A rare intracranial recording shows how a low-frequency brain signal vanished during tirzepatide-associated symptom relief and resurfaced weeks before dysregulated eating returned.
Study: Brain activity associated with breakthrough food preoccupation in an individual on tirzepatide. Image Credit: Chandan Tripathy / Shutterstock
In a recent study in Nature Medicine, researchers examined how tirzepatide, a therapy used for diabetes and weight management, may be associated with changes in brain activity linked to food preoccupation.
They found that tirzepatide use coincided with periods when a neural biomarker linked to severe food preoccupation was either present or absent, suggesting a possible association rather than a confirmed causal effect. This suggests it could be a useful intervention for dysregulated eating, though the exact mechanism remains unclear.
Neural Biomarkers and Food Preoccupation
Obesity and related metabolic disorders often involve distressing preoccupation with food, which can lead to loss-of-control eating or binge-like episodes.
These behaviors arise from disruptions in both homeostatic systems, which regulate energy balance, and hedonic systems, which assign reward and motivation to food cues. The mesolimbic circuitry, especially the nucleus accumbens (NAc), plays a central role in the hedonic and motivational aspects of eating.
Dysregulation within this system is strongly linked to impulsive or compulsive food-related thoughts and actions, especially in those with obesity or binge-eating tendencies.
Incretin Pathways Influencing Reward Circuits
Incretin-based medications such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonists, including tirzepatide, have become important treatments for obesity and diabetes.
These drugs may influence metabolic pathways. They may also affect reward-related circuits, as incretin receptors are highly expressed in the NAc and other brain regions involved in appetite and motivation.
Although some early evidence suggests these therapies can reduce food preoccupation, emerging observations indicate that some individuals may experience reduced benefit over time in prior studies. However, this case study was not designed to evaluate tolerance. Crucially, the neural mechanisms through which incretin-based therapies affect dysregulated eating remain unexplored in humans.
Direct measurement of brain activity using intracranial electroencephalography (iEEG) offers a rare opportunity to identify biomarkers in the NAc that could clarify how these treatments influence reward processing and potentially guide future interventions.
iEEG Monitoring in Treatment-Refractory Obesity
This study leveraged an ongoing early-feasibility clinical trial involving individuals with treatment-refractory obesity and recurrent loss-of-control eating. Participants were implanted with bilateral depth electrodes targeting the ventral NAc, enabling the collection of iEEG recordings during daily life.
Neural activity was captured through patient-triggered “magnet swipe” events that recorded brain signals during self-reported severe food preoccupation episodes or during relaxed control states. The researchers focused on delta–theta (≤7 Hz) power, which two earlier participants had shown to increase during dysregulated eating episodes.
Comparing Neural Activity Across Tirzepatide Exposure
For this case study, data from a third participant were examined before and after a dose increase of tirzepatide prescribed solely for diabetes management rather than as part of the research protocol. The study compared neural signatures between months with minimal food preoccupation (months 2–4) and months with re-emerging symptoms (months 5–7).
Statistical analyses included permutation testing with cluster correction to determine frequency-specific differences between conditions. Additional comparisons with preliminary data from two previous participants provided context for identifying consistent electrophysiological markers.
Body-weight changes, the frequency of severe food-preoccupation episodes, and temporal correlations between biomarker emergence and symptom recurrence were also evaluated to explore associations, rather than causal effects, between tirzepatide exposure and NAc oscillatory activity.
The authors noted that differences in recorded episode counts partly reflected limitations in device storage and triggering.
Month 1 was excluded from symptom comparisons because of a potential implantation effect.
Delta–Theta Activity Patterns Across Participants
In the two earlier participants, severe food preoccupation was reliably associated with significant increases in delta–theta (≤7 Hz) power in both hemispheres of the ventral NAc, supporting its role as a potential biomarker of dysregulated eating. For the third participant, however, the pattern differed depending on tirzepatide timing.
During months 2–4, when the tirzepatide dosage had recently increased, the participant had almost no severe food-preoccupation episodes, alongside a 7% weight reduction.
During this same period, delta–theta activity during food preoccupation was indistinguishable from that in control states in both hemispheres, contrasting sharply with the elevated biomarker observed in earlier participants. An algorithmic analysis confirmed that these months represented a distinct low-activity period.
Beginning in month 5, the participant started experiencing renewed severe food preoccupation episodes despite maximal tirzepatide dosing. Correspondingly, delta–theta (≤7 Hz) power became significantly elevated during preoccupation episodes, particularly in the left NAc, where effect sizes were strongest. This suggests a possible laterality bias noted by the authors. A prominent low-frequency oscillatory waveform reappeared, and symptom frequency increased to seven episodes per month.
Cross-correlation suggested that biomarker changes preceded behavioral relapse by approximately 7 weeks. Collectively, across all three participants, increased delta–theta activity closely tracked periods of heightened food preoccupation, while its absence aligned with symptom reduction.
Implications for Tirzepatide’s Neural Effects
This rare human case study suggests that tirzepatide may be associated with the modulation of a delta–theta (≤7 Hz) NAc biomarker linked to severe food preoccupation. The biomarker’s emergence in month 5 and its reappearance weeks before behavioral relapse underscore its potential as a marker of heightened vulnerability to dysregulated eating.
These patterns support the possibility that this oscillation reflects heightened vulnerability to dysregulated eating and could serve as a target-engagement biomarker to guide treatment. Strengths include direct measurement of human NAc electrophysiology, longitudinal within-participant tracking, and comparison with multiple implanted participants.
However, the findings are preliminary and limited by the single-case design, the lack of a control condition without tirzepatide, uncertainty about whether the observed neural changes result from tirzepatide or unrelated factors, and potential confounding from postoperative recovery or behavioral variability.
The neural specificity of tirzepatide’s action, whether via GLP-1, GIP, or indirect mechanisms, remains unclear. Broader generalizability is also uncertain, especially beyond individuals with severe obesity and loss-of-control eating.
Journal reference:
Choi, W., Nho, Y.-H., Qiu, L., Chang, A., Campos, G., Seilheimer, R. L., Wilent, W. B., Bakalov, D., Firdous, N., Kerr, M., Joshi, D., Maze, G., Topalovic, U., Batista, D., Suthana, N., Amaro, A., Hayes, M. R., Cajigas, I., Cristancho, M., Allison, K. C., Pesaran, B., Scangos, K. W., Gold, J. I., Wadden, T. A., Halpern, C. H. (2025). Brain activity associated with breakthrough food preoccupation in an individual on tirzepatide. Nature Medicine. DOI: 10.1038/s41591-025-04035-5, https://www.nature.com/articles/s41591-025-04035-5