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

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.     

New potential stimulation targets for noninvasive brain stimulation treatment of chronic insomnia

BackgroundNoninvasive brain stimulation (NIBS) was recently used as a therapeutic application in patients with insomnia. Most of the previous NIBS treatments for insomnia directly selected the dorsolateral prefrontal cortex (DLPFC) as the stimulation site. As the NIBS target is an important factor in the efficacy of NIBS, it is necessary to detect more potential cortical sites for NIBS in insomnia.MethodsA neuroimaging study-based meta-analysis was used to examine sleep-related brain regions. A sleep-associated brain region-based functional connectivity (FC) map was constructed in 50 patients with chronic insomnia disorder (CID) without any comorbidity. We also combined the meta-analysis and FC results to examine the potential surface targets for NIBS for CID.ResultsThe results identified the bilateral supplementary motor area (SMA), left superior temporal gyrus (STG), bilateral DLPFC, precentral lobule, supramarginal gyrus, angular gyrus, superior frontal gyrus, middle temporal gyrus and middle occipital gyrus as potential brain stimulation targets for insomnia treatment. Notably, the bilateral SMA, right DLPFC and left STG were identified in the FC and meta-analyses. In addition, the SMA and DLPFC were positively and STG was negatively connected with other sleep related brain regions, which indicated inhibitory and excitatory stimulation for NIBS treatment for CID, respectively.ConclusionOur study suggests the SMA, DLPFC and STG as preferentially selected brain targets of NIBS for CID treatment. We recommend an inhibitory stimulation over SMA and DLPFC, and an excitatory stimulation over STG for NIBS treatment. Future studies should test these new targets using NIBS treatment for insomnia.     

Downregulation of hypothalamic insulin receptor expression elicits depressive-like behaviors in rats

Ongoing epidemiological studies estimate that greater than 60% of the adult US population may be categorized as either overweight or obese. There is a growing appreciation that the complications of obesity extend to the central nervous system (CNS) and may result in increased risk for neurological co-morbidities like depressive illness. One potential mechanistic mediator linking obesity and depressive illness is the adipocyte derived hormone leptin. We previously demonstrated that lentivirus-mediated downregulation of hypothalamic insulin receptors increases body weight, adiposity and plasma leptin levels, which is consistent with features of the metabolic syndrome. Using this novel model of obesity, we examined performance in the forced swim test (FST), the sucrose preference test and the elevated plus maze (EPM), approaches that are often used as measures of depressive-like and anxiety-like behaviors, in rats that received third ventricular injections of either an insulin receptor antisense lentivirus (hypo-IRAS) or a control lentivirus (hypo-Con). Hypo-IRAS rats exhibited significant increases in immobility time and corresponding decreases in active behaviors in the FST and exhibited anhedonia as measured by decreased sucrose intake compared to hypo-Con rats. Hypo-IRAS rats also exhibited increases in anxiety-like behaviors in the EPM. Plasma, hippocampal and amygdalar brain-derived neurotrophic factor (BDNF) levels were reduced in hypo-IRAS rats, suggesting that the obesity/hyperleptinemic phenotype may elicit this behavioral phenotype through modulation of neurotrophic factor expression. Collectively, these data support the hypothesis for an increased risk for mood disorders in obesity, which may be related to decreased expression of hippocampal and amygdalar BDNF.     

Neuroplasticity-dependent and -independent mechanisms of chronic deep brain stimulation in stressed rats

Chronic ventromedial prefrontal cortex (vmPFC) deep brain stimulation (DBS) improves depressive-like behaviour in rats via serotonergic and neurotrophic-related mechanisms. We hypothesise that, in addition to these substrates, DBS-induced increases in hippocampal neurogenesis may also be involved. Our results show that stress-induced behavioural deficits in the sucrose preference test, forced swim test, novelty-suppressed feeding test (NSFT) and elevated plus maze were countered by chronic vmPFC DBS. In addition, stressed rats receiving stimulation had significant increases in hippocampal neurogenesis, PFC and hippocampal brain-derived neurotrophic factor levels. To block neurogenesis, stressed animals given DBS were injected with temozolomide. Such treatment reversed the anxiolytic-like effect of stimulation in the NSFT without significantly affecting performance in other behavioural tests. Taken together, our findings suggest that neuroplastic changes, including neurogenesis, may be involved in specific anxiolytic effects of DBS without affecting its general antidepressant-like response.     

Outcomes,management, and potential mechanisms of interleaving deep brain stimulation settings

IntroductionDBS is a therapeutic option for patients with Parkinson disease (PD), tremor and dystonia. In patients who experience suboptimal clinical results with conventional programming (monopolar, double monopolar or bipolar settings), interleaved pulses can sometimes be used to provide differential therapeutic benefits with the possibility of fewer side effects. Interleaving allows a clinician to define two “programs” that automatically alternate. The goal of this paper is to 1) present clinical scenarios where DBS interleaving was used across two clinics to provide improved symptom control in three patients with suboptimal results from conventional programming; 2) address the potential mechanisms of interleaving; and 3) provide practical tips on the use of interleaving.MethodsThree patients were formally compared for therapeutic benefit on interleaved and conventional parameter settings.ResultsInterleaving is most likely to be useful in two clinical scenarios: 1) different contacts are beneficial for specific symptoms, but each at a different stimulation amplitude; or 2) symptoms are resolved incompletely, and further voltage increase is limited by side effects. The factors underpinning the differences in outcomes with interleaving are unknown but may be highly dependent on specific symptoms and to electrode positioning. Interleaving is a relatively new programming platform and there is no data to demonstrate long-term benefits.ConclusionsInterleaving is a tool that may augment outcomes, and possibly obviate the need for surgical revisions, although in our experience across two large centers it has been effective for only a small number of patients.     

Endovascular deep brain stimulation: Investigating the relationship between vascular structures and deep brain stimulation targets

BackgroundEndovascular delivery of current using ‘stentrodes’ – electrode bearing stents – constitutes a potential alternative to conventional deep brain stimulation (DBS). The precise neuroanatomical relationships between DBS targets and the vascular system, however, are poorly characterized to date.ObjectiveTo establish the relationships between cerebrovascular system and DBS targets and investigate the feasibility of endovascular stimulation as an alternative to DBS.MethodsNeuroanatomical targets as employed during deep brain stimulation (anterior limb of the internal capsule, dentatorubrothalamic tract, fornix, globus pallidus pars interna, medial forebrain bundle, nucleus accumbens, pedunculopontine nucleus, subcallosal cingulate cortex, subthalamic nucleus, and ventral intermediate nucleus) were superimposed onto probabilistic vascular atlases obtained from 42 healthy individuals. Euclidian distances between targets and associated vessels were measured. To determine the electrical currents necessary to encapsulate the predefined neurosurgical targets and identify potentially side-effect inducing substrates, a preliminary volume of tissue activated (VTA) analysis was performed.ResultsSix out of ten DBS targets were deemed suitable for endovascular stimulation: medial forebrain bundle (vascular site: P1 segment of posterior cerebral artery), nucleus accumbens (vascular site: A1 segment of anterior cerebral artery), dentatorubrothalamic tract (vascular site: s2 segment of superior cerebellar artery), fornix (vascular site: internal cerebral vein), pedunculopontine nucleus (vascular site: lateral mesencephalic vein), and subcallosal cingulate cortex (vascular site: A2 segment of anterior cerebral artery). While VTAs effectively encapsulated mfb and NA at current thresholds of 3.5 V and 4.5 V respectively, incremental amplitude increases were required to effectively cover fornix, PPN and SCC target (mean voltage: 8.2 ± 4.8 V, range: 3.0–17.0 V). The side-effect profile associated with endovascular stimulation seems to be comparable to conventional lead implantation. Tailoring of targets towards vascular sites, however, may allow to reduce adverse effects, while maintaining the efficacy of neural entrainment within the target tissue.ConclusionsWhile several challenges remain at present, endovascular stimulation of select DBS targets seems feasible offering novel and exciting opportunities in the neuromodulation armamentarium.     

Pedunculopontine nucleus electric stimulation alleviates akinesia independently of dopaminergic mechanisms

The symptom of Parkinson's disease that is most disabling and difficult to treat is akinesia. We have previously shown that low-frequency stimulation of the pedunculopontine nucleus can alleviate such akinesia in a macaque rendered Parkinsonian using 1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine. Here, we have extended that study to show that adding stimulation of the pedunculopontine nucleus to levodopa treatment in this Parkinsonian monkey increased its motor activity significantly more than levodopa alone. This additivity suggests that pedunculopontine nucleus stimulation may improve movement by acting at a site downstream from where levodopa therapy affects the basal ganglia.     

Neurogenic hippocampal targets of deep brain stimulation

Deep brain stimulation (DBS) is being used to treat movement, neurological, and psychiatric disorders; recently it has been successfully applied to patients with treatment-resistant depression or in minimally conscious state. In addition to its clinical importance, DBS presents a powerful approach to target specific neural circuits and determine the functional relationship between the components of these circuits. We examined the effect of high-frequency stimulation of a crucial component of the limbic circuitry, the anterior thalamic nuclei (ATN), on the generation of new neurons in the dentate gyrus (DG) of the hippocampus, another component of the same circuitry. Adult hippocampal neurogenesis emerges as a strong correlate of antidepressant treatments; however, in most cases, the progenitor cell population targeted by a specific treatment is not known. Using reporter mouse lines designed to quantify changes in selected classes of neural progenitors, we found that high-frequency stimulation of the ATN increases symmetric divisions of a defined class of neural progenitors in the DG; this effect is later manifested as an increased number of new neurons. The affected class of neural progenitors is also affected by the antidepressant fluoxetine (Prozac) and physical exercise (running). This indicates that neurogenic stimuli of different natures can converge on the same neurogenic target in the DG. Our results also suggest that hippocampal neurogenesis may be used as a sensitive indicator of the limbic circuitry activation induced by DBS.     

Deep brain stimulation in Tourette's syndrome: Two targets?

In this report, we describe the effects of bilateral thalamic stimulation in one patient and of bilateral pallidal stimulation in another patient. Both patients suffered from intractable Tourette's syndrome (TS). Any conservative treatment had failed or had been stopped because of unbearable side effects in the 2 patients. In both cases, there was no comorbidity except for associated behavioral symptoms (compulsions). Electrodes were implanted at the level of the medial part of the thalamus (centromedian nucleus, the substantia periventricularis, and the nucleus ventro-oralis internus) in one patient and in the posteroventral part of the globus pallidus internus (GPi) in the other patient. In both cases, deep brain stimulation (DBS) resulted in a substantial reduction of tics and compulsions. These data show that bilateral DBS of the thalamus as well as of the GPi can have a good effect on tics and behavioral symptoms in patients suffering from intractable TS.     

Enriched environment decreases microglia and brain macrophages inflammatory phenotypes through adiponectin-dependent mechanisms: Relevance to depressive-like behavior

Regulation of neuroinflammation by glial cells plays a major role in the pathophysiology of major depression. While astrocyte involvement has been well described, the role of microglia is still elusive. Recently, we have shown that Adiponectin (ApN) plays a crucial role in the anxiolytic/antidepressant neurogenesis-independent effects of enriched environment (EE) in mice; however its mechanisms of action within the brain remain unknown. Here, we show that in a murine model of depression induced by chronic corticosterone administration, the hippocampus and the hypothalamus display increased levels of inflammatory cytokines mRNA, which is reversed by EE housing. By combining flow cytometry, cell sorting and q-PCR, we show that microglia from depressive-like mice adopt a pro-inflammatory phenotype characterized by higher expression levels of IL-1β, IL-6, TNF-α and IκB-α mRNAs. EE housing blocks pro-inflammatory cytokine gene induction and promotes arginase 1 mRNA expression in brain-sorted microglia, indicating that EE favors an anti-inflammatory activation state. We show that microglia and brain-macrophages from corticosterone-treated mice adopt differential expression profiles for CCR2, MHC class II and IL-4recα surface markers depending on whether the mice are kept in standard environment or EE. Interestingly, the effects of EE were abolished when cells are isolated from ApN knock-out mouse brains. When injected intra-cerebroventricularly, ApN, whose level is specifically increased in cerebrospinal fluid of depressive mice raised in EE, rescues microglia phenotype, reduces pro-inflammatory cytokine production by microglia and blocks depressive-like behavior in corticosterone-treated mice. Our data suggest that EE-induced ApN increase within the brain regulates microglia and brain macrophages phenotype and activation state, thus reducing neuroinflammation and depressive-like behaviors in mice.     

Resuscitation therapy for traumatic brain injuryinduced coma in rats:mechanisms of median nerve electrical stimulation

In this study, rats were put into traumatic brain injury-induced coma and treated with median nerve electrical stimulation. We explored the wake-promoting effect, and possible mechanisms, of median nerve electrical stimulation. Electrical stimulation upregulated the expression levels of orexin-A and its receptor OX1 R in the rat prefrontal cortex. Orexin-A expression gradually increased with increasing stimulation, while OX1 R expression reached a peak at 12 hours and then decreased. In addition, after the OX1 R antagonist, SB334867, was injected into the brain of rats after traumatic brain injury, fewer rats were restored to consciousness, and orexin-A and OXIR expression in the prefrontal cortex was downregulated. Our findings indicate that median nerve electrical stimulation induced an up-regulation of orexin-A and OX1 R expression in the prefrontal cortex of traumatic brain injury-induced coma rats, which may be a potential mechanism involved in the wake-promoting effects of median nerve electrical stimulation.     

Mechanisms and targets of deep brain stimulation in movement disorders

Chronic electrical stimulation of the brain, known as deep brain stimulation (DBS), has become a preferred surgical treatment for medication-refractory movement disorders. Despite its remarkable clinical success, the therapeutic mechanisms of DBS are still not completely understood, limiting opportunities to improve treatment efficacy and simplify selection of stimulation parameters. This review addresses three questions essential to understanding the mechanisms of DBS. 1) How does DBS affect neuronal tissue in the vicinity of the active electrode or electrodes? 2) How do these changes translate into therapeutic benefit on motor symptoms? 3) How do these effects depend on the particular site of stimulation? Early hypotheses proposed that stimulation inhibited neuronal activity at the site of stimulation, mimicking the outcome of ablative surgeries. Recent studies have challenged that view, suggesting that although somatic activity near the DBS electrode may exhibit substantial inhibition or complex modulation patterns, the output from the stimulated nucleus follows the DBS pulse train by direct axonal excitation. The intrinsic activity is thus replaced by high-frequency activity that is time-locked to the stimulus and more regular in pattern. These changes in firing pattern are thought to prevent transmission of pathologic bursting and oscillatory activity, resulting in the reduction of disease symptoms through compensatory processing of sensorimotor information. Although promising, this theory does not entirely explain why DBS improves motor symptoms at different latencies. Understanding these processes on a physiological level will be critically important if we are to reach the full potential of this powerful tool.     

Tremor habituation to deep brain stimulation: Underlying mechanisms and solutions

DBS of the ventral intermediate nucleus is an extremely effective treatment for essential tremor, although a waning benefit is observed after a variable time in a variable proportion of patients (ranging from 0% to 73%), a concept historically defined as “tolerance.” Tolerance is currently an established concept in the medical community, although there is debate on its real existence. In fact, very few publications have actually addressed the problem, thus making tolerance a typical example of science based on “eminence rather than evidence.” The underpinnings of the phenomena associated with the progressive loss of DBS benefit are not fully elucidated, although the interplay of different—not mutually exclusive—factors has been advocated. In this viewpoint, we gathered the evidence explaining the progressive loss of benefit observed after DBS. We grouped these factors in three categories: disease‐related factors (tremor etiology and progression); surgery‐related factors (electrode location, microlesional effect and placebo); and stimulation‐related factors (not optimized stimulation, stimulation‐induced side effects, habituation, and tremor rebound). We also propose possible pathophysiological explanations for the phenomenon and define a nomenclature of the associated features: early versus late DBS failure; tremor rebound versus habituation (to be preferred over tolerance). Finally, we provide a practical approach for preventing and treating this loss of DBS benefit, and we draft a possible roadmap for the research to come. © 2019 International Parkinson and Movement Disorder Society     

Deep brain stimulation surgery for Parkinson's disease: mechanisms and consequences

Despite the introduction of new medications, motor fluctuations and dyskinesias disable a significant proportion of Parkinson's disease patients. This has lead to renewed interest in stereotactic neurosurgery. A skilled team is needed to ensure that patient assessment and selection, operative technique, intraoperative monitoring, and post-operative management are optimised. High frequency stimulation has similar effects to ablative surgery, and is generally preferred. The clinical effects and possible mechanisms of action of deep brain stimulation of the subthalamic nucleus and globus pallidus are reviewed.     

Cortical and spinal mechanisms of facilitation to brain stimulation

Compound muscle action potentials (CMAPs) evoked by magnetic brain stimuli are larger if the subject provides a steady background voluntary contraction of the target muscle. This facilitation could be due either to cortical or spinal mechanisms, or both. Both magnetic and electrical stimuli given immediately after the onset of a ballistic contraction also evoke markedly facilitated CMAPs. By contrast, responses some 200 ms after the onset of such a contraction are facilitated if stimuli are magnetic but not if they are electrical. This second phase of facilitation is largely cortical in origin. By comparing the size of CMAPs evoked by magnetic stimuli at two different delays after electromyogram onset, the total facilitation could be dissected into its spinal and cortical components. The relationship between CMAP area in the first dorsal interosseous and stimulus intensity was different in the two phases of facilitation, suggesting a constant background level of spinal facilitation upon which an increasing descending volley operated. In experiments in which ballistic contractions at increasing force levels were performed, it was found that at low force levels, spinal facilitation predominated, but at forces greater than 10% maximum there were roughly equal contributions from increased spinal cord and cortex excitability. © 1996 John Wiley & Sons, Inc.