Abnormal Habenula Activation Profile in Major Depression

MRI scans could predict patients at risk of major depressive disorder
MRI scans could predict patients at risk of major depressive disorder
Aversive conditioned stimulus-elicited habenula response decreased in individuals diagnosed with major depression.

Abnormal activation of the habenula during processing of aversive information is observed in individuals diagnosed with major depression, according to a new study published in Molecular Psychiatry.1

Recent neuroimaging technology advances enabled high-resolution image acquisition of the human habenula, the part of the brain that links the forebrain with the hindbrain and that is primarily associated with motivational control of behavior. Aside from playing a critical role in motivation, the habenula is also involved in learning, sleep, and reward, aversion, and pain processing.2 Its dysfunction has been implicated in numerous disease states including drug addiction, schizophrenia, and mood disorder such as major depressive disorder (MDD).3

One of the core symptoms associated with development of depression is anhedonia, a reduced ability to gain pleasure from typically enjoyable experiences.4 Based on previous findings, the habenula was hypothesized to be hyperactive in response to certain stimuli in individuals diagnosed with MDD, which would thus contribute to behavioral and affective alterations associated with anhedonia such as impaired motivation and atypical reward processing.5

In the present study, investigators affiliated with the Institute of Cognitive Neuroscience at University College, London, were specifically interested in examining phasic or stimulus-evoked habenula function. They used high-resolution functional magnetic resonance imaging (fMRI) to measure activation of the habenula in 25 individuals meeting DSM-IV criteria for MDD and in 25 healthy control participants during a Pavlovian conditioning procedure. Symptom severity of depression was assessed using the Beck Depression Inventory (BDI), Fatigue Sensitivity Scale (FSS), Hamilton Rating Scale for Depression (HAM-D), and Snaith-Hamilton Pleasure Scale (SHAPS). During fMRI, participants in both groups were exposed to abstract images that served as conditioned stimuli (CS), which were then followed by 1 of 4 outcomes: high or low probability of reinforcement and high or low probability of punishment.

The researchers first confirmed that the experimental and control group participants learned the CS-outcome relationship to a similar degree. Also, analysis of habenula volume, as well as tonic (resting-state) habenula function, revealed no significant differences between the 2 groups. Independent of the experimental condition, symptom severity of depression, including greater anhedonia but not fatigue, was associated with smaller habenula volume.

In line with previous reports, as the CS became a better predictor of punishment (mild shock), habenula response increased in control participants. However, contrary to the authors’ original hypothesis, the opposite was true for individuals diagnosed with MDD; as the CS became more shock predicting, blood oxygen level-dependent (BOLD) signals in the habenula decreased.

“One possibility is that this opposite response leads to a loss of capacity for active avoidance, specifically for primary punishments. This suggestion is consistent with recent optogenetic studies that demonstrate that activation of the lateral habenula promotes active behavioral avoidance of stimuli associated with negative consequences,” the authors note in their publication.

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1. Lawson RP, Nord CL, Seymour B, et al. Disrupted habenula function in major depression. Mol Psychiatry. 2016. doi: 10.1038/mp.2016.81. [Epub ahead of print]

2. Strotmann B, Heidemann RM, Anwander A, et al. High-resolution MRI and diffusion-weighted imaging of the human habenula at 7 tesla. J Magn Reson Imaging. 2014;39:1018-1026.

3. Benarroch EE. Habenula: recently recognized functions and potential clinical relevance. Neurology. 2015;85:992-1000.

4. Rizvi SJ, Pizzagalli DA, Sproule BA, Kennedy SH. Assessing anhedonia in depression: potentials and pitfalls. Neurosci Biobehav Rev. 2016;65:21-35.

5. Sartorius A, Henn FA. Deep bran stimulation of the lateral habenula in resistant major depression. Med Hyptotheses. 2007;69:1305-1308.