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Nucleus Accumbens as a Novel Target for Deep Brain Stimulation in the Treatment of Addiction: A Hypothesis on the Neurochemical and Morphological Basis
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.271239
Keywords: Addiction, alcoholism, deep brain stimulation, neuromodulation, nucleus accumbens, substance abuse
According to World Health Organization, alcohol causes 2.5 million deaths annually and 50% of crimes related to violence. Futhermore, nearly 25% of deaths in industrialized countries are due to abuse of psychotropic substances.[1],[2] The definition of addiction by Merriam-Webster dictionary is a “compulsive need for and use of a habit forming substance characterized by tolerance and by well-defined physiologic symptoms upon withdrawal”. There is a continued use or substance or behavior in spite of the adverse consequences[3] characterized by enduring hypersensitivity and incentive sensitization.[4] The intensive and pathological cycle representing the behavior has three interactive stages: the “binge/intoxication stage,” the “withdrawal/negative affect stage,” and the “preoccupation/anticipation stage”.[5],[6] Anatomical substrates in the brain for these three stages are interdependent and dopamine-mediated, located in the ventral trigeminal area (VTA) for “binge intoxication”, in the extended amygdala [composed of central nucleus of amygdala, bed nucleus of the stria terminalis, and medial (shell) region of nucleus accumbens (NA)] for “withdrawal/negative affect stage” and the craving “preoccupation/anticipation” stage. In addition, the cricuit connecting medial prefrontal cortex, NA, and ventral pallidum plays a pivotal role. The latter craving stage is the defining feature of the addiction as a chronic relapsing disorder resulting from interactions between the striatum (dorsal and ventral parts) and the thalamus.[7]
Contribution for addiction circuits comes from multiple regions and sometimes changes are seen specific to certain substances. Methamphetamine had shown long-lasting decrements in striatal dopamine transporter, not seen with cocaine or alcohol. Animal models during acute withdrawal stage of all drugs exhibited activation of corticotrophin-releasing factor in striatum.[7] Following deep brain stimulation (DBS) of the nucleus (STN), dopamine dysregulation has been observed.[8] STN metabolism decreased by cocaine administration[9] and lesions of STN decreased motivation to cocaine intake in rats.[10] DBS of NA in rats decreased alcohol consumption[11] and cocaine seeking.[12] Dopamine in striatum was increased in humans on brain images with drug induction in the region of and areas of the ventral striatum as a reward phenomenon (pleasure, euphoria, and high). The brain structures involved in all the three stages of addiction include the striatum, hippocapmpus, insula, basal frontal cortex (for craving), and dorsolateral/inferior frontal gyrus with cingulate gyrus (for disrupted inhibition). All of these areas could be construed as targets for effective DBS.[13] The claims its preferred place based on the circuit network proposed by Koob and Volkow.[7] The is located between the caudate nucleus and putamen in the basal forebrain in each hemisphere as a constituent of ventral striatum and the basal ganglia.
DBS of NA (either core or shell) in animals reduced the drug-induced behavior significantly regarding ethanol, cocaine, and morphine.[11],[12],[14] Remarkably, the NA DBS did not produce unusual behavior or effects on water consumption. Earlier observations also supported this finding that encoding circuits in the NA were different for cocaine as opposed to natural needs like water and food.[15] The has a core and a shell, two regions different from each other by anatomy and physiology. The core receives anterior cingulate and dorsal prelimbic projections, while the shell connects with infralimbic and ventral prelimbic cortex.[16],[17] Alcohol consumption was reduced with DBS of either of these regions, but for attenuation of cocaine habits, stimulation of the shell was only effective.[12],[18] DBS had region-specific effects and its efficacy can be improved by precise target locations in the for effective management of specific substance abusers.[12]
The as the DBS target: Anatomical network There are two distinct morphological divisions in the NA, of animals known as the shell and core differentiated by their expression of neuropeptides and afferents.[19] The core is involved in learning-based behavior and the shell is related to the reward-seeking behavior.[20] Accordingly, different responses are elicited on simulation in rodents.[21] However, in primates this demarcation is less prominent as the shell region shrinks but has functional coordination with the core and carries the receptors for dopamine, opioids, and various other peptides unique to the shell seen in rodents.[22] The of the NA in the regulation of motivation and reward is very important in the development of addiction.[6] The mesocortical and the mesolimbic pathways are crucial neurochemical connections operated by the addictive substances in the brain reward system. The mesolimbic pathways connect the to the VTA of the midbrain along the medial forebrain bundle mediating natural rewards as well as most substances of abuse. This process produces an increased concentration of extracellular dopamine. This dopamine activity differs between natural rewards and addictive materials as the latter induces sensitization of the dopamine transmission in the NA. In addition, dopamine activity fails to adapt in case of repeated exposures to addictive drugs.[23],[24] They exert a powerful repetitive and reinforcing stimuli. The NA has a pivotal position both by function and anatomical connections involved in the addiction cycle engaging the VTA, lateral hypothalamus, amygdala, hippocampus, striatum, and prefrontal lobe making it a preferred target for DBS modulating the neuroadaptive changes in addiction [Figure 1]. High-frequency (HF) DBS of NA in rodents suppressed pyramidal cell firing and activated corticostriatal inhibition along with region-specific changes in field potentials.[25] Both spontaneous and evoked LFP responses of the addiction circuits involving prefrontal, lateral orbitofrontal cortices, and mediodorsal thalamus were affected by HF DBS of NA thus proposing therapeutic effects.[26] HF DBS of NA shell or core reduced alcohol intake in self-administration rodent model significantly without altering water intake.[14]
On the other hand, stimulation of the striatum did not change cocaine reinstatement, while DBS of NA significantly attenuated the addiction behavior in the rat model. Here also the stimulation did not change the reinstatement of food-seeking (normal behavior).[12] These studies demonstrate, not propose that modulation of NA by DBS could significantly improve the addiction patterns like intake, reinstatement, and craving. The substrate for DBS of NA in addiction There are rapid increases in dopamine noted in association with reinforcing abuse with chronic addiction, whereas dopamine is drastically decreased during withdrawal which causes dysfunction of prefrontal, basifrontal lobes, and cingulate gyri. Neurochemical studies showed that these changes result in altered frontal lobe functions and decreased sensitivity to natural reinforcers.[27] At present, advanced neuroimaging studies such as functional magnetic resonance imaging (fMRI) demonstrated activation of the frontal lobe areas during drug intoxication or craving, especially in the area of the NA for reward, orbitofrontal cortex for motivation, and amygdalohippocampal region for memory. In addition, the increased extracellular dopamine was noted in striatum (NA region) in normal and addicted individuals upon administration of substances of abuse, while those experiencing intense effects like “high” or “euphoria” had higher levels of dopamine.[28] Studies show that the NA plays a key role in reward processing and also in the transition from voluntary user to a compulsive drug user and relapses. Changes were noted in structure and function of the NA in both acute and long-term abuses.[7],[29],[30] NA stimulation possibly can normalize striatal dysfunction reducing craving and promoting sensitivity to natural reinforcers. The major concern is that the reduced dopamine levels in striatum might be responsible for desensitization of natural reinforcers.[27] DBS of NA also can modulate the dysfunctional neuronal activity between the orbitofrontal cortex and the thalamocortical circuit, as shown in electrophysiological animal studies.[25],[26] Brain imaging studies of addicted people demonstrated a decreased activity of the cingulate gyrus and prefrontal loves suggestive of altered inhibition.[27],[31] DBS could possibly modulate this metwork leading to better self-control[32] through monoamine neurotransmitters. Recent studies show that the NA shell (not core) stimulation reduced both dopamine and serotonin turnover in rodents, suggesting the possibility of multiple mechanisms playing a role.[33]
As of now, only less than 50% of alcohol-addicted individuals can be effectively treated by de-addiction programs and new strategies to improve this outcome are lacking. Similarly, methamphetamine involving 25 million people is a global epidemic causing high mortality among youth.[34] There was a 3-fold increase in deaths from drug overdose in recent years with a marked increase in heroin abuse,[35] indicating the failure of traditional behavior and medical management methods. Notwithstanding the experimental basis mentioned above, the utility of DBS of NA for addiction was an accidental observation in a patient who had bilateral DBS for agoraphobia with panic attacks. The patient abstained from drinking after surgery and the authors reviewed their experience for similar incidents.[36] Three of 10 patients (30%) who had DBS of NA (for Tourette's syndrome, obsessive compulsive disorder, and anxiety disorders) stopped smoking without any necessity for supportive treatment, which is far superior to the intentional abstinence of 9% reported in general population.[37],[38] Another report of a patient with nicotine addiction followed.[39] In a pilot study, Muller et al. demonstrated significant long-lasting effects of NA DBS in five individuals with alcohol addiction.[40],[41] Intraoperative recording of LFP supported the data earlier reported from fMRI, as alcohol-related cues generated changes in the NA.[42] Cognitive tasks were recorded on positron emission tomography scan in another patient with and without DBS of NA. Without stimulation, the patient demonstrated higher risk-taking pattern in a gambling paradigm supporting previous observations that alcohol addiction induces negative effects on reward processing. DBS of NA reversed this behavior to a normal response.[43] A similar reversal of alcohol induced dysfunction in the NA was observed by Kuhn et al. utilizing on and off DBS.[44] NA stimulation was also effective in heroin addiction not only during active DBS but after explantation also; the therapeutic effect continued for several months.[45],[46] A recent review of experience reported by Muller et al. recounted follow-ups on five patients for 8 years with affirmative abstinence from cigarette smoking in all cases.[47] However, the largest experience with NA comes from a study of bilateral ablative surgery in 272 patients with heroin addiction from China, which had shown a nonrelapse rate of 50% in a sample of 150 patients.[48] This study had to be terminated in view of ethical issues confronted by the authors. DBS is reversible, unlike lesion surgery, and has been in clinical practice for over two decades with acceptable risks related to the procedure and the current technology. The negative impact of addiction on society and economic burden are far greater compared to these adverse events. Several ethical issues (similar to those experienced by the Chinese study) might play major role in popularizing this treatment, but the loss of life and function as well as the the high failure rates of the existing therapeutic options must also be considered.
The experience on DBS of NA has been limited to case reports [Table 1], which unfortunately do not provide a strong enough evidence to analyze conclusively. The Chinese study, on the other hand, although terminated due to ethical issues, offers strong support to the therapeutic possibilities of neuromodulation of NA in patients with addiction. The review provided here is aimed to stimulate further studies in neuromodulation of NA as a beneficial therapeutic option to control addiction to harmful substances including nicotine, alcohol, cocaine, heroin, and amphetamines.
The incidence of substance abuse and mortality associated with addiction has been on the rise globally with serious implications on growth and the development of young populations. The present-day therapeutics have high relapse rates. DBS has acceptable risks and has been in clinical use for two decades. In addition, the technology is rapidly evolving towards better safety. Experimental evidence and advanced neuroimaging techniques implicate dopaminergic pathways in addiction, attributing pivotal role to NA based on its anatomical and physiological connections with prefrontal/basifrontal cortex, amygdala, hippocampus, and striatum. The NA was shown to respond to stimulation to control drug-seeking behavior while normal food and water-seeking pattern remains unaffected. Limited case series of DBS performed for addiction and nonaddiction demonstrated the encouraging role of NA in promoting nonrelapse and abstinence without any additional requirement for behavioral and pharmacological treatment. However, structured multicenter studies in larger groups of patients are required to establish evidence for DBS of NA in the management of addiction. The hypothesis that NA modulation alters the dopaminergic pathways of the addiction cycle supports such a therapeutic option. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.
[Figure 1]
[Table 1]
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