residential post-acute rehabilitation facility were administered the FIM instrument and the NAB-SM upon admission. Hierarchical regression analysis was used to examine the relationship between the variables from these two assessment measures. RESULTS: Hierarchical models revealed that (1) the NAB-SM Total score was significantly associated with the FIM instrument Total score as well as the Motor and Cognition sub-scale scores, above and beyond the contribution of demographic variables, (2) the NAB-SM Language, Memory and Spatial domain scores were significantly associated with of the FIM instrument Cognition sub-scale score and (3) the NAB-SM Spatial domain score was significantly associated with of the FIM instrument Total and Motor sub-scale scores. CONCLUSIONS: The current findings support previous research and provide strong evidence for the ecological validity of the NAB-SM with regard to functional abilities as assessed by the FIM instrument.

Relationship between self-reported apathy and executive dysfunction in nondemented patients with Parkinson disease.

OBJECTIVE: The prevalence of apathy was assessed across select cognitive and psychiatric variables in 32 nondemented patients with Parkinson disease (PD) and 29 demographically matched healthy control participants. BACKGROUND: Apathy is common in PD, although differentiating apathy from motor, cognitive, and/or other neuropsychiatric symptoms can be challenging. Previous studies have reported a positive relationship between apathy and cognitive impairment, particularly executive dysfunction. METHOD: Patients were categorized according to apathy symptom severity. Stringent criteria were used to exclude patients with dementia. RESULTS: Approximately 44% of patients endorsed significant levels of apathy. Those patients performed worse than patients with nonsignificant levels of apathy on select measures of verbal fluency and on a measure of verbal and nonverbal conceptualization. Further, they reported a greater number of symptoms related to depression and behavioral disturbance than did those patients with nonsignificant levels of apathy. Apathy was significantly related to self-report of depression and executive dysfunction. Performance on cognitive tasks assessing verbal fluency, working memory, and verbal abstraction and also on a self-report measure of executive dysfunction was shown to significantly predict increasing levels of apathy. CONCLUSIONS: Our findings suggest that apathy in nondemented patients with PD seems to be strongly associated with executive dysfunction.

An examination of executive dysfunction associated with frontostriatal circuitry in Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative movement disorder presenting with subcortical pathology and characterized by motor deficits. However, as is frequently reported in the literature, patients with PD can also exhibit cognitive and behavioral (i.e., nonmotor) impairments, cognitive executive deficits and depression being the most prominent. Considerable attention has addressed the role that disruption to frontostriatal circuitry can play in mediating nonmotor dysfunction in PD. The three nonmotor frontostriatal circuits, which connect frontal cortical regions to the basal ganglia, originate from the dorsolateral prefrontal cortex (DLPFC), anterior cingulate cortex (ACC), and orbitofrontal cortex (OFC). The objective of the current study was to use our understanding of frontostriatal circuit function (via literature review) to categorize neuropsychological measures of cognitive and behavioral executive functions by circuit. To our knowledge, such an approach has not been previously attempted in the study of executive dysfunction in PD. Neuropsychological measures of executive functions and self-report behavioral inventories, categorized by circuit function, were administered to 32 nondemented patients with Parkinson's disease (NDPD) and to 29 demographically matched, healthy normal control participants (NC). Our findings revealed significant group differences for each circuit, with the PD group performing worse than the NC group. Among the patients with PD, indices of impairment were greater for tasks associated with DLPFC function than with OFC function. Further, only an index of DLPFC test performance was demonstrated to significantly discriminate individuals with and without PD. In conclusion, our findings suggest that nondemented patients with PD exhibit greater impairment on neuropsychological measures associated with DLPFC than with ACC or OFC circuit function.

Posed prosodic emotional expression in unilateral stroke patients: recovery, lesion location, and emotional perception.

Recovery of emotional functioning following stroke has received limited attention in the neuropsychological literature. By emotional functioning, we refer to a range of processing modes, including perception, expression, experience, and behavior. The aim of the current study was to evaluate the course of prosodic emotional expression over time in individuals with stroke. Posed prosodic expression tasks from the New York Emotion Battery were administered to right brain-damaged (RBD), left brain-damaged (LBD), and demographically matched normal control (NC) participants at two separate testing times (median interval of 25 months). Posers (i.e., individuals producing the emotional expressions) were required to produce neutral-content sentences using four different emotional tones (happiness, sadness, anger, and fear). Raters judged poser output for accuracy, intensity, and confidence. For accuracy ratings, RBDs and LBDs were impaired relative to NCs at baseline. In terms of recovery, there was a tendency for LBDs to improve over time, and there was a significant decline for RBDs. Inspection of the group mean data suggested that frontal lesions had a negative impact on prosodic emotional expression in RBDs and that lesion extent did not systematically influence performance at baseline or over time. Participants maintained their relative standing on the NYEB expression tasks over time. Finally, no significant relationships were found between participant performance on prosodic emotional perception and expression tasks at either testing time, suggesting that these two processing modes are relatively independent.

Neuroimaging of Parkinson's disease and atypical parkinsonism.

The basal ganglia and its associated circuitry can be assessed with a variety of neuroimaging methods that can provide information regarding specific neurotransmitter systems, the functional activity of brain regions, and the structural integrity of these regions. In Parkinson's disease (PD) and related atypical parkinsonian syndromes (APS), these imaging methods may be useful for many reasons, including aiding in differential diagnosis and measuring the efficacy of new therapies. This paper reviews recent developments in the application of neuroimaging to the assessment of PD and related APS.

A review of the cognitive and behavioral sequelae of Parkinson's disease: relationship to frontostriatal circuitry.

BACKGROUND: Parkinson's disease is a neurodegenerative hypokinetic movement disorder presenting with subcortical pathology and characterized by motor deficits. However, as is frequently reported in the literature, patients with Parkinson's disease can also exhibit cognitive and behavioral impairments. These impairments may be attributed to dysfunction of multiple systems associated with the disease process in Parkinson's disease that are not necessarily related to motor symptoms. In recent years, considerable attention has addressed the circuits connecting the frontal cortical regions and the basal ganglia (i.e., frontostriatal circuits) and how they mediate cognition and behavior in humans. It has been suggested that these same circuits are disrupted in Parkinson's disease and may be responsible for the frontal/executive deficits predominantly reported in this patient population. OBJECTIVE: The current survey of the literature provides a critique and analysis of the neuropsychological profile of Parkinson's disease, including cognitive impairments, behavioral alterations, and emotional processing deficits. A special feature of this paper is to ascertain how frontostriatal circuitry might provide the substrate for the neuropsychological impairments exhibited in Parkinson's disease. In so doing, studies involving nonhuman subjects, neurologically healthy adults, brain-lesioned individuals, and patients with Parkinson's disease are reviewed to provide a novel perspective in conceptualizing and categorizing the cognitive and behavioral sequelae concomitant to specific frontostriatal circuit dysfunction in Parkinson's disease. CONCLUSIONS: The current review suggests that the neuropsychological profile of Parkinson's disease, which predominantly reflects frontal/executive dysfunction, may be attributed to disruption of the frontostriatal circuitry. The information generated from this review can serve as a guide in the assessment of frontal/executive dysfunction in Parkinson's disease with suggestions for a clinical neuropsychological test battery.