One hypothetical mediating mechanism between circadian desynchronization or misalignment and cognitive dysfunction involves the impact of psychological stress on the brain via the hypothalamic-pituitary-adrenocortical (HPA) system with the increased secretion of cortisol (Lundberg, 2005). Briefly, stress causes the
hypothalamus to release a corticotrophin releasing hormone (CRH) which stimulates the pituitary gland to produce adrenocorticotropic hormone (ACTH). ACTH causes the adrenal cortex to release cortisol into the blood circulation, activating the sympathetic nervous system. Negative feedback to the pituitary gland via a loop incorporating the hippocampus and amygdala via glucocorticoid receptors
terminates the stress response. Chronic stress appears to cause down-regulation of glucocorticoid receptors, impairing the negative feedback mechanism, which results in over-activation of the HPA axis (Jameison & Dinan, 2001).
Disruptions of the sleep-wake cycle, such as sleep deprivation, night shift work and jet lag following rapid transmeridian flight, cause transient internal
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Constant or prolonged sleep disruption, resulting in repeated disturbance of
synchronization of the circadian system to the environment, can be considered as a physiological stressor (Winget et al., 1984).
Cognitive and neuroendocrine effects of chronic jet lag have been reported by Cho and colleagues (Cho, 2001; Cho et al., 2000). Cho and colleagues (2000) showed that flight attendants experiencing transmeridian flights, whereby crossing of several time zones results in desynchronization internal circadian rhythm from external light-dark cycle, had significantly higher average daily cortisol secretion (as measured by salivary cortisol level) than ground crew and cortisol elevation in female flight attendants, but not ground crew, was significantly correlated (r = -.78) with poorer visual working memory performance on visual delayed-match-to-sample tasks. This evidence supports the hypothesis that chronic circadian rhythm disruption resulting from repeated exposure to jet lag leads to significantly elevated cortisol levels and related neurocognitive deficits.
Cho (2001) compared temporal lobe volume (MRI scans corrected for head size), performance responses to an experimental visual spatial cognitive task and cortisol levels between two groups of female flight attendants, one had less than five days between transmeridian flights, whereas the other had more than 14 days in between, controlling for five working years and total flight exposure during this period. The results showed that the short recovery group, as compared to the long recovery group, had significantly reduced right temporal lobe volume, made more errors and were significantly slower on the visual-spatial task. There was also a strong and significant negative correlation between chronic elevation of cortisol levels and right temporal lobe atrophy (r = -.78) for the short recovery group only, suggesting a possible association between chronic jet lag induced stress and right temporal lobe atrophy, although longer periods between transmeridian flights may circumvent this effect.
Studies on the nature of circadian dysregulation of rotating night shift workers showed mixed results. For example, Lac and Chamoux (2003) demonstrated a significant increase in overall cortisol production while Zuzewicz, Kwarecki, and Waterhouse (2000) found lower cortisol level in night shift workers. Similarly, while Touitou and colleagues (1990) found dysregulation of the circadian markers of
cortisol rhythm with no phase shift, others demonstrated phase shift (Goichot et al., 1998; Motohashi, 1992). To complicate matters, different shift systems (3 days work 2 days rest vs. 7 days work 5 days rest) appear to cause different effects to the
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circadian markers of the cortisol rhythm (Lac & Chamoux, 2004). Moreover, Roden, Koller, Pirich, Vierhapper, and Waldhauser (1993) reported no differences in plasma cortisol rhythm characteristics (acrophase, amplitude, average secretion, and phase relationship with melatonin) between seven male controls and nine long-term, full-time, male night shift workers with high levels of work satisfaction. Overall, there is a general trend for cortisol rhythm dysregulation associated with shift work but the relationships between different circadian markers and different shift systems are complex. In addition, there seem to be large inter-individual differences in the tolerance of different shift schedules.
Notwithstanding this, it has become increasingly clear from research on HPA axis reactivity that chronically high or low levels of cortisol and problems with the up- or down-regulation of cortisol in response to stress are associated with difficulties in cognitive and behavioural self-regulation. The relation between cortisol and these brain functions generally follows an inverted U-shaped (Blair, Granger, & Razza, 2005). In children, moderate increase in cortisol followed by down-regulation of this
increase, in mildly challenging situations, was positively associated with measures of executive function and self-regulation (Blair et al., 2005).
Wright, Hull, Hughes, Ronda, and Czeisler (2006) assessed learning in healthy patients who lived under shift-work conditions in a laboratory devoid of time cues. They compared improvements on the Mathematical Addition Test and the Digit Symbol Substitution Task between a synchronized group, where the normal relationship between sleep-wakefulness and internal circadian time was maintained, and a non-synchronized group mimicking the shift work condition, with both groups allowed to have 8 hours of scheduled sleep. Cognitive performance improved (i.e., learning) in the synchronized group, whereas learning was significantly impaired in the non-synchronized group. Hence, short-term circadian misalignment was found to be detrimental to learning in subjects who failed to adapt to their imposed
schedule of sleep and wake, even though the total sleep time appears to be sufficient; in other words, proper alignment between sleep-wakefulness and internal circadian time is crucial for enhancement of cognitive performance (Wright et al., 2006). In addition, alertness and cognitive processes may be especially impaired during the transition from day work to a series of night shifts, as many individuals will attempt to stay awake throughout the whole first day and night (Santhi, Horowitz, Duffy, & Czeisler, 2007). Acute circadian misalignment (and sleep deprivation to a lesser extent) associated with transition onto the first night shift was enough to significantly
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affect the response times on tests of visual selective attention in a shift-work simulation study (Santhi et al., 2007).
Nevertheless, as mentioned previously, memory consolidation, learning, alertness and performance have been shown to be negatively affected by sleep deprivation, even in the absence of circadian misalignment (Dijk et al., 1992; Walker & Stickgold, 2005).