Deep brain stimulation increases impulsivity in two patients with obsessive-compulsive disorder

Deep brain stimulation (DBS) is an adjustable, reversible, nondestructive neurosurgical intervention using implanted electrodes to deliver electrical pulses to areas in the brain. DBS has recently shown promising results as an experimental treatment of refractory obsessive-compulsive disorder (OCD). The novelty of the treatment requires careful observation of symptoms and possible side effects in patients. This case report describes two patients with treatment-refractory OCD in whom increased voltage of deep brain stimulation targeted at the nucleus accumbens increased impulsivity. Voltage increase of stimulation resulted in an immediate inflation of self-confidence, irritability and impulsive behaviour and was reversed only after lowering the voltage. The mechanisms behind DBS are not yet fully understood. Possibly, stimulation in the area of the nucleus accumbens affects the corticostriatal circuitry, which plays an important role in impulsivity. Location and amplitude of stimulation might be critical in inducing these behaviours. These two cases underline the importance of a careful clinical assessment of impulsive behaviours during DBS for OCD.     

Limbic versus cognitive target for deep brain stimulation in treatment-resistant depression: Accumbens more promising than caudate

High-frequency deep brain stimulation (DBS) represents a major stake for treatment for treatment-resistant depression (TRD). We describe a preliminary trial of DBS of two potential brain targets in chronic TRD: the nucleus accumbens (Acb) and, in the event of failure, the caudate nucleus. Patients were followed for 6 months before surgery (M0). From M1 to M5, they underwent stimulation of the Acb target. PET scans allowed us to track metabolic modifications resulting from this stimulation. The caudate target of nonresponders was stimulated between M5 and M9. Patients then entered an extension phase, in which it was possible to adapt stimulation parameters and treatments. Six patients were included and four were operated on. At M5, none of the patients were either responders or remitters, but we did observe a decrease in Hamilton Depression Rating Scale (HDRS) scores. Three patients were switched to caudate stimulation, but no improvement was observed. During the extension phase, the Acb target was stimulated for all patients, three of whom exhibited a significant response. A decrease in glucose metabolism was observed after Acb stimulation, in the posterior cingulate gyrus, left frontal lobe, superior and medial gyrus, and bilateral cerebellum. An increase in metabolism was observed in the bilateral frontal lobe (superior gyrus), left frontal lobe (medial gyrus), and right limbic lobe (anterior cingulate gyrus). The results of this trial suggest that Acb is a more promising target than the caudate. NCT01569711.     

伏隔核电刺激对大鼠吗啡条件性位置偏爱重现的影响

目的:为寻找防治药物依赖新方法,本文以大鼠条件性位置偏爱(CPP)为模型,探讨伏隔核电刺激对阿片类物质奖赏效应的影响.方法:20只成年大鼠分为两组:深部脑刺激(deep brain stimulation,DBS)组和假DBS组.用立体定位手术将DBS装置的电极部分植入一侧伏隔核(NAc)核心部,与脉冲发生器(IPG)...     

Deep brain stimulation for the treatment of addiction: basic and clinical studies and potential mechanisms of action

Rationale

Deep brain stimulation (DBS) has achieved substantial success as a treatment for movement disorders such as Parkinson’s disease. The therapeutic efficacy and relative lack of serious side effects resulted in the expansion of DBS into the treatment of many other diseases, including obsessive–compulsive disorder, Tourette’s, and depression, among others. More recently, a limited number of basic and clinical studies indicated that DBS may also be useful in the treatment of various addictions.

Objectives

Here, we briefly summarize the history of DBS and review the basic and clinical studies focused on DBS and addiction. We also examine the potential mechanisms that may underlie the effects of DBS.

Results and conclusions

The available data indicate that DBS is a promising therapeutic modality for the treatment of addiction. Thus far, the nucleus accumbens and subthalamic nucleus are the most promising sites for DBS, reversing aspects of addiction. The mechanisms underlying DBS are complex and likely vary from region to region. Emerging evidence indicates that DBS of the nucleus accumbens produces its effects, at least in part, by antidromic activation of cortico-accumbal afferents that stimulate inhibitory medial prefrontal cortex interneurons via recurrent collaterals.     

Deep Brain Stimulation of the Human Reward System for Major Depression—Rationale,Outcomes and Outlook

Deep brain stimulation (DBS) as a putative approach for treatment-resistant depression (TRD) has now been researched for about a decade. Several uncontrolled studies—all in relatively small patient populations and different target regions—have shown clinically relevant antidepressant effects in about half of the patients and very recently, DBS to a key structure of the reward system, the medial forebrain bundle, has yielded promising results within few days of stimulation and at much lower stimulation intensities. On the downside, DBS procedures in regions are associated with surgical risks (eg, hemorrhage) and psychiatric complications (suicidal attenuation, hypomania) as well as high costs. This overview summarizes research on the mechanisms of brain networks with respect to psychiatric diseases and—as a novelty—extrapolates to the role of the reward system in DBS for patients with treatment-resistant depression. It further evaluates relevant methodological aspects of today''s research in DBS for TRD. On the scientific side, the reward system has an important yet clearly under-recognized role in both neurobiology and treatment of depression. On the methodological side of DBS research in TRD, better animal models are clearly needed to explain clinical effects of DBS in TRD. Larger sample sizes, long-term follow-up and designs including blinded sham control are required to draw final conclusions on efficacy and side effects. Practical research issues cover study design, patient tracking, and the discussion of meaningful secondary outcome measures.     

Contents of monoamines in forebrain regions of alcohol-preferring (P) and -nonpreferring (NP) lines of rats

The contents of monoamine neurotransmitters and metabolites were assayed in the frontal cortex, nucleus accumbens and anterior striatum of rats from the selectively bred alcohol-preferring P and nonpreferring NP lines. Lower levels of serotonin (20-30%) in all three brain regions of P as compared with NP rats lends support to the hypothesis that a decreased metabolic activity and/or innervation by serotonin neurons is associated with the abnormally high volitional intake of ethanol. Of additional interest, however, were the approximately 25% lower contents of dopamine and its major metabolites in the nucleus accumbens of the P rats. This observation may indicate that P rats have a specific deficiency in the dopaminergic projections from the ventral tegmental area to the nucleus accumbens and, since the accumbens is an important structure in brain reward circuitry, it might also be an important determinant of the excessive volitional intake of alcohol by P rats.     

Long-Term Effects of Nucleus Accumbens Deep Brain Stimulation in Treatment-Resistant Depression: Evidence for Sustained Efficacy

Deep brain stimulation (DBS) to the nucleus accumbens (NAcc-DBS) was associated with antidepressant, anxiolytic, and procognitive effects in a small sample of patients suffering from treatment-resistant depression (TRD), followed over 1 year. Results of long-term follow-up of up to 4 years of NAcc-DBS are described in a group of 11 patients. Clinical effects, quality of life (QoL), cognition, and safety are reported. Eleven patients were stimulated with DBS bilateral to the NAcc. Main outcome measures were clinical effect (Hamilton Depression Rating Scale, Montgomery-Asperg Rating Scale of Depression, and Hamilton Anxiety Scale) QoL (SF-36), cognition and safety at baseline, 12 months (n=11), 24 months (n=10), and last follow-up (maximum 4 years, n=5). Analyses were performed in an intent-to-treat method with last observation carried forward, thus 11 patients contributed to each point in time. In all, 5 of 11 patients (45%) were classified as responders after 12 months and remained sustained responders without worsening of symptoms until last follow-up after 4 years. Both ratings of depression and anxiety were significantly reduced in the sample as a whole from first month of NAcc-DBS on. All patients improved in QoL measures. One non-responder committed suicide. No severe adverse events related to parameter change were reported. First-time, preliminary long-term data on NAcc-DBS have demonstrated a stable antidepressant and anxiolytic effect and an amelioration of QoL in this small sample of patients suffering from TRD. None of the responders of first year relapsed during the observational period (up to 4 years).     

Dopamine Modulates Reward System Activity During Subconscious Processing of Sexual Stimuli

Dopaminergic medication influences conscious processing of rewarding stimuli, and is associated with impulsive–compulsive behaviors, such as hypersexuality. Previous studies have shown that subconscious subliminal presentation of sexual stimuli activates brain areas known to be part of the ‘reward system''. In this study, it was hypothesized that dopamine modulates activation in key areas of the reward system, such as the nucleus accumbens, during subconscious processing of sexual stimuli. Young healthy males (n=53) were randomly assigned to two experimental groups or a control group, and were administered a dopamine antagonist (haloperidol), a dopamine agonist (levodopa), or placebo. Brain activation was assessed during a backward-masking task with subliminally presented sexual stimuli. Results showed that levodopa significantly enhanced the activation in the nucleus accumbens and dorsal anterior cingulate when subliminal sexual stimuli were shown, whereas haloperidol decreased activations in those areas. Dopamine thus enhances activations in regions thought to regulate ‘wanting'' in response to potentially rewarding sexual stimuli that are not consciously perceived. This running start of the reward system might explain the pull of rewards in individuals with compulsive reward-seeking behaviors such as hypersexuality and patients who receive dopaminergic medication.     

Drugs of abuse: anatomy, pharmacology and function of reward pathways.

Drugs of abuse are very powerful reinforcers, and even in conditions of limited access (where the organism is not dependent) these drugs will motivate high rates of operant responding. This presumed hedonic property and the drugs' neuropharmacological specificity provide a means of studying the neuropharmacology and neuroanatomy of brain reward. Three major brain systems appear to be involved in drug reward--dopamine, opioid and GABA. Evidence suggests a midbrain-forebrain-extrapyramidal circuit with its focus in the nucleus accumbens. Data implicating dopamine and opioid systems in indirect sympathomimetic and opiate reward include critical elements in both the nucleus accumbens and ventral tegmental areas. Ethanol reward appears to depend on an interaction with the GABAA receptor complex but may also involve common elements such as dopamine and opioid peptides in this midbrain-forebrain-extrapyramidal circuit. These results suggest that brain reward systems have a multidetermined neuropharmacological basis that may involve some common neuroanatomical elements.     

Intake of saccharin,salt, and ethanol solutions is increased by infusion of a mu opioid agonist into the nucleus accumbens

RATIONALE: Endogenous opioids have been implicated in the hedonic evaluation of food and palatability. Opioids may also be involved in alcohol intake, as there is a positive correlation between alcohol drinking and preference for sweets and fats. Our previous studies have shown that mu opioid stimulation of the nucleus accumbens preferentially augments intake of palatable food containing sucrose and fat. OBJECTIVE: The first goal of the present study was to further explore the nature of the involvement of mu opioids within the nucleus accumbens in ingestive behavior by investigating the importance of orosensory reward in opioid-mediated feeding, using non-caloric tasty substances (saccharin and salt). Second, we investigated whether mu opioid receptors within the nucleus accumbens also regulate alcohol consumption. METHODS: The mu agonist, D-Ala2, NMe-Phe4, Glyol5-enkephalin (DAMGO; 0, 0.025 and 0.25 microg/0.5 microl per side), was microinfused into the nucleus accumbens, and intake of 0.6% saline, 0.15% sodium saccharin, water, and 6% ethanol was measured. RESULTS: Microinfusion of DAMGO into the nucleus accumbens increased the drinking of salt and saccharin solutions in non-deprived rats. However, water intake was not increased by this treatment in water-deprived rats. Mu opioid stimulation of the nucleus accumbens also augmented ethanol intake in rats not deprived of fluid, while leaving water intake unchanged when water was concurrently available. CONCLUSION: These results provide evidence to suggest that the mu opioid system within the ventral striatum regulates ingestive behavior via a mechanism related to the hedonic assessment of taste. In addition, the nucleus accumbens may be a key brain area where ethanol interacts with endogenous opioid systems, and thus may be a common neural substrate for both food palatability and alcohol drinking.     

Deep brain stimulation of the nucleus accumbens reduces ethanol consumption in rats

Recent studies have shown that deep brain stimulation (DBS) of the nucleus accumbens (NAcc) has an inhibitory effect on drug-seeking behaviors including reinstatement responding for cocaine. The objective of the present study was to expand on these findings by assessing the effects of DBS on behaviors related to alcohol consumption. The specific aim of this study was to determine whether DBS delivered to either the shell or core of the NAcc would reduce ETOH intake in rats using a two-bottle choice limited access procedure. Long Evans rats were induced to drink a 10% ethanol solution using a saccharin fading procedure. Bipolar electrodes were implanted bilaterally into either the core or shell of the NAcc. During testing animals received DBS 5 min prior to and during a 30-minute test session in which both ETOH and water bottles were accessible. Current was delivered at amplitudes ranging from 0 to 150 µA. ETOH consumption was significantly reduced from baseline levels at the 150 µA current for both shell and core electrode placements. A significant current effect was not found for water consumption for either site. These results provide evidence that DBS delivered either to the nucleus accumbens core or shell subregions can significantly reduce ethanol intake in the rat.     

The effect of repetitive transcranial magnetic stimulation on monoamine outflow in the nucleus accumbens shell in freely moving rats

Evidence exists that modulation of neuronal activity in nucleus accumbens shell region may re-establish normal function in various neuropsychiatric conditions such as drug-withdrawal, obsessive–compulsive disorder, depression and chronic pain. Here, we study the effects of acute repetitive transcranial magnetic stimulation on monoamine outflow in the nucleus accumbens shell in awake and freely moving rats using in vivo microdialysis. To scale the biochemical results to the induced electric field in the rat brain, we obtained a realistic simulation of the stimulation scenario using a finite element model. Applying 20 Hz repetitive transcranial magnetic stimulation in 6 trains of 50 stimuli with 280 μs pulse width at a magnetic field strength of 130% of the individual motor threshold, dopamine as well as serotonin outflow in the nucleus accumbens shell significantly increased compared to sham stimulation. Since the electric field decays rapidly with depth in the rat brain, we can conclude that the modulation in neurotransmitter outflow from the nucleus accumbens shell is presumably a remote effect of cortical stimulation.     

Repetitive transcranial magnetic stimulation increases the release of dopamine in the nucleus accumbens shell of morphine-sensitized rats during abstinence.

Recent studies in rodents have shown that withdrawal from chronic drug abuse is associated with a significant decrease in dopamine (DA) release in mesolimbic structures, especially in the shell region of the nucleus accumbens. Since the DA system is known to play an important role in reward processes, a withdrawal-associated impairment in mesolimbic DA-mediated transmission could possibly implicate reward deficit and thus enhance vulnerability to drug craving and relapse. We have previously demonstrated that acute repetitive transcranial magnetic stimulation (rTMS) has a modulatory effect on DA release in several areas of the rat brain, including dorsal striatum, hippocampus, and nucleus accumbens shell. In the present study, we investigated the possible use of rTMS as a tool in re-establishing the dysregulated DA secretion observed during withdrawal in morphine-sensitized male Sprague-Dawley rats. Using intracerebral microdialysis, we monitored the effects of acute rTMS (20 Hz) on the intra-accumbal release-patterns of DA in freely moving animals that were subjected to a morphine sensitization scheme for a period of 8 days. We provide first evidence that acute rTMS (20 Hz) is able to increase DA concentration in the shell region of the nucleus accumbens in both control animals and morphine-sensitized rats during abstinence. The DA release in morphine-sensitized rats was significantly higher than in controls. rTMS, therefore, might gain a potential therapeutic role in the treatment of dysphoric and anhedonic states during drug withdrawal in humans.     

Chronic effects of cannabis use on the human reward system: An fMRI study

Cannabis is one of the most used drugs of abuse. It affects the brain reward system in animals, and has proven rewarding and addictive potential in humans. We used functional MRI to measure brain activity during reward anticipation in a monetary reward task. Long-term cannabis users were compared to healthy controls. An additional control group consisting of nicotine users was included. Cannabis users showed attenuated brain activity during reward anticipation in the nucleus accumbens compared to non-smoking controls, but not compared to smoking controls. Cannabis users showed decreased reward anticipation activity in the caudate nucleus, compared to both non-smoking and smoking controls. These data suggest that nicotine may be responsible for attenuated reward anticipation activity in the accumbens, but that differences in the caudate are associated with the use of cannabis. Our findings imply that chronic cannabis use as well as nicotine, may cause an altered brain response to rewarding stimuli.     

Effort-related functions of nucleus accumbens dopamine and associated forebrain circuits

BACKGROUND: Over the last several years, it has become apparent that there are critical problems with the hypothesis that brain dopamine (DA) systems, particularly in the nucleus accumbens, directly mediate the rewarding or primary motivational characteristics of natural stimuli such as food. Hypotheses related to DA function are undergoing a substantial restructuring, such that the classic emphasis on hedonia and primary reward is giving way to diverse lines of research that focus on aspects of instrumental learning, reward prediction, incentive motivation, and behavioral activation. OBJECTIVE: The present review discusses dopaminergic involvement in behavioral activation and, in particular, emphasizes the effort-related functions of nucleus accumbens DA and associated forebrain circuitry. RESULTS: The effects of accumbens DA depletions on food-seeking behavior are critically dependent upon the work requirements of the task. Lever pressing schedules that have minimal work requirements are largely unaffected by accumbens DA depletions, whereas reinforcement schedules that have high work (e.g., ratio) requirements are substantially impaired by accumbens DA depletions. Moreover, interference with accumbens DA transmission exerts a powerful influence over effort-related decision making. Rats with accumbens DA depletions reallocate their instrumental behavior away from food-reinforced tasks that have high response requirements, and instead, these rats select a less-effortful type of food-seeking behavior. CONCLUSIONS: Along with prefrontal cortex and the amygdala, nucleus accumbens is a component of the brain circuitry regulating effort-related functions. Studies of the brain systems regulating effort-based processes may have implications for understanding drug abuse, as well as energy-related disorders such as psychomotor slowing, fatigue, or anergia in depression.     

Reward Processing in Unipolar and Bipolar Depression: A Functional MRI Study

Differentiating bipolar disorders (BD) from unipolar depression (UD) remains a major clinical challenge. The identification of neurobiological markers may help to differentiate these disorders, particularly during depressive episodes. This cross-sectional study, including 33 patients with UD, 33 patients with BD, and 34 healthy controls, is one of the first to directly compare UD and BD with respect to reward processing. A card-guessing paradigm was employed and brain activity associated with reward processing was investigated by means of fMRI. A 3 (group) × 2 (condition: reward>control, loss>control) ANOVA was conducted using the nucleus accumbens (NAcc) as ROI. Furthermore, a whole-brain approach was applied. A functional connectivity analysis was performed to characterize diagnosis-related alterations in the functional coupling between the NAcc and other brain areas. The ANOVA revealed higher activity for healthy controls (HCs) than for BD and UD in the NAcc during reward processing. Moreover, UD showed a higher functional connectivity between the NAcc and the VTA than HC. The patients groups could be differentiated in that BD showed a decreased activation, in the reward condition, of the NAcc, caudate nucleus, thalamus, putamen, insula, and prefrontal areas compared with UD. These results may help to refine the understanding of neural correlates of reward processing in both disorders, and to understand the neural underpinnings of anhedonia, a core symptom of depressive episodes.     

深部脑刺激治疗药物成瘾的研究进展

深部脑刺激主要用于治疗帕金森病﹑难治性强迫症﹑癫痫和抑郁症等精神疾病,与手术和其他电刺激技术相比深部脑刺激具有靶点明确、可选择性、可调节性、可逆性、微创性和安全性高等优点。深部脑刺激的疗效在很大程度上依赖于刺激靶点与疾病的相关性,只有在疾病相关的靶点施加深部脑刺激,才有可能取得理想的治疗效果,尽管最近在动物和人身上发现深部脑刺激能有效地干预治疗难治性药物成瘾患者,但是尚未有完全明确的脑区作为治疗靶点。因此,该文将近年来深部脑刺激在治疗药物成瘾研究中主要作用的靶点作一综述,并进一步探讨深部脑刺激作用的可能机制。     

Role of histaminergic and cholinergic transmission in cognitive processes

Mutual modulatory and functional interactions exist between the histaminergic and cholinergic systems in the brain. The activity of histaminergic neurons is permanently modulated by neighboring cholinergic neurons via muscarinic M(1) receptors, cholinergic transmission by histaminergic neurons through H(1), H(2), H(3A) and H(3B) receptors. In the nucleus accumbens, glutamatergic neurons originating from the hippocampus modulate cholinergic transmission in a direct way via stimulation of NMDA receptors located on cholinergic neurons. Additionally, glutamatergic neurons of the hippocampus modulate the activity of cholinergic neurons in an indirect way by stimulating histaminergic neurons within the nucleus accumbens. Reciprocal regulatory influences and neurotransmission are subjected to the global modulatory influence of nitric oxide. Both histaminergic and cholinergic systems in the nucleus accumbens are implicated in the response to aversive stimuli. Memory acquisition is associated with activation of cholinergic transmission in the nucleus accumbens, while stimulation of histaminergic neurons facilitates memory in a way that is independent of the cholinergic system. Hence, both histaminergic and cholinergic transmission within the nucleus accumbens and interactions between the two systems seem to play a predominant role in cognition.     

Role of dopamine in the behavioural actions of nicotine related to addiction

Experimental impairment of dopamine function by 6-hydroxydopamine lesions or by dopamine receptor antagonists shows that dopamine is involved in nicotine's discriminative stimulus properties, nicotine-induced facilitation of intracranial self-stimulation, intravenous nicotine self-administration, nicotine conditioned place-preference and nicotine-induced disruption of latent inhibition. Therefore, nicotine depends on dopamine for those behavioural effects that are most relevant for its reinforcing properties and are likely to be the basis of the abuse liability of tobacco smoke. On the other hand, in vivo monitoring studies show that nicotine stimulates dopamine transmission in specific brain areas and in particular, in the shell of the nucleus accumbens and in areas of the extended amygdala. These effects of nicotine resemble those of a reward like food except that nicotine-induced release of dopamine does not undergo single-trial, long-lasting habituation. It is speculated that repeated non-habituating stimulation of dopamine release by nicotine in the nucleus accumbens shell abnormally facilitates associative stimulus-reward learning. Acute effects of nicotine on dopamine transmission undergo acute and chronic tolerance; with repeated, discontinuous exposure, sensitization of nicotine-induced stimulation of dopamine release in the nucleus accumbens core takes place while the response in the shell is reduced. It is speculated that these adaptive changes are the substrate of a switch from abnormal incentive responding controlled by consequences (action-outcome responding) into abnormal habit responding, triggered by conditional stimuli and automatically driven by action schemata relatively independent from nicotine reward. These two modalities might coexist, being utilized alternatively in relation to the availability of tobacco. Unavailability of tobacco disrupts the automatic, implicit modality of abnormal habit responding switching responding into the explicit, conscious modality of incentive drug-seeking and craving.     

Lithium modulates striatal reward anticipation and prediction error coding in healthy volunteers

Lithium is one of the most effective mood-stabilizing medications in bipolar disorder. This study was designed to test whether lithium administration may stabilize mood via effects on reward processing. It was hypothesized that lithium administration would modulate reward processing in the striatum and affect both anticipation and outcome computations. Thirty-seven healthy human participants (18 males, 33 with suitable fMRI data) received 11 (±1) days of lithium carbonate or placebo intervention (double-blind), after which they completed the monetary incentive delay task while fMRI data were collected. The monetary incentive delay task is a robust task with excellent test-retest reliability and is well suited to investigate different phases of reward processing within the caudate and nucleus accumbens. To test for correlations with prediction error signals a Rescorla–Wagner reinforcement-learning model was applied. Lithium administration enhanced activity in the caudate during reward anticipation compared to placebo. In contrast, lithium administration reduced caudate and nucleus accumbens activity during reward outcome. This latter effect seems related to learning as reward prediction errors showed a positive correlation with caudate and nucleus accumbens activity during placebo, which was absent after lithium administration. Lithium differentially modulates the anticipation relative to the learning of rewards. This suggests that lithium might reverse dampened reward anticipation while reducing overactive reward updating in patients with bipolar disorder. This specific effect of lithium suggests that a targeted modulation of reward learning may be a viable approach for novel interventions in bipolar disorder.Subject terms: Reward, Bipolar disorder, Motivation