HJNO May/Jun 2022

HEALTHCARE JOURNAL OF NEW ORLEANS I  MAY / JUN 2022 27 where signs of disease can be detected using brain imaging, such asAlzheimer’s and Par- kinson’s disease, a scan is best used in con- junction with clinical acumen when making the diagnosis. Thus, the requirement that addiction be detectable with a brain scan in order to be classified as a disease does not recognize the role of neuroimaging in the clinic. For the foreseeable future, the main objective of imaging in addiction research is not to diagnose addiction, but rather to improve our understanding of mechanisms that underlie it. The hope is that mechanistic insights will help bring forward new treat- ments, by identifying candidate targets for them, by pointing to treatment-responsive biomarkers, or both [52]. Developing inno- vative treatments is essential to address unmet treatment needs, in particular in stimulant and cannabis addiction, where no approved medications are currently available. Although the task to develop novel treatments is challenging, prom- ising candidates await evaluation [53]. A particular opportunity for imaging-based research is related to the complex and het- erogeneous nature of addictive disorders. Imaging-based biomarkers hold the prom- ise of allowing this complexity to be decon- structed into specific functional domains, as proposed by the RDoC initiative [54] and its application to addiction [55, 56]. This can ultimately guide the development of per- sonalized medicine strategies to addiction treatment. Countless imaging studies have reported differences in brain structure and function between people with addictive disorders and those without them. Meta-analyses of structural data show that alcohol addiction is associated with gray matter losses in the prefrontal cortex, dorsal striatum, insula, and posterior cingulate cortex [57], and sim- ilar results have been obtained in stimulant- addicted individuals [58]. Meta-analysis of functional imaging studies has demon- strated common alterations in dorsal stria- tal, and frontal circuits engaged in reward and salience processing, habit formation, and executive control, across different sub- stances and task-paradigms [59]. Molecu- lar imaging studies have shown that large and fast increases in dopamine are associ- ated with the reinforcing effects of drugs of abuse, but that after chronic drug use and during withdrawal, brain dopamine func- tion is markedly decreased and that these decreases are associated with dysfunction of prefrontal regions [60]. Collectively, these findings have given rise to a widely held view of addiction as a disorder of fronto- striatal circuitry that mediates top-down regulation of behavior [61]. Critics reply that none of the brain imag- ing findings are sufficiently specific to dis- tinguish between addiction and its absence, and that they are typically obtained in cross- sectional studies that can at best establish correlative rather than causal links. In this, they are largely right, and an updated ver- sion of a conceptualization of addiction as a brain disease needs to acknowledge this. Many of the structural brain findings reported are not specific for addiction, but rather shared across psychiatric disorders [62]. Also, for now, the most sophisticated tools of human brain imaging remain crude in face of complex neural circuit function. Importantly however, a vast literature from animal studies also documents functional changes in fronto-striatal circuits, as well their limbic and midbrain inputs, associated with addictive behaviors [63–68]. These are circuits akin to those identified by neuro- imaging studies in humans, implicated in positive and negative emotions, learning processes and executive functions, altered function of which is thought to underlie addiction. These animal studies, by virtue of their cellular and molecular level resolu- tion, and their ability to establish causality under experimental control, are therefore an important complement to human neu- roimaging work. Nevertheless, factors that seem remote from the activity of brain circuits, such as policies, substance availability and cost, as well as socioeconomic factors, also are criti- cally important determinants of substance use. In this complex landscape, is the brain really a defensible focal point for research and treatment?The answer is “yes”. As pow- erfully articulated by Francis Crick [69], “You, your joys and your sorrows, your memories and your ambitions, your sense of personal identity and free will, are in fact no more than the behavior of a vast assem- bly of nerve cells and their associated mol- ecules”. Social and interpersonal factors are critically important in addiction, but they can only exert their influences by impact- ing neural processes. They must be encoded as sensory data, represented together with memories of the past and predictions about the future, and combined with representa- tions of interoceptive and other influences to provide inputs to the valuation machin- ery of the brain. Collectively, these inputs drive action selection and execution of behavior—say, to drink or not to drink, and then, within an episode, to stop drinking or keep drinking. Stating that the pathophysi- ology of addiction is largely about the brain does not ignore the role of other influences. It is just the opposite: it is attempting to understand how those important influences contribute to drug seeking and taking in the context of the brain, and vice versa. But if the criticism is one of emphasis rather than of principle— i.e., toomuch brain, too little social and environmental factors – then neuroscientists need to acknowledge that they are in part guilty as charged. Brain- centric accounts of addiction have for a long time failed to pay enough attention to the inputs that social factors provide to neural processing behind drug seeking and tak- ing [9]. This landscape is, however, rapidly changing. For instance, using animal mod- els, scientists are finding that lack of social play early in life increases the motivation to take addictive substances in adulthood [70]. Others find that the opportunity to interact with a fellow rat is protective against addic- tion-like behaviors [71]. In humans, a rela- tionship has been found between perceived social support, socioeconomic status, and the avail- ability of dopamine D2 receptors [72, 73], a biological marker of addiction