Actigraphic correlates of neuropsychiatric symptoms in adults with focal epilepsy.

OBJECTIVES: Disability in patients with epilepsy (PWEs) is multifactorial: beyond seizure frequency/severity, PWEs are prone to a range of neuropsychiatric, cognitive, and somatic comorbidities that significantly affect quality of life. Here, we explored how variations in seizure severity and the burden of self-reported somatic/neuropsychiatric symptoms correlate with disruptions to 24 h activity patterns (rest-activity rhythms [RARs]), determined through wrist accelerometry/actigraphy. METHODS: Multiday wrist-actigraphy recordings were obtained from 59 adult patients with focal epilepsy (44% male, ages 18-72), who contemporaneously responded to validated psychometric instruments to measure anxiety, depression, sleepiness, and somatic symptoms. We conducted a similar in silico psychometric-actigraphic correlation in a publicly available data set of 1747 Hispanic subjects (35% male, ages 18-65) from the Study of Latinos (SOL) Sueño Ancillary Study. RARs were analyzed via a sigmoidally-transformed cosine model (quantifying amplitude, steepness, acrophase, and robustness) and nonparametric measures to estimate RAR stability, fragmentation, and sleep. RESULTS: Compared with matched SOL subjects, RARs from PWE subjects featured a significantly lower amplitude, a wider rest phase, and significantly more total daily sleep. Within PWEs, similar RAR distortions were associated with seizure intractability and/or anticonvulsant polytherapy, whereas high anxiety, depression, and somatic symptom scores were associated with lower RAR robustness and acrophase delay. We applied the SOL data set to train logistic regression models to dichotomously classify subjective anxiety, depression, and sleepiness symptoms using demographic and RAR parameters. When tested on PWEs, these models predicted prevalent anxiety and depression symptom burden (accuracy ~70%) but failed to predict subjective sleepiness. SIGNIFICANCE: Together these results demonstrate that RAR features may encode prevalent depression and anxiety symptoms in patients with focal epilepsy, potentially offering wearable-derived endpoints to adjunct clinical care and drug/device trials. With larger PWE-specific actigraphic-psychometric data sets, we may identify RAR signatures that may more precisely correlate with varying seizure frequency, the burden of anticonvulsant therapy, and prevalent mood/anxiety symptoms.

Rest-Activity Rhythm Phenotypes in Adults with Epilepsy and Intellectual Disability.

Objective: Sleep and rest-activity rhythms (RARs) are perturbed in many forms of neuropsychiatric illness. In this study, we applied wrist actigraphy to describe the extent of RAR perturbations in adults with epilepsy and intellectual disability ("E+ID"), using a cross-sectional case-control design. We examined whether RAR phenotypes correlated with epilepsy severity, deficits in adaptive function and/or comorbid psychopathology. Methods: Primary caregivers of E+ID adults provided informed consent during routine ambulatory clinic visits and were asked to complete standardized surveys of overall epilepsy severity (GASE, Global Assessment of Severity of Epilepsy), adaptive function (ABAS-3, Adaptive Behavior Assessment System-3) and psychopathology (ABCL, Adult Behavior Checklist). Caregivers were also asked to ensure that subjects wore an Actiwatch-2 device continuously on their nondominant wrist for at least ten days. From recorded actograms, we calculated RAR amplitude, acrophase, robustness, intradaily variability (IV), interdaily stability (IS) and estimates of sleep quantity and timing. We compared these RAR metrics against those from (i) a previously published cohort of adults with epilepsy without ID (E-ID), and (ii) a cohort of age- and sex-matched intellectually able subjects measured within the Study of Latinos (SOL) Ancillary actigraphy study (SOL). Within E+ID subjects, we applied k-means analysis to divide subjects into three actigraphically distinct clusters. Results: 46 E+ID subjects (median age 26 [20-68], 47% female) provided a median recording duration of 11 days [range 6-27]. Surveys reflected low to extremely low levels of adaptive function (ABAS3 General Adaptive Composite score: median 50 [49-75]), and low/subclinical levels of psychopathology (ABCL total score: median 54.5 [25-67]). Compared with E-ID (n=57) and SOL (n=156) cohorts, E+ID subjects displayed significantly lower RAR amplitude, robustness and IS, with significantly higher IV and total daily sleep. K-means clustering of E+ID subjects recognized an intermediate cluster "B", with RAR values indistinguishable to E-ID. Cluster "A" subjects displayed pronounced hypoactivity and hypersomnia with high rates of rhythm fragmentation, while cluster "C" subjects featured hyper-robust and high amplitude RARs. All three clusters were similar in age, body mass index, antiseizure medication (ASM) polytherapy, ABAS3 and ABCL scores. We qualitatively describe RAR examples from all three clusters. Interpretation: We show that adults with epilepsy and intellectual disability display a wide spectrum of RAR phenotypes that do not neatly correlate with measures of adaptive function or epilepsy severity. Prospective studies are necessary to determine whether continuous actigraphic monitoring can sensitively capture changes in chronobiological health that may arise with disease progression, iatrogenesis (e.g., ASM toxicity) or acute health deteriorations (e.g., seizure exacerbation, pneumonia). Similar long-term data is necessary to recognize whether behavioral interventions targeted to 'normalize' RARs may promote improvements in adaptive function and therapy engagement.

Stability and Volatility of Human Rest-Activity Rhythms: Insights from Very Long Actograms (VLAs).

Importance: Wrist-worn activity monitors provide biomarkers of health by non-obtrusively measuring the timing and amount of rest and physical activity (rest-activity rhythms, RARs). The morphology and robustness of RARs vary by age, gender, and sociodemographic factors, and are perturbed in various chronic illnesses. However, these are cross-sectionally derived associations from recordings lasting 4-10 days, providing little insights into how RARs vary with time. Objective: To describe how RAR parameters can vary or evolve with time (~months). Design Setting and Participants: 48 very long actograms ("VLAs", ≥90 days in duration) were identified from subjects enrolled in the STAGES (Stanford Technology, Analytics and Genomics in Sleep) study, a prospective cross-sectional, multi-site assessment of individuals > 13 years of age that required diagnostic polysomnography to address a sleep complaint. A single 3-year long VLA (author GD) is also described. Exposures/Intervention: None planned. Main Outcomes and Measures: For each VLA, we assessed the following parameters in 14-day windows: circadian/ultradian spectrum, pseudo-F statistic ("F"), cosinor amplitude, intradaily variability, interdaily stability, acrophase and estimates of "sleep" and non-wearing. Results: Included STAGES subjects (n = 48, 30 female) had a median age of 51, BMI of 29.4kg/m2, Epworth Sleepiness Scale score (ESS) of 10/24 and a median recording duration of 120 days. We observed marked within-subject undulations in all six RAR parameters, with many subjects displaying ultradian rhythms of activity that waxed and waned in intensity. When appraised at the group level (nomothetic), averaged RAR parameters remained remarkably stable over a ~4 month recording period. Cohort-level deficits in average RAR robustness associated with unemployment or high BMI (>29.4) also remained stable over time. Conclusions and Relevance: Through an exemplary set of months-long wrist actigraphy recordings, this study quantitatively depicts the longitudinal stability and dynamic range of human rest-activity rhythms. We propose that continuous and long-term actigraphy may have broad potential as a holistic, transdiagnostic and ecologically valid monitoring biomarker of changes in chronobiological health. Prospective recordings from willing subjects will be necessary to precisely define contexts of use.

Home-cage behavior in the Stargazer mutant mouse.

In many childhood-onset genetic epilepsies, seizures are accompanied by neurobehavioral impairments and motor disability. In the Stargazer mutant mouse, genetic disruptions of Cacng2 result in absence-like spike-wave seizures, cerebellar gait ataxia and vestibular dysfunction, which limit traditional approaches to behavioral phenotyping. Here, we combine videotracking and instrumented home-cage monitoring to resolve the neurobehavioral facets of the murine Stargazer syndrome. We find that despite their gait ataxia, stargazer mutants display horizontal hyperactivity and variable rates of repetitive circling behavior. While feeding rhythms, circadian or ultradian oscillations in activity are unchanged, mutants exhibit fragmented bouts of behaviorally defined "sleep", atypical licking dynamics and lowered sucrose preference. Mutants also display an attenuated response to visual and auditory home-cage perturbations, together with profound reductions in voluntary wheel-running. Our results reveal that the seizures and ataxia of Stargazer mutants occur in the context of a more pervasive behavioral syndrome with elements of encephalopathy, repetitive behavior and anhedonia. These findings expand our understanding of the function of Cacng2.