Pleasure systems in the brain

Abstract

Pleasure is mediated by well-developed mesocorticolimbic circuitry and serves adaptive functions. In affective disorders, anhedonia (lack of pleasure) or dysphoria (negative affect) can result from breakdowns of that hedonic system. Human neuroimaging studies indicate that surprisingly similar circuitry is activated by quite diverse pleasures, suggesting a common neural currency shared by all. Wanting for reward is generated by a large and distributed brain system. Liking, or pleasure itself, is generated by a smaller set of hedonic hot spots within limbic circuitry. Those hot spots also can be embedded in broader anatomical patterns of valence organization, such as in a keyboard pattern of nucleus accumbens generators for desire versus dread. In contrast, some of the best known textbook candidates for pleasure generators, including classic pleasure electrodes and the mesolimbic dopamine system, may not generate pleasure after all. These emerging insights into brain pleasure mechanisms may eventually facilitate better treatments for affective disorders.

Figure 1. Causal hedonic hotspots and coldspots in the brain

A) Top shows positive hedonic orofacial expressions (‘liking’) elicited by sucrose taste in rat, orangutan, and newborn human infant. Negative aversive (‘disgust’) reactions are elicited by bitter taste. B) shows sagittal view of hedonic hotspots in rat brain containing nucleus accumbens, ventral pallidum, and prefrontal cortex. Hotspots (red) depict sites where opioid stimulation enhances ‘liking’ reactions elicited by sucrose taste. Coldspots (blue) show sites where the same opioid stimulation oppositely suppresses ‘liking’ reactions to sucrose. C) Nucleus accumbens blow-up of medial shell shows effects of opioid microinjections in NAc hotspot and coldspot. (red/orange dots in hotspot = >200% increases in ‘liking’ reactions; blue dots in coldspot = 50% reductions in ‘liking’ reactions to sucrose). Panels show separate hedonic effects of mu opioid, delta opioid and kappa opioid stimulation via microinjections in NAc shell on sweetness ‘liking’ reactions. Bottom row shows effects of mu, delta or kappa agonist microinjections on establishment of a learned place preference (i.e., red/orange dots in hotspot) or place avoidance (blue dots). Surprisingly similar patterns of anterior hedonic hotspots and posterior suppressive coldspots are seen for all three major types of opioid receptor stimulation. Modified from (Castro and Berridge, 2014).

Figure 2. Three-dimensional comparison of hedonic sites in rat brain (left) and human brain (right)

A. Rat brain shows hedonic hotspots (red) and coldspots (blue) in coronal, sagittal, horizontal planes and in 3D fronto-lateral perspective view (clockwise from top left). B. Human brain shows extrapolation of rat causal hotspots to analogous human sites in NAc and VP (red), and shows fMRI coding sites for positive affective reactions in green (from text). Human views are also in coronal, sagittal, horizontal and 3D perspective (clockwise from top left of B). The tentative functional networks between the different hotspots and coldspots have been added to give an impression of the topology of a pleasure network. The functional connection lines are not meant to imply direct anatomical projections between two connected structures, but rather a functional network in mediating hedonic ‘liking’ reactions and subjective pleasure ratings. Abbreviations: VP, ventral pallidum; NAc, nucleus accumbens; PBN, parabrachial nucleus; mOFC, medial orbitofrontal cortex; lOFC, lateral orbitofrontal cortex; midOFC, mid-anterior orbitofrontal cortex; dACC, dorsal anterior cingulate cortex; rACC, rostral anterior cingulate cortex; PAG, periaqueductal gray.

Figure 3. Hedonic coding in the human orbitofrontal cortex (OFC)

In humans, the orbitofrontal cortex is an important hub for pleasure coding, albeit heterogeneous, where different sub-regions are involved in different aspects of hedonic processing. A) Neuroimaging investigations have found differential activity to rewards depending on context in three subregions: the medial OFC (mOFC), mid-anterior OFC (midOFC) and lateral OFC (lOFC). B) A meta-analysis of neuroimaging studies showing task-related activity in the OFC demonstrated different functional roles for these three sub-regions. In particular, the midOFC appears to best code the subjective experience of pleasure such as food and sex (orange), while mOFC monitors the valence, learning and memory of reward values (green area and round blue dots). However, unlike the midOFC, activity in the mOFC is not sensitive to reward devaluation and thus may not so faithfully track pleasure. In contrast, the lOFC region is active when punishers force a behavioural change (purple and orange triangles). Furthermore, the meta-analysis showed a posterior-axis of reward complexity such that more abstract rewards (such as money) will engage more anterior regions to more sensory rewards (such as taste). C) Further investigations into the role of the OFC on the spontaneous dynamics during rest found broadly similar sub-divisions in terms of functional connectivity (Kahnt et al., 2012) with an optimal hierarchical clustering of four to six OFC regions. This included medial (1), posterior central (2), central (3) and lateral (4–6) clusters with the latter spanning an anterior-posterior gradient (bottom of Fig 3B), and connected to different cortical and subcortical regions (top of Figure 3B). Taken together, both the task-related and resting-state activity provides evidence for a significant role of the OFC in a common currency network. It is also compatible with a relatively simple model where primary sensory areas feed reinforcer identity to the OFC where it is combined to form multi-modal representations and assigned a reward value to help guide adaptive behaviour (Kringelbach and Rolls, 2004). Images in A are reproduced from (Kringelbach et al., 2004; Kringelbach et al., 2003).

Figure 4. Affective keyboard in nucleus accumbens for desire and/or dread

Top: A rostrocaudal keyboard pattern of generators in NAc for appetitive versus fearful behaviors, showing consequences of microinjections of either glutamate AMPA antagonist or GABA agonist microinjections at rostrocaudal sites in medial shell. Rostral green sites produced 600% increases in food consumption (desire only). Caudal red sites generated purely increased fearful reactions at levels up to 600% over normal (escape attempts, distress calls, defensive bite attempts; spontaneous anti-predator treading/burying e). Photos show examples of antipredator treading/burying behavior elicited by threat stimuli: ground squirrel toward rattlesnake predator, rat toward electric-shock prod in lab. The same antipredator behaviors occurs without any specific threat stimulus after DNQX or muscimol microinjections in posterior NAc: denoted by red dots. Yellow sites released both desire and fearful behaviors in the same rats during the same 1-hr test. Just as a keyboard has many notes, bars reflect the many graded mixtures of affective desire-dread released as microinjection sites move rostrocaudal location in medial shell (appetitive desire to eat at top; fearful dread reactions at bottom). Bottom: Environmental ambience retuned the NAc keyboard. A comfortable ‘home environment’ (the rat’s own home room: dark, quiet, smell and sound of conspecifics in the room) suppressed fearful behaviors, and expanded zone for appetitive behaviors, produced by microinjections that block glutamate AMPA receptors (DNQX). A standard laboratory environment rebalances the keyboard into nearly equal halves for desire versus dread. A stressfully over-stimulating sensory environment (bright lights plus loud rock music) tilted the causal keyboard toward dread, and shrank the zoned that generated appetitive desire. Squirrel photo by Cooke from (Coss and Owings, 1989). Figure data modified from (Richard et al., 2013a), based on data from (Reynolds and Berridge, 2008; Richard and Berridge, 2011).

Figure 5. False pleasure electrodes?

Reconstruction of sites for original self-stimulation electrode locations in rat of Olds & Milner (1954) (left) and of Heath (1972) in patient B-10. For both rat and humans, electrode sites would now be recognized to be located in or near the nucleus accumbens. Thick line shows electrode shaft, and red dots show stimulation points. In human brain, representation of ventral pallidum has been moved forward into the coronal plane of the electrode to show relative positions of NAc and VP. Modified from Smith et al. 2010.