Deep brain stimulation for addiction: why the subthalamic nucleus should be favored
Highlights
► Deep brain stimulation is spreading from neurology to psychiatry, then addiction. ► The lateral hypothalamus, amygdala and lateral habenula are not very good targets. ► Nucleus accumbens is the current chosen target, but not necessarily a good choice. ► The dorsal striatum, prefrontal cortex might be better choices for addiction. ► We explain why the subthalamic nucleus is the right target for addiction.
Introduction
Surgery for the treatment of addiction has been used in the 1970s with dramatic side effects that have led to a long-lasting strong resistance against this strategy for such a psychiatric disorder. During the 1980s and 1990s, psychosurgery that consisted in ablative surgery (lobotomy and cingulotomy), stereotaxic surgery involving also chronic electrical stimulation has been abandoned because of abuses, side effects and the beginning of neuroleptic treatments [1•]. In the early 1990s, surgical therapy has been proposed and used successfully for the treatment of neurological disorders such as Parkinson's disease, where deep brain stimulation (DBS) was applied into the subthalamic nucleus (STN) [2].
In Parkinson's disease, the dopaminergic nigrostriatal system deficiency is accompanied by an abnormal activity in the STN. Since both lesions and DBS at high frequency of the STN in the parkinsonian monkey had proven to be beneficial on the motor symptoms [3, 4], it has first been considered that high frequency stimulation (HFS) induced an inhibition of the target structure. It has then been demonstrated by electrophysiological experiments that STN HFS results in an inhibition of STN neurons in the rat, the monkey and the PD patient (for review [5]). However, HFS does not act via a simple mechanism that would be limited to inhibition of the target area. It has been shown to also activate the passing fibers in the area surrounding the electrode, thus resulting in increased synaptic output. It has also been reported that HFS can activate the afferent axon terminals (e.g., the cortical inputs in the case of STN or accumbens) [6, 7]. It thus occurs that the functional outcome of DBS will depend on the target structure and the location of the electrodes and the pathway of the passing fibers recruited.
In some of the PD patients subjected to STN DBS and suffering as well from obsessive compulsive disorder (OCD), it was reported that the treatment could be beneficial for the compulsive behavior [8]. This observation on 3 individual cases, following the pioneer work by Nuttin in the internal capsule for OCD [9] and by Vandewalle in the thalamus for Gilles de la Tourette syndrome [10], re-opened the door to surgical strategies for the treatment of psychiatric disorders. For the treatment of OCD patients, STN DBS has been further proven efficient [11], but other targets (internal capsule and nucleus accumbens) have also been stimulated with success [12, 13]. DBS has also been extended to treatment-resistant depressive patients. In fact, in the case of severe depression, the first target selected was the subgenual cingulate gyrus [14]. Further studies have also shown positive results when DBS was applied in the internal capsule [15], or in the nucleus accumbens [12]. When applied with success in patients, surgery is less a matter of debate, although the procedure is heavy and not always deprived of side-effects. In the case of addiction, after we had published data from rats suggesting that STN DBS could represent an interesting strategy for the treatment of addiction [1•, 16••, 17••] there was a controversy whether it was too early or not to consider DBS for addiction [18]. Choosing an invasive procedure for a treatment always raises ethical issues, but for extreme severe treatment-resistant cases, or when there is no real efficient treatment, as for certain forms of addiction, surgery can be the best option. Since DBS is reversible, it appears to be a safer option than the lesion surgery. Considering that DBS mechanisms result in both stimulation of fibers and inactivation of body cells in the target area, it is interesting to review the various selected targets in the case of addiction and discuss why they could be, or not, possible interesting targets for the treatment of addiction in light of what has been previously published.
Treatment efficacy for addiction should not only depend on its ability to favor abstinence and prevent relapse but should also be devoid of unspecific effects. We will comment the pertinence of targeting each proposed structure in terms of efficacy and safety, according to the empirical finding and theories of addiction.
Section snippets
Nucleus accumbens
Clinical application of the DBS for addicts has so far been restricted to the nucleus accumbens (NAcc) and most of the current data assessing the relevance of alternative targets for DBS have been undergone in preclinical settings. We argue that consideration of the NAcc as therapeutical targets for DBS in addicted patients has been favored on theoretical grounds, which have much or perhaps less support than for other structures. Considering addictive behaviors as an incentive sensitization
Lateral hypothalamus (LH)
In accordance with reports from addicted individuals describing withdrawal as a ‘hunger’ and the effects of drugs as ‘satiation’, the hypothalamic drive control of food motivated behavior has been extended to drug reward (for review [42]). In addition, compulsive drug intake is associated with extensive transcriptional modifications in the lateral hypothalamus (LH) [43]. This would argue in favor of LH as an interesting target to act against addiction.
However, it was also reported that
Amygdala
The extended amygdala is responsible for the negative state of withdrawal that might provide a negative motivational incentive to compulsively drug use (for review [46]). Committing a compulsive behavior such as drug taking generates anxiety and stress from which the subject can only be relieved by performing the behavior. However, such a state might actually result from reduced functionality of the extended amygdala. Human alcoholics and cocaine addicts show reduced amygdala volume, which is
Lateral habenula (LHb)
The lateral habenula (LHb) is another structure involved in negative reinforcement. Furthermore, the repeated use of drugs of abuse has been shown to induce selective degeneration of the fasciculus retroflexus that projects from the habenula to mesolimbic regions. However deep brain stimulation of the LHb applied at low frequency, supposedly increasing the activity of the targeted structure, increases cocaine self administration, while more conventional high frequency stimulation did not have
Dorsal striatum: a better target?
Both sensitivity to devaluation on instrumental responding and impact of pavlovian instrumental transfer have been shown to be dependent on the activity of the lateral dorsal striatum (for review [41]), which show altered functional and structural changes in human addicts [20]. Pharmacological inactivation of the dorsolateral striatum restored the goal-directedness of cocaine or alcohol seeking, that is, rendered it sensitive to the devaluation of drug taking (for review [41]). In addition,
Conclusion–discussion
The best target to select for the treatment of addiction is still a matter of debate [69•], although the only one that has been tested in human addicts is the nucleus accumbens. Given the knowledge regarding the role of accumbens in mediating motivation for any type of reinforcement, it seems difficult to imagine that DBS applied in the NAc could selectively reduce the motivation for the object of addiction, leaving intact the rewarding properties of all other rewarding activities and the
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
This reported work has been supported by grants from the ‘Centre National de la Recherche Scientifique’ (CNRS), the ‘Université de Provence’ and ‘Aix-Marseille University’, the ‘Agence Nationale pour la Recherche’ (ANR-05-JC05_48262, ANR-09-MNPS-028-01 and ANR 2010-NEUR-005-01 in the framework of the ERA-Net NEURON), the MILDT-InCa-INSERM grants, the Fondation pour la Recherche sur le Cerveau, and the IREB (Institut de Recherches Scientifiques sur les Boissons).
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