Analysis offers new insights into the placebo effect and how to harness its therapeutic potential


A network of brain regions activated by the placebo effect overlaps several regions targeted by brain stimulation therapy for depression, according to a new analysis from a team including several researchers from Massachusetts General Hospital (MGH), who collaborated with colleagues from Sunnybrook Health University of Toronto Science Centre. The results of this study published in Molecular Psychiatry, will help understand the neurobiology of placebo effects and may influence how the results of brain stimulation clinical trials are interpreted. This work may also offer insights into how to exploit placebo effects for the treatment of various conditions.

The placebo effect occurs when a patient’s symptoms improve because they expect a therapy to help them (due to various factors), but not because of the specific effects of the treatment. -same. Recent research indicates that there is a neurological basis to the placebo effect, with imaging studies identifying a pattern of changes that occur in certain regions of the brain when a person experiences this phenomenon.

The use of brain stimulation techniques for patients with depression who do not respond adequately to medication or psychotherapy has become widespread in recent years. Transcranial Magnetic Stimulation (TMS) is a non-invasive treatment in which a clinician applies a coil to the patient’s head and delivers electromagnetic pulses to the brain. The effect of TMS on brain activity has been established over the past three decades in animal and human research studies, with several TMS devices approved by the Food and Drug Administration for the treatment of depression. Additionally, there is a growing body of research on the use of deep brain stimulation (DBS, which requires an implanted device) for difficult-to-treat depression as well.

The main author of Molecular psychiatry article, Emiliano Santarnecchi, PhD, director of the precision neuroscience and neuromodulation program at the Gordon Center for Medical Imaging at MGH, saw brain stimulation studies as a unique opportunity to learn more about the neurobiology of the effect placebo. Santarnecchi and his co-researchers conducted a meta-analysis and review of neuroimaging studies involving healthy subjects and patients to create a “map” of brain regions activated by the placebo effect. They also analyzed studies of people treated with TMS and DBS for depression to identify brain regions targeted by the therapies. The team found that several brain sites that are activated by the placebo effect overlap with brain regions targeted by TMS and DBS.

Santarnecchi and his colleagues believe this overlap is critically important in interpreting research findings on brain stimulation for conditions such as depression. In clinical trials, a significant portion of depressive patients given brain stimulation improve – but many patients given a (fictitious) placebo treatment, in which no stimulation is given, have sown confusion about the benefits of the therapy . One possible explanation is “there is a significant placebo effect when you perform any form of brain stimulation intervention,” Santarnecchi says. Unlike taking a pill, receiving TMS involves treatment in a surgical-like setting, with imaging monitors and a clinician applying a coil to the patient’s head. There are loud clicks with each pulse delivered. “So the patient thinks, ‘Wow, they’re really turning my brain on,’ so you have a lot of expectations,” Santarnecchi says.

The high placebo effects associated with brain stimulation may create problems when studying the intervention, says the paper’s first author, cognitive neurologist Matthew Burke, MD, of Sunnybrook Health Sciences Center in Toronto. If brain stimulation and the placebo effect overlap in activating the same brain regions, then these circuits could be maximally activated by the placebo effects, which could make it difficult to demonstrate any additional benefit of TMS or DBS, explains Burke. If true, this article may help explain why clinical trials of neurostimulation for depression and other conditions have had such variable results. Separating the placebo component of brain stimulation interventions from their direct impact on brain activity will help design studies where the true potential of techniques such as TMS will be more easily quantified, thereby enhancing the effect of treatment protocols.

The results of this study also suggest broad applications for the placebo effect, Santarnecchi says. “We believe this is an important starting point for understanding the placebo effect in general and learning how to modulate and harness it, including using it as a potential therapeutic tool by intentionally activating regions brain effects of the placebo network to achieve positive effects on symptoms,” he says. Santarnecchi and his colleagues are now designing trials that they hope will “unravel” the effects of brain stimulation from placebo effects and offer insights into how they can be exploited in a clinical setting.

Santarnecchi is an associate professor of neurology at Harvard Medical School.

This study was supported by funding from the Liu Fu Yu Charity Foundation and

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Materials provided by Massachusetts General Hospital. Note: Content may be edited for style and length.


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