A study of individuals suffering from treatment-resistant depression found that deep brain stimulation of the ventral anterior limb of the internal capsule, a bundle of white matter in the cerebrum region of the brain, can make these individuals more alert and attentive to their environment. This contributes to the overall antidepressant effect of deep brain stimulation. The research was published in Molecular Psychiatry.
Treatment-resistant depression is a term used to describe a form of major depressive disorder that does not respond adequately to conventional treatments, such as antidepressant medications and psychotherapy. Typically, treatment-resistant depression is diagnosed when a patient has failed to achieve a satisfactory response to at least two different antidepressant treatments of adequate dose and duration. The exact causes of treatment-resistant depression are not fully understood, but they are believed to involve a combination of genetic, biological, environmental, and psychological factors.
A promising novel intervention for treatment-resistant depression is deep brain stimulation. Deep brain stimulation is a surgical procedure that involves implanting electrodes in specific areas of the brain to deliver electrical impulses and modulate abnormal brain activity in this way. Studies have shown that deep brain stimulation of the ventral anterior limb of the internal capsule (vALIC) results in improvement in approximately 40% of individuals with treatment-resistant depression after one year of treatment. The interior capsule is a bundle of white matter (axons) located in the cerebrum region of the brain that connects the frontal cortex with subcortical regions of the brain.
Study author Nora Runia and her colleagues wanted to explore the mechanism through which deep brain stimulation of vALIC results in improving the symptoms of treatment-resistant depression. Their hypothesis was that this activity normalizes the functioning of the amygdala region of the brain. The amygdala is a small, almond-shaped structure in the brain’s temporal lobe that is involved in processing emotions, particularly fear and anxiety. It also plays a key role in memory formation and emotional learning.
Previous studies have linked abnormal functioning of this region with emotion dysregulation, one of the hallmarks of depression. The research team conducted a longitudinal study to explore this.
The study included eleven adults diagnosed with treatment-resistant depression for over two years and sixteen healthy individuals matched for age, sex, and educational level. The latter group was selected based on the absence of psychiatric illnesses in themselves or their immediate family.
The researchers implanted electrodes in the patients’ brains and allowed a three-week recovery period, followed by an optimization phase to identify the most effective stimulation patterns. This phase continued until a stable response was observed for at least four weeks, with the entire process capped at 52 weeks.
Participants were then split into two groups: one received active deep brain stimulation for one to six weeks, followed by a sham (inactive) period, and the other began with the sham period before switching to active stimulation. The participants were unaware of the stimulation status during these phases.
Functional magnetic resonance imaging (fMRI) was conducted before electrode implantation, after optimizing deep brain stimulation parameters, and after each treatment phase to assess the amygdala’s function. Healthy participants also underwent MRI scans at two points, five months apart. During scans, participants viewed sets of emotional faces to allow for a more detailed examination of the amygdala’s functioning. Additionally, depression assessments (using the Hamilton Depression Rating Scale -17) were conducted at each time point.
The results indicated that participants with depression experienced significantly reduced symptom severity after active deep brain stimulation compared to the sham stimulation period. By the end of the study, their symptoms had also markedly improved from the start. Reaction speed tests showed that healthy individuals had quicker responses than depressed participants, but deep brain stimulation treatments improved the reaction speeds of those with depression.
Analysis of amygdala activity revealed that, at the study’s outset, participants with treatment-resistant depression showed decreased responsiveness in the right amygdala region. Long-term deep brain stimulation of the vALIC normalized this responsiveness, leading to quicker reaction times in depressed participants. Moreover, DBS treatment enhanced the connectivity between the amygdala and the sensorimotor and cingulate cortices of the brain.
“In conclusion, the antidepressant effect of vALIC DBS [deep brain stimulation of the ventral anterior limb of the internal capsule] was associated with normalization of blunted baseline amygdala responsivity that was independent of emotional valence, as well as an increase in vigilance as reflected by faster reaction times,” the study authors concluded.
“In addition, active stimulation increased amygdala connectivity with cingulate and sensorimotor regions compared to sham stimulation [the period when the stimulation was turned off]. Together, these results suggest that vALIC DBS improves depressive symptoms in part by reversing amygdala pathophysiology in MDD [major depressive disorder].”
The study sheds light on the neural mechanisms of depression and makes a valuable contribution to understanding the way a powerful novel treatment for depression produces its effects. However, it should be noted that deep brain stimulation equipment used in this study was not compatible with magnetic resonance imaging. Due to this, it had to be turned off during scans, denying the researchers the possibility to observe the effects of the stimulation on the brain in real time. Additionally, the number of participants who completed the study procedures was very small.
The paper, “Deep brain stimulation normalizes amygdala responsivity in treatment-resistant depression,” was authored by Nora Runia, Isidoor O. Bergfeld, Bart P. de Kwaasteniet, Judy Luigjes, Jan van Laarhoven, Peter Notten, Guus Beute, Pepijn van den Munckhof, Rick Schuurman, Damiaan Denys, and Guido A. van Wingen.
