Major depressive disorder is frequently accompanied by sleep disturbances, which affect more than 80% of patients and manifest primarily as insomnia. These disturbances impair quality of life, predict suicidal risk, and often persist after treatment, thereby being associated with the onset of new episodes. Yet most antidepressants suppress rapid eye movement (REM) sleep, and some may even degrade the quality of rest. A substantial proportion of patients—estimated at up to 30%—do not respond to conventional treatments, which justifies the development of experimental therapies such as deep brain stimulation. The medial forebrain bundle (MFB) is one of the emerging targets for treatment-resistant depression, but its effects on sleep have remained poorly understood.
To investigate this question, the authors used the Flinders Sensitive Line rat strain, a validated model of depression. The animals were fitted with bilateral stimulation electrodes in the MFB, surface electrodes for recording the electrocorticogram and electromyogram for sleep classification, as well as electrodes implanted in the prelimbic cortex, the nucleus accumbens, and the dorsal hippocampus. Sleep and oscillatory activity were recorded before and after twenty-four hours of stimulation, while the behavioral antidepressant effects were assessed using the forced swim test.
The recordings revealed, during slow-wave sleep, abnormalities not previously described in these rats: a decreased circadian amplitude of their rhythm, reduced slow-wave activity, and elevated oscillations in the gamma band. The REM sleep deficits already established in this model were also confirmed. MFB stimulation produced an antidepressant effect on behavior without significantly altering sleep architecture; however, it suppressed the excess gamma activity observed during slow-wave sleep, both in the electrocorticogram and in the prelimbic cortex signals. A normalization of delta activity during the early stages of sleep was also suggested as a possible longer-term effect.
According to the authors, these findings highlight the importance of slow-wave sleep as a state of dysfunction in affective disorders, alongside REM sleep disinhibition. As the generation of gamma oscillations relies largely on the activity of GABAergic interneurons, their elevation could reflect a pathophysiology that prevents the production of adequate slow oscillations and disrupts synaptic plasticity processes. The fact that stimulation acts on behavior and sleep physiology without affecting sleep architecture suggests an independent modulation of circuits that share many biological substrates. Modulation of gamma activity could thus constitute a component of the antidepressant mechanism, a hypothesis that will need to be validated in patients.