Cerebral ischemia is one of the leading causes of death and disability in the United States and worldwide. Circadian rhythms are daily processes where the physiological function and activity changes follow the 24h cycle. Many studies have shown the relationship between stroke incidence and alterations of circadian rhythm (Ripamonti et al., 2017; Stubblefield and Lechleiter, 2019). Circadian rhythm may influence and affect the outcomes of acute stroke in the long term. The immediate consequence of stroke includes permanent cognitive deficits, paralysis, visual impairment, and sensory disturbances. Stroke also results in long-term dysregulation of sleep and mood, which may equally participate in causing disabilities in stroke patients.

There are three main types of stroke: ischemic stroke, intracerebral hemorrhage (ICH), and subarachnoid hemorrhage (SAH). In the US, ischemic strokes account for 87% of total strokes, ICH accounts for 10%, and SAH is 3%. Studies also suggest that apart from acute stroke, ICH and SAH are also affected by circadian rhythm, and clock gene regulation plays a vital role in both ICH (Gong et al., 2021; Nagakane et al., 2006; Zheng et al., 2016) and SAH (Nyquist et al., 1999, 2001; Schallner et al., 2017).

Ischemic stroke incidence follows a circadian rhythm, with a higher frequency during the day, especially in the morning between 6 and 10 am, and a lower frequency in the nighttime. Clinical and preclinical studies have shown the relationship between stroke incidence and alterations of the circadian rhythm (Meng et al., 2008). However, many reports indicated that acute strokes tended to occur during sleep (Agnoli et al., 1975; Elliott, 1998; Marshall, 1977). Zeitgeber time (ZT) is a unit of the time period, such as 12h light and 12h dark cycles. There are four ZT times ZT0: 6 am, ZT6: 12 pm, ZT12: 6 pm, and ZT18: 12 am (Fig. 1). Rodents are nocturnal and active in the laboratory setting between ZT12 and ZT0.

The underlying mechanism behind stroke dependency on circadian rhythm is still unclear, apart from the fact that various chronic health conditions linked to irregular rhythms include diabetes, obesity, depression, bipolar disorder, and sleep disorders. Elevation in mean arterial blood pressure in the morning, along with changes in metabolic activity and hormone levels and a prothrombotic state with increases in plasminogen activator inhibitor 1, can stimulate the initiation of a stroke (Bilo et al., 2018). However, other factors such as lower mean arterial pressure and heart rate at night may contribute to the onset of ischemic stroke through a hemodynamic mechanism during the sleep hours, particularly in thrombotic stroke (Bassetti and Aldrich, 1999; Fodor et al., 2021; Lago et al., 1998). Because of these patterns, most explanations for the circadian dependence of cerebrovascular events have focused on circadian rhythm changes along with platelet aggregation, thrombolysis, blood pressure, heart rate, and catecholamine concentrations that occur after awaking with the resumption of physical and mental activities. One study suggests that low mean diastolic blood pressure may predispose people to the nighttime onset of cerebrovascular events, augmenting the sleep-related fall in blood pressure (Millar-Craig et al., 1978). In addition, another finding also suggested a relation between nighttime hypotension and silent stroke (Watanabe et al., 1996) and recurrent stroke (Nakamura et al., 1995).