August 2019 issue
August 31, 2019 | Two new neuromodulation approaches for treating obesity have emerged in recent months, one using closed-loop implanted brain stimulation and the other using noninvasive stimulation paired with genomics. The new therapeutic strategies add to the list of previous neuromodulation efforts, which include VNS, gastric stimulation, DBS, and TMS.
Earlier this month, NeuroPace announced that they will use the company’s RNS system in a clinical investigation to examine whether neuromodulation could be effective as a means of managing loss-of-control eating for patients with body mass index of 45-60 kg/m2 for whom medication and gastric bypass surgery have not been effective treatments, and for whom loss-of-control eating is a contributing factor.
“Loss-of-control eating” refers to a feeling that one cannot control what or how much one is eating. This typically takes one of two forms, either eating objectively large amounts of food or eating continuously, and can compromise even the most aggressive of obesity treatments, such as bariatric surgery. There is evidence to suggest that long-term alterations in brain function, particularly in the reward and impulse control circuitry, occur with eating disorders, including loss-of-control eating. In addition, there is growing evidence to suggest that there are discrete changes in brain activity, or biomarkers, which immediately precede loss-of-control eating events.
A recent research study published in PNAS demonstrated that applying stimulation to the nucleus accumbens when a specific pattern of brain activity was detected could suppress binge-eating behavior in mice. The study also observed similar changes in activity in the homologous brain region in people when they were anticipating a reward, opening up the possibility of using a closed-loop therapeutic approach in humans.
Meanwhile, a Brazilian team has advanced a new approach combining genomic analysis with tDCS stimulation to treat obesity. Previous efforts using tDCS have produced mixed results, with positive results only in some subjects. New findings published in the journal Appetite by researchers at the University of São Paulo help elucidate the reason for the variability. “The patient’s genetic profile, especially variations in the gene COMT, appears to be a key factor in determining the outcome,” said Priscila Giacomo Fassini, first author of the article.
Fassini conducted a double-blind sham-controlled randomized clinical trial to test the efficacy of tDCS in reducing appetite and weight. In the case of obesity, the aim is to modulate neuron excitability in the left dorsolateral prefrontal cortex. “In our trial, we used a current of only 2 mA, which is too weak to be felt by patients,” Fassini said. Sham stimulation involved the same procedure, but the current lasted only 30 seconds, a timeframe too short to affect neurons. The researchers selected 38 women aged 20 to 40 as participants in the trial. For all subjects, BMI was between 30 and 35, corresponding to class 1 (mild) obesity. The selected volunteers were given 17 30-minute sessions of tDCS over the course of a month. Appetite and weight were monitored for six months. According to Fassini, previous trials had only investigated the immediate effects of tDCS on appetite, involved fewer sessions, and performed no follow-up.
The clinical trial comprised four stages. In the first stage, volunteers were given a single tDCS session and then immediately took a test measuring working memory. According to Fassini, the aim was to confirm that the correct brain region was being stimulated, since the LDLPFC is associated with both working memory and appetite. In both cases, there is evidence that the effects of neuromodulation are mediated by the release of dopamine.
In stage two, the volunteers were given 10 tDCS sessions and then returned to their normal routines. In stage three, volunteers were admitted to the hospital for two weeks and placed on supervised, individualized low-calorie diets with a 30 percent reduction in energy intake. During this period, they were also given six more tDCS session. The fourth stage consisted of weight and appetite monitoring for six months after the end of the intervention period. The effects of the treatment on appetite during and after neuromodulation were measured using standard scales for the assessment of hunger, fullness, desire to eat, and prospective food consumption.
Genomic DNA obtained from whole blood samples taken during stage one was sequenced to genotype. The team investigated polymorphisms in COMT, which encodes catechol-O-methyltransferase, an enzyme that plays a critical role in the degradation of dopamine in prefrontal cortex. “Previous research showed that a polymorphism called Val158Met affects the enzyme’s activity and makes it less effective at degrading dopamine. The availability of extracellular dopamine in the prefrontal cortex is higher in people with this variant of the COMT gene,” Fassini said.
The results of her trial did, in fact, point to a significant reduction in appetite over time only in individuals with the Met allele of COMT who also received active neuromodulation treatment. “These individuals responded better to treatment because of higher dopamine availability, displaying lower levels of hunger, less desire to eat, and less prospective food consumption over time,” Fassini said.
However, the most striking discovery from the clinical trial, she continued, was the paradoxical effect observed in noncarriers of the COMT Met allele. In these women, tDCS had the opposite effect, increasing their hunger, desire to eat, and food consumption throughout the intervention period.
