Unmasking the mysteries of the habenula in pain and analgesia

Abstract

The habenula is a small bilateral structure in the posterior-medial aspect of the dorsal thalamus that has been implicated in a remarkably wide range of behaviors including olfaction, ingestion, mating, endocrine and reward function, pain and analgesia. Afferent connections from forebrain structures send inputs to the lateral and medial habenula where efferents are mainly projected to brainstem regions that include well-known pain modulatory regions such as the periaqueductal gray and raphe nuclei. A convergence of preclinical data implicates the region in multiple behaviors that may be considered part of the pain experience including a putative role in pain modulation, affective, and motivational processes. The habenula seems to play a role as an evaluator, acting as a major point of convergence where external stimuli is received, evaluated, and redirected for motivation of appropriate behavioral response. Here, we review the role of the habenula in pain and analgesia, consider its potential role in chronic pain, and review more recent clinical and functional imaging data of the habenula from animals and humans. Even through the habenula is a small brain structure, advances in structural and functional imaging in humans should allow for further advancement of our understanding of its role in pain and analgesia.

Fig. 1

Habenula neuroanatomy. (A) Rat habenula. A Nissl stain coronal segment of the rat brain, clearly demonstrates the relatively large (when compared with whole brain) rat habenula. This image is from an online atlas (http://brainmaps.org/, accessed May 2011). (B) Monkey habenula. A Nissl stain habenula in the monkey (Hikosaka, 2010 with permission). (C) Human habenula. (C1) An anatomical MRI image of the coronal, sagittal and horizontal view of the human habenula (from fsl). Numbers indicate the slice coordinates. (C2) Localization of the habenula in a coronal magnetic resonance imaging section (Savitz et al., 2011 with permission); (C3) Nissl and fiber staining of a coronal axial slice of the human brain. This image is from ZoomableHuman Brain Atlas (http://zoomablebrain.bio.uci.edu/, accessed May 2011).

Fig. 2

Habenula afferent and efferent connections. Key: FrCtx = frontal cortex, NAc = nucleus accumbens, Lateral Hypo = lateral hypothalamus, EP = entopenduncular nucelus, CPu = caudate/putamen, Hippo = hippocampus, M = medial habenula, L = lateral habenula, P = pineal, IPN = interpeduncular nucleus, PAG = periaqueductal gray, Raphe = raphe nuclei, VTA = ventral tegmental area, and SNc = substantia nigra pars compacta. Adapted from Bianco and Wilson (2009) with permission.

Fig. 3

Conceptual model of habenula circuits in chronic pain. (A) Normal condition. The figure shows habenula circuit-loops that confer potential functions of the structure. The formulation of the loops is based on known afferent outputs to structures that may have connections to other brain regions that send efferents to the habeula. Thus, four basic loops are shown: (1) analgesia/hyperalgeic loop – reflects the integration of outputs from the lateral habenula to regions of the brain that have known pain inhibitory or pain facilitatory action; (2) reward-aversion loop – outputs from the lateral habenula to the VTA through dopaminergic process and connections to the frontal cortex; (3) stress loop – medial habenula projections to the IPN send afferents to the hippocampus a region involved in a number of processes including stress response (but also memory); and the (4) sensory-motor loop – from the lateral habenula connections from the SNc project to basal ganglia regions; the complexity of function may include sensory, emotional and cognitive features and not simply sensory-motor integration. (B) Acute pain. Under acute pain conditions the activity of the habenula is shown to increase all circuits. This is a homeostatic response to a reversible physiological stimulus. (C) Chronic pain. Under chronic pain conditions loop homeostasis is disrupted. For example, the chronic pain state is an aversive state that is a hedonic deficit state where reward systems become dysfunctional; outputs from the pain modulator regions (normally inhibit pain) may now facilitate pain and thus signals form the periphery are enhanced. Stress loop may show enhanced drive with consequent alterations in the hippocampus that may include altered memory in chronic pain. Shown in the bottom right of each figure is the expected activation profile that is low in the normal/no pain condition, increases in response to evoked pain under acute pain conditions, and displays maximal drive in chronic pain conditions.

Fig. 4

Human habenula stimulation. The transversal and coronal view from fluorodeoxyglucose positron emission tomography (FDG-PET) imaging of the metabolic effects from LHb deep brain stimulation of a treatment resistant depression patient is used with permission (Sartorius et al., 2010). Note the regional correspondence to the anatomical image in Fig. 1.

Fig. 5

Activation in habenula to pain. (A) Fos activation. Fos increase with pain representative digitized image of the LHb, is used with permission (Smith et al., 1997). Key: 3V = third ventricle, PVp = paraventricular thalamus, and fr = fasciculus retroflexus. (B) 2-DG measures of chronic pain activation. Spinal cord injury-induced activation in the rat habenula, is used with permission (Paulson et al., 2005); in the upper right corner contrast with a control rat to the left, and in diabetic neuropathic pain, is used with permission (Paulson et al., 2007); pictured on the bottom right versus a control rat habenula pictured to the immediate left. (C) fMRI activation to pain in humans. Coghill et al. (2003) with permission.