16 May 2017
by Lesley McCollum
As the 2017 ICOSR meeting wrapped up on the afternoon of Tuesday, March 29, in San Diego, California, researchers gathered for a provocative plenary talk by neurosurgeon Aviva Abosch of the University of Colorado, who discussed the controversial approach of using deep brain stimulation (DBS) to treat schizophrenia, particularly in patients whose symptoms don’t respond to medications.
Abosch argued that the success of DBS in movement disorders is building support for its use: Stunning examples demonstrate the immediate calming of tremor in Parkinson’s disease patients with just the flip of a switch. DBS has also been used for years for essential tremor and dystonia, and has even broken into the psychiatric field as an approved treatment for severe obsessive-compulsive disorder that doesn’t respond to other treatments. Although some promising results have been obtained in depression as well, the treatment is not approved for non-research use.
Scientists have a range of hypotheses to explain the effect, but how the technique works remains a mystery. Unfortunately, the idea of physical manipulation of the brain without strong understanding of mechanisms harks back to psychiatry’s dark history of psychosurgery. Recently, the focus of a New York Times Retro Report video, the practice of lobotomy left most patients no better or worse off, and with permanent brain damage. Although any new approaches to psychosurgery will have to overcome this stained record, they warrant investigation despite this history. As with the rest of medicine, psychiatry has made substantial advances since its early days, both in understanding the brain and in rigor for approving new treatments.
In her talk, Abosch emphasized the reversible, tunable, and minimally invasive nature of DBS. An electrode lowered into the brain through a small hole in the skull can be used to deliver electrical stimulation to a targeted region. The complexity of schizophrenia, which reaches just about every corner of the brain, makes for a long list of potential targets. Abosch proposed several, including the hippocampus, ventral striatum, associative striatum, mediodorsal thalamus, and medial prefrontal cortex, based on evidence of pathology in these regions but also because of their interconnectedness with other regions, which could invoke more targets and widen the effect of DBS. The use of DBS in some of these regions has already garnered FDA approval for other diseases, such as the hippocampus for epilepsy and ventral striatum for obsessive-compulsive disorder.
Unpublished reports of individual cases demonstrating a benefit of DBS in schizophrenia lend support its use, and some researchers who see potential in the approach are advancing the technique to small clinical trials. Two Phase 1 trials are currently enrolling patients to test DBS for treatment-resistant schizophrenia, one at the Hospital Sant Pau in Barcelona, Spain, targeting the nucleus accumbens and medial prefrontal cortex in eight patients (see description), and another at Johns Hopkins University in Baltimore, Maryland, targeting the substantia nigra in three patients (see description). A third trial was withdrawn after being unable to find patients to enroll.
The pilot study in Barcelona recently reported data on seven of its subjects at the 2017 meeting of the American Association of Neurological Surgeons (see AANS press release). The preliminary findings were that the treatment was effective against both social withdrawal and auditory hallucinations, but the researchers do not want to claim success until they have completed their study.
The audience expressed concern about the lack of understanding of how the approach works. One researcher raised the question of the consequences of DBS on excitability of a given brain region and wanted to know about the potential effects on related circuits. According to Abosch, hyperactivity of a region is not a prerequisite for DBS, and the situation is more complicated. She referred to its use in Parkinson’s disease and epilepsy to normalize or reset abnormal patterns of activity in a brain region rather than simply turning activity up or down. Others raised questions regarding the symptoms at which DBS would be aimed to treat in schizophrenia, suggesting that brain targets should be identified from a specified symptom domain, as it is unlikely that any target would address all symptoms of the disorder.
The unanswered fundamental questions of what symptoms to treat and which brain regions to target underscore the exploratory status of the idea. Researchers pursuing the approach still have a steep hill to climb to address these questions and to convince the many researchers who remain skeptical, but Abosch’s talk began an important discussion on the changing field of psychiatry and innovative ways to treat such a challenging disorder.