Circadian Rhythms, Diet and Neuronal Excitability

Summary

Many aspects of normal biological function are governed by circadian rhythms, including metabolism, ingestive behaviors, and sleep-wake cycles. Certain pathological processes as well are also affected by circadian rhythms. For example, it is well known that seizure occurrence can be influenced by the sleep-wake cycle. The ketogenic diet (KD) is a high-fat, low-carbohydrate diet with proven efficacy in the treatment of intractable epilepsies. While the mechanisms underlying the clinical effects of the KD remain unclear, there are emerging links between circadian rhythms and KD action. Such factors should be considered when planning and administering the KD to patients.

The ketogenic diet (KD) is a high-fat, low-carbohydrate diet used to treat patients with medically intractable epilepsy. For years, the efficacy of the KD was thought to be a direct consequence of ketone body action, with these substrates replacing glucose as the primary energy source for neurons and providing protection against seizures through as yet an undetermined mechanism. If this hypothesis is correct (and there remains considerable controversy regarding this matter), understanding how the body processes the food is critical for improving clinical implementation of the KD. Whether or not ketone bodies are the critical mediators, the goal of this review is introduce the novel concept that when using the KD to treat epilepsy, it is important to think not only about the constituents of the diet but also about when the food is consumed. This is critical for two reasons. First, the body metabolizes food differently during different times of the activity-sleep cycle. Time of day and activity level may be critical variables in determining how food is metabolized, which may be critically important when attempting to manipulate blood chemistry. Second, the time of day may also be important in the timing of seizure onset.

Virtually every organism that has been studied demonstrates a day-night difference in activity that is mediated by an endogenous time-keeping system. These physiological rhythms, which oscillate with a period of 24 hours, are termed circadian rhythms. In mammals, the master circadian oscillator is located in the suprachiasmatic nucleus (SCN), a small bilateral structure located in the ventral hypothalamus. Many SCN neurons possess a molecular clock consisting of interconnected positive and negative gene transcription feedback loops that keep time (Herzog et al., 1998; Welsh et al., 1995). SCN neurons send afferent projections to other hypothalamic regions that control a variety of homeostatic processes, including the timing of activity and sleep, hormone release, feeding behavior, body temperature, and energy metabolism. Disruption of the circadian timing system in animal models produces significant metabolic dysregulation characterized by increases in cholesterol, triglycerides and glucose levels (Turek et al., 2005). These physiological changes have many of the hallmarks of the metabolic syndrome. Several investigators have proposed that disruption of circadian rhythms and sleep may contribute to the development of obesity, diabetes and the metabolic syndrome (Laposky et al., 2007; Trenell et al., 2007; Spiegel et al., 2005).

Dietary changes may feed back onto the circadian clock mechanism as well. Rodents fed a high-fat diet had altered expression of genes for enzymes involved in generating circadian time and metabolizing food. Molecular circadian clocks are also found in many peripheral organs including the liver, pancreas, kidney, adrenal gland, and lung where they are thought to regulate, in part, the expression of metabolic enzymes. The SCN is responsible for synchronizing the activity of these peripheral circadian clocks (Yamazaki et al., 2000). It will be important to determine whether consumption of the KD alters the central or peripheral circadian clocks and their regulation of physiological and metabolic rhythms.

The sleep-wake cycle is undoubtedly one of the most important output functions of the circadian clock. In humans, sleep is consolidated in an approximately 8-hour period during which there are significant changes in neuronal activity, metabolic function and a reduction in physical activity. A prominent feature of sleep is the stage-dependent change in brain electrical activity. Sleep wave frequency decreases during the 4 stages of non-rapid eye movement (non-REM) sleep. During REM sleep, brain waves have a faster frequency and lower amplitude. Disruption of the circadian and sleep wake-cycles is a risk factor for a variety of health problems including obesity, diabetes, and cardiovascular disease (Laposky et al., 2007; Trenell et al., 2007; Spiegel et al., 2005; Van Cauter et al., 1997).

Changes in neuronal activity occurring during the transitions between sleep states may contribute to the onset of seizure activity. Furthermore, the timing of seizure onset during the day-night cycle is not random, reflecting an interaction between the circadian timing and sleep systems and the epileptic lesion. In fact, it has been known for millenia that seizures can be triggered by the onset of sleep or wakefulness (Dinner, 2002; Malow, 2005). Different epilepsy syndromes show unique timing. For example, there are more seizures during sleep in frontal lobe epilepsy than in temporal lobe epilepsy. Epileptic seizures can have profound effects on sleep and circadian rhythms. Depending on the timing and severity of the seizures, the phase of the circadian clock or its entrainment to the light-dark cycle may be altered (Quigg, 2000). A significant number of patients with epilepsy report excessive daytime sleepiness, which may reflect a reduction in the quantity and quality of sleep due to seizures (Foldvary-Schaefer & Grigg-Damberger, 2006). These observations demonstrate that vulnerability to and onset of seizure activity may reflect a complex interaction between circadian timing, metabolic state, and sleep status.

In addition to changes in brain electrical activity, significant changes occur in metabolic activity during sleep and at different times of the circadian cycle. Consumption of oral glucose produces higher peaks of blood glucose the later in the day with the highest levels occurring during the night. If young healthy adults are fed a standard meal, the resulting blood glucose levels are larger the later in the day the meal is consumed (Van Cauter et al., 1997; Van Cauter, 1990). During the night, in humans, sleep is a period in which food is not consumed. In spite of this extended fasting period, blood glucose levels remain fairly stable (Clore et al., 1989). These data indicate that homeostatic metabolic processes are activated during sleep to regulate the glucose levels, which are required to support neural activity Van Cauter et al., 1997; Clore et al., 1989).

An important question, therefore, is how circadian time and sleep affect metabolism of the KD. Significantly more research is needed on this topic. It is known that consumption of a diet high in fat and low in carbohydrate by rodents maintained on a 12 hour light-12 hr dark cycle increases blood ketones (β-hydroxybutyrate and acetoacetate) (De Gasquet et al., 1977). The β-hydroxybutyrate and acetoacetate levels were significantly higher than animals fed the KD than a low fat diet. Furthermore, the β-hydroxybutyrate levels were highest in the late night, which corresponds to the rodent's activity period, while acetoacetate levels showed no time dependence or cyclical pattern. These data indicate that the activity of β-hydroxybutyrate dehydrogenase, an important enzyme in ketone body metabolism is higher during the night then during the day. Therefore, the maximal ketone body concentration in the blood shows a diurnal rhythm with the highest level in the late evening. If ketone bodies have anticonvulsant properties, one could hypothesize that in a rodent model of seizures, the KD would be maximally protective against seizure onset in the late night.

In summary, the metabolism of dietary constituents and seizure onset will vary with the time of day and sleep-wake state. A better understanding of how the circadian timing system and sleep state regulates ketone metabolism may lead to more successful implementation of the KD for control of intractable epilepsy.