Neuromodulation Methodologies to Treat Obesity and Type 2 Diabetes

Introduction and Rationale

The global increase in obesity represents one of the major drivers of the exponential rise in type 2 diabetes mellitus (T2D). Obesity and T2D share a complex pathophysiological basis characterized by insulin resistance, alterations in mitochondrial function, systemic inflammation, and dysregulation of the microbiota–gut–brain axis. In this context, the regulation of food intake does not depend exclusively on peripheral metabolic signals but also involves brain circuits implicated in reward processing, motivation, impulse control, and hunger and hedonic eating. The persistence of these alterations may contribute to the maintenance of excess body weight and to difficulties in achieving and sustaining weight loss.

Currently available interventions, including lifestyle modifications, pharmacological therapy, and bariatric surgery, represent fundamental tools for the management of obesity and its metabolic complications. However, they may be associated with limitations in efficacy, high costs, the need for prolonged treatment, or adverse effects. This highlights the need to develop innovative, safe therapeutic strategies that can potentially be integrated with dietary interventions and physical activity. In this regard, non-invasive neuromodulation techniques represent a particularly promising approach, as they allow the modulation of brain circuits involved in appetite regulation and eating behavior.

In particular, repetitive transcranial magnetic stimulation (rTMS), and specifically deep transcranial magnetic stimulation (dTMS), has been investigated as a potential adjunctive treatment for obesity. The protocol developed by the research group involves high-frequency stimulation (18 Hz) over a 5-week period, consisting of three sessions per week, each lasting approximately 30 minutes, using a coil capable of reaching deep brain regions, including the insula and bilateral prefrontal cortex. The modulation of these circuits has been investigated in relation to hedonic hunger, food craving, and the neurobehavioral mechanisms that may influence food intake and weight control. The rationale underlying the present project therefore stems from the hypothesis that neuromodulation may serve as a complementary intervention to dietary and physical activity programs, potentially benefiting both body weight and metabolic profile.

Preliminary evidence from the research group provided the scientific basis for the development of this protocol. In the first randomized, double-blind, sham-controlled study, Ferrulli et al. (2019) evaluated 33 individuals with obesity who were randomized to receive high-frequency dTMS (18 Hz), low-frequency dTMS (1 Hz), or sham stimulation. Treatment was administered over 5 weeks, and participants were assessed at the end of treatment and during follow-up for up to 1 year. In the high-frequency group, a significant reduction in body weight was observed compared with the sham group (−7.83 ± 2.28 kg; P = 0.0009), accompanied by a reduction in BMI (−2.83 ± 0.83 kg/m²; P = 0.0009). A trend toward reduced food craving was also observed, while several metabolic parameters and measures related to physical activity showed significant improvement. The authors concluded that dTMS, combined with a hypocaloric diet and physical activity, was safe and effective in reducing body weight, with the effects maintained for up to 1 year.

Subsequent publications have contributed to characterizing the potential mechanisms through which neuromodulation may influence eating behavior. In 2021, Luzi et al. reported a reduction in impulsivity in individuals with obesity undergoing dTMS, supporting the hypothesis that this intervention may affect psychobehavioral traits associated with the regulation of food intake. During the same period, a functional connectivity study documented changes in functional brain integration following dTMS targeting the insula and prefrontal cortex bilaterally, providing further evidence supporting an effect on neural circuits involved in the regulation of eating behavior.

Taken together, these findings suggest that neuromodulation may represent an innovative therapeutic option for obesity, supporting the need for prospective studies aimed at confirming its efficacy and safety and further investigating its effects in patients with obesity, with or without concomitant T2D.