Therapeutic Use of Noninvasive Neuromodulation for Addictions

Introduction

Addictive disorders are chronic relapsing brain disorders, characterized by the compulsion to seek and take the drug, loss of control in limiting the intake despite harmful consequences, and negative emotional state when access to the drug is prevented. Progress in understanding the neurobiology of addiction has been made through the study of either animal models or brain imaging studies in addicted individuals. Understanding the neurobiological mechanisms underlying addictive disorders might allow the development of specific and more effective therapeutic interventions based on the involved brain network circuits. There has been a growing interest in designing neural circuit-based therapeutic interventions for addicted individuals. By using noninvasive brain stimulation (NIBS) approaches, both preclinical and clinical studies have been investigating the hypothesis that brain stimulation could target the disrupted circuits and revert some of the drug-induced neuronal adaptations and addictive behaviors.

Neurobiology of Addiction

A neurobiological model of addiction has been proposed to explain molecular, cellular, and neurocircuitry changes mediating the transition from occasional, controlled substance use to loss of control in drug intake. Compelling evidence has shown that the initial exposure to the substance of abuse exerts a reinforcing effect by activating reward circuits in the brain, mainly encoding for a voluntary behavior, whereas repeated drug administration progressively impairs brain functions by altering self-control over drug-seeking and drug-taking behaviors. Classically, addictive disorders are conceptualized as three stages of a complex recurring cycle, worsening over time and involving neuroplastic changes in three major circuits: (1) reward−basal ganglia system in the binge/intoxication stage, (2) extended amygdala and stress response system dysfunctions related to the withdrawal negative affect stage, and (3) prefrontal cortex (PFC) and executive function systems related to the preoccupation/anticipation stage ( Fig. 75.1 ). The projecting areas of the ascending mesocorticostriatal dopamine systems have a key role in the rewarding properties of nearly all drugs of abuse. Several studies indicated that new reward, and the cues associated with it, triggers phasic dopamine cell firing and activation of dopamine D1 receptors. This process allows previously neutral stimuli to become endowed with incentive salience and strengthens the learned association with repeated exposure to the cues, which creates strong motivation to seek a reward (e.g., a drug). Moreover, drug-induced phasic dopamine signaling in basal ganglia circuits further increases the ability of drug-paired cues of releasing dopamine. ^, Following an intoxicating dose of drugs, the fast and steep release of dopamine and opioid peptides into the ventral striatum is associated with the subjective sensation of a so-called high.

The withdrawal/negative affect stage consists of key motivational elements, such as chronic irritability, emotional pain, dysphoria, alexithymia, states of stress, and loss of motivation for natural rewards. The increased vulnerability to stress, a consequence of the impairment of the motivational circuits involving the ventral striatum, extended amygdala, and habenula, combined with the decreased functioning of reward processes, contributes to a shift in compulsive drug-seeking behavior and, thus, in addiction. ^,

Finally, chronic exposure to drugs induces long-term neuroadaptations due to the repeated hyperactivity of dopaminergic transmission and results in alterations of cortical neurotransmission and excitability, involving frontal cortical areas. Neuroimaging studies of addicted individuals showed alterations within key frontal brain regions, including the dorsolateral prefrontal cortex (DLPFC) that regulates goal-directed behavior; the orbitofrontal cortex (OFC) related to decision making, impulsivity, and behavioral inhibition; and the nucleus accumbens (NAc) involved in error detection. ^, Abnormalities within the PFC-striato-thalamic circuits are believed to play a central role in compulsive drug-seeking behavior and relapse. Indeed, neuropsychological findings suggest that frontal circuitry dysfunction reduces the ability to inhibit behavioral responses in favor of drug seeking.