The habenula as a novel link between the homeostatic and hedonic pathways in cancer-associated weight loss: a pilot study

Maria Maldonado, David L Molfese, Humsini Viswanath, Kaylah Curtis, Ashley Jones, Teresa G Hayes, Marco Marcelli, Sanjay Mediwala, Philip Baldwin, Jose M Garcia, Ramiro Salas, Maria Maldonado, David L Molfese, Humsini Viswanath, Kaylah Curtis, Ashley Jones, Teresa G Hayes, Marco Marcelli, Sanjay Mediwala, Philip Baldwin, Jose M Garcia, Ramiro Salas

Abstract

Background: Little is known about the brain mechanisms underlying cancer-associated weight loss (C-WL) in humans despite this condition negatively affecting their quality of life and survival. We tested the hypothesis that patients with C-WL have abnormal connectivity in homeostatic and hedonic brain pathways together with altered brain activity during food reward.

Methods: In 12 patients with cancer and 12 healthy controls, resting-state functional connectivity (RSFC, resting brain activity observed through changes in blood flow in the brain which creates a blood oxygen level-dependent signal that can be measured using functional magnetic resonance imaging) was used to compare three brain regions hypothesized to play a role in C-WL: the hypothalamus (homeostatic), the nucleus accumbens (hedonic), and the habenula (an important regulator of reward). In addition, the brain reward response to juice was studied. Participants included 12 patients with histological diagnosis of incurable cancer (solid tumours), a European Cooperative Oncology Group performance status of 0-2, and a ≥5% involuntary body weight loss from pre-illness over the previous 6 months and 12 non-cancer controls matched for age, sex, and race. RSFC between the hypothalamus, nucleus accumbens, and habenula and brain striatum activity as measured by functional MRI during juice reward delivery events were the main outcome measures.

Results: After adjusting for BMI and compared with matched controls, patients with C-WL were found to have reduced RSFC between the habenula and hypothalamus (P = 0.04) and between the habenula and nucleus accumbens (P = 0.014). Patients with C-WL also had reduced juice reward responses in the striatum compared with controls.

Conclusions: In patients with C-WL, reduced connectivity between both homeostatic and hedonic brain regions and the habenula and reduced juice reward were observed. Further research is needed to establish the relevance of the habenula and striatum in C-WL.

Trial registration: ClinicalTrials.gov NCT01614990.

Keywords: Cancer anorexia; Cancer cachexia; Habenula; Hypothalamus; Nucleus accumbens; Resting-state functional connectivity.

Published 2018. This article is a U.S. Government work and is in the public domain in the USA. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of the Society on Sarcopenia, Cachexia and Wasting Disorders.

Figures

Figure 1
Figure 1
Significant regions of interest used in analysis: nucleus accumbens (peach), hypothalamus (green), and habenula (yellow). (A) axial view and (B) sagittal view.
Figure 2
Figure 2
Mean resting‐state function connectivity of control participants compared with paticipants with cancer‐associated weight loss controlling for BMI. The resting‐state function connectivity between habenula and nucleus accumbens was significantly lower in participants with cancer‐associated weight loss as compared with control participants (P = 0.014). The resting‐state function connectivity between habenula and hypothalamus is also significantly lower in participants with cancer‐associated weight loss (P = 0.04). This pattern of lower resting‐state function connectivity does not hold for nucleus accumbens and hypothalamus directly. All analysis performed controlling for BMI, the only variable significantly different between groups.
Figure 3
Figure 3
Juice reward activity in healthy controls (A axial; B sagittal) and patients with cancer‐associated weight loss (C axial; D sagittal). A dorsal striatum mask was used. Activity within the dorsal striatum mask was observed in controls (P < 0.05, family‐wise error rate corrected) but not in cancer‐associated weight loss. Group activity is shown over a standard Montreal Neuroscience Institute template image of the brain (http://www.bic.mni.mcgill.ca).
Figure 4
Figure 4
Integration of homeostatic and hedonic inputs. In the control group, homeostatic hunger signals from the hypothalamus modulate the perception of food reward through the habenula. The habenula projects to the nucleus accumbens thus heightening the negative reward of forgoing food within the hedonic pathway. Participants with cancer‐associated weight loss had lower levels of connectivity between the hypothalamus and the habenula and between the habenula and the nucleus accumbens thus decreasing the negative reward of forgoing food and decreasing motivation for food and food intake, which translates in less reward‐related dorsal striatal activity. Large solid arrows indicate pathways active in non‐cancer, healthy controls; dotted arrows indicate same pathways that are downregulated in subjects with cancer‐associated weight loss, and small arrows indicate anatomical location of these brain structures.

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