Repetitive transcranial magnetic stimulation: A potential therapeutic option for obesity in a patient with Prader‐Willi syndrome

To the Editor: Hyperphagia and, consequently, obesity, are the most serious problems in patients with Prader-Willi syndrome (PWs), leading to decreased quality of life, increased morbidity, and even mortality. An aberrant activation in the following brain areas (i.e. hypothalamus, insula, dorsolateral prefrontal cortex [DLPFC], specifically, the orbitofrontal cortex [OFC] and midbrain reward system) has been shown in patients with PWs both after eating, and in the fasting condition. Recently, a lack of food-anticipatory cerebellar activity has also been described in individuals with PWs, with consequent impairment of the facilitating effects of cerebellar output on striatal dopamine release. Through a functional magnetic resonance imaging study, we showed that a 5-week treatment with high-frequency repetitive transcranial magnetic stimulation (rTMS), targeted to the DLPFC and the insula bilaterally, can enhance the functional connectivity of the OFC in patients with obesity, by reflecting an increased inhibitory activity of the PFC, specifically of the OFC, on eating behaviour. This mechanism is thought to mainly underlie the effectiveness of rTMS in controlling food craving and promoting long-term weight loss in individuals with obesity, as first shown in our previous clinical trial, and replicated by other studies. Whereas rTMS seems to promote the control of food craving by acting on the same brain areas that have been shown to be dysfunctional in patients with PWs, we hypothesized that rTMS may represent an effective treatment for the control of hyperphagia in PWs. Moreover, rTMS has been proposed as a non-invasive and well-tolerated treatment. Repetitive TMS was also shown to improve the cognitive functions in patients with cognitive disorders. We now present our experience in the first application of rTMS to treat hyperphagia and severe obesity in a patient with PWs, with combined monitoring of body weight and cognitive status. The patient undergoing rTMS treatment was a 23-year-old man. He had received a diagnosis of PWs after birth. Severe hyperphagia and obesity had developed by the eighth year of life. Extreme body weight gain (about 25 kg) occurred in the last 3-4 years (body weight 127.4 kg, height 159 cm, body mass index [BMI] 50.4 kg/m). Frequent episodes of ‘binge eating’ have been reported by the patient and by his caregiver familiar. Despite enormous efforts by the patient and his family, his weight gain could not be controlled after any period of short-term weight loss, and weight regain occurred immediately. His obesity resulted in metabolic disorders (e.g. hyperinsulinaemia and type 2 diabetes), arterial hypertension, hypogonadism and obstructive sleep apnoea syndrome. The patient was also taking therapy with metformin 500 mg three times a day (stable dose for at least 6 months), amlodipine 10 mg per day and testosterone enanthate 250 mg every 15 days by injection. The patient had never received growth hormone replacement therapy. Screening assessments included taking a blood sample for metabolic variables, and indirect calorimetry (resting energy expenditure, respiratory quotient). Evaluation of cognitive status was performed through the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MOCA) tests, at the baseline, at the end of rTMS treatment, and at the 3-month follow-up visit. Other specific questionnaires were administered at beginning and at the end of the rTMS intervention (Food Craving Questionnaire-Trait, Barratt Impulsiveness Scale, Rosenberg's Self-Esteem Scale, Short Form-36 Health Survey), to quantify the patient's desire for food, impulsiveness and behaviour, self-esteem and quality of life (Table 1). The protocol was approved by IRCCS Multimedica hospital's ethics committee as ‘compassionate treatment’. The patient was fully informed of potential risks and benefits of the treatment and gave his full consent. The deep rTMS was performed using a Neuro-MS/D magnetic stimulator (Neurosoft Ltd). Neurostimulation was addressed to bilaterally stimulate the PFC and the insula, according to our previous protocol for obesity. During the rTMS treatment, the patient lost about 1 kg per week, with a total weight loss of 4.4 kg (3.5%) at the end of the 5-week intervention, and of 5.9 kg (4.6%) at the 3-month follow-up. BMI changed from 50.4 to 48.6 kg/m at the end of the 5-week intervention, and to 48.0 kg/m at the 3-month follow-up (Figure 1). A robust improvement in the MMSE score (corrected for age and scholarization) was found compared with baseline (from 22 [severe impairment] to 27 [moderate impairment] at the end of the 5-week rTMS treatment, and to 29, at the 3-month follow-up). The improvement in the cognitive status assessed through the MOCA test was confirmed, although perceptually weaker (17/30 to 19/30 at the end of the 5-week rTMS treatment and to 20/30 at the 3-month follow-up). The patient regularly completed all the rTMS planned sessions and underwent the follow-up visit. The patient did not experience severe adverse events throughout the duration of the study. Received: 22 June 2022 Revised: 27 July 2022 Accepted: 8 August 2022