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Review
. 2022 Jan;27(1):e12958.
doi: 10.1111/adb.12958. Epub 2020 Aug 12.

Closing the brain-heart loop: Towards more holistic models of addiction and addiction recovery

David Eddie  1   2 , Marsha E Bates  3   4 , Jennifer F Buckman  3   4
Affiliations
Review

Closing the brain-heart loop: Towards more holistic models of addiction and addiction recovery

David Eddie et al. Addict Biol. 2022 Jan.

Abstract

Much research seeks to articulate the brain structures and pathways implicated in addiction and addiction recovery. Prominent neurobiological models emphasize the interplay between cortical and limbic brain regions as a main driver of addictive processes, but largely do not take into consideration sensory and visceral information streams that link context and state to the brain and behavior. Yet these brain-body information streams would seem to be necessary elements of a comprehensive model of addiction. As a starting point, we describe the overlap between one current model of addiction circuitry and the neural network that not only regulates cardiovascular system activity but also receives feedback from peripheral cardiovascular processes through the baroreflex loop. We highlight the need for neurobiological, molecular, and behavioral studies of neural and peripheral cardiovascular signal integration during the experience of internal states and environmental contexts that drive alcohol and other drug use behaviors. We end with a call for systematic, mechanistic research on the promising, yet largely unexamined benefits to addiction treatment of neuroscience-informed, adjunctive interventions that target the malleability of the cardiovascular system to alter brain processes.

Keywords: autonomic nervous system; central autonomic network; substance use disorder.

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Conflict of interest statement

CONFLICT OF INTEREST

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Figures

FIGURE 1
FIGURE 1
Integration of neural circuitry associated with Koob and Volkow’s addiction model and the central autonomic network (CAN). Koob and Volkow mapped specific neural circuits onto a three-stage addiction model that includes a binge/intoxication stage (blue), withdrawal/negative affect stage (red), and preoccupation/anticipation/craving stage (green). These structures are heavily interconnected with the constellation of connected brain structures known as the CAN (gold/gold outline). LEFT: A three-dimensional rendering of the brain showing the integration of the CAN with structures implicated in the binge/intoxication stage (blue), withdrawal/negative affect stage (red), and preoccupation/anticipation/craving stage (green) of addiction. Overlap between these structures and the CAN are demarcated in blue, red, and green with a gold outline. RIGHT: A schematic of the brain to body (descending) and body to brain (ascending) pathways showing connectivity among the structures of the three-stage addiction cycle model, and the structures of the CAN (gold / gold outline). Note: for simplicity, not all projections noted below are shown. During the binge/intoxication stage (blue), the CAN likely participates through ascending pathways that integrate autonomic/visceral information via the thalamus. During the withdrawal/negative affect stage (red), the primary intersection of CAN and addiction circuitry appears to occur via projections to the extended amygdala. The CAN also shares significant overlap with the structures implicated in the preoccupation/anticipation/craving stage (green), including the medial prefrontal, orbitofrontal, insula, and anterior cingulate cortices, as well as the basolateral amygdala. Independent of the proposed neural circuitry of addiction, evidence from decades of research on the CAN suggests that brain stem nuclei are key integration centers of autonomic/visceral information, and that these structures are highly interconnected to higher order brain structures. At the bottom right of the schematic is the nucleus tractus solitarius (NTS), the first central relay (ascending) for all medullary reflexes controlling cardiovascular functions (cardiac and baroreflex reflexes) and respiration (carotid chemoreflex and pulmonary mechanoreflexes). It receives and responds to stimuli from the heart, baroreceptors, lungs and gut, and directly communicates to higher brain areas like the hypothalamus and cortex. It further relays information to subcortical and cortical centers via the parabrachial nuclei (PN), periaqueductal gray (PAG) region, and raphe nuclei (RN). The parabrachial nuclei are key regulators of cardiovascular, respiratory, and gastrointestinal functioning with ascending projections to the hypothalamus, amygdala, and insular and infralimbic cortex, as well as descending projections to the nucleus ambiguus (NAm). The parabrachial nuclei also receive converging visceral, nociceptive, and thermoreceptive inputs from the spinal cord and convey this information to the hypothalamus, amygdala, and thalamus. The periaqueductal gray likewise plays a critical role in autonomic regulation, motivated behavior, and behavioral responses to stress, as well as pain modulation via its extensive inputs from higher brain areas including the cortex, amygdala, and hypothalamus, with outputs to brainstem areas like the reticular formation (RF) and raphe nuclei. The raphe nuclei have a diverse range of roles including pain inhibition via the dorsal horn, temperature regulation, and modulation of circadian rhythms and alertness. Finally, the dorsal motor vagal nucleus (DMVN) provides primary descending parasympathetic control of the heart and is the motor operator for cardiac, baroreflex, and pulmonary reflexes; it receives indirect inputs from the cortex as well as direct inputs from the nucleus tractus solitarius. Abbreviations: ACC, anterior cingulate cortex; BLA, basolateral amygdala; BNST, bed nucleus of the stria terminalis; CeA, central amygdala; DS, dorsal striatum; GP, globus pallidus; NAc, nucleus accumbens; OFC, orbitofrontal cortex; RN, raphe nuclei; SNc, substantia nigra pars compacta; VGP, ventral globus pallidus; DGP, dorsal globus pallidus; VS, ventral striatum; VTA, ventral tegmental area
FIGURE 2
FIGURE 2
Bidirectional neuro-cardiovascular pathways. Dynamic control of heart rate is maintained via efferent pathways from the brain via cranial (parasympathetic) and sympathetic nerve fibers of the autonomic nervous system. These efferent nerve fibers converge on the heart, mainly at the sinoatrial and atrioventricular nodes, to modulate moment-to-moment heart rate. Dynamic changes in blood pressure are likewise maintained via efferent sympathetic pathways that directly and indirectly control arterial tone (i.e., constricting or dilating blood vessels) through innervation of the arteries, and the secretion of epinephrine and norepinephrine via the adrenal medulla gland. These end organs then convey feedback to the brain via stretch receptors, called baroreceptors, in the aorta and carotid arteries. Activation of baroreceptors is relayed to the nucleus tractus solitarius and higher order central autonomic network (CAN) structures, thereby ensuring real-time information about blood pressure and heart rate is propagated to neural centers that control cardiovascular processes, as well as behavioral responding
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