New intracranial recordings show that a distinct neural rhythm in the brain’s reward center surges during intense food preoccupation, and may explain why cravings can return even during high-dose tirzepatide therapy.
Study: Brain activity associated with breakthrough food preoccupation in an individual on tirzepatide. Image Credit: peterschrieber.media / Shutterstock.com
A recent study published in Nature Medicine investigates how the use of tirzepatide may be associated with changes in food preoccupation by examining activity within the brain’s mesolimbic circuitry.
Human eating behaviors and their regulation
Eating behavior is a complex interplay of psychological, physiologic, social, and genetic factors that influence an individual’s mealtime, food preferences, and food intake. It is important for researchers to identify the key factors that drive food selection to address the epidemics of obesity, cardiovascular disease, and diabetes.
Eating behaviors are regulated by hedonic and homeostatic processes, which are associated with brain activity. Homeostatic processes involve hypothalamic and brainstem circuits that regulate eating in response to energy needs. The hedonic process, which involves the mesolimbic circuit, including the nucleus accumbens (NAc), leads to eating for pleasure. These brain regions are highly interactive and often influenced by other areas that process complex motivational processes related to ingestion.
Unknown aspects of obesity and diabetes management therapies
Incretin-based therapies, such as glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1)-based receptor agonists, have been developed to manage obesity and type 2 diabetes. These treatments target the central nervous system nuclei, particularly the hypothalamus and NAc, which regulate energy balance and reward processing.
To date, it remains unclear how incretin-based therapies affect the mesolimbic circuitry to alter human eating behaviors. Considering the involvement of the mesolimbic system in food-related motivation, its dysregulation could induce a persistent reaction to food cues, a phenomenon collectively referred to as food preoccupation.
Although obese patients show abnormalities in the mesocorticolimbic system, hypothalamus, and brain stem, similar anomalies have also been identified in patients with binge eating disorders. The degree of reward hypersensitivity and food impulsivity involves varying levels of mesocorticolimbic dysregulation in patients with obesity and binge eating disorder.
Mechanistic insights into tirzepatide for treating obesity
In the current study, intracranial electroencephalography (iEEG) was used to measure neural activity within human brain circuitry directly. The researchers were particularly interested in the role of this neural activity in food preoccupation, as the conceptual shift in eating behaviors results from disruptions in both hedonic and homeostatic processes.
A total of three individuals were included in the current study. Both participants 1 (51-year-old woman) and 2 (61-year-old woman) had severe treatment-resistant obesity and distressing food preoccupation, even after bariatric surgery. Participant 3 was a 60-year-old woman with severe treatment-resistant obesity despite bariatric surgery who was also diagnosed with type 2 diabetes.
In participant 3, tirzepatide was prescribed for her type 2 diabetes in addition to bilateral responsive deep-brain stimulation (rDBS) implantation in the NAc. To better manage her diabetes and reduce surgical risks, the patient’s clinical team recommended increasing the tirzepatide dose before device implantation.
Ambulatory iEEG recordings from the NAc in participants 1 and 2 were analyzed during the biomarker discovery phase. Significantly higher delta-theta band power was observed in the ventral NAc of both participants during this phase compared to control states in the left and right hemispheres. Both study participants also exhibited a high number of severe food preoccupation episodes.
After discovering the biomarker and applying several months of responsive stimulation, the delta-theta band power in the ventral NAc during severe food preoccupation was similar to that of control states in both hemispheres for both participants. Notably, the frequency of severe food-preoccupation episodes during the stimulation phase also decreased.
Based on these findings, the researchers proposed that delta-theta band power could be used as a biomarker to identify increased risk of severe food preoccupation. They further hypothesized that in participant 3, tirzepatide’s effects on food preoccupation may be associated with changes in this delta-theta band biomarker within the NAc, a central part of the mesolimbic reward system where incretin receptors are present.
Unlike participants 1 and 2, participant 3 experienced a prolonged absence of severe food preoccupation, lasting between two and four months after surgery, following a pre-implantation increase in the tirzepatide dose. During this period, delta-theta band power during preoccupation episodes was similar to control states in both hemispheres, with no changes in higher frequencies. The duration of this quiescent period was confirmed by an algorithm that detected a significant shift in delta-theta band power values.
Between five and seven months after the surgery, the delta-theta band biomarker emerged, and the participant experienced renewed severe food preoccupation, despite being prescribed the highest tirzepatide dose. Delta-theta power during these episodes was significantly higher than in control states in both hemispheres. Following this biomarker shift, the frequency of severe food preoccupation episodes increased to seven per month. The recurrent symptoms despite maximal dosing are consistent with prior suggestions of possible tolerance to incretin-based therapies, though this remains speculative.
Potential neural biomarkers associated with tirzepatide use
Tirzepatide may alter or coincide with changes in the delta-theta band biomarker in the human NAc, which is linked to severe food preoccupation. All study participants exhibited increased delta-theta power during food preoccupation, with exploratory analysis in participant 3 suggesting a seven-week lag between biomarker appearance and symptoms.
These findings suggest that delta-theta band oscillation could be used as a target-engagement biomarker. However, the relationship between the delta-theta band and preoccupation requires further validation, and the tirzepatide-related findings come from a single uncontrolled case study.
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