Stimulating progress in the brain: Using deep brain stimulation (DBS) to treat refractory psychiatric disorders

Stimulating progress in the brain: Using deep brain stimulation (DBS) to treat refractory psychiatric disorders

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Dr. Nir Lipsman
Scientist, Physical Sciences, Hurvitz Brain Sciences Research Program, Sunnybrook Research Institute
Neurosurgeon, Sunnybrook Health Sciences Centre
Assistant Professor, Department of Surgery, University of Toronto
Director, Harquail Centre for Neuromodulation, Sunnybrook Health Sciences Centre

By: Mathura Thiyagarajah
Photo By: Dorsa Derakshan

When conventional methods of intervention for psychiatric conditions fail, patients and physicians alike turn to novel approaches for relief. Deep brain stimulation (DBS) is gaining traction as an emerging intervention for treatment-resistant psychiatric and neurologic disorders, due in part to the work by Dr. Nir Lipsman and colleagues.

DBS is a minimally invasive form of neurosurgery where electrodes are implanted in the brain to modulate neural circuitry. While DBS has primarily been employed for the treatment of movement disorders such as Parkinson’s disease since the 1980s, Dr. Lipsman’s research has fostered its novel application in the psychiatric conditions of anorexia nervosa, post-traumatic stress disorder (PTSD), obsessive compulsive disorder (OCD), and alcohol use disorder.

“My interest has always been in the interface between brain disease and technology,” Dr. Lipsman explains. More specifically, he is interested in “how we can harness the power of technology to treat the most challenging and treatment-resistant neurologic and psychiatric disorders.” This passion led him to become a neurosurgeon and Director of the Harquail Centre for Neuromodulation at Sunnybrook Health Sciences Centre, in which his clinical and research practice focuses on ways to interact with the brain through the neuromodulation methods of DBS and focused-ultrasound (FUS) therapy.

Dr. Lipsman first helped break scientific ground in DBS research in 2013, with the publication of the world-first clinical trial of DBS in anorexia nervosa during his PhD at IMS under the supervision of neurosurgeon Dr. Andres Lozano, together with their collaborator Dr. Blake Woodside.1 Anorexia nervosa is an eating disorder marked by an intense fear of weight gain, persistent behaviours to prevent weight gain, and disturbances in the way weight or body shape is experienced. It has the highest mortality rate of psychiatric disorders and many patients are unresponsive to treatment.2

The Phase 1 pilot trial followed six patients with chronic and severe anorexia nervosa who had suffered from years of unsuccessful treatments and numerous hospitalizations.1 In 2017, a follow-up paper was published with 16 additional patients who underwent DBS treatment.3 While starvation and malnourishment are the most visible physical manifestations of anorexia nervosa, the researchers did not target brain areas related to appetite regulation and feeding behaviour. Rather, stimulation was directed at the subcallosal cingulate, an area associated with mood and anxiety, which are the recognized driving factors underlying the illness. Researchers found that the DBS treatment significantly increased body mass index (BMI), decreased depressive symptoms, and improved mood regulation in patients.3  

The neurosurgical procedure of DBS in these trials is completed in two stages within the same day. The first stage involves stereotactic implantation of the electrodes into specific bilateral positions of the brain while the patient is awake under local anaesthetic. Dr. Lipsman explains that this allows for the “study of the brain in real-time as you are intervening”, since patients can answer questions about how they feel when the electrodes are turned on and identify any possible side effects. Once the team is satisfied with the positions of the electrodes, the patient is put under general anaesthetic for the second stage, in which batteries connected to the electrodes are placed in the chest under the collarbone.

Next, the patient is seen by a psychiatrist to activate the device and adjust stimulation settings over time, which is analogous to establishing an effective dosing regimen of a pharmaceutical to maximize benefits while minimizing side effects. The device is similar to a pacemaker for the heart in that it is always on, except it is constantly stimulating the brain. The stimulation can modulate dysfunctional brain circuits associated with a disorder that are hyperactive or hypoactive, though they may appear visibly normal on a computerized tomography (CT) or magnetic resonance imaging (MRI) scan.

Currently, Dr. Lipsman is targeting brain areas specific to other disorders as well. He is the principal investigator in Phase 1 clinical trials investigating the safety, tolerability, and efficacy of DBS treatment in refractory alcohol use disorder, OCD, and PTSD. The trial in treatment-resistant chronic alcoholism, currently the project of IMS PhD student Dr. Ben Davidson, is among the first systematic prospective trials using DBS to stimulate the nucleus accumbens, an area involved in the brain’s reward pathway that is significantly associated with addictive behaviours.

The next step would be larger, multicenter trials that are sham-controlled. He explains that one of the advantages of DBS is that electrodes can be inserted without activation. As such, patients and raters can be blinded to whether the stimulation is turned on in a scientifically objective and ethical manner. This allows researchers to distinguish between the effects of the patient’s expectations of stimulation compared to actual active stimulation on treatment success.

Ethical implications of DBS are of great interest to Dr. Lipsman, particularly in light of the historical era of lobotomy that still tarnishes conceptions of the field of psychiatric surgery today. “Given those transgressions, it is important that we do things in a systematic, scientifically rigorous, and safe way,” Dr. Lipsman warns.

Respecting patient autonomy is paramount in his clinical and research work, as are patient education and managing participant expectations. Though DBS is minimally invasive compared to other neurosurgeries, explaining the risks of surgery is integral to the intervention process. He stresses the importance of scientists not taking advantage of patient desperation, as the patients involved in these trials have a higher severity of sickness with poorer prospective outcomes. However, this is also why Dr. Lipsman believes “there is a lot at stake in not treating some of those patients.”

In terms of the technology involved, the concept of implanting electrodes in the brain to influence brain circuitry in psychiatric disorders is still fairly new. Dr. Lipsman notes improvements in the physical electrodes and leads involved. Directional lead models allow surgeons to steer stimulation current in a precise direction, thus permitting the stimulation of certain fibres in pathways that may be more important than others. This can be especially important as Dr. Lipsman explains, “We know that no two brains are truly alike and so where we put the electrodes matter a lot.”

Overall, he views DBS as an adjunctive therapy in which brain stimulation can perturb the neural circuits in a way that facilitates the actions of additional interventions, including medical, pharmacological, radiation, and other surgical treatments: “By harnessing all the tools at our disposal, we can try to achieve additive and cumulative therapeutic effects for these disorders.”

Dr. Lipsman is especially enthusiastic about the multidisciplinary and collaborative nature of this work. On an average week, he works closely with neuropsychologists, psychiatrists, and neurologists to develop a treatment strategy and must consider the pharmacology, neuroimaging, and surgery involved. Developments in the design of devices and treatment strategy are made in parallel with advancements in the understanding of brain circuitry of these challenging illnesses.

“All of these fields are developing at the same time, so I think that is what the hope is: that all of these multidisciplinary advancements will come together to develop new therapies,” says Dr. Lipsman.

References

  1. Lipsman N, Woodside DB, Giacobbe P, et al. Subcallosal cingulate deep brain stimulation for treatment-refractory anorexia nervosa: a phase 1 pilot trial. Lancet. 2013;381(9875):1361-70.
  2. Arcelus J, Mitchell AJ, Wales J, et al. Mortality rates in patients with anorexia nervosa and other eating disorders: a meta-analysis of 36 studies. Arch Gen Psychiatry. 2011;68(7):724-31.
  3. Lipsman N, Lam E, Volpini M, et al. Deep brain stimulation of the subcallosal cingulate for treatment-refractory anorexia nervosa: 1 year follow-up of an open-label trial. Lancet Psychiatry. 2017;4(4):285-94.