This article reviews scientific advances in the prevention and treatment of substance-use disorder and related developments in public policy. In the past two decades, research has increasingly supported the view that addiction is a disease of the brain. Although the brain disease model of addiction has yielded effective preventive measures, treatment interventions, and public health policies to address substance-use disorders, the underlying concept of substance abuse as a brain disease continues to be questioned, perhaps because the aberrant, impulsive, and compulsive behaviors that are characteristic of addiction have not been clearly tied to neurobiology. Here we review recent advances in the neurobiology of addiction to clarify the link between addiction and brain function and to broaden the understanding of addiction as a brain disease. We review findings on the desensitization of reward circuits, which dampens the ability to feel pleasure and the motivation to pursue everyday activities; the increasing strength of conditioned responses and stress reactivity, which results in increased cravings for alcohol and other drugs and negative emotions when these cravings are not sated; and the weakening of the brain regions involved in executive functions such as decision making, inhibitory control, and self-regulation that leads to repeated relapse. We also review the ways in which social environments, developmental stages, and genetics are intimately linked to and influence vulnerability and recovery. We conclude that neuroscience continues to support the brain disease model of addiction. Neuroscience research in this area not only offers new opportunities for the prevention and treatment of substance addictions and related behavioral addictions (e.g., to food, sex, and gambling) but may also improve our understanding of the fundamental biologic processes involved in voluntary behavioral control. In the United States, 8 to 10% of people 12 years of age or older, or 20 to 22 million people, are addicted to alcohol or other drugs. 1 The abuse of tobacco, alcohol, and illicit drugs in the United States exacts more than $700 billion annually in costs related to crime, lost work productivity, and health care. 2-4 After centuries of efforts to reduce addiction and its related costs by punishing addictive behaviors failed to produce adequate results, recent basic and clinical research has provided clear evidence that addiction might be better considered and treated as an acquired disease of the brain (see Box 1 for definitions of substance-use disorder and addiction). Research guided by the brain disease model of addiction has led to the development of more effective methods of prevention and treatment and to more informed public health policies. Notable examples include the Mental Health Parity and Addiction Equity Act of 2008, which requires medical insurance plans to provide the same coverage for substance-use disorders and other mental illnesses that is provided for other illnesses, 5 and the proposed bipartisan Senate legislation that From the National Institute on Drug Abuse (N.D.V.) and the National Institute of Alcohol Abuse and Alcoholism (G.F.K.) — both in Bethesda, MD; and the Treatment Research Institute, Philadelphia (A.T.M.). Address reprint requests to Dr. Volkow at the National Institute on Drug Abuse, 6001 Executive Bld., Rm. 5274, Bethesda, MD 20892, or at nvolkow@ nida . nih . gov.

Review Article: Neurobiologic Advances from the Brain Disease Model of Addiction

The prefrontal cortex (PFC) is not only important in executive functions, but also pain processing. The latter is dependent on its connections to other areas of the cerebral neocortex, hippocampus, periaqueductal gray (PAG), thalamus, amygdala, and basal nuclei. Changes in neurotransmitters, gene expression, glial cells, and neuroinflammation occur in the PFC during acute and chronic pain, that result in alterations to its structure, activity, and connectivity. The medial PFC (mPFC) could serve dual, opposing roles in pain: (1) it mediates antinociceptive effects, due to its connections with other cortical areas, and as the main source of cortical afferents to the PAG for modulation of pain. This is a 'loop' where, on one side, a sensory stimulus is transformed into a perceptual signal through high brain processing activity, and perceptual activity is then utilized to control the flow of afferent sensory stimuli at their entrance (dorsal horn) to the CNS. (2) It could induce pain chronification via its corticostriatal projection, possibly depending on the level of dopamine receptor activation (or lack of) in the ventral tegmental area-nucleus accumbens reward pathway. The PFC is involved in biopsychosocial pain management. This includes repetitive transcranial magnetic stimulation, transcranial direct current stimulation, antidepressants, acupuncture, cognitive behavioral therapy, mindfulness, music, exercise, partner support, empathy, meditation, and prayer. Studies demonstrate the role of the PFC during placebo analgesia, and in establishing links between pain and depression, anxiety, and loss of cognition. In particular, losses in PFC grey matter are often reversible after successful treatment of chronic pain.

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Role of the Prefrontal Cortex in Pain Processing.

Ever since the brain was identified as an insulin-sensitive organ, evidence has rapidly accumulated that insulin action in the brain produces multiple behavioral and metabolic effects, influencing eating behavior, peripheral metabolism, and cognition. Disturbances in brain insulin action can be observed in obesity and type 2 diabetes (T2D), as well as in aging and dementia. Decreases in insulin sensitivity of central nervous pathways, i.e., brain insulin resistance, may therefore constitute a joint pathological feature of metabolic and cognitive dysfunctions. Modern neuroimaging methods have provided new means of probing brain insulin action, revealing the influence of insulin on both global and regional brain function. In this review, we highlight recent findings on brain insulin action in humans and its impact on metabolism and cognition. Furthermore, we elaborate on the most prominent factors associated with brain insulin resistance, i.e., obesity, T2D, genes, maternal metabolism, normal aging, inflammation, and dementia, and on their roles regarding causes and consequences of brain insulin resistance. We also describe the beneficial effects of enhanced brain insulin signaling on human eating behavior and cognition and discuss potential applications in the treatment of metabolic and cognitive disorders.

Brain Insulin Resistance at the Crossroads of Metabolic and Cognitive Disorders in Humans

The specific eating pattern of Binge Eating Disorder (BED) patients has provoked the assumption that BED might represent a phenotype within the obesity spectrum that is characterized by increased impulsivity. Following the guidelines of the PRISMA statement (preferred reporting items for systematic reviews and meta-analyses), we here provide a systematic update on the evidence on food-related impulsivity in obese individuals, with and without BED, as well as normal-weight individuals. We separately analyzed potential group differences in the impulsivity components of reward sensitivity and rash-spontaneous behavior. Our search resulted in twenty experimental studies with high methodological quality. The synthesis of the latest evidence consolidates conclusions drawn in our initial systematic review that BED represents a distinct phenotype within the obesity spectrum that is characterized by increased impulsivity. Rash-spontaneous behavior in general, and specifically towards food, is increased in BED, while food-specific reward sensitivity is also increased in obese individuals without BED, but potentially to a lesser degree. A major next step for research entails the investigation of sub-domains and temporal components of inhibitory control in BED and obesity. Based on the evidence of impaired inhibitory control in BED, affected patients might profit from interventions that address impulsive behavior.

https://www.mdpi.com/2072-6643/9/11/1170/pdf

Food-Related Impulsivity in Obesity and Binge Eating Disorder—A Systematic Update of the Evidence

Fat mass and obesity-associated gene (FTO) is a member of the Fe (II)- and oxoglutarate-dependent AlkB dioxygenase family and is linked to both obesity and intellectual disability. The role of FTO in neurodevelopment and neurogenesis, however, remains largely unknown. Here we show that FTO is expressed in adult neural stem cells and neurons and displays dynamic expression during postnatal neurodevelopment. The loss of FTO leads to decreased brain size and body weight. We find that FTO deficiency could reduce the proliferation and neuronal differentiation of adult neural stem cells in vivo, which leads to impaired learning and memory. Given the role of FTO as a demethylase of N6-methyladenosine (m6A), we went on to perform genome-wide m6A profiling and observed dynamic m6A modification during postnatal neurodevelopment. The loss of FTO led to the altered expression of several key components of the brain derived neurotrophic factor pathway that were marked by m6A. These results together suggest FTO plays important roles in neurogenesis, as well as in learning and memory.

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Fat Mass and Obesity-associated (FTO) Protein Regulates Adult Neurogenesis.

Body, weight and shape related obsessions and ruminations are characteristic traits of individuals with eating disorders (ED) that are found to predate the onset of the disorder. Individuals with c ...

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Assessment of Function, Structure and Working Memory in Adolescents with a Recent Diagnosis of an Eating Disorder

Parkinson's disease (PD) has traditionally been viewed as an α‐synucleinopathy brain pathology. Yet evidence based on postmortem human and animal experimental models indicates that the spinal cord may also be affected.

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/mds.29354

Altered Spinal Cord Functional Connectivity Associated with Parkinson's Disease Progression

Increased temporo-parietal activation is associated with the disrupting effects of subliminal food images during a working memory task in adolescents with an eating disorder

Linda Solstrand Dahlberg

Papers

Assessment of Function, Structure and Working Memory in Adolescents with a Recent Diagnosis of an Eating Disorder

Altered Spinal Cord Functional Connectivity Associated with Parkinson's Disease Progression

Increased temporo-parietal activation is associated with the disrupting effects of subliminal food images during a working memory task in adolescents with an eating disorder