Our findings demonstrated an increase in SWA in young to middle aged women with unipolar MDD. Moreover, increases in SWA in MDD women primarily occurred during the first portion of the night and were most prominent in prefrontal regions. In contrast, men with MDD did not demonstrate significant changes in SWA, corroborating prior investigations that demonstrate sex-specific differences in SWA in MDD
[29, 30]. Strengths of this investigation include age and sex-matching of subjects, which allowed for analyses stratified by sex, as well as lack of confounding psychotropic medications and use of hdEEG for spectral analysis. These results highlight the importance of both sex and EEG topography in the evaluation of SWA in mood disorders.
The findings of this study must be taken in context of the ratio of women to men, which was roughly 2:1, approximating the differential prevalence of MDD by sex in the general population
. Notably, two known prior studies in the literature that have demonstrated similarly increased SWA or delta counts (using period amplitude analysis) in depressive illness relative to controls have both had disproportionately high ratios of female to male MDD subjects of greater than 3:1; however, neither study stratified their analyses by sex
[47, 48]. Our stratified analysis found that in women with MDD, SWA was globally increased relative to female HC, but was most prominently increased in bilateral prefrontal cortical regions, consistent with multiple structural and functional neuroimaging investigations which have demonstrated the importance of the prefrontal cortex in the neurobiology of depression
[49, 50]. However, it is currently not clear how increased SWA in women with MDD is related to the pathophysiology of the disorder.
This study highlights the importance of electrode placement in the evaluation of SWA during sleep in mood disorders. Notably, we did not find a significant difference in SWA between MDD and control subjects in central channels, including analyses stratified by sex. Since the previous scientific literature regarding SWA in depression has utilized central EEG derivations, it is conceivable that the aforementioned inconsistencies between previous studies may be in part due to a lack of topographical resolution or increased variability of SWA in central regions. Thus, the findings of this study suggest spectral analysis of sleep using central derivations may be inadequate to capture the alterations in SWA occurring across the cortex in mood disorders.
There are limitations of this study that merit discussion. Although a prior investigation has demonstrated decreases in SWA in men with MDD
, we did not find statistically significant differences in men with MDD relative to matched HC subjects. However, it is possible that our study was underpowered to detect differences in SWA or decline of SWA across sleep among males. It is also possible that significant prefrontal increases in SWA in MDD in the unstratified analysis would not have been demonstrated had the ratio of men to women been proportionate. Furthermore, subjects did not have an adaptation night in the sleep laboratory, which may have affected results, if groups were differentially affected by first-night effects. Although delta EEG activity is not significantly different in the luteal versus follicular phase of the menstrual cycle in either healthy subjects or patients with severe premenstrual syndrome, it is also possible that not assessing menstrual status at the time of polysomnography may have influenced the results
. Finally, subjects were young to middle aged, and thus, results may not be applicable to older subjects with MDD, as it has been suggested alterations in SWA in MDD are more apparent in young to middle aged cohorts
This study was not able to determine whether increased SWA in MDD is a causal phenomenon for the disorder or an epiphenomenon resulting from chronic sleep disruption associated with the illness. Topographic increases in SWA in depressed women observed in this study are not specific to MDD, as such findings are also seen during recovery sleep following acute sleep deprivation
[33–35]. It is intriguing that increases in SWA are observed in both MDD and sleep deprivation paradigms, as both are associated with impairments in cognitive functions such as attention and working memory, as well as subjective fatigue
[52, 53]. Given the results of this study, further experiments are warranted that examine the relationship between sleep homeostatic processes and executive function in MDD, using sleep restriction and/or sleep delay paradigms
, and the effects of sex on these parameters.
Our results suggest that increased SWA, particularly during early portions of the night, may be related to the pathophysiology of MDD in women. In accordance with this hypothesis, it has been previously proposed that increases in NREM sleep intensity may be depressogenic
, and a recent demonstration that selective slow-wave deprivation has an acute antidepressant response supports this contention
. In addition, when compared to healthy controls, young MDD women exhibited greater low-frequency EEG activity in frontal regions during extended wakefulness
, which has been demonstrated to be a waking correlate of sleep homeostasis
[34, 57]. Both increased SWA during baseline sleep and an enhanced homeostatic response to sleep deprivation paradigms have also been reported, suggesting that MDD women live with an elevated level of homeostatic sleep pressure
[31, 58, 59]. Although our results would support this contention, our experimental design did not include manipulations of sleep homeostasis, and thus only provides partial evidence for this hypothesis. Moreover, given our cross-sectional design, we were not able to determine whether increased SWA in MDD is a state or trait marker for MDD in women, nor are we able to determine if increased SWA is causative for depressive symptoms or an epiphenomenon of some other neurobiological process, which may be mediated by sex-related differences in neurobiology.
The differences in brain structure and function between men and women, and how these alterations may relate to the pathophysiology of mood disorders is a complex topic, as dissecting which components are biologically determined and which are the consequence of environmental conditioning due to gender-related sociocultural experience is fraught with difficulty
. Still, there is significant evidence that there are sex-related differences in gene expression, epigenetic regulatory mechanisms, hypothalamus-pituitary-adrenal axis regulation, and modulation of neurotransmitter systems by neurosteroids between men and women, which may relate to differences in susceptibility to neuropsychiatric illness
[61–63]. It is currently not clear how our neurophysiologic finding of increased SWA in women with MDD may be related to any of these mechanisms, and thus, further research that examines SWA in relation to sex-dependent hormonal, genetic, and epigenetic mechanisms in mood disorders may provide deeper insights into this conceptual framework.