Effects of Circadian Phase Tailored Light Therapy on Sleep, Mood, and Cognition in Alzheimer’s Disease: Preliminary Findings in a Pivotal Study

It is shown that the circadian system is affected in patients with Alzheimer’s disease (AD) even at an early stage of the disease and that such dysfunction may be detrimental to sleep, mood, and cognitive functioning. Light is a strong central modulator of the circadian rhythms and is potentially beneficial to mood and cognitive functioning via a direct effect or indirectly via its modulating effects on circadian rhythms. This study focuses on tracking the effect of light therapy on sleep quality, mood, and cognition in AD of mild/moderate severity. We performed a single-blind randomized controlled trial to investigate the effects of a light therapy treatment tailored to the individual circadian phase as measured by dim light melatonin onset (DLMO). Such a treatment induced an objective circadian phase shift consistent with the melatonin phase response curve to light exposure, led to a shortening of the phase angle DLMO-falling asleep time, and was associated with an improvement in subjective sleep quality and cognitive performance.

Rest-Activity Pattern and Circadian Phase Alterations Across the Alzheimer’s Disease Clinical Spectrum

Actigraphy-derived locomotor activity recordings are novel and critical tools for evaluating rest-activity pattern and circadian phase in humans. We conducted a narrative review assessing rest-activity pattern and circadian phase alterations within various stages of Alzheimer’s disease, in consideration of the reciprocal associations between neurodegeneration and circadian rhythm disruption in patients with Alzheimer’s disease. The goal of this review was to characterize possible associations between circadian rhythm disruption and neurodegeneration in Alzheimer’s disease. To the best of our knowledge, only two studies have assessed rest-activity pattern and circadian phase alterations in the preclinical Alzheimer’s disease stage and the results of the studies were inconsistent. Several studies have evaluated rest-activity pattern and circadian phase alterations in patients with Alzheimer’s dementia. The most replicated findings were delayed phase and increased activity fragmentation, represented as increased intra-daily variability. Unfortunately, many studies performed in dementia patients have not examined neuroimaging biomarkers or structured neuropsychological tests, thus limiting the specification of dementia clinical diagnoses. Future studies should consider a more comprehensive evaluation of various clinical and biomarker characteristics in patients with dementia or Alzheimer’s disease.

Machine Learning and In-Vivo Expression Analyses Reveal Circadian Clock Features Predictive of Anxiety in Humans

Mood disorders, including anxiety, are associated with disruptions in circadian rhythms and are linked to polymorphisms in circadian clock genes. Molecular mechanisms underlying these connections may be direct—via transcriptional activity of clock genes on downstream mood pathways in the brain, or indirect—via clock gene influences on the phase and amplitude of circadian rhythms which, in turn, modulate physiological processes influencing mood. Employing machine learning combined with statistical approaches, we explored clock genotype combinations that predict risk for anxiety symptoms in a deeply phenotyped population. We identified multiple novel circadian genotypes predictive of anxiety, with the PER3B-AG/CRY1-CG genotype being the strongest predictor of anxiety risk in males. Molecular chronotyping, using clock gene expression oscillations, revealed that advanced circadian phase and robust circadian amplitudes are associated with high levels of anxiety symptoms. Further analyses revealed that individuals with advanced phases and pronounced circadian misalignment were at higher risk for severe anxiety symptoms. Our results support both direct and indirect influences of clock gene variants on mood: while sex-specific clock genotype combinations predictive of anxiety symptoms suggest direct effects on mood pathways, the mediation of PER3B effects on anxiety via diurnal preference measures and the association of circadian phase with anxiety symptoms provide evidence for indirect effects of the molecular clockwork on mood. Unraveling the complex molecular mechanisms underlying the links between circadian physiology and mood is essential to identifying the core clock genes to target in future functional studies, thereby advancing the development of non-invasive treatments for anxiety-related disorders.

Thalamic deep brain stimulation modulates cycles of seizure risk in epilepsy

Chronic brain recordings suggest that seizure risk is not uniform, but rather varies systematically relative to daily (circadian) and multiday (multidien) cycles. Here, one human and seven dogs with naturally occurring epilepsy had continuous intracranial EEG (median 298 days) using novel implantable sensing and stimulation devices. Two pet dogs and the human subject received concurrent thalamic deep brain stimulation (DBS) over multiple months. All subjects had circadian and multiday cycles in the rate of interictal epileptiform spikes (IES). There was seizure phase locking to circadian and multiday IES cycles in five and seven out of eight subjects, respectively. Thalamic DBS modified circadian (all 3 subjects) and multiday (analysis limited to the human participant) IES cycles. DBS modified seizure clustering and circadian phase locking in the human subject. Multiscale cycles in brain excitability and seizure risk are features of human and canine epilepsy and are modifiable by thalamic DBS.

Distinct Circadian Assessments From Wearable Data Reveal Social Distancing Promoted Internal Desynchrony Between Circadian Markers

Mobile measures of human circadian rhythms (CR) are needed in the age of chronotherapy. Two wearable measures of CR have recently been validated: one that uses heart rate to extract circadian rhythms that originate in the sinoatrial node of the heart, and another that uses activity to predict the laboratory gold standard and central circadian pacemaker marker, dim light melatonin onset (DLMO). We first find that the heart rate markers of normal real-world individuals align with laboratory DLMO measurements when we account for heart rate phase error. Next, we expand upon previous work that has examined sleep patterns or chronotypes during the COVID-19 lockdown by studying the effects of social distancing on circadian rhythms. In particular, using data collected from the Social Rhythms app, a mobile application where individuals upload their wearable data and receive reports on their circadian rhythms, we compared the two circadian phase estimates before and after social distancing. Interestingly, we found that the lockdown had different effects on the two ambulatory measurements. Before the lockdown, the two measures aligned, as predicted by laboratory data. After the lockdown, when circadian timekeeping signals were blunted, these measures diverged in 70% of subjects (with circadian rhythms in heart rate, or CRHR, becoming delayed). Thus, while either approach can measure circadian rhythms, both are needed to understand internal desynchrony. We also argue that interventions may be needed in future lockdowns to better align separate circadian rhythms in the body.

Exploring light exposure of hospital nurses working rapidly rotating shifts in relation to sleepiness and sleep

Nightshift work can negatively impact sleep, performance, and health. Careful manipulation of light exposure patterns can help reduce these negative effects but is challenging in conditions of rapidly rotating shiftwork and due to individual differences. As chronotype is related to shiftwork tolerance, we explored patterns of sleep, sleepiness, and light exposure during the first day of nightshift work between earlier and later chronotypes, based on data from an observational field study among rapidly rotating hospital nurses. Due to the limited sample size, only descriptive analyses and visual inspection were conducted. In line with findings of lower shiftwork tolerance, earlier chronotypes (N=6) seemed to be sleepier during work and sleep less than later types (N=7). Differences were also observed in light exposure patterns, revealing potential for light exposure interventions, and suggesting a contribution to shiftwork tolerance. For future intervention studies in aiming to identify a light exposure strategy, our findings highlight the importance of investigating light exposure relative to the individual circadian phase.

Associations of Actigraphy-derived Rest-activity Patterns and Circadian Phase Parameters With Clinical Symptoms and Polysomnography Results in Patients With Chronic Insomnia

We explored the associations of actigraphy-derived rest-activity patterns and circadian phase parameters with clinical symptoms and level 1 polysomnography (PSG) results in patients with chronic insomnia to evaluate the clinical implications of actigraphy-derived parameters for PSG performance. Seventy-five participants underwent actigraphy assessments and level 1 PSG. Exploratory correlation analyses between parameters derived from actigraphy, PSG, and clinical assessments were performed. Study participants were classified into two groups, and group differences were investigated after adjusting for potential covariates. Participants with poorer rest-activity patterns on actigraphy (low inter-day stability and high intra-daily variability) exhibited higher insomnia severity index scores compared to participants with better rest-activity patterns. No between-group differences in PSG parameters were observed. Late-phase participants (late least active 5-h and most active 10-h onset times) exhibited higher insomnia severity scores, longer sleep latency, longer rapid eye movement latency, and lower apnea-hypopnea index compared to early-phase participants. These associations remained significant even after adjusting for potential covariates. Some actigraphy-derived rest-activity patterns and circadian phase parameters were significantly associated with clinical symptoms and PSG results, suggesting a possible adjunctive role of actigraphy-derived rest-activity patterns and circadian phase parameters in deriving plans for PSG lights-off time and assessing the possible insomnia pathophysiology.