What are the therapeutic mechanisms of deep-brain stimulation?

Hundreds of thousands of people worldwide benefit from treatment with deep-brain stimulation. But how does this actually work? A new study from the Netherlands Institute for Neuroscience sheds light on this question.

Deep-brain stimulation (DBS) has been used as a therapy for neurological disorders such as Parkinson’s disease for decades. More recently, it also gained attention as a treatment for psychiatric disorders. Patients suffering from various conditions such as depression and obsessive-compulsive disorder (OCD) can be helped with DBS after all other traditional treatment attempts failed. However, although effective, the mechanisms underlying its therapeutic effect remain unclear, resulting in long optimization periods and sub-optimal response rates.

For DBS treatment, electrodes are surgically implanted into the brain to stimulate specific areas. For OCD patients, the internal capsule (IC), a fiber bundle connecting the cortex with deep-brain regions, is often targeted. After electrode implantation, patients are monitored to examine DBS-induced changes in their symptoms: Whenever the patients do not experience reduced symptoms within a few weeks, DBS parameters are changed, and symptoms are re-evaluated. This trial-and-error process can take months and, in some cases, more than a year. And unfortunately, some patients do not respond to DBS treatment at all. To improve DBS therapy, the big question is: What precisely is DBS doing to the brain?

Mouse model for OCD

To gain insight into the mechanisms of DBS, Bastijn van den Boom and his colleagues, under the supervision of Dr. Ingo Willuhn, measured neuronal activity in a mouse model for OCD. The compulsive-like nature of excessive grooming in the mouse model resembles the compulsive actions seen in OCD patients. By analyzing activity in cortico-striatal regions (thought to be involved in compulsive behaviors), they discovered several mechanisms that probably underly the therapeutic effects of DBS.

Contrary to popular belief, DBS does not manifest itself as a “reversible lesion”, but instead changes dysfunctional activity in brain-wide networks. Importantly, these effects were only present in awake mice, suggesting that that they require activity throughout the entire brain and are not only dependent locally on the stimulated region. In addition to these wide-spread effects, the authors identified an important role for the medial orbitofrontal cortex (mOFC) in the suppression of compulsive-like grooming. This finding was corroborated by selective optogenetic stimulation of the mOFC, mimicking the DBS effects on this region.

Interference of electricity

Bastijn van den Boom: “One of the reasons why it is challenging to study DBS is due to its disturbing interference of electrophysiological recordings of brain-cell activity, a technique commonly used to measure neuronal activity. The resulting electrical artifacts hamper the interpretability of such recordings. We’ve circumvented this problem by using an alternative technique employing light to infer neuronal activity, called calcium imaging. Using miniaturized, head-mounted microscopes in freely-behaving mice, we were able to examine the effects of DBS.”

“In addition to testing a mouse model for OCD, we conducted experiments in normal mice, which allowed us to distinguish the general effects of DBS from the effects on compulsivity. Together, our findings provide mechanistic insight into the effects of DBS on brain-wide circuits, as well as its effects on regions potentially involved in the suppression of compulsive-like grooming.”

Various psychiatric disorders

These new research findings provide insight into the mechanisms of DBS and pave the way for novel questions related to the effects of DBS in various psychiatric disorders – questions the lab is working on. For example, depending on the hospital, OCD patients might be stimulated in the IC, ventral striatum, or subthalamic nucleus. Experience shows that DBS of all these brain targets results in similar clinical effects.

This raises the question whether these targets share similar DBS effects or might suppress compulsivity via unique mechanisms. In addition, given the broad, brain-wide effects of DBS, these results suggest that DBS in the IC might be effective in many psychiatric disorders. Answers to these questions will advance our understanding of the therapeutic effects of DBS and will hopefully result in improved treatment for many patients suffering from psychiatric disorders.

Source: Nature Communications