Releasing “brakes” in the brain

When certain connections in the brain do not function correctly, disorders such as Parkinson’s disease, dystonia, obsessive-compulsive disorder (OCD), and Tourette’s syndrome may result. Targeted stimulation of specific areas in the brain can help alleviate symptoms. To pinpoint the exact therapeutic target areas of the brain, a team led by researchers from Charité – Universitätsmedizin and Brigham and Women’s Hospital analyzed data from patients across the globe who had undergone implantation of tiny electrodes to stimulate the brain. The result is a unique map of disrupted brain networks that has now been published in Nature Neuroscience.*

Neurological and neuropsychiatric disorders present with a broad spectrum of different symptoms, from mood and information processing disorders to motor deficits. But they do have one thing in common: They are all attributable to malfunctioning connections between specific regions of the brain. In simplified terms, when brain circuits become dysfunctional, they may act as brakes on the brain functions that the circuit usually carries out.

Deep brain stimulation (DBS) targets these kinds of malfunctional circuits and can be instrumental in alleviating symptoms in various areas. In this neurosurgical approach, small electrodes are implanted into precisely defined target brain areas. The electrodes then chronically emit weak electrical pulses to the surrounding tissue. The stimulation effects travel along neural pathways to more distant areas of the brain to unfold their full impact. But stimulation is not always successful. Even small discrepancies in electrode placement can lead to weaker effects of the treatment.

Which specific brain circuits need to be stimulated to achieve optimal outcomes when treating a range of symptoms was the question for an international team headed by neuroscientists Prof. Andreas Horn and Dr. Ningfei Li at Charité and Brigham and Women’s Hospital. “Our goal was to better understand where in the brain possible ‘brakes’ can be released through neuromodulation to normalize the symptoms of Parkinson’s disease, for example,” says Ningfei Li.

Exploring a seeming paradox

The researchers’ work addresses a seeming paradox that has been known for a while in this field. A specific area of the basal ganglia called the subthalamic nucleus is considered an effective target for DBS to treat the symptoms of Parkinson’s disease and dystonia, which are both on the spectrum of movement disorders. Recently, the same region of the brain was also identified as a successful target for treating neuropsychiatric disorders such as OCD and tic disorders.

This raised the question of how such a small nucleus, only about one centimeter long, could be an effective target for symptoms of such different brain dysfunctions. To investigate this question, the team analyzed data from 534 DBS electrodes implanted in 261 patients across the globe. Of this cohort, 70 patients were diagnosed with dystonia, 127 with Parkinson’s disease, 50 with OCD, and 14 with Tourette’s syndrome. Using software developed by the team, the researchers reconstructed the precise location of each electrode. Computer simulations were then used to map neural tracts that were activated in patients with optimal or suboptimal treatment outcomes.

Using these results, they were able to identify specific brain circuits that had become dysfunctional in each of the four disorders. They were associated with the relevant regions of the frontal part of the brain that play an important role in motor functions, impulse control, and information processing. “The circuits we identified partially overlapped, which to us implies that the malfunctions reflected in the symptoms studied are not wholly independent from each other,” says Barbara Hollunder, a PhD fellow at the Einstein Center for Neurosciences at Charité and the first author of the study.

This means that as the first step, the researchers have succeeded in localizing the exact networks in the forebrain and midbrain that are crucial to treating Parkinson’s disease, dystonia, obsessive-compulsive disorder, and Tourette’s syndrome. Applying this same approach across disorders with different symptoms gradually yields a map that denotes how specific brain circuits are associated with certain symptoms. “By analogy to the terms ‘connectome,’ which describes a comprehensive map of all neural connections existing in the brain, and ‘genome,’ which is used for the full set of genetic information found in an organism, we have coined the term human ‘dysfunctome.’ One day, we hope the dysfunctome will describe the entirety of brain circuits that may typically become dysfunctional as a result of network disorders,” Hollunder explains.

Initial success with treatment in the course of the study

The researchers’ findings have already benefited the first few patients. Fine-tuning and precision electrode placement made it possible to alleviate the symptoms of severe, treatment-resistant OCD, for example. “We plan to refine this technique and zero in even more precisely on dysfunctional brain circuits for specific symptoms. For example, we could isolate the circuits involved in obsessions or compulsions in OCD, or other comorbid symptoms commonly found in these patients, like depression and anxiety disorders, to individualize treatment further,” says Ningfei Li, looking to the future.

The researchers also believe that more than one region of the brain may be responsible for improvement of a given symptom. They suspect that neural networks themselves transmit the therapeutic effects, which can be modulated from various points in the brain. This means the study provides not only valuable insights for targeted neurosurgical treatment, but may also inspire approaches for noninvasive neuromodulation such as transcranial magnetic stimulation (TMS), in which magnetic fields are used to stimulate certain areas of the brain from outside of the brain, without the need for surgery.

*Hollunder, Barbara et al. Mapping Dysfunctional Circuits in the Frontal Cortex Using Deep Brain Stimulation. Nature Neuroscience 2024. Feb 22. doi: 10.1038/s41593-024-01570-1

A summary of the article has also been published by Nature Neuroscience as a research briefing: Hollunder, Barbara & Horn, Andreas. Mapping the dysfunctome provides an avenue for targeted brain circuit therapy. Nature Neuroscience 2024. Feb 22.

About the study
Researchers at ten specialized centers in seven countries provided data for the study and contributed to the findings. The work received support from the Einstein Center for Neurosciences Berlin (ECN), the Berlin Institute of Health at Charité (BIH), the Benign Essential Blepharospasm Research Foundation, private supporters Larry and Kana Miao, the Agence nationale de la recherche, the NIHR UCLH Biomedical Research Centre, Scuola Superiore Sant'Anna, the German Research Foundation (DFG), the German Aerospace Center (DLR), the Else Kröner-Fresenius-Stiftung, the Italian Ministry of Health, the Medical Research Council UK, the National Institutes of Health (NIH), and the New Venture Fund.

Links

Original publication
Department of Neurology with Experimental Neurology
Movement Disorders and Neuromodulation Unit (in German)