1. Multiscale Regulatory Function of the Circadian System in Health and Disease
One of the most puzzling phenomena in modern physiology is the existence of fractal patterns in a wide range of physiological systems (i.e., the structures of fluctuations are similar at different time scales). The physiological importance of fractal control is demonstrated in numerous studies and is exemplified by reduced fractal cardiac and activity controls with aging and under pathological conditions. Most importantly, this physiological importance is demonstrated by the predictive value of reduced fractal cardiac control for decreased survival. Fractal physiology appears to impart some adaptive advantage, and in this context, the existence of fractal patterns challenges the traditional theory of homeostasis in maintaining physiologic constancy. Despite the clear importance of this fractal phenomenon, to date, no underlying mechanism has been established for fractal control in any neural or physiological system. Our recent studies indicate that the endogenous circadian system is critically involved in the fractal control of motor activity at multiple time scales. To further understand the underlying mechanisms of fractal control and to apply the concept to diagnosis and prognosis of diseases, we have several on-going projects including, but not limited to, the following:
Fractal Regulation and Pathology of Alzheimer’s Disease
- Goal: to determine the contributions of the degradation of fractal regulation to brain dysfunction and the pathological progression of Alzheimer’s disease (AD) in older adults.
Network modeling of the impacts of the circadian system on the rhythmicity and fractal regulation
- Goal: to establish a mathematical model explaining the previously observed finding that disrupting the circadian control not only affects the rhythmicity of behavior and physiology but also disturbs fractal motor activity and cardiac dynamics at multiple time scales.
Fractal motor activity regulation and the risk for Alzheimer’s disease in middle-to-old aged adults
- Goal: to determine the ability of fractal regulation in motor activity as a means of predicting the risk of AD in people at their middle to old ages.
2. Nonlinear Coupling in Brain Activity Rhythms
Brain activity recorded through electroencephalography (EEG) shows complex fluctuations at different time scales (e.g., alpha, beta, gamma, delta, and theta waveforms). Recent studies revealed that these brain rhythms/fluctuations are not independent; but rather they exhibit cross-frequency coupling (CFC). The coupling changes with sleep and plays an important role in memory and learning. We are more specifically interested in one type of CFC, the phase-amplitude coupling (PAC), in which the amplitude of a high-frequency oscillation (e.g., gamma: ~40-180Hz) is modulated by the phase of the other waveform at a lower frequency (e.g., theta: ~4-10Hz). One of the on-going projects in which the technique is utilized is in modeling schizophrenia. NMDA hypofunction is one of the leading hypotheses of schizophrenic pathophysiology. In collaboration with Prof. Bernat Kocsis at Beth Israel Deaconess Medical Center, the project is designed to investigate how the effects of NMDAR antagonism on brain function, cognition, and behavior depend differentially on NMDA receptor subtype and region-specific effects. In this project, animal models are used and the phase-amplitude coupling between potentiated high frequency oscillations (HFOs, ∼140 Hz) and other slow brain rhythms (e.g., theta and delta) are examined.
3. Circadian Rhythms of Behavior and Physiology
Many physiological functions including sleep, cognition, and cardiac function display circadian rhythms of ~24 h that are generated and coordinated by the circadian timing system which prepares the body for the anticipated environmental and behavioral cycles. In mammals, the central circadian clock of the circadian system is the hypothalamic suprachiasmatic nucleus (SCN). The circadian system normally orchestrates ~24 rhythms of physiological functions in synchrony with daily behavioral cycles for optimally integrated functions within the body; however, the synchronization can be disrupted. Circadian misalignment occurs when behaviors (e.g., sleep, wake, and work) are mistimed, such as in experiences of shift work or jet lag. It is believed that circadian misalignment may underlie many adverse health consequences of shift work, including increased risk of obesity, diabetes, cardiovascular disease, sleep disorders, and cancer. We have several on-going projects to investigate the physiological importance of the circadian control and the factors/interventions that can influence this control.
Sleep-wake regularity and cardiac autonomic function in college students
- Goal: To determine how disrupting normal sleep-wake cycles affects cardiac autonomic function and its daily rhythm in college students.
Chronic Pain in Shift Workers
- Goal: to examine whether shift work increases the risk for chronic pain via its adverse influences on the circadian regulation of autonomic function.
Fractal motor activity regulation and the risk for Alzheimer’s Disease in middle to old aged adults
- Goals: to determine the degradation in fractal activity regulation from middle to old ages, the genetics underpinnings of fractal activity degradation, its associated neuroanatomical changes in the brain, and its ability to predict the risk for Alzheimer’s disease.
Integrated motor activity biomarker for the risk of Alzheimer’s dementia
- Goal: to develop an integrated, non-invasive biomarker for the risk of Alzheimer’s disease using motor activity recordings.
Prediction of dementia in older adults using EEG holo-spectrum and deep learning
- Goal: to establish the EEG-based biomarker for dementia using the novel Holo-spectrum analysis and artificial intelligence technique.
Effects of circadian misalignment on cerebral metabolism and cognition
- Goal: to determine whether the adverse effect of shift work on cognition is affected by the influences of disrupted circadian rhythms on blood and oxygen supply to the brain.
CLOCK 3111TC genetic variant: linking the circadian system and obesity
- Humans carrying the genetic variant C at the circadian gene CLOCK (Circadian Locomotor Output Cycles Kaput) 3111T/C have difficulty losing weight (weight loss resistance) compared to non-carriers of the gene. The goal of this project is to determine the role of the endogenous circadian clock— the body’s regulatory clock which prepares the body for the anticipated environmental and behavioral cycles — in weight-loss resistance for C carriers.
Circadian disruption and neuroanatomical changes in the development of delirium and postoperative cognitive dysfunction (POCD)
- This project examines the effects of circadian/sleep disruption in middle-age on the incidence of later life delirium following hospitalization. We also examine neuroanatomical and functional differences as a result of long-term circadian disruption that may increase the risk of delirium and POCD.