PSYC 50: Neuroscience of Mental Illness

How might sleep deprivation alleviate symptoms of depression?

Major Depressive Disorder (MDD) is a common mental illness, affecting 2-6% of people (Taraku et al., 2023, p. 2). While many cases are treatable, it may take time to find a treatment which is especially effective. Furthermore, antidepressant medications can take several weeks before beneficial effects appear, and are not effective for all patients (Shi et al. 2023, p. 100; Taraku et al., 2023, p. 2). In some cases, an immediate intervention may be required in order to get a depressed patient to a state where they can take on more intensive treatment.

Losing sleep is generally associated with cognitive deficits, and unstable sleep tends to worsen anxiety and depression (Taraku et al., 2023, p. 2). However, sleep deprivation therapies have paradoxically been found to produce temporary, rapid antidepressant effects in around half of patients with MDD (Boland et al. 2017, p. e1033; Taraku et al., 2023, p. 2). This warrants study not only because research may help refine sleep deprivation as a specific therapy for MDD, but because understanding the parts of the brain implicated and how sleep deprivation affects them might lead to a broader understanding of MDD and its neural substrates.

Shi, S., Zhang, M., Xie, W., Ju, P., Chen, N., Wang, F., Lyu, D., Wang, M., & Hong, W. (2023). Sleep deprivation alleviates depression-like behaviors in mice via inhibiting immune and inflammatory pathways and improving neuroplasticity. Journal of Affective Disorders, 340, 100-112. https://doi.org/10.1016/j.jad.2023.07.119

The research reported in this article is related to my question because the researchers attempt to answer with certainty whether sleep deprivation (SD) therapy can swiftly improve depressive symptoms. They do this using a mouse model, but it is likely that the underlying mechanisms of the symptoms and treatment are the same in humans. They found that after gently keeping the mice awake for six hours, symptoms of depression were significantly reduced. To model MDD, chronic restraint stress, or CRS, was used to produce lack of motivation, despair, anhedonia, and weight loss. This was correlated with three key changes in the brains of the mice. First, on the genetic level, the researchers found that several genes related to inflammation and immune response were overexpressed in the anterior cingulate cortex (ACC) of the CRS mice (the ACC is central to MDD and its treatment), as though the mice were fighting an infectious disease. After SD, the expression of these genes returned to baseline. A similar effect was observed in microglia, the immune cells of the brain. Finally, SD improved neuroplasticity of the prefrontal cortex (PFC) and ACC—even though SD is sometimes found to impair neuroplasticity. This helps me understand what depression might be doing to the brain which SD can reverse (causing inflammation and hindering neuroplasticity) and what areas of the brain might be important to focus on (the ACC and PFC, and the researchers highlight the amygdala-cingulate circuit as an area to explore further). The paper doesn’t address how SD might help symptoms of MDD in humans, or how the duration of SD modulates these benefits.

Taraku, B., Zavaliangos-Petropulu, A., Loureiro, J. R., Al-Sharif, N. B., Kubicki, A., Joshi, S. H., Woods, R. P., Espinoza, R., Narr, K. L., & Sahib, A. K. (2023). White matter microstructural perturbations after total sleep deprivation in depression. Frontiers in Psychiatry, 14. https://doi.org/10.3389/fpsyt.2023.1195763

The research reported in this article is related to my question because the researchers attempt to get a clearer picture of why 24 hours of total sleep deprivation (TSD) has therapeutic effects in human patients with MDD. These researchers combine diffusion tensor imaging (DTI, which is frequently used to measure microstructural abnormalities of white matter, or WM, in depressed patients) with TSD, which has been studied as a fact-acting antidepressant intervention. They found that fractional anisotropy (FA) was significantly reduced in major WM pathways; notably, the anterior corona radiata, which connects frontal regions like the PFC and ACC to deeper structures in the brain. This was associated with improvements in rumination in the depressed patients. Interestingly, FA increased in healthy controls, which suggests that the benefits of TSD on depressed patients might only apply for those patients. So this paper helps highlight the superior corona radiata as an area specifically implicated in MDD, and confirms that TSD alleviates rumination, one specific symptom of the disorder. However, one limitation of DTI in this case is that it doesn’t explain the exact mechanisms by which this effect is produced, or how closely those mechanisms are related to depression (the changes could be related more to sleep).

The research reported in this article is related to my question because the researchers attempt to get a clearer picture of why 24 hours of total sleep deprivation (TSD) has therapeutic effects in human patients with MDD. These researchers combine diffusion tensor imaging (DTI, which is frequently used to measure microstructural abnormalities of white matter, or WM, in depressed patients) with TSD, which has been studied as a fact-acting antidepressant intervention. They found that fractional anisotropy (FA) was significantly reduced in major WM pathways; notably, the anterior corona radiata, which connects frontal regions like the PFC and ACC to deeper structures in the brain. This was associated with improvements in rumination in the depressed patients. Interestingly, FA increased in healthy controls, which suggests that the benefits of TSD on depressed patients might only apply for those patients. So this paper helps highlight the superior corona radiata as an area specifically implicated in MDD, and confirms that TSD alleviates rumination, one specific symptom of the disorder. However, one limitation of DTI in this case is that it doesn’t explain the exact mechanisms by which this effect is produced, or how closely those mechanisms are related to depression (the changes could be related more to sleep).

Integrate the findings of the articles you cited to address the question you posed.

Do the two articles converge on a clear conclusion? Are there elements that are contradictory?

What issues remain unresolved? What research could be done that might provide further insights?

Based on what you learned, how would you answer the question you posed?

What are the implications of these findings for understanding mental illness? The implications will depend on your question and what you learned from the research. Examples of implications might be in terms understanding the neural basis of a particular disorder, what might help with prevention or early intervention, potential avenues for treatment, etc. You do not need to address all of these factors! Focus on what is relevant to your question and the research you reported.

The findings of both articles identify clear benefits of sleep deprivation on symptoms of depression in both mice and humans. However, because of the different methods they use, their results point to different areas of the brain. The study on mice found anti-inflammatory and pro-neuroplasticity effects in the ACC and PFC. We understand the ACC to be involved in emotion regulation and processing; if it was functioning abnormally or rigidly, that might make it harder to feel strongly, which we can tie back to the anhedonia observed in the mice. The ACC and PFC are also involved in motivation and reward anticipation/processing; this might tie into the lack of interest or self-preservation observed in the mice. Sleep deprivation being able to temporarily “reset” these parts of the brain back to normal function has implications for treatment of human patients with MDD – it could give patients the executive control to take stock of their situation and the motivation/reward to pursue further interventions. These areas of the brain are connected to the anterior corona radiata, which was found to be affected by total sleep deprivation in the study on humans. We might speculate that decreased FA in this area, associated with decreased structural integrity of its white matter, possibly disrupts some overactive circuits that are associated with rumination. This, too, has clinical implications, as it might point to total sleep deprivation being more effective for specific symptoms of MDD, including rumination. The studies also help us understand the pathophysiology of depression better, with regard to inflammation/immune responses and white matter abnormalities.

Further research can hopefully find ways to reproduce these effects without requiring sleep deprivation, which has only short-term benefits in depressed patients and can have other cognitive drawbacks. Additionally, while both studies identified concrete evidence for the positive effects of sleep deprivation, much is still left to be understood as to their underlying mechanisms. However, I would say this is enough to go forward with more clinical research on sleep deprivation as a treatment for MDD and hopefully figure out what amounts/situations are best.

Additional Work Cited

Boland, E., Rao, H., Dinges, D., Smith, R., Goel, N., Detre, J., Basner, M., Sheline, Y., Thase, M., & Gehrman, P. (2017). Meta-analysis of the antidepressant effects of acute sleep deprivation. Journal of Clinical Psychiatry, 78(8), e1020-e1034. https://doi.org/10.4088/jcp.16r11332