Tunable White Light for Elders (TWLITE): A Protocol Demonstrating Feasibility and Acceptability for Deployment, Remote Data Collection, and Analysis of a Home-Based Lighting Intervention in Older Adults.

Sleep disturbances are common in older adults and may contribute to disease progression in certain populations (e.g., Alzheimer's disease). Light therapy is a simple and cost-effective intervention to improve sleep. Primary barriers to light therapy are: (1) poor acceptability of the use of devices, and (2) inflexibility of current devices to deliver beyond a fixed light spectrum and throughout the entirety of the day. However, dynamic, tunable lighting integrated into the native home lighting system can potentially overcome these limitations. Herein, we describe our protocol to implement a whole-home tunable lighting system installed throughout the homes of healthy older adults already enrolled in an existing study with embedded home assessment platforms (Oregon Center for Aging & Technology-ORCATECH). Within ORCATECH, continuous data on room location, activity, sleep, and general health parameters are collected at a minute-to-minute resolution over years of participation. This single-arm longitudinal protocol collected participants' light usage in addition to ORCATECH outcome measures over a several month period before and after light installation. The protocol was implemented with four subjects living in three ORCATECH homes. Technical/usability challenges and feasibility/acceptability outcomes were explored. The successful implementation of our protocol supports the feasibility of implementing and integrating tunable whole-home lighting systems into an automated home-based assessment platform for continuous data collection of outcome variables, including long-term sleep measures. Challenges and iterative approaches are discussed. This protocol will inform the implementation of future clinical intervention trials using light therapy in patients at risk for developing Alzheimer's disease and related conditions.

Validation of Visually Identified Muscle Potentials during Human Sleep Using High Frequency/Low Frequency Spectral Power Ratios.

Surface electromyography (EMG), typically recorded from muscle groups such as the mentalis (chin/mentum) and anterior tibialis (lower leg/crus), is often performed in human subjects undergoing overnight polysomnography. Such signals have great importance, not only in aiding in the definitions of normal sleep stages, but also in defining certain disease states with abnormal EMG activity during rapid eye movement (REM) sleep, e.g., REM sleep behavior disorder and parkinsonism. Gold standard approaches to evaluation of such EMG signals in the clinical realm are typically qualitative, and therefore burdensome and subject to individual interpretation. We originally developed a digitized, signal processing method using the ratio of high frequency to low frequency spectral power and validated this method against expert human scorer interpretation of transient muscle activation of the EMG signal. Herein, we further refine and validate our initial approach, applying this to EMG activity across 1,618,842 s of polysomnography recorded REM sleep acquired from 461 human participants. These data demonstrate a significant association between visual interpretation and the spectrally processed signals, indicating a highly accurate approach to detecting and quantifying abnormally high levels of EMG activity during REM sleep. Accordingly, our automated approach to EMG quantification during human sleep recording is practical, feasible, and may provide a much-needed clinical tool for the screening of REM sleep behavior disorder and parkinsonism.

Inflammatory Signaling in Post-Stroke Fatigue and Depression.

BACKGROUND: In the United States, stroke continues to be the cause for long-term disability. Of the patients with a first stroke, up to 75% will experience post-stroke fatigue (PSF) in the first year following stroke. PSF is one of the most disabling symptoms in stroke survivors; it decreases quality of life, increases mortality, and is a barrier to stroke rehabilitation. Given the incidence of stroke and the prevalence and detrimental impact of PSF on quality of life, independent living, and overall survival, efficient management of PSF must be a priority in stroke rehabilitation. The cause of PSF remains unknown. The burden of fatigue in stroke survivors is influenced by other stroke-related symptoms, most notably post-stroke depression (PSD). It is well known that stroke induces a systemic inflammatory response that is the trigger for sickness behavior, of which fatigue and depression are predominant symptoms. SUMMARY: To date, only a handful of studies have sought to explore the relationship between stroke-induced inflammation and PSF and PSD. In this review, we describe this evidence, highlight the strengths and weaknesses of these existing studies, and suggest further experiments that may further support the association between stroke-related inflammatory processes and stroke-related symptoms. Key Messages: The current concept and further research are important for a more specific therapeutic intervention for PSF and PSD.

The role of IL-1ß and TNF-α signaling in the genesis of cancer treatment related symptoms (CTRS): a study using cytokine receptor-deficient mice.

Cytotoxic chemotherapeutic agents often induce a cluster of cancer treatment related symptoms (CTRS). The purpose of this study was to develop a mouse model of CTRS to examine the role of IL-1ß and TNF-α signaling in the genesis of these symptoms. CTRS (change in wheel running activity, food intake, and body weight from baseline) were examined in wild type (WT) mice or mice lacking the TNF-α p55 (type 1) receptor (TNFR1-/-) and/or IL-1ß type 1 receptor (IL-1R1-/-) injected with four doses of cyclophosphamide/Adriamycin/5-fluorouracil (CAF) at 20-day intervals. Inflammatory cytokines in blood and tissues were measured using multiplex immunoassays and quantitative RT-PCR. ANOVA was used to examine differences between genotype and/or treatment group. Kaplan-Meier analysis was used to estimate survival rate. CAF rapidly increased IL-1ß and TNF-α signaling in WT mice. CAF induced acute CTRS immediately following drug injection which returned to baseline prior to the next CAF dose. Persistent CTRS were evident 3weeks after the 4th CAF dose. Acute but not persistent CTRS were associated with increased levels of IL-7, IL-9, KC, MCP-1, GCSF, and IP-10. This CAF induced inflammatory response was blunted in IL-1R1 deficient mice and absent in IL-1R1/TNFR1-deficient mice. IL-1R1-/- mice showed an identical pattern of CTRS to their WT counterparts. The assessment of CTRS in IL-1R1/TNF-R1-deficient mice was precluded by severe toxicity. Our data suggest that an important function of the IL-1ß and TNF-α driven inflammatory cascade is to promote recovery following exposure to cytotoxic agents.

Excitability, Inhibition, and Neurotransmitter Levels in the Motor Cortex of Symptomatic and Asymptomatic Individuals Following Mild Traumatic Brain Injury.

Purpose: The purpose of this study was to determine the level of excitability and inhibition, as well as the concentrations of excitatory and inhibitory neurotransmitters, in the motor cortex of individuals with acute and chronic symptoms from mTBI. Methods: Fifty-three individuals were assigned to one of four groups: (i) without history of mTBI (Control), (ii) within 72-h of diagnosis of mTBI (Acute), (iii) with history of mTBI and no remaining symptoms (Chronic Asymptomatic), and (iv) with chronic symptoms from mTBI, lasting at least 3 months post-injury (Chronic Symptomatic). Measures of corticospinal excitability and inhibition were obtained using transcranial magnetic stimulation (TMS). On the same day, measures of glutamate and GABA concentrations were obtained from the primary motor cortex (M1) using proton magnetic resonance spectroscopy. Results: MEP amplitude and area were both significantly lower in the Chronic Symptomatic group compared to the Control and Chronic Asymptomatic groups (p ≤ 0.05). Intracortical inhibition was not significantly different among groups (p = 0.14). The concentration of glutamate in M1 was similar between groups (p = 0.93) while there was a trend for a lower concentration of GABA in the Chronic Symptomatic group compared to the Acute group (p = 0.06). Conclusions: Individuals with chronic mTBI symptoms appear to have lower corticospinal excitability compared with acutely-injured individuals and asymptomatic controls, but the absence of differences in intracortical inhibition, and concentrations of excitatory and inhibitory neurotransmitters in M1 suggests that neurotransmitter changes in the human brain post-mTBI do not follow the pattern typically seen in the animal literature.

Posttraumatic stress disorder increases the odds of REM sleep behavior disorder and other parasomnias in Veterans with and without comorbid traumatic brain injury.

STUDY OBJECTIVES: To describe the crude prevalence of rapid eye movement (REM) sleep behavior disorder (RBD) following traumatic brain injury (TBI) and posttraumatic stress disorder (PTSD) in Veterans, given potential relationships between TBI, PTSD, RBD, and neurodegeneration. METHODS: Veterans (n = 394; 94% male; 54.4 ± 15.5 years of age) were prospectively/cross-sectionally recruited from the VA Portland Health Care System and completed in-lab video-polysomnography and questionnaires. TBI and PTSD were assessed via diagnostic screening and medical record review. Subjects were categorized into four groups after assessment of REM sleep without atonia (RSWA) and self-reported dream enactment: (1) "Normal," neither RSWA nor dream enactment, (2) "Other Parasomnia," dream enactment without RSWA, (3) "RSWA," isolated-RSWA without dream enactment, and (4) "RBD," RSWA with dream enactment. Crude prevalence, prevalence odds ratio, and prevalence rate for parasomnias across subjects with TBI and/or PTSD were assessed. RESULTS: Overall prevalence rates were 31%, 7%, and 9% for Other Parasomnia, RSWA, and RBD, respectively. The prevalence rate of RBD increased to 15% in PTSD subjects [age adjusted POR: 2.81 (1.17-4.66)] and to 21% in TBI + PTSD subjects [age adjusted POR: 3.43 (1.20-9.35)]. No subjects met all diagnostic criteria for trauma-associated sleep disorder (TASD), and no overt dream enactment was captured on video. CONCLUSIONS: The prevalence of RBD and related parasomnias is significantly higher in Veterans compared with the general population and is associated with PTSD and TBI + PTSD. Considering the association between idiopathic-RBD and synucleinopathy, it remains unclear whether RBD (and potentially TASD) associated with PTSD or TBI + PTSD similarly increases risk for long-term neurologic sequelae.

Strong correlation of novel sleep electroencephalography coherence markers with diagnosis and severity of posttraumatic stress disorder.

Objective biomarkers of the presence and severity of posttraumatic stress disorder (PTSD) are elusive, yet badly needed. Electroencephalographic (EEG) coherence represents a promising approach to identifying and understanding brain biomarker activity in PTSD. Overnight polysomnography data containing EEG across sleep and wake states was collected in n = 76 Veterans with and without PTSD from a single site under IRB approval. Brain coherence markers (BCM) were calculated from EEG signals using a novel approach to produce one index for PTSD diagnosis (PTSDdx), and another index for PTSD severity (PTSDsev). PTSDdx showed strong sensitivity to the presence of PTSD in the awake state, during non-rapid eye movement (NREM) stage N2 sleep, and in a hybrid BCM incorporating both awake and NREM sleep states. PTSDsev showed a strong correlation with PTSD symptom severity (using the PTSD Checklist 5, or PCL5 survey) in the awake state, during N2 sleep, and in a hybrid BCM incorporating both awake and NREM sleep states. Thus, sleep EEG-based brain coherence markers can be utilized as an objective means for determining the presence and severity of PTSD. This portable, inexpensive, and non-invasive tool holds promise for better understanding the physiological mechanisms underlying PTSD and for tracking objective responses to treatment.

Effects of traumatic brain injury on sleep and enlarged perivascular spaces.

Clearance of perivascular wastes in the brain may be critical to the pathogenesis of amyloidopathies. Enlarged perivascular spaces (ePVS) on MRI have also been associated with amyloidopathies, suggesting that there may be a mechanistic link between ePVS and impaired clearance. Sleep and traumatic brain injury (TBI) both modulate clearance of amyloid-beta through glymphatic function. Therefore, we sought to evaluate the relationship between sleep, TBI, and ePVS on brain MRI. A retrospective study was performed in individuals with overnight polysomnography and 3T brain MRI consented from a single site (n = 38). Thirteen of these individuals had a medically confirmed history of TBI. ePVS were visually assessed by blinded experimenters and analyzed in conjunction with sleep metrics and TBI status. Overall, individuals with shorter total sleep time had significantly higher ePVS burden. Furthermore, individuals with TBI showed a stronger relationship between sleep and ePVS compared to the non-TBI group. These results support the hypothesis that ePVS may be modulated by sleep and TBI, and may have implications for the role of the glymphatic system in ePVS.