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A new brain imaging study provides evidence that deep brain stimulation of a specific brain region called the ventral anterior limb of the internal capsule (vALIC) may change how key emotional and cognitive areas in the brain interact in people with severe, treatment-resistant depression. Published in the journal Psychological Medicine, the findings suggest that the treatment induces long-term changes centered around the amygdala, a brain structure linked to emotional processing, and shorter-term effects focused on the insula, a region involved in internal bodily awareness and emotional states.
The results help explain how deep brain stimulation could help people with depression who have not responded to standard interventions such as medication, psychotherapy, or even electroconvulsive therapy. They also provide new insights into how the brain’s emotional networks adapt to stimulation over time.
Deep brain stimulation is a neurosurgical procedure in which electrodes are implanted deep into specific brain areas. These electrodes deliver controlled electrical pulses to modulate abnormal brain activity. The treatment is most commonly used to manage symptoms in conditions like Parkinson’s disease and obsessive-compulsive disorder. Over the past two decades, researchers have also explored its use in severe depression, particularly for patients who have not responded to any conventional treatments.
In depression, brain imaging studies have consistently shown altered activity in areas involved in mood regulation, including the amygdala, prefrontal cortex, and striatum. Some areas, such as the amygdala and insula, tend to show heightened activity, while others, like parts of the prefrontal cortex, appear underactive. Deep brain stimulation aims to restore balance in these networks, though the exact mechanisms remain unclear.
“Deep brain stimulation is under investigation as new treatment for patients with major depressive disorder, or depression for short. We have performed one of the only positive controlled clinical trials which suggests that it is effective compared to sham (fake) stimulation,” said study author Guido van Wingen, a professor of neuroimaging in psychiatry at Amsterdam UMC.
“The question for the current study was to investigate how it actually works. Depression is thought to be caused by altered interactions between distant brain regions. We therefore investigated how DBS alters the interactions of brain regions that are key for particular depression symptoms: the nucleus accumbens for reduced pleasure (anhedonia) and the amygdala for negative mood.”
The researchers recruited individuals with long-standing depression who had not improved after trying multiple classes of antidepressants, mood stabilizers, and electroconvulsive therapy. Participants received deep brain stimulation targeting the vALIC, which is located near another brain region often implicated in mood disorders—the nucleus accumbens.
The study included both patients and a control group of healthy participants. Patients were scanned using functional magnetic resonance imaging (fMRI) before and after the stimulation settings were optimized for each individual. This optimization process could take up to a year and involved biweekly clinical evaluations and adjustments to the stimulation parameters. After this period, patients entered a randomized, double-blind phase during which the stimulator was turned on and off in alternating blocks, allowing researchers to assess the immediate effects of stimulation.
The imaging data were analyzed in two ways. One method looked at overall functional connectivity—how strongly different brain regions are linked during rest. The second method, known as effective connectivity analysis, used a mathematical model to estimate the direction and strength of influence that one region exerts on another, helping to clarify whether certain brain areas were exciting or inhibiting each other.
One major finding was that connectivity between the amygdala and the left insula increased in patients who received deep brain stimulation, whereas it decreased over time in healthy controls. This connection is thought to be important for linking emotional experiences with awareness of internal bodily states. Previous studies have reported that this pathway is often weaker in people with depression, so an increase in connectivity might suggest a return toward more typical emotional processing.
In contrast, connectivity between the nucleus accumbens and the ventromedial prefrontal cortex decreased in patients following stimulation. This was true for both the left and right nucleus accumbens. The ventromedial prefrontal cortex is often linked to self-referential thinking and rumination, a pattern of repetitive negative thoughts common in depression. While previous studies have shown mixed results regarding the direction of this connectivity in depression, the decrease observed here suggests a shift in how reward and decision-making circuits interact during rest.
Additional changes were observed in the connection between the amygdala and the precentral gyrus, a brain region typically associated with motor planning but also implicated in emotional responding. Patients showed an increase in connectivity between these regions after treatment, while healthy controls showed a decrease over time.
In the short-term crossover phase, when stimulation was switched on and off, the researchers found different patterns of change. The amygdala showed stronger self-inhibition when the device was turned on, making it less responsive to signals from other brain areas. At the same time, communication between the insula and the prefrontal cortex weakened, suggesting a dampening of circuits involved in emotional and internal monitoring.
The study also found that the balance of influence between the insula and the nucleus accumbens shifted during stimulation. When the stimulator was active, the nucleus accumbens exerted more inhibition over the insula, and the insula had less influence over the nucleus accumbens. These effects appeared only during the short-term crossover phase and were not observed after the longer optimization period.
“We found that long-term deep brain stimulation indeed changes functional connectivity of the nucleus accumbens and amygdala with brain regions involved in the regulation (prefrontal cortex) and experience (insula) of emotions and feelings,” van Wingen told PsyPost. “Short-term cessation of deep brain stimulation resulted in more subtle rebalancing of how these brain regions influenced each other.”
The study sheds light on how deep brain stimulation reshapes emotional brain networks. But there are some limitations. The sample size was small, as is often the case in studies involving neurosurgical interventions. Only nine patients had usable imaging data from both the preoperative and post-optimization phases. This limited the researchers’ ability to examine individual differences or explore how factors like medication use or stimulation settings might influence outcomes.
The study was also limited to a predefined set of brain regions, chosen based on earlier work in obsessive-compulsive disorder. While this allowed for targeted analysis, it means that other relevant brain areas might have been overlooked.
The researchers plan to replicate their findings in future studies with larger samples. A better understanding of how deep brain stimulation influences emotional and cognitive networks could help refine the procedure and tailor it more effectively for individuals with depression.
The study, “Deep brain stimulation modulates directional limbic connectivity in major depressive disorder,” was authored by Egill A. Fridgeirsson, Isidoor Bergfeld, Bart P. de Kwaasteniet, Judy Luigjes, Jan van Laarhoven, Peter Notten, Guus Beute, Pepijn van den Munckhof, Rick Schuurman, Damiaan Denys, and Guido van Wingen.
