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

Abstract

BackgroundLittle 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.MethodsIn 12 patients with cancer and 12 healthy controls, resting‐state functional connectivity (RSFC, resting brain activity observed through changes in https://en.wikipedia.org/wiki/Cerebral_blood_flow in the brain which creates a https://en.wikipedia.org/wiki/Blood-oxygen-level_dependent signal that can be measured using https://en.wikipedia.org/wiki/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.ResultsAfter 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.ConclusionsIn 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.

Transcriptomic Characterization of the Human Habenula Highlights Drug Metabolism and the Neuroimmune System

“…In mice, the medial habenula was shown to regulate of hedonic state ( Hsu et al, 2014 ). In patients with cancer-associated weight loss reduced functional connectivity was observed between the habenula and nucleus accumbens during a reward task ( Maldonado et al, 2018 ). Differences in habenula volume has been associated with anhedonia symptoms in depressed and healthy individuals ( Lawson et al, 2017 ).…”

Neural Mechanisms of Cancer Cachexia

“…Research dedicated to unveiling CNS mechanisms of cachexia has historically focused on the hypothalamus, a central coordinator of several homeostatic processes that are known to be awry during cachexia, including appetite, sleep, activity level, wakefulness and macronutrient distribution, to name a few. However, recent work in this field has implicated additional CNS structures involved in cachexia symptoms, including the brainstem and parabrachial nucleus [2,6,7]. These advances in the field demonstrate that not only is our understanding of the hypothalamic mechanisms of cachexia incomplete at this time, but also that our understanding of how other brain structures and their CNS circuitry influence cachexia is in its infancy.…”

Altered habenula to locus coeruleus functional connectivity in past anorexia nervosa suggests correlation with suicidality: a pilot study

“…To our knowledge, previous studies have not investigated a possible role of the Hb in AN, except for our work on cancer cachexia/anorexia, which showed altered habenular connectivity in those patients [11]. This study aimed to determine RSFC alterations between the Hb and its major a targets in pAN.…”

“…Hb activation affects downstream neurotransmitter systems that are involved in altered reward (dopamine), mood (serotonin), and anxiety/stress (norepinephrine). The hedonic reward of food may be altered in patients with AN, and Hb functional connectivity may contribute to this process [11]. The prediction error (difference between expected and obtained reward, signaled by the Hb), which is critically important for survival as it allows for reward-based learning, is altered in AN patients [12], and sensitivity to reward and punishment are extremely important features of AN [13].…”