Although the relationships between fatigue, sleep and quality of life have been previously reported,14
this study is the first to extend the adverse impact of these factors to compromised neurocognitive functioning among adult survivors of childhood cancer. The relative risk for neurocognitive impairment associated with fatigue and sleep disturbance was roughly equivalent to that seen with high-dose radiation. When describing impairment observed among childhood cancer survivors, previous models of cognitive functioning have emphasized the direct insults associated with cancer treatment whereas these findings suggest the additive contributions of less direct pathways (such as poor sleep and fatigue).
It is interesting to note that more predictors were significantly associated with task efficiency than any other outcome variable. Specifically, all four of the primary variables related to fatigue, vitality, sleep quality, and daytime sleepiness predicted impaired task efficiency, as did use of antidepressant medication, high dose cranial radiation therapy, current age, and household income. Questions within this scale are generally related to attention and processing speed, which are often areas of vulnerability associated with late effects of cancer treatments, traumatic brain injury, pain, and psychological disorders such as depression. It is important to highlight that the impact of fatigue, vitality, daytime sleepiness, and poor sleep quality on task efficiency was independent of the significant effects of cranial radiation therapy, and use of antidepressant medication.
Although female sex was not a significant predictor of impaired task efficiency, organization problems or memory problems, it did contribute to the risk for problems with emotional regulation. Recent research demonstrates sex specificity to the attention problems detected in cancer survivors,37
though current measures may not be specific enough to demonstrate this differential pattern. Emotional regulation is associated with increased lability and tendencies for emotional explosiveness,38
and the current data suggests that female survivors are more prone to report these symptoms. On the other hand, males may be less likely to acknowledge problems with emotional regulation or they may truly experience better emotional control. Of note, increased depression and anxiety were also identified risk factors for problems with emotional regulation. Problems with emotional regulation suggests increased emotional lability and/or explosiveness, and do not require the content of the lability to include either negative or positive emotions. However, the increased risk of poor emotional regulation found in those survivors reporting significant symptoms of depression and/or anxiety, suggests that the increased lability or explosiveness is likely to involve negative emotions such as sadness, frustration, and nervousness.
Poor sleep quality was identified as being significantly associated with attention and processing speed problems (Task Efficiency) and memory problems. Rapid eye movement (REM) sleep is particularly important for healthy memory functions,39
and specific disruption of REM cycles has been associated with memory impairment in aging adult populations.40
Clearly, the PSQI does not permit identification of separate REM sleep stages. However, the association between the PSQI and memory problems is consistent with the literature on REM sleep and its role in memory consolidation. As such, REM deprivation may be part of the pathway underlying this association. In addition, sleep disorder in children often mimic symptoms of attention-deficit/hyperactivity disorder, including primary problems with inattention.41
Our data would suggest that although good sleep quality may not be necessary for emotional regulation and organization skills, it is related to attention and memory functions.
Decreased vitality and increased fatigue were also strongly associated with neurocognitive impairment, even when controlling for sleep quality. Although fatigue and low vitality may result from poor sleep quality, physical and mental fatigue can also be associated with metabolic or neuroendocrine dysfunction,42, 43
as well as cardiovascular disease.44
Since survivors of childhood cancer are at increased risk for symptoms related to these medical conditions,44, 45
the role they play in neurocognitive outcomes should be examined. We are in the process of conducting just such an investigation.
Because many quality of life outcomes are mediated by neurocognitive functions, the identification of modifiable risk factors that are associated with cognitive outcomes is a valuable and important target for intervention. In the case of childhood cancer survivors, results from this study highlight the importance of considering interventions to improve sleep hygiene and/or physical fitness as nonpharmacological mechanism for improving neurocognitive functioning. The direct relationships between poor sleep and fatigue with self-reported neurocognitive outcomes were evidenced in our study. However, the more applied consequences of insomnia and fatigue extend to specific “real world” outcomes including serious accidents, illness-related restricted activities, and psychiatric disorders, along with decreased work productivity.46
Interventions to improve sleep quality have the potential not only to enhance neurocognitive functioning, but may also have beneficial effects that extend to symptoms of depression, anxiety, and somatization, along with fatigue and vitality. Research suggests that the “first line” interventions to improve sleep in this population should be behavioral in nature as the use of hypnotics may be contraindicated due to increased risk for medical problems (including pulmonary, hepatic and renal disease) secondary to cancer treatment.47, 48
Future research examining factors impacting neurocognitive functioning in survivors could be improved by the utilization of standardized direct performance measures to supplement self-report questionnaires like the CCSS-NSQ. For example, a computerized continuous performance test would provide separate indices of processing speed and sustained attention, constructs that are combined in the CCSS-NCQ Task Efficiency scale. Although reliance on self-report measures does not represent the “gold standard” of a comprehensive neurocognitive direct performance assessment, self-report has been shown to be a valid and convenient method of measuring neurocognitive functioning.29
Still, direct performance measures may provide additional details and identify more specific neurocognitive processes impacted by sleep disruption. For example, use of the California Verbal Learning Test would permit separation of poor memory encoding from retrieval deficits, which may suggest reduced functioning in hippocampal structures. The use of polysomnographic methods would also be advantageous and permit the characterization of sleep architecture, while at the same time, allowing for the examination of affected sleep states and their impact on neurocognitive outcomes.
In the healthy population, disrupted cycles on the sleep-wake continuum, such as rapid eye movement (REM) and slow wave sleep (SWS) adversely affect memory consolidation, perceptual and motor learning, and cognitive flexibility,49, 50
but the interaction between disrupted sleep cycles and childhood cancer treatment on neuropsychological outcomes has not yet been examined. Understanding the causal means by which factors such as reduced vitality, fatigue, daytime sleepiness, or sleep quality affect neurocognitive functioning will be important for improving the quality of life among survivors of childhood cancer. Clarity regarding the timing of neurocognitive compromise and the anatomical systems affected is also needed so that future therapies can reduce neurocognitive impairment or preserve further insult. Several of our significant findings related to covariate predictors also substantiate the need for future research to utilize comprehensive approaches which include the consideration of sociodemographic and psychological factors in predicting neurocognitive outcomes. Through this approach, we will maximize the likelihood of developing the most relevant models of cognitive functioning which will have the greatest impact on quality of life outcomes among survivors of childhood cancer.