Targeted Intervention Improves Symptoms and Impairments in Patients With Mild Traumatic Brain Injury With Chronic Symptom: A Prospective, Multiple Interventional Research Trial.

BACKGROUND: Mild traumatic brain injury (mTBI) and its potential long-term consequences is a primary concern for the US military. The purpose of the study is to evaluate if participants improved in anxiety/mood symptoms, sleep quality, and vestibular/ocular symptoms following a 6-month active intervention, and to explore the effect of targeted treatment for those with specific symptoms/impairments (e.g., psychological, sleep, ocular, vestibular). MATERIALS AND METHODS: A multidisciplinary clinical team adjudicated participants (n=72, 35.8±8.6 years old, 19% female) to have one of the following primary clinical trajectories: psychological (PSYCH; n=34), sleep (SLEEP; n=25) and vestibular/ocular (VESTIB/OCULAR; n=18). Participants returned for follow-up assessment 6 months later. Assessments included the Post-Concussion Symptom Scale [PCSS], Generalized Anxiety Disorder-7 [GAD-7], Pittsburgh Sleep Quality Index [PSQI], and Dizziness Handicap Inventory [DHI]. Change in concussion symptoms and primary outcome for the given trajectory (i.e., PSYCH=GAD-7, SLEEP=PSQI, VESTIB/OCULAR=DHI) was assessed. RESULTS: Following the 6-month intervention, participants reduced PCSS Score (-14.5±2.4; p<.001; η2=0.34), GAD-7 (-3.1±0.5; p<.001; η2=0.34), PSQI (-2.7±0.5; p<.001; η2=0.34) and DHI (-9.2±2.0; p<.001; η2=0.23). PSYCH (n=34) reduced PCSS score (-17.9±3.6; p<.001; η2=0.45) and GAD-7 (-3.1±0.7; p<.001; η2=0.38). SLEEP (n=25) reduced PCSS score (-8.8±4.4; p=.06; η2=0.15) and PSQI (-3.6±0.9; p<.001; η2=0.45) scores. VESTIB/OCULAR (n=18) reduced PCSS score (-16.7±4.8; p=.03; η2=0.45), and DHI (-15.7±5.5; p=.012; η2=0.35). CONCLUSIONS: Large effects were observed for concussion, anxiety, sleep, and dizziness symptom reduction over 6-month treatment. Each primary outcome demonstrated a larger treatment effect for the given trajectory than the overall sample, indicating that targeted treatment can reduce symptom burden in patients with mTBI with chronic symptoms.

[18F]FDG, [11C]PiB, and [18F]AV-1451 PET Imaging of Neurodegeneration in Two Subjects With a History of Repetitive Trauma and Cognitive Decline.

Background: Trauma-related neurodegeneration can be difficult to differentiate from multifactorial neurodegenerative syndromes, both clinically and radiographically. We have initiated a protocol for in vivo imaging of patients with suspected TBI-related neurodegeneration utilizing volumetric MRI and PET studies, including [18F]FDG indexing cerebral glucose metabolism, [11C]PiB for Aß deposition, and [18F]AV-1451 for tau deposition. Objective: To present results from a neuroimaging protocol for in vivo evaluation of TBI-related neurodegeneration in patients with early-onset cognitive decline and a history of TBI. Methods: Patients were enrolled in parallel TBI studies and underwent a comprehensive neuropsychological test battery as well as an imaging protocol of volumetric MRI and PET studies. Findings from two patients were compared with two age-matched control subjects without a history of TBI. Results: Both chronic TBI patients demonstrated cognitive deficits consistent with early-onset dementia on neuropsychological testing, and one patient self-reported a diagnosis of probable early-onset AD. Imaging studies demonstrated significant [18F]AV-1451 uptake in the bilateral occipital lobes, substantial [11C]PiB uptake throughout the cortex in both TBI patients, and abnormally decreased [18F]FDG uptake in the posterior temporoparietal areas of the brain. One TBI patient also had subcortical volume loss. Control subjects demonstrated no appreciable [18F]AV-1451 or [11C]PiB uptake, had normal cortical volumes, and had normal cognition profiles on neuropsychological testing. Conclusions: In the two patients presented, the [11C]PiB and [18F]FDG PET scans demonstrate uptake patterns characteristic of AD. [11C]PiB PET scans showed widespread neocortical uptake with less abnormal uptake in the occipital lobes, whereas there was significant [18F]AV-1451 uptake in both occipital lobes.

Impact of Multi-Disciplinary Care and Clinical Coach Coordinators on Participant Satisfaction and Retention in TBI Clinical Trials: A TEAM-TBI Study.

BACKGROUND: Targeted Evaluation Action and Monitoring of Traumatic Brain Injury (TEAM-TBI) is a monitored, multiple interventional research identifying clinical profiles and assigns individualized, evidence-based treatment program. The objective of the current study was to assess overall participant satisfaction of the multi-disciplinary care team and approach. METHODS: Between 2014 and 2017, 90 participants completed the 4-day TEAM-TBI clinical intake evaluation resulting in individualized treatment recommendations followed by a six-month intervention phase follow-up. Inclusion criteria were: age 18-60, history of chronic TBI (>6 months post-injury) with refractory clinical sequelae at screening (Post-Concussion Symptom Scale [PCSS] score >30). RESULTS: A total of 85/90 (94%) participants completed the survey at baseline focusing on intake evaluation and approach; 90% of eligible participants also completed the follow-up time-point. Hundred percent of participants had a mean score of >4 across all questions at the initial time point." CONCLUSIONS: The multi-disciplinary care approach and individualized treatment plans of the TEAM-TBI study yielded high participant retention and satisfaction scores. The Clinical Coach component of the trial was one of the highest rated aspects of the program and was associated with participant motivation and high retention rates.

Preliminary Evidence for Improvement in Symptoms, Cognitive, Vestibular, and Oculomotor Outcomes Following Targeted Intervention with Chronic mTBI Patients.

Introduction: To determine if targeted, active interventions would improve symptoms and impairment in previously intractable patients with chronic mild traumatic brain injury (mTBI). Materials and Methods: Twenty-six (20 males; 6 females) out of 51 (51%) former military and civilian patients with chronic (1-3 yr) mTBI enrolled in the TEAM traumatic brain injury (TBI) study completed both an initial and 6-mo post-intervention comprehensive mTBI assessment including symptoms (Post-concussion Symptom Scale [PCSS], Dizziness Handicap Inventory [DHI]), cognitive (Immediate Post-concussion Assessment and Cognitive Testing [ImPACT]), vestibular/oculomotor (Vestibular/Ocular Motor Screening [VOMS]), balance (Activities-specific Balance Confidence [ABC] scale, Balance Error Scoring System [BESS]), and cervical (Neck Disability Index [NDI]). Patients were prescribed progressive, targeted interventions and therapies (e.g., behavioral, vestibular, vision, and exertion) that matched their mTBI clinical profile. A series of paired t-tests adjusted for multiple corrections were used to compare pre- and post-intervention assessment scores. Results: Patients demonstrated significant improvement from pre- to post-intervention on total symptoms (t = 2.69, p = 0.01), verbal memory (t = -1.96, p = 0.05), ABC balance score (t = -2.05, p = 0.05), smooth pursuits (t = 2.32, p = 0.04), near-point convergence distance (t = -3.58, p = 0.01), vestibular ocular reflex (t = 2.31, p = 0.03), and visual motion sensitivity (t = 2.43, p = 0.03). Conclusions: Previously recalcitrant patients with chronic complex mTBI demonstrated significant improvement in symptoms, cognitive, vestibular, oculomotor, and balance function following targeted interventions.

Amyloid-Beta Deposition is Associated with Increased Medial Temporal Lobe Activation during Memory Encoding in the Cognitively Normal Elderly.

BACKGROUND: Much is unknown about changes that occur in the brain in the years preceding the cognitive and functional impairment associated with Alzheimer disease (AD). This period before mild cognitive impairment is present has been referred to as preclinical AD, and is thought to begin with amyloid-beta deposition and then progress to neurodegeneration and functional brain circuit alterations. Prior studies have shown that there is increased medial temporal lobe activation on functional magnetic resonance imaging (fMRI) early in the course of mild cognitive impairment. It is unknown, however, whether this altered fMRI activity precedes cognitive impairment. The purpose of this study is to address this question using Pittsburgh Compound-B (PiB) imaging and fMRI in a sample of cognitively normal older adults. METHODS: Forty-four cognitively normal older adults underwent both PiB imaging and fMRI with a face-name memory task: 21 were classified as PiB(+) and 23 were PiB(-). Additionally, thorough cognitive and neuropsychological test batteries were administered outside the scanner. The main outcome measure in this study is fMRI activation in the medial temporal lobe during a face-name memory-encoding task. RESULTS: PiB(+) subjects showed higher fMRI activation during the memory task in the hippocampus relative to PiB(-) participants. CONCLUSIONS: The increased medial temporal lobe activation in preclinical AD, observed in this study, may serve as an early biomarker of neurodegeneration. Future studies are needed to clarify whether this functional biomarker can stratify AD risk among PiB(+) older adults.

White Matter Hyperintensity Accumulation During Treatment of Late-Life Depression.

White matter hyperintensities (WMHs) have been shown to be associated with the development of late-life depression (LLD) and eventual treatment outcomes. This study sought to investigate longitudinal WMH changes in patients with LLD during a 12-week antidepressant treatment course. Forty-seven depressed elderly patients were included in this analysis. All depressed subjects started pharmacological treatment for depression shortly after a baseline magnetic resonance imaging (MRI) scan. At 12 weeks, patients underwent a follow-up MRI scan, and were categorized as either treatment remitters (n=23) or non-remitters (n=24). Among all patients, there was as a significant increase in WMHs over 12 weeks (t(46)=2.36, P=0.02). When patients were stratified by remission status, non-remitters demonstrated a significant increase in WMHs (t(23)=2.17, P=0.04), but this was not observed in remitters (t(22)=1.09, P=0.29). Other markers of brain integrity were also investigated including whole brain gray matter volume, hippocampal volume, and fractional anisotropy. No significant differences were observed in any of these markers during treatment, including when patients were stratified based on remission status. These results add to existing literature showing the association between WMH accumulation and LLD treatment outcomes. Moreover, this is the first study to demonstrate similar findings over a short interval (ie 12 weeks), which corresponds to the typical length of an antidepressant trial. These findings serve to highlight the acute interplay of cerebrovascular ischemic disease and LLD.

Machine learning approaches for integrating clinical and imaging features in late-life depression classification and response prediction.

OBJECTIVE: Currently, depression diagnosis relies primarily on behavioral symptoms and signs, and treatment is guided by trial and error instead of evaluating associated underlying brain characteristics. Unlike past studies, we attempted to estimate accurate prediction models for late-life depression diagnosis and treatment response using multiple machine learning methods with inputs of multi-modal imaging and non-imaging whole brain and network-based features. METHODS: Late-life depression patients (medicated post-recruitment) (n = 33) and older non-depressed individuals (n = 35) were recruited. Their demographics and cognitive ability scores were recorded, and brain characteristics were acquired using multi-modal magnetic resonance imaging pretreatment. Linear and nonlinear learning methods were tested for estimating accurate prediction models. RESULTS: A learning method called alternating decision trees estimated the most accurate prediction models for late-life depression diagnosis (87.27% accuracy) and treatment response (89.47% accuracy). The diagnosis model included measures of age, Mini-mental state examination score, and structural imaging (e.g. whole brain atrophy and global white mater hyperintensity burden). The treatment response model included measures of structural and functional connectivity. CONCLUSIONS: Combinations of multi-modal imaging and/or non-imaging measures may help better predict late-life depression diagnosis and treatment response. As a preliminary observation, we speculate that the results may also suggest that different underlying brain characteristics defined by multi-modal imaging measures-rather than region-based differences-are associated with depression versus depression recovery because to our knowledge this is the first depression study to accurately predict both using the same approach. These findings may help better understand late-life depression and identify preliminary steps toward personalized late-life depression treatment.

White matter hyperintensity burden and disability in older adults: is chronic pain a contributor?

OBJECTIVE: To primarily explore differences in global and regional white matter hyperintensities (WMH) in older adults with self-reported disabling and nondisabling chronic low back pain (CLBP) and to examine the association of WMH with gait speed in all participants with CLBP. To secondarily compare WMH of the participants with CLBP with the pain-free controls. DESIGN: A cross-sectional, case-control study. SETTING: University of Pittsburgh. PARTICIPANTS: Twenty-four community-dwelling older adults: 8 with self-reported disabling CLBP, 8 with nondisabling CLBP, and 8 were pain-free. Exclusions were psychiatric or neurologic disorders (either central or peripheral), substance abuse, opioid use, or diabetes mellitus. METHODS: All participants underwent structural brain magnetic resonance imaging, and all participants with CLBP underwent the 4-m walk test. MAIN OUTCOME MEASUREMENTS: All the participants were assessed for both global and regional WMH by using an automated localization and segmentation method, and gait speed of participants with CLBP. RESULTS: The disabled group demonstrated statistically significant regional WMH in a number of left hemispheric tracts: anterior thalamic radiation (P = .0391), lower cingulate (P = .0336), inferior longitudinal fasciculus (P = .0367), superior longitudinal fasciculus (P = .0011), and the superior longitudinal fasciculus branch to the temporal lobe (P = .0072). Also, there was a statistically significant negative association (rs = -0.57; P = .0225) between the left lower cingulate WMH and the gait speed in all the participants with CLBP. There was a statistical difference in global WMH burden (P = .0014) and nearly all regional tracts (both left and right hemispheres) when comparing CLBP with pain-free participants. CONCLUSIONS: Our findings suggest that WMH is associated with, and hence, may be accelerated by chronic pain manifesting as perceived disability, given the self-reported disabled CLBP patients had the greatest burden, and the pain free the least, and manifesting as measurable disability, given increasing WMH was associated with decreasing gait speed in all chronic pain participants.

fMRI correlates of white matter hyperintensities in late-life depression.

OBJECTIVE: This study tests whether or not the structural white matter lesions that are characteristic of late-life depression are associated with alterations in the functional affective circuits of late-life depression. This study used an emotional faces paradigm that has been shown to engage the affective limbic brain regions. METHOD: Thirty-three elderly depressed patients and 27 nondepressed comparison subjects participated in this study. The patients were recruited through the NIMH-sponsored Advanced Center for Interventions and Services Research for the Study of Late-Life Mood Disorders at the University of Pittsburgh Center for Bioethics and Health Law. Structural and functional MRI was used to assess white matter hyperintensity (WMH) burden and functional magnetic resonance imaging (fMRI) blood-oxygen-level-dependent (BOLD) response on a facial expression affective-reactivity task in both elderly participants with nonpsychotic and nonbipolar major depression (unmedicated) and nondepressed elderly comparison subjects. RESULTS: As expected, greater subgenual cingulate activity was observed in the depressed patients relative to the nondepressed comparison subjects. This same region showed greater task-related activity associated with a greater burden of cerebrovascular white matter change in the depressed group. Moreover, the depressed group showed a significantly greater interaction of WMH by fMRI activity effect than the nondepressed group. CONCLUSIONS: The observation that high WMH burden in late-life depression is associated with greater BOLD response on the affective-reactivity task supports the model that white matter ischemia in elderly depressed patients disrupts brain mechanisms of affective regulation and leads to limbic hyperactivation.

Altered cerebral blood flow patterns associated with pathologic worry in the elderly.

BACKGROUND: Generalized anxiety disorder (GAD) is the most prevalent anxiety disorder among the elderly and has high functional and cognitive morbidity. However, late-life GAD is relatively understudied and its functional neuroanatomy is uncharted. Several imaging studies have suggested abnormalities in the cognitive control systems of emotion regulation in anxiety disorders in young adults. The aim of this study was to examine the neural correlates of emotion regulation in late-life GAD. METHOD: We compared 7 elderly GAD subjects and 10 elderly nonanxious comparison subjects using functional MRI. Regional cerebral blood flow (rCBF) was measured using pulsed arterial spin labeling perfusion MRI at rest and during an emotion regulation paradigm. RESULTS: Relative to the rest condition, elderly nonanxious comparison subjects had increased rCBF during worry induction (WI) in the right insula, bilateral amygdala, and associative temporooccipital areas. Elderly GAD subjects had increased rCBF during WI in the associative temporooccipital areas, but not in the insula or the amygdala. During worry suppression (WS), elderly nonanxious comparison subjects had increased rCBF in the prefrontal cortex (PFC) and dorsal ACC. Elderly GAD subjects had no changes in rCBF during WS in the PFC. CONCLUSIONS: When attempting to regulate their emotional responses, elderly anxious subjects failed to activate prefrontal regions involved in the downregulation of negative emotions. These results, showing that elderly anxious subjects are not effectively engaging the PFC in suppressing worry, may be clinically relevant for developing personalized therapeutic strategies for the treatment of late-life GAD.