Diminished circadian and ultradian rhythms in pathological brain tissue in human in vivo

Chronobiological rhythms, such as the circadian rhythm, have long been linked to neurological disorders, but it is currently unknown how pathological processes affect the expression of biological rhythms in the brain. Here, we use the unique opportunity of long-term, continuous intracranially recorded EEG from 38 patients (totalling 6338 hours) to delineate circadian and ultradian rhythms in different brain regions. We show that functional circadian and ultradian rhythms are diminished in pathological tissue, independent of regional variations. We further demonstrate that these diminished rhythms are persistent in time, regardless of load or occurrence of pathological events. These findings provide the first evidence that brain pathology is functionally associated with persistently diminished chronobiological rhythms in vivo in humans, independent of regional variations or pathological events. Future work interacting with, and restoring, these modulatory chronobiological rhythms may allow for novel therapies

A Hidden Markov Factor Analysis Framework for Seizure Detection in Epilepsy Patients

Approximately 1% of the world population suffers from epilepsy. Continuous long-term electroencephalographic (EEG) monitoring is the gold-standard for recording epileptic seizures and assisting in the diagnosis and treatment of patients with epilepsy. Detection of seizure from the recorded EEG is a laborious, time consuming and expensive task. In this study, we propose an automated seizure detection framework to assist electroencephalographers and physicians with identification of seizures in recorded EEG signals. In addition, an automated seizure detection algorithm can be used for treatment through automatic intervention during the seizure activity and on time triggering of the injection of a radiotracer to localize the seizure activity. In this study, we developed and tested a hidden Markov factor analysis (HMFA) framework for automated seizure detection based on different features such as total effective inflow which is calculated based on connectivity measures between different sites of the brain. The algorithm was tested on long-term (2.4-7.66 days) continuous sEEG recordings from three patients and a total of 16 seizures, producing a mean sensitivity of 96.3% across all seizures, a mean specificity of 3.47 false positives per hour, and a mean latency of 3.7 seconds form the actual seizure onset. The latency was negative for a few of the seizures which implies the proposed method detects the seizure prior to its onset. This is an indication that with some extension the proposed method is capable of seizure prediction

Effects of circadian rhythm phase alteration on physiological and psychological variables: Implications to pilot performance (including a partially annotated bibliography)

The effects of environmental synchronizers upon circadian rhythmic stability in man and the deleterious alterations in performance and which result from changes in this stability are points of interest in a review of selected literature published between 1972 and 1980. A total of 2,084 references relevant to pilot performance and circadian phase alteration are cited and arranged in the following categories: (1) human performance, with focus on the effects of sleep loss or disturbance and fatigue; (2) phase shift in which ground based light/dark alteration and transmeridian flight studies are discussed; (3) shiftwork; (4)internal desynchronization which includes the effect of evironmental factors on rhythmic stability, and of rhythm disturbances on sleep and psychopathology; (5) chronotherapy, the application of methods to ameliorate desynchronization symptomatology; and (6) biorythm theory, in which the birthdate based biorythm method for predicting aircraft accident susceptability is critically analyzed. Annotations are provided for most citations

Sleep Loss Reduces the DNA-Binding of BMAL1, CLOCK, and NPAS2 to Specific Clock Genes in the Mouse Cerebral Cortex

We have previously demonstrated that clock genes contribute to the homeostatic aspect of sleep regulation. Indeed, mutations in some clock genes modify the markers of sleep homeostasis and an increase in homeostatic sleep drive alters clock gene expression in the forebrain. Here, we investigate a possible mechanism by which sleep deprivation (SD) could alter clock gene expression by quantifying DNA-binding of the core-clock transcription factors CLOCK, NPAS2, and BMAL1 to the cis-regulatory sequences of target clock genes in mice. Using chromatin immunoprecipitation (ChIP), we first showed that, as reported for the liver, DNA-binding of CLOCK and BMAL1 to target clock genes changes in function of time-of-day in the cerebral cortex. Tissue extracts were collected at ZT0 (light onset), −6, −12, and −18, and DNA enrichment of E-box or E'-box containing sequences was measured by qPCR. CLOCK and BMAL1 binding to Cry1, Dbp, Per1, and Per2 depended on time-of-day, with maximum values reached at around ZT6. We then observed that SD, performed between ZT0 and −6, significantly decreased DNA-binding of CLOCK and BMAL1 to Dbp, consistent with the observed decrease in Dbp mRNA levels after SD. The DNA-binding of NPAS2 and BMAL1 to Per2 was also decreased by SD, although SD is known to increase Per2 expression in the cortex. DNA-binding to Per1 and Cry1 was not affected by SD. Our results show that the sleep-wake history can affect the clock molecular machinery directly at the level of chromatin binding thereby altering the cortical expression of Dbp and Per2 and likely other targets. Although the precise dynamics of the relationship between DNA-binding and mRNA expression, especially for Per2, remains elusive, the results also suggest that part of the reported circadian changes in DNA-binding of core clock components in tissues peripheral to the suprachiasmatic nuclei could, in fact, be sleep-wake driven

Abnormal cognition, sleep, EEG and brain metabolism in a novel knock-in Alzheimer mouse, PLB1

Peer reviewedPublisher PD

Rai1 frees mice from the repression of active wake behaviors by light.

Besides its role in vision, light impacts physiology and behavior through circadian and direct (aka 'masking') mechanisms. In Smith-Magenis syndrome (SMS), the dysregulation of both sleep-wake behavior and melatonin production strongly suggests impaired non-visual light perception. We discovered that mice haploinsufficient for the SMS causal gene, Retinoic acid induced-1 (Rai1), were hypersensitive to light such that light eliminated alert and active-wake behaviors, while leaving time-spent-awake unaffected. Moreover, variables pertaining to circadian rhythm entrainment were activated more strongly by light. At the input level, the activation of rod/cone and suprachiasmatic nuclei (SCN) by light was paradoxically greatly reduced, while the downstream activation of the ventral-subparaventricular zone (vSPVZ) was increased. The vSPVZ integrates retinal and SCN input and, when activated, suppresses locomotor activity, consistent with the behavioral hypersensitivity to light we observed. Our results implicate Rai1 as a novel and central player in processing non-visual light information, from input to behavioral output

The Past, Present and Future of Sleep Measurement in Mild Cognitive Impairment and Early Dementia – Towards a Core Outcome Set:A Scoping Review

STUDY OBJECTIVES: Sleep abnormalities emerge early in dementia and may accelerate cognitive decline. Their accurate characterization may facilitate earlier clinical identification of dementia and allow for assessment of sleep intervention efficacy. This scoping review determines how sleep is currently measured and reported in Mild Cognitive Impairment (MCI) and early dementia, as a basis for future core outcome alignment. METHODS: This review follows the PRISMA Guidelines for Scoping Reviews. CINAHL, Embase, Medline, Psychinfo, and British Nursing Index databases were searched from inception—March 12, 2021. Included studies had participants diagnosed with MCI and early dementia and reported on sleep as a key objective/ outcome measure. RESULTS: Nineteen thousand five hundred and ninety-six titles were returned following duplicate removal with 188 studies [N] included in final analysis. Sleep data was reported on 17 139 unique, diagnostically diverse participants (n). “Unspecified MCI” was the most common diagnosis amongst patients with MCI (n = 5003, 60.6%). Despite technological advances, sleep was measured most commonly by validated questionnaires (n = 12 586, N = 131). Fewer participants underwent polysomnography (PSG) (n = 3492, N = 88) and actigraphy (n = 3359, N = 38) with little adoption of non-PSG electroencephalograms (EEG) (n = 74, N = 3). Sleep outcome parameters were reported heterogeneously. 62/165 (37.6%) were described only once in the literature (33/60 (60%) in interventional studies). There was underrepresentation of circadian (n = 725, N = 25) and micro-architectural (n = 360, N = 12) sleep parameters. CONCLUSIONS: Alongside under-researched areas, there is a need for more detailed diagnostic characterization. Due to outcome heterogeneity, we advocate for international consensus on core sleep outcome parameters to support causal inference and comparison of therapeutic sleep interventions

Revisiting the alerting effect of light: A systematic review

Light plays an essential role in maintaining alertness levels. Like other non-image-forming responses, the alerting effect of light is influenced by its spectral wavelength, duration and intensity. Alertness levels are also dependent on circadian rhythm (Process C) and homeostatic sleep pressure (Process S), consistent with the classic two-process model of sleep regulation. Over the last decade, there has been increasing recognition of an additional process (referred to as the third process) in sleep regulation. This third process seems to receive sensory inputs from body systems such as digestion, and is usually synchronised with Process C and Process S. Previous studies on the alerting effect of light have been mostly conducted in laboratories. Although these studies are helpful in delineating the impact of Process C and Process S, their ability to assist in understanding the third process is limited. This systematic review investigated the factors that influence the alerting effect of light by examining randomized controlled trials and randomized or counterbalanced crossover studies. Factors that influence light’s alerting effect were examined with reference to the three-process model. The post-illuminance alerting effect was examined separately due to its potential to offer flexible workplace-based light interventions to increase or maintain employees’ alertness

Great nature’s second course: Introduction to the special issue on the behavioral neuroscience of sleep

Sleep is necessary for normal psychological functioning, and psychological function in turn affects sleep integrity. Recent investigations delineate the relation of sleep to a broad array of processes ranging from learning and memory to emotional reactivity and mood, and use a variety of methodological approaches (imaging, electrophysiological, behavioral) to reveal the complex relations between sleep and the functioning of the awake brain. The articles in this issue advance our fundamental knowledge of the relation of sleep to psychological function. In addition, several of the articles discuss how sleep is affected by or affects human clinical conditions, including insomnia, epilepsy, mild cognitive impairment, bipolar disorder, and cancer. Together, the articles of this special issue highlight recent progress in understanding the behavioral neuroscience of sleep and identify promising areas for future research, including the possibility of sleep-based interventions to improve psychological health.Accepted manuscrip