https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(11)60602-8.pdf

Major depressive disorder: new clinical, neurobiological, and treatment perspectives

There is increasing interest among functional neurosurgeons in the potential for novel therapies to impact upon diseases beyond movement disorders and pain. A target of increasing interest is the nucl

/pdf/the-nucleus-accumbens-a-comprehensive-review-1vordconw6.pdf

The Nucleus Accumbens: A Comprehensive Review

https://archive-ouverte.unige.ch/unige:95921/ATTACHMENT01

Deep brain stimulation : from neurology to psychiatry?

Background: Imaging techniques have been in widespread use in the scientific community for more than 3 decades. They facilitate noninvasive, in vivo studies of the human brain in both healthy and diseased persons. These brain-imaging techniques have contributed significantly to our understanding of the effects of alcohol abuse and dependence on structural and functional changes in the human brain. A systematic review summarizing these contributions has not previously been conducted, and this is the goal of the current paper.

Methods:  The databases PubMed, PsycINFO, and PSYNDEX were searched using central key words. Fulfilling the inclusion criteria were 140 functional and structural imaging studies, together comprising data from more than 7,000 patients and controls. The structural imaging techniques we considered were cranial computerized tomography and various magnetic resonance imaging–based techniques, including voxel-based morphometry, deformation-based morphometry, diffusion tensor magnetic resonance imaging, and diffusion-weighted magnetic resonance imaging. The functional methods considered were magnetic resonance spectroscopy, positron emission tomography, single photon emission computed tomography, and functional magnetic resonance imaging.

Results:  Results from studies using structural imaging techniques have revealed that chronic alcohol use is accompanied by volume reductions of gray and white matter, as well as microstructural disruption of various white matter tracts. These changes are partially reversible following abstinence. Results from functional imaging methods have revealed metabolic changes in the brain, lower glucose metabolism, and disruptions of the balance of neurotransmitter systems. Additionally, functional imaging methods have revealed increased brain activity in the mesocorticolimbic system in response to alcohol-themed pictures relative to nondrug-associated stimuli, which might be of predictive value with regard to relapse.

Conclusions:  There has been tremendous progress in the development of imaging technologies. Use of these technologies has clearly demonstrated the structural and functional brain abnormalities that can occur with chronic alcohol use. The study of the alcoholic brain provides an heuristic model which furthers our understanding of neurodegenerative changes in general, as well as their partial reversibility with sustained abstinence. Additionally, functional imaging is poised to become an important tool for generating predictions about individual brain functioning, which can then be used as a basis for personalized medicine.

Alcohol and the human brain: a systematic review of different neuroimaging methods.

Deep brain stimulation (DBS) is an adjustable, reversible, non-destructive neurosurgical intervention using implanted electrodes to deliver electrical pulses to areas in the brain. DBS is currently investigated in psychiatry for the treatment of refractory obsessive-compulsive disorder, Tourette syndrome and depressive disorder. Although recent research in both animals and humans has indicated that DBS may be an effective intervention for patients with treatment-refractory addiction, it is not yet entirely clear which brain areas should be targeted. The objective of this review is to provide a systematic overview of the published literature on DBS and addiction and outline the most promising target areas using efficacy and adverse event data from both preclinical and clinical studies. We found 7 animal studies targeting six different brain areas: nucleus accumbens (NAc), subthalamic nucleus (STN), dorsal striatum, lateral habenula, medial prefrontal cortex (mPFC) and hypothalamus, and 11 human studies targeting two different target areas: NAc and STN. Our analysis of the literature suggests that the NAc is currently the most promising DBS target area for patients with treatment-refractory addiction. The mPFC is another promising target, but needs further exploration to establish its suitability for clinical purposes. We conclude the review with a discussion on translational issues in DBS research, medical ethical considerations and recommendations for clinical trials with DBS in patients with addiction.

Deep brain stimulation in addiction: a review of potential brain targets

Chronic consumption of alcohol represents one of the greatest health and socioeconomic problems worldwide. We report on a 54-year-old patient with a severe anxiety disorder and secondary depressive disorder in whom bilateral deep brain stimulation (DBS) of the nucleus accumbens was carried out. Despite the absence of desired improvement in his primary disorder, we observed a remarkable although not primarily intended alleviation of the patient's comorbid alcohol dependency. Our case report demonstrates the extremely effective treatment of alcohol dependency by means of DBS of the nucleus accumbens and may reveal new prospects in overcoming therapy resistance in dependencies in general.

/pdf/remission-of-alcohol-dependency-following-deep-brain-2dafqcjcxh.pdf

Remission of alcohol dependency following deep brain stimulation of the nucleus accumbens: valuable therapeutic implications?

Chronic consumption of alcohol represents one of the greatest health and socioeconomic problems worldwide. We report on a 54-year-old patient with a severe anxiety disorder and secondary depressive disorder in whom bilateral deep brain stimulation (DBS) of the nucleus accumbens was carried out. Despite the absence of desired improvement in his primary disorder, we observed a remarkable although not primarily intended alleviation of the patient’s comorbid alcohol dependency. Our case report demonstrates the extremely effective treatment of alcohol dependency by means of DBS of the nucleus accumbens and may reveal new prospects in overcoming therapy resistance in dependencies in general.

In the late 1980s a team of researchers in Grenoble, led by the neurosurgeon A. L. Benabit, introduced the technique of chronic stimulation of subcortical regions of the brain to treat movement disorders (e1, e2). This procedure, known as deep brain stimulation (DBS), involves stereotactic implantation of electrodes that then continuously emit short high-frequency electrical impulses in order to modulate functional neuronal circuits (Figure 1; eSupplement 1). The tip of each electrode contains at least four poles. Postoperatively, this permits a wide range of modes of stimulation from outside the brain. Each electrode is connected via a lead to the impulse generator, which is usually implanted under the collarbone (eSupplement 2).



Figure 1

Target areas for deep brain stimulation in psychiatric diseases: Th, Thalamus; STh, subthalamic nucleus; Ac, nucleus accumbens; Cg25, subgenual area of cingulum, Figure: Jurgen Stoffels, Medizin Foto Koln




Supplement 1: Effect of High-Frequency Stimulation on Brain Structures

The mechanisms of action of deep brain stimulation (DBS) are not yet fully understood. Reversible functional inhibition of the stimulated target structures by depolarization blockade of the neurons around the electrode, or of the voltage-dependent ion channels on the cell membrane, constitutes one explanation (e50). The inhibition of the physiological activity of stimulated cells, which persists for about 5 minutes after the end of stimulation, correlates with the almost immediate and reversible effect of DBS on Parkinson-plus symptoms and tremor, depending on the functional status of the impulse generator (on/off). Synaptically mediated neuronal inhibition by antidromic excitation of inhibitory GABAergic afferents has also been discussed (e51). A third feasible mechanism is synaptic depression by orthodromic stimulation of efferent axons and consecutive inhibition of transmission by exhaustion of the neurotransmitter pool (e52).

In dystonia and in psychiatric disorders the positive effect of DBS – like that of psychopharmaceuticals when first prescribed – often kicks in only after a number of weeks. This phenomenon cannot be wholly explained by a directly inhibiting mechanism; rather, the system evidently behaves in a plastic manner. Functional adaptation via complex and long-term modulation of neuronal systems seems to enable the effect. Functional magnetic resonance imaging, positron emission tomography (PET), and animal studies show, partially and in certain modalities, an elevation of the hemodynamic response and glucose metabolism of stimulated deep brain structures and their efferent projection areas—a sign of additional excitatory mechanisms of action (e53– e55).

It can be assumed that the action of DBS rests on a large number of effects and interferences, which—depending on stimulation site, stimulation parameters, and the underlying disease—vary in importance and modulate the pathophysiological processes in various ways (e56– e58).

Summarized very simply, DBS influences disordered neuronal networks and circuits by altering the distribution of excitation in the area of the target structure. The aim of DBS is to modulate and ideally eliminate the pathological signal transmission. Reconfiguration of the neuronal activity has a positive impact on the patient’s disease.



Supplement 2: DBS Procedure (Planning and Operation) in the Cologne Study Group

The procedure for deep brain stimulation (DBS) in patients with psychiatric disorders is analogous to that in movement disorders. Shortly before surgery the patient undergoes cranial magnetic resonance imaging with various weightings and particular modalities—the so-called planning MRI. Furthermore, after application of the stereotactic frame using sedation and local anesthesia, intraoperative computed tomography (CT) is performed. On the basis of the data obtained, and after consulting stereotactic atlases, the target is selected and the electrode pathways visualized in three dimensions.

Following borehole trepanation the electrodes are implanted. Quadripolar (or multipolar) electrodes are used; by selection of the actively stimulating pole, these permit postoperative adjustment and modification of the stimulation site. A previous microdischarge, routine in DBS for movement disorders and serving to check correct positioning of the electrodes, is often performed in psychiatric diseases but is not regularly described. The localization of the electrodes can be checked by postoperative X-ray or cranial CT (and under certain circumstances also MRI). MRI is often not possible after implantation of electrodes because of the potential adverse effects. The initial parameter settings are mostly decided on the basis of empirical experience. The stimulation parameters can vary as follows: amplitude of current from 1 to 6 V, pulse duration from 60 to 200 µs, and stimulation frequency from 120 to 180 Hz.

Surgery is completed in a second session with the infraclavicular implantation of the impulse generator.

In DBS for the treatment of movement disorders the operation is usually performed without symptom-specific medication in order to be able to tell whether the desired effects are achieved with the intraoperative test stimulation. As yet there is no consensus whether medication should be continued or discontinued for DBS of psychiatric diseases, partly because the desired effects of DBS mostly appear only after a considerable interval. If intraoperative exposure and test stimulation are planned, however, it is advisable to reduce the dosage of specific medication as much as possible or interrupt it entirely.


In Parkinson’s disease and essential tremor, DBS has proved so effective that it has been licensed as a treatment option (e3). Furthermore, there have been promising case studies on DBS treatment of certain subtypes of refractory epilepsy (e4, e5), dystonia (e6, e7), and chronic cluster headache (e8, e9). The DBS technique that has been in use for more than 20 years has become well known, and despite its invasive nature is associated with only minor adverse effects.

The idea of extending DBS to the treatment of psychiatric disorders is based on the following considerations:


In various cases, psychiatric adverse effects (induction of depressivity and hypomanic states) were observed in DBS-treated Parkinson’s disease patients. This gave rise to the proposal to employ DBS for primary modulation of psychopathological states (e10, e11).


In recent years knowledge of the mechanisms of origin of psychiatric diseases has grown, largely due to modern imaging procedures. The underlying pathophysiological processes and disordered neuronal networks have to some extent been determined and localized. It is thus now possible to identify potential stimulation sites for DBS.


The lesional procedures employed in the past as a last resort in cases of refractory psychiatric disease—anterior capsulotomy, cingulotomy, limbic leukotomy, etc.—achieved positive results (e12, e13). They do not come into question, however, because of the irreversible brain damage and their severe adverse-effect profile. The DBS technique, which is much less invasive, potentially reversible, and capable of modulation, can be applied to similar anatomic structures and may enable adjustment of the profile of action in the direction of the desired effects.

Wolfgang Huff

Papers

Remission of alcohol dependency following deep brain stimulation of the nucleus accumbens: valuable therapeutic implications?

Remission of alcohol dependency following deep brain stimulation of the nucleus accumbens: valuable therapeutic implications?

Deep Brain Stimulation for Psychiatric Disorders