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Textbook of Neuromodulation
Abstract
Addiction remains one of the most serious public health problems worldwide. The successful use of deep brain stimulation (DBS) for treating movement disorders has prompted researchers to consider whether DBS might be a promising treatment modality for addiction as well. Indeed, there is emerging evidence from preliminary case reports of patients suffering from alcohol and heroin addiction, respectively, that indicates abstinence after DBS within the nucleus accumbens (NAc). These findings are further supported by translational studies showing modulation of addictive behavior patterns in animals by stimulating the NAc and other structures related to the brain’s intrinsic reward system. Explanations for the positive effect of DBS on abstinence are modulative mechanisms on the dysfunctional reward system. Moreover, we intend to expand this by giving a more general view that also includes alternative neurostimulatory techniques different from classical DBS, such as transcranial magnet stimulation (TMS) and transcranial direct current stimulation (tDCS) for evaluating their possible virtues in treating different issues of addiction.
... Recent animal and human studies have shown that DBS can also be an effective treatment modality for addiction [20]. Preclinical studies evaluated the effects of DBS on the response to various drug abuse and showed promising results in stimulating different regions of the brain reward system [21,22]. Preclinical and clinical studies also suggested that DBS of the nucleus accumbens (NAc), a limbic structure that is critical in reinforcing and reinstating the effects of substance abuse, can reduce alcohol [23], heroin [24], and cocaine consumption [25] and propose this region as the primary target for DBS [26]. ...
Addiction to psychostimulants significantly affects public health. Standard medical therapy is often not curative. Deep brain stimulation (DBS) is a promising treatment that has attracted much attention for addiction treatment in recent years. The present review aimed to systematically identify the positive and adverse effects of DBS in human and animal models to evaluate the feasibility of DBS as a treatment for psychostimulant abuse. The current study also examined the possible mechanisms underlying the therapeutic effects of DBS. In February 2022, a comprehensive search of four databases, including Web of Science, PubMed, Cochrane, and Scopus, was carried out to identify all reports that DBS was a treatment for psychostimulant addiction. The selected studies were extracted, summarized, and evaluated using the appropriate methodological quality assessment tools. The results indicated that DBS could reduce relapse and the desire for the drug in human and animal subjects without any severe side effects. The underlying mechanisms of DBS are complex and likely vary from region to region in terms of stimulation parameters and patterns. DBS seems a promising therapeutic option. However, clinical experiences are currently limited to several uncontrolled case reports. Further studies with controlled, double-blind designs are needed. In addition, more research on animals and humans is required to investigate the precise role of DBS and its mechanisms to achieve optimal stimulation parameters and develop new, less invasive methods.
... Electromagnetic brain stimulation could regulate activity in specific brain regions. Recent studies have explored the application of noninvasive neurostimulation for the treatment of substance dependence (22)(23)(24)(25). ...
Substance addiction and food addiction are significant social problems worldwide. In previous studies of substance addiction, transcranial direct current stimulation (tDCS) has been used to influence craving of substance or food. However, the reported effects are not always consistent due to inconsistent experimental settings. The way modulators influence the effect of tDCS on substance addiction is worth exploring. This meta-analysis was conducted to estimate the effect size of tDCS on substance and food craving and to investigate the influence of potential modulators. We systemically identified and reviewed studies on substance/food craving using tDCS that were published between January 2008 to January 2020. A total of 32 eligible studies were identified. Hedges' g was computed as an indicator of the effect of tDCS and some potential moderators (substance type, stimulation sites, current intensities, number of sessions, duration of stimulation, and study design) were examined using subgroup analysis. Random effects analysis revealed a total medium effect size [Hedges' g = 0.536, 95% confidence interval (CI): 0.389–0.683, after adjusting Hedges' g = 0.416, 95% CI: 0.262–0.570] preferring active over sham stimulation to reduce craving. A significant difference was observed between the number of sessions (repeated stimulation was better than single stimulation). The duration of stimulation may have a positive influence on the effects of tDCS. No other significant differences were found in other subgroups analysis. In conclusion, our results provided evidence that tDCS can be an effective way to reduce craving of substance or food, and longer multiple stimulus durations in all can more effectively reduce craving; however, the influences of modulators still need be to be examined in depth in future.
The striatum is the largest input nucleus to the basal ganglia and associated with reward-based behavior. We assessed whether acute ethanol (EtOH) exposure could modulate synaptic efficacy in the dorsolateral striatum of juvenile Wistar rats. Since acute EtOH administration can both increase and decrease the probability of release of different neurotransmitters from synaptic terminals, we used field potential recordings to evaluate the net effect of EtOH on striatal output. We showed that 50mM EtOH but not 20, 80 or 100mM, depresses population spike (PS) amplitude in the dorsolateral striatum. This depression of synaptic output is insensitive to the N-methyl-d-aspartic acid (NMDA) receptor inhibitor DL-2-amino-5-phosphonopentanoic acid (AP-5, 50μM), but is blocked in slices treated with glycine receptor antagonists (strychnine, 1μM; PMBA, 50μM), nicotinic acetylcholine receptor antagonists (mecamylamine, 10μM; methyllycaconitine citrate (MLA), 40nM), or GABA(A) receptor inhibitors (picrotoxin, 100μM; bicuculline, 2μM, 20μM). A long-term facilitation of synaptic output, which is more pronounced in slices from adult Wistar rats, is detected following EtOH washout (50, 80, 100mM). This long-term enhancement of PS amplitude is regulated by cholinergic interneurons and completely blocked by mecamylamine, MLA or the non-selective muscarinic antagonist scopolamine (10μM). Administration of 100mM EtOH significantly depresses PS amplitude in scopolamine-treated slices, suggesting that EtOH exerts dual actions on striatal output that are initiated instantly upon drug wash-on. In conclusion, EtOH modulates striatal microcircuitry and neurotransmission in a way that could be of importance for understanding the intoxicating properties as well as the acute reward sensation of EtOH.
Recent research suggests that adaptations elicited by drugs of abuse share common features with traditional learning models, and that drugs of abuse cause long-term changes in behavior by altering synaptic function and plasticity. In this study, endocannabinoid (eCB) signaling in the dorsolateral striatum, a brain region vital for habit formation, was evaluated in acutely isolated brain slices from ethanol (EtOH)-consuming rats and control rats. EtOH-consuming rats had free access to a 20% EtOH solution for three 24 hour sessions a week during seven weeks and consumed an average of 3.4 g/kg per session. eCB-mediated long-lasting disinhibition (DLL) of population spike (PS) amplitude induced by moderate frequency stimulation was impaired in EtOH-consuming rats, and was not restored by the muscarinic receptor antagonist scopolamine (10 μM). The lack of DLL could be linked to a reduced GABA(A) receptor tone, since bicuculline-mediated disinhibition of striatal output was significantly reduced in slices from EtOH-consuming rats. However, eCB signaling induced by high frequency stimulation (HFS) was also impaired in slices from EtOH-consuming rats and isolated control rats. Activation of presynaptic cannabinoid 1 receptors (CB1R) with WIN55,212-2 (250 nM, 1 μM) significantly modulated PS amplitude in slices from age-matched control rats while slices from EtOH-consuming rats remained unaffected, indicating that eCB signaling is inhibited at a level that is downstream from CB1R activation. Intermittent alcohol intake for seven weeks might thus be sufficient to modulate a presynaptic mechanism that needs to be synergized with CB1R activation for induction of long-term depression (LTD). In conclusion, alcohol consumption inhibits striatal eCB signaling in a way that could be of importance for understanding the neurological underpinnings of addictive behavior.
The authors tested the hypothesis that deep brain stimulation (DBS) in the nucleus accumbens (NAcc) decreases alcohol intake in alcohol-preferring (P) rats after each animal has established a stable, large alcohol intake and after P rats with an established intake have been deprived of alcohol for 4-6 weeks.
Bipolar stimulating electrodes were bilaterally placed in the NAcc using stereotactic coordinates. In the first study, P rats (9 animals) were allowed to establish a stable pattern of alcohol intake (about 5-7 g/day) over approximately 2 weeks, and the acute effects of DBS in the NAcc (140-150 Hz, 60-microsec pulse width, and 200-microA current intensity) on alcohol intake and alcohol preference were studied. Each animal acted as its own control and received 1 hour of DBS followed by 1 hour of sham-DBS or vice versa on each of 2 sequential days. The order of testing (sham-DBS vs DBS) was randomized. In the second study, each animal was allowed to establish a stable alcohol intake and then the animal was deprived of alcohol for 4-6 weeks. Animals received DBS (6 rats) or sham-DBS (5 rats) in the NAcc for 24 hours starting when alcohol was reintroduced to each animal.
Deep brain stimulation in the NAcc, as compared with a period of sham-DBS treatment in the same animals, acutely decreased alcohol preference. Furthermore, alcohol consumption and preference were significantly reduced in the DBS group compared with the sham treatment group during the first 24 hours that alcohol was made available after a period of forced abstinence.
The NAcc plays a key role in the rewarding and subsequent addictive properties of drugs of abuse in general and of alcohol in particular. Deep brain stimulation in the NAcc reduced alcohol consumption in P rats both acutely and after a period of alcohol deprivation. Therefore, DBS in the NAcc coupled with other neurophysiological measurements may be a useful tool in determining the role of the NAcc in the mesocorticolimbic reward circuit. Deep brain stimulation in the NAcc may also be an effective treatment for reducing alcohol consumption in patients who abuse alcohol and have not responded to other forms of therapy.
Deep brain stimulation (DBS), an established treatment for some movement disorders, is now being used experimentally to treat psychiatric disorders as well. In a number of recently published case series, DBS yielded an impressive therapeutic benefit in patients with medically intractable psychiatric diseases.
This review of the use of DBS to treat psychiatric disorders is based on literature retrieved from a selective Pubmed search for relevant keywords, reference works on the topic, and the authors' own research.
Studies have been performed on the use of DBS to treat medically intractable obsessive-compulsive disorder, depressive disorders, and Tourette syndrome. The case numbers in the cited publications were small, yet at least some of them involved a methodologically sound investigation. Thus, in some studies, the strength of the effect was controlled with a double-blinded interval in which the stimulation was turned off. In general, the primary symptoms were found to improve markedly, by 35% to 70%, although not all patients responded to the treatment. Adverse effects of DBS were very rare in most studies and could usually be reversed by changing the stimulation parameters.
The results of DBS for psychiatric disorders that have been published to date are encouraging. They open up a new perspective in the treatment of otherwise intractable disorders. Nonetheless, the efficacy, mechanism of action, and adverse effects of DBS for this indication still need to be further studied in methodologically adequate trials that meet the highest ethical standard.
Deep brain stimulation (DBS) is a reversible technique that is currently used for the treatment of Parkinson disease and may be suitable for the treatment of psychiatric disorders. Whether DBS inactivates the target structure is still a matter of debate. Here, from findings obtained in rats, we propose DBS of the subthalamic nucleus (STN) as a possible treatment for cocaine addiction to be further tested in human studies. We show that STN DBS reversibly reduces the motivation to work for an i.v. injection of cocaine, and it increases motivation to work for sucrose pellets. These opposite effects may result from STN DBS effect on the positive affective properties of these rewards. Indeed, we further show that STN DBS reduces the preference for a place previously associated with the rewarding properties of cocaine, and it increases the preference for a place associated with food. Because these findings are consistent with those observed after STN lesions [Baunez C, Dias C, Cador M, Amalric M (2005) Nat Neurosci 8:484-489], they suggest that STN DBS mimics an inactivation of the STN on motivational processes. Furthermore, given that one of the major challenges for cocaine addiction is to find a treatment that reduces the craving for the drug without diminishing the motivation for naturally rewarding activities, our findings validate STN as a good target and DBS as the appropriate technique for a promising therapeutic strategy in the treatment of cocaine addiction.
Treatment of alcohol dependence remains one of the biggest challenges in psychiatry, since only about half of all patients achieve long-term abstinence by the currently available therapies. Dysfunction of the nucleus accumbens, one of the main areas of the brain's reward system, seems to play a central role in addiction and treatment resistance. Following the recent advances of neuromodulation therapy by deep brain stimulation, we designed an off-label single patient study protocol to treat patients with severe and long-standing alcoholism in whom other treatment options had failed. We report here on the first three patients with alcoholism who received deep brain stimulation. In the one-year follow-up period, two remained abstinent, while one showed a remarkable reduction of days while drinking and none had any significant adverse effects.
Deep brain stimulation of the nucleus accumbens (NAC) region is an effective therapeutic avenue for several psychiatric disorders that are not responsive to traditional treatment strategies. Nonetheless, the mechanisms by which DBS achieves therapeutic effects remain unclear. We showed previously that high-frequency (HF) NAC DBS suppressed pyramidal cell firing and enhanced slow local field potential (LFP) oscillations in the orbitofrontal cortex (OFC) via antidromic activation of corticostriatal recurrent inhibition. Using simultaneous multisite LFP recordings in urethane-anesthetized rats, we now show that NAC DBS delivered for 90 min at high or low frequency (LF) selectively affects spontaneous and evoked LFP oscillatory power and coherence within and between the medial prefrontal cortex (mPFC), lateral OFC, mediodorsal thalamus (MD), and NAC. Compared with LF or sham DBS, HF DBS enhanced spontaneous slow oscillations and potentiated evoked LFP responses only in OFC. HF DBS also produced widespread increases in spontaneous beta and gamma power and enhanced coherent beta activity between MD and all other regions. In contrast, LF DBS elevated theta power in MD and NAC. Analysis of acute NAC-induced oscillations showed that HF DBS increased and LF DBS decreased induced relative gamma coherence compared with sham DBS. These data suggest that HF (therapeutic) and LF (possibly deleterious) NAC DBS produce distinct region-specific and frequency band-specific changes in LFP oscillations. NAC DBS may achieve therapeutic effects by enhancing rhythmicity and synchronous inhibition within and between afferent structures, thereby normalizing function of a neural circuit that shows aberrant activity in obsessive-compulsive disorder and depression.
The Nucleus accumbens (Nacc) has been proposed to act as a limbic-motor interface. Here, using invasive intraoperative recordings in an awake patient suffering from obsessive-compulsive disease (OCD), we demonstrate that its activity is modulated by the quality of performance of the subject in a choice reaction time task designed to tap action monitoring processes. Action monitoring, that is, error detection and correction, is thought to be supported by a system involving the dopaminergic midbrain, the basal ganglia, and the medial prefrontal cortex. In surface electrophysiological recordings, action monitoring is indexed by an error-related negativity (ERN) appearing time-locked to the erroneous responses and emanating from the medial frontal cortex. In preoperative scalp recordings the patient's ERN was found to be significantly increased compared to a large (n = 83) normal sample, suggesting enhanced action monitoring processes. Intraoperatively, error-related modulations were obtained from the Nacc but not from a site 5 mm above. Importantly, cross-correlation analysis showed that error-related activity in the Nacc preceded surface activity by 40 ms. We propose that the Nacc is involved in action monitoring, possibly by using error signals from the dopaminergic midbrain to adjust the relative impact of limbic and prefrontal inputs on frontal control systems in order to optimize goal-directed behavior.
Increasing evidence suggests that deep brain stimulation (DBS), which is currently being used as a therapy for neurological diseases, may be effective in the treatment of psychiatric disorders as well. Here, we examined the influence of DBS of the nucleus accumbens shell on cocaine priming-induced reinstatement of drug seeking, an animal model of relapse. Rats were allowed to self-administer cocaine (0.25 mg, i.v.) 2 h daily for 21 d and then cocaine-seeking behavior was extinguished by replacing cocaine with saline. During the reinstatement phase, DBS was administered bilaterally to the nucleus accumbens shell through bipolar stainless steel electrodes. Biphasic symmetrical pulses were delivered at a frequency of 160 Hz and a current intensity of 150 muA. DBS began immediately after a priming injection of cocaine (0, 5, 10, or 20 mg/kg, i.p.) and continued throughout each 2 h reinstatement session. Results indicated that only the higher doses of cocaine (10 and 20 mg/kg) produced robust and reliable reinstatement of cocaine seeking. DBS of the nucleus accumbens shell significantly attenuated the reinstatement of drug seeking precipitated by these higher cocaine doses. Additional experiments indicated that this DBS effect was both anatomically and reinforcer specific. Thus, DBS of the dorsal striatum had no influence on cocaine reinstatement and DBS of the accumbens shell did not affect the reinstatement of food seeking. Together, these results suggest that DBS of the nucleus accumbens shell may be a potential therapeutic option in the treatment of severe cocaine addiction.
Deep-brain stimulation through an electrode implanted in the thalamus was developed as an alternative to thalamotomy for the treatment of drug-resistant tremor. Stimulation is thought to be as effective as thalamotomy but to have fewer complications. We examined the effects of these two procedures on the functional abilities of patients with drug-resistant tremor due to Parkinson's disease, essential tremor, or multiple sclerosis.
Sixty-eight patients (45 with Parkinson's disease, 13 with essential tremor, and 10 with multiple sclerosis) were randomly assigned to undergo thalamotomy or thalamic stimulation. The primary outcome measure was the change in functional abilities six months after surgery, as measured by the Frenchay Activities Index. Scores for this index can range from 0 to 60, with higher scores indicating better function. Secondary outcome measures were the severity of tremor, the number of adverse effects, and patients' assessment of the outcome.
Functional status improved more in the thalamic-stimulation group than in the thalamotomy group, as indicated by increases in the score for the Frenchay Activities Index (from 31.4 to 36.3 and from 32.0 to 32.5, respectively; difference between groups, 4.4 points; 95 percent confidence interval, 2.0 to 6.9). After adjustment for base-line characteristics, multivariate analysis also showed that the thalamic-stimulation group had greater improvement (difference between groups, 5.1 points; 95 percent confidence interval, 2.3 to 7.9). Tremor was suppressed completely or almost completely in 27 of 34 patients in the thalamotomy group and in 30 of 33 patients in the thalamic-stimulation group. One patient in the thalamic-stimulation group died perioperatively after an intracerebral hemorrhage. With the exception of this incident, thalamic stimulation was associated with significantly fewer adverse effects than thalamotomy. Functional status was reported as improved by 8 patients in the thalamotomy group, as compared with 18 patients in the thalamic-stimulation group (P=0.01).
Thalamic stimulation and thalamotomy are equally effective for the suppression of drug-resistant tremor, but thalamic stimulation has fewer adverse effects and results in a greater improvement in function.
The modern therapeutic approach to most psychiatric diseases involves a combination of well-supervised psychotherapy, pharmacotherapy, and electroconvulsive therapy. Patients who fail to adequately respond to these modern treatment methods and remain severely disabled may be considered for surgical intervention. Cingulotomy, capsulotomy, subcaudate tractotomy, and limbic leucotomy are the most common psychosurgical procedures performed today, with response rates in the 35% to 65% range. Modern stereotactic techniques have reduced complication rates, but controversy remains regarding the optimal surgical procedure. The major psychiatric diagnostic categories that might respond to surgery include treatment-refractory major affective disorders, obsessive-compulsive disorder, and chronic anxiety states. Surgery should be considered as one part of an entire treatment plan and must be followed by an appropriate psychiatric rehabilitation program. It should only be carried out by an expert multidisciplinary team consisting of a neurologist a neurosurgeon, and a psychiatrist with experience in these disorders. Surgical intervention remains a reasonable therapeutic option for select patients with a disabling psychiatric disease and may be underutilized.
Objective.
—To identify and quantify the major external (nongenetic) factors that contribute to death in the United States.Data Sources.
—Articles published between 1977 and 1993 were identified through MEDLINE searches, reference citations, and expert consultation. Government reports and compilations of vital statistics and surveillance data were also obtained.Study Selection.
—Sources selected were those that were often cited and those that indicated a quantitative assessment of the relative contributions of various factors to mortality and morbidity.Data Extraction.
—Data used were those for which specific methodological assumptions were stated. A table quantifying the contributions of leading factors was constructed using actual counts, generally accepted estimates, and calculated estimates that were developed by summing various individual estimates and correcting to avoid double counting. For the factors of greatest complexity and uncertainty (diet and activity patterns and toxic agents), a conservative approach was taken by choosing the lower boundaries of the various estimates.Data Synthesis.
—The most prominent contributors to mortality in the United States in 1990 were tobacco (an estimated 400000 deaths), diet and activity patterns (300 000), alcohol (100 000), microbial agents (90 000), toxic agents (60 000), firearms (35 000), sexual behavior (30 000), motor vehicles (25 000), and illicit use of drugs (20 000). Socioeconomic status and access to medical care are also important contributors, but difficult to quantify independent of the other factors cited. Because the studies reviewed used different approaches to derive estimates, the stated numbers should be viewed as first approximations.Conclusions.
—Approximately half of all deaths that occurred in 1990 could be attributed to the factors identified. Although no attempt was made to further quantify the impact of these factors on morbidity and quality of life, the public health burden they impose is considerable and offers guidance for shaping health policy priorities.(JAMA. 1993;270:2207-2212)
The modern therapeutic approach to most psychiatric diseases involves a combination of well-supervised psychotherapy, pharmacotherapy, and electroconvulsive therapy. Patients who fail to adequately respond to these modern treatment methods and remain severely disabled may be considered for surgical intervention. Cingulotomy, capsulotomy, subcaudate tractotomy, and limbic leucotomy are the most common psychosurgical procedures performed today, with response rates in the 35% to 65% range. Modern stereotactic techniques have reduced complication rates, but controversy remains regarding the optimal surgical procedure. The major psychiatric diagnostic categories that might respond to surgery include treatment-refractory major affective disorders, obsessive-compulsive disorder, and chronic anxiety states. Surgery should be considered as one part of an entire treatment plan and must be followed by an appropriate psychiatric rehabilitation program. It should only be carried out by an expert multidisciplinary team consisting of a neurologist a neurosurgeon, and a psychiatrist with experience in these disorders. Surgical intervention remains a reasonable therapeutic option for select patients with a disabling psychiatric disease and may be underutilized.
The nucleus accumbens (nAc) is the primary target for the mesolimbic dopamine system and a key brain region for the reinforcing effects displayed by drugs of abuse, including ethanol. During the transition from recreational to compulsive consumption of reinforcing drugs, however, the dorsal striatum seems to be recruited. Understanding how synaptic activity is altered in a sub-region specific manner in the striatum during the course of long-term drug consumption thus could be essential for understanding the long-lasting changes produced by addictive substances, including ethanol. Here we evaluated synaptic activity in the dorsolateral striatum (DLS) and ventral striatum (nucleus accumbens, nAc) of single-housed Wistar rats consuming water, or water and ethanol, for up to 10 months. Even though ethanol intake was moderate, it was sufficient to decrease input/output function in response to stimulation intensity in the DLS, while recorded population spike (PS) amplitudes in the nAc were unaffected. Striatal disinhibition induced by the GABAA receptor antagonist bicuculline had a slower onset in rats that had consumed ethanol for 2 months, and was significantly depressed in slices from rats that had consumed ethanol for 4 months. Bicuculline-induced disinhibition in the nAc, on the other hand, was not significantly altered by long-term ethanol intake. Changes in PS amplitude induced by taurine or the glycine receptor antagonist strychnine were not significantly altered by ethanol in any brain region. Even though input/output function was not significantly affected by age, there was a significant decline in antagonist-induced disinhibition in brain slices from aged rats. The data presented here suggest that even modest consumption of ethanol is sufficient to alter neurotransmission in the striatum, while synaptic activity appears to be relatively well-preserved in the nAc during the course of long-term ethanol consumption.
Deep brain stimulation (DBS) of the nucleus accumbens (NAcc) has been recently reported to modulate substance-induced dysfunction and to promote an alteration of addictive behavior.1, 2, 3, 4 Here, we describe DBS-induced sustained heroin abstinence in two therapy-resistant opioid addicted patients treated during the piloting phase to our clinical trial NCT01245075. Inclusion was based on (1) longtime heroin addiction according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) (2) at least one detoxification (here: up to 20 detoxifications) without a prolonged phase of abstinence and (3) longtime opiate replacement therapy with a constant dose of levomethadone (Ethics approval has been obtained for both pilot testing and clinical trial.
Background:
Surgical ablation of select brain areas has been frequently used to alleviate psychological dependence on opiate drugs in certain countries. However, ablative brain surgery was stopped in China in 2004 due to the related ethical controversy and possible side effects. Deep brain stimulation (DBS), a less invasive, reversible and adjustable process of neuromodulation, was adopted to attenuate relapses in studies of drug addiction.
Methods:
Preclinical experiments were designed to assess the long-term effects of DBS of the nucleus accumbens (NAc) on cue- and heroin-induced reinstatement of drug seeking behaviors. After a rat self-administration model of heroin relapse was established, DBS was administered bilaterally or unilaterally to the NAc core through concentric bipolar electrodes. A 1-h long continuous stimulation (130 Hz, 100 μs, 0-150 μA) was given daily for 7 days during the abstinence session. Drug seeking behaviors were elicited by conditioned cues or a small dose of heroin.
Results:
75 μA and 150 μA bilateral NAc DBS attenuated cue- and heroin-induced reinstatement of drug seeking, and unilateral DBS of the right NAc achieved effects almost equivalent to bilateral DBS. Additional experiments showed that DBS had no long-term influence on locomotor activity and spatial learning and retention capabilities in Morris water maze tasks. Subsequent immunohistochemistry measurements revealed that the behavioral consequences were associated with a significant increase in the expression of pCREB and a reduction in the expression of ΔFosB in the NAc.
Conclusions:
These findings indicate that the NAc DBS could be an effective and safe therapeutic option for preventing relapse to heroin addiction.
Deep brain stimulation (DBS) of the nucleus accumbens (NAc) is effective in treatment-refractory obsessive-compulsive disorder and major depressive disorder. However, little is known about the neurobiological mechanisms underlying the rapid and effective changes of DBS. One of the hypotheses is that DBS modulates activity of monoamine neurotransmitters. In this study we evaluated the effects of DBS in the NAc core on the extracellular concentration of monoaminergic neurotransmitters in the medial (mPFC) and orbital prefrontal cortex (OFC). Freely moving rats were bilaterally stimulated in the NAc core for 2 hours while dopamine, serotonin, their metabolites and noradrenaline using in vivo microdialysis was measured in the mPFC and the OFC. We report rapid increases in the release of dopamine and serotonin to a maximum of 177% and 127% in the mPFC and an increase up to 171% and 166% for dopamine and noradrenaline in the OFC after onset of stimulation in the NAc core. These results provide further evidence for the distal effects of DBS and corroborate previous clinical and preclinical findings of altered neuronal activity in prefrontal areas. © 2012 International Society for Neurochemistry, J. Neurochem. (2012) 10.1111/jnc.12054.
Brain-derived neurotrophic factor (BDNF) is a key positive regulator of neural plasticity, promoting, for example, the actions
of stimulant drugs of abuse such as cocaine. We discovered a surprising opposite role for BDNF in countering responses to
chronic morphine exposure. The suppression of BDNF in the ventral tegmental area (VTA) enhanced the ability of morphine to
increase dopamine (DA) neuron excitability and promote reward. In contrast, optical stimulation of VTA DA terminals in nucleus
accumbens (NAc) completely reversed the suppressive effect of BDNF on morphine reward. Furthermore, we identified numerous
genes in the NAc, a major target region of VTA DA neurons, whose regulation by BDNF in the context of chronic morphine exposure
mediated this counteractive function. These findings provide insight into the molecular basis of morphine-induced neuroadaptations
in the brain’s reward circuitry.
This paper summarises data for the prevalence, correlates, and probable adverse health consequences of problem use of amphetamines, cannabis, cocaine, and opioids. We discuss findings from systematic reviews of the prevalence of illicit drug use and dependence, remission from dependence, and mortality in illicit drug users, and evidence for acute and chronic effects of illicit drug use. We outline the regional and global distribution of use and estimated health burden from illicit drugs. These distributions are likely to be underestimates because they have not included all adverse outcomes of drug use and exclude those of cannabis--the mostly widely used illicit drug. In high-income countries, illicit drug use contributes less to the burden of disease than does tobacco but a substantial proportion of that due to alcohol. The major adverse health effects of cannabis use are dependence and probably psychotic disorders and other mental disorders. The health-related harms of cannabis use differ from those of amphetamine, cocaine, and opioid use, in that cannabis contributes little to mortality. Intelligent policy responses to drug problems need better data for the prevalence of different types of illicit drug use and the harms that their use causes globally. This need is especially urgent in high-income countries with substantial rates of illicit drug use and in low-income and middle-income countries close to illicit drug production areas.
Drug-evoked synaptic plasticity is observed at many synapses and may underlie behavioural adaptations in addiction. Mechanistic investigations start with the identification of the molecular drug targets. Cocaine, for example, exerts its reinforcing and early neuroadaptive effects by inhibiting the dopamine transporter, thus causing a strong increase in mesolimbic dopamine. Among the many signalling pathways subsequently engaged, phosphorylation of the extracellular signal-regulated kinase (ERK) in the nucleus accumbens is of particular interest because it has been implicated in NMDA-receptor and type 1 dopamine (D1)-receptor-dependent synaptic potentiation as well as in several behavioural adaptations. A causal link between drug-evoked plasticity at identified synapses and behavioural adaptations, however, is missing, and the benefits of restoring baseline transmission have yet to be demonstrated. Here we find that cocaine potentiates excitatory transmission in D1-receptor-expressing medium-sized spiny neurons (D1R-MSNs) in mice via ERK signalling with a time course that parallels locomotor sensitization. Depotentiation of cortical nucleus accumbens inputs by optogenetic stimulation in vivo efficiently restored normal transmission and abolished cocaine-induced locomotor sensitization. These findings establish synaptic potentiation selectively in D1R-MSNs as a mechanism underlying a core component of addiction, probably by creating an imbalance between distinct populations of MSNs in the nucleus accumbens. Our data also provide proof of principle that reversal of cocaine-evoked synaptic plasticity can treat behavioural alterations caused by addictive drugs and may inspire novel therapeutic approaches involving deep brain stimulation or transcranial magnetic stimulation.
Following recent advances in neuromodulation therapy for mental disorders, we treated one patient with severe alcohol addiction with deep brain stimulation (DBS) of the nucleus accumbens (NAc). Before and one year following the surgery, we assessed the effects of DBS within the NAc on the addiction as well as on psychometric scores and electrophysiological measures of cognitive control. In our patient, DBS achieved normalization of addictive behavior and craving. An electrophysiological marker of error processing (the error-related negativity) linked to anterior mid-cingulate cortex (aMCC) functioning was altered through DBS, an effect that could be reversed by periods without stimulation. Thus, this case supports the hypothesis that DBS of the NAc could have a positive effect on addiction trough a normalization of craving associated with aMCC dysfunction.
The nucleus accumbens and medial frontal cortex (MFC) are part of a loop involved in modulating behavior according to anticipated rewards. However, the precise temporal landscape of their electrophysiological interactions in humans remains unknown because it is not possible to record neural activity from the nucleus accumbens using noninvasive techniques. We recorded electrophysiological activity simultaneously from the nucleus accumbens and cortex (via surface EEG) in humans who had electrodes implanted as part of deep-brain-stimulation treatment for obsessive-compulsive disorder. Patients performed a simple reward motivation task previously shown to activate the ventral striatum. Spectral Granger causality analyses were applied to dissociate "top-down" (cortex → nucleus accumbens)- from "bottom-up" (nucleus accumbens → cortex)-directed synchronization (functional connectivity). "Top-down"-directed synchrony from cortex to nucleus accumbens was maximal over medial frontal sites and was significantly stronger when rewards were anticipated. These findings provide direct electrophysiological evidence for a role of the MFC in modulating nucleus accumbens reward-related processing and may be relevant to understanding the mechanisms of deep-brain stimulation and its beneficial effects on psychiatric conditions.
Addictive drugs have in common that they are voluntarily self-administered by laboratory animals (usually avidly), and that they enhance the functioning of the reward circuitry of the brain (producing the 'high' that the drug user seeks). The core reward circuitry consists of an 'in-series' circuit linking the ventral tegmental area, nucleus accumbens and ventral pallidum via the medial forebrain bundle. Although originally believed to simply encode the set point of hedonic tone, these circuits are now believed to be functionally far more complex, also encoding attention, expectancy of reward, disconfirmation of reward expectancy, and incentive motivation. 'Hedonic dysregulation' within these circuits may lead to addiction. The 'second-stage' dopaminergic component in this reward circuitry is the crucial addictive-drug-sensitive component. All addictive drugs have in common that they enhance (directly or indirectly or even transsynaptically) dop-aminergic reward synaptic function in the nucleus accumbens. Drug self-administration is regulated by nucleus accumbens dopamine levels, and is done to keep nucleus accumbens dopamine within a specific elevated range (to maintain a desired hedonic level). For some classes of addictive drugs (e.g. opiates), tolerance to the euphoric effects develops with chronic use. Postuse dysphoria then comes to dominate reward circuit hedonic tone, and addicts no longer use drugs to get high, but simply to get back to normal ('get straight'). The brain circuits mediating the pleasurable effects of addictive drugs are anatomically, neurophysiologically and neurochemically different from those mediating physical dependence, and from those mediating craving and relapse. There are important genetic variations in vulnerability to drug addiction, yet environmental factors such as stress and social defeat also alter brain-reward mechanisms in such a manner as to impart vulnerability to addiction. In short, the 'bio-psycho-social' model of etiology holds very well for addiction. Addiction appears to correlate with a hypodopaminergic dysfunctional state within the reward circuitry of the brain. Neuroimaging studies in humans add credence to this hypothesis. Credible evidence also implicates serotonergic, opioid, endocannabinoid, GABAergic and glutamatergic mechanisms in addiction. Critically, drug addiction progresses from occasional recreational use to impulsive use to habitual compulsive use. This correlates with a progression from reward-driven to habit-driven drug-seeking behavior. This behavioral progression correlates with a neuroanatomical progression from ventral striatal (nucleus accumbens) to dorsal striatal control over drug-seeking behavior. The three classical sets of craving and relapse triggers are (a) reexposure to addictive drugs, (b) stress, and (c) reexposure to environmental cues (people, places, things) previously associated with drug-taking behavior. Drug-triggered relapse involves the nucleus accumbens and the neurotransmitter dopamine. Stress-triggered relapse involves (a) the central nucleus of the amygdala, the bed nucleus of the stria terminalis, and the neurotransmitter corticotrophin-releasing factor, and (b) the lateral tegmental noradrenergic nuclei of the brain stem and the neurotransmitter norepinephrine. Cue-triggered relapse involves the basolateral nucleus of the amygdala, the hippocampus and the neurotransmitter glutamate. Knowledge of the neuroanatomy, neurophysiology, neurochemistry and neuropharmacology of addictive drug action in the brain is currently producing a variety of strategies for pharmacotherapeutic treatment of drug addiction, some of which appear promising.
This study examined whether a 20-min session of prefrontal transcranial direct current stimulation (tDCS) (anode over the right prefrontal cortex and cathode over the left prefrontal cortex) would reduce food cravings and increase the self-reported ability to resist foods in 19 healthy individuals who reported frequent food cravings. Participants viewed computerized images of food and used computerized visual analogue scales to rate food cravings and inability to resist foods before, during, and after receiving either real or sham tDCS. This study employed a randomized within-subject crossover design; participants received both real and sham tDCS and were blind to the condition. Food cravings ratings were reduced in both conditions, however, the percent change in cravings ratings from pre- to post-stimulation was significantly greater for real stimulation than for sham. The percent change in inability to resist food from pre- to post-stimulation also showed a greater decrease in the real condition than for sham. Post hoc analyses suggest that active prefrontal tDCS acutely and significantly decreased food cravings ratings for sweet foods and carbohydrates more so than sham tDCS. No significant differences were seen in the amount of food ingested between real and sham tDCS. These findings in healthy subjects indicate that tDCS is able to temporarily reduce food cravings and improve the self-reported ability to resist foods.
Cognitive deficits that are reported in heavy marijuana users (attention, memory, affect perception, decision-making) appear to be completely reversible after a prolonged abstinence period of about 28 days. However, it remains unclear whether the reversibility of these cognitive deficits indicates that (1) chronic marijuana use is not associated with long-lasting changes in cortical networks or (2) that such changes occur but the brain adapts to and compensates for the drug-induced changes. Therefore, we examined whether chronic marijuana smokers would demonstrate a differential pattern of response in comparison to healthy volunteers on a decision-making paradigm (Risk Task) while undergoing sham or active transcranial direct current stimulation (tDCS) of the dorsolateral prefrontal cortex (DLPFC). Twenty-five chronic marijuana users who were abstinent for at least 24h were randomly assigned to receive left anodal/right cathodal tDCS of DLPFC (n=8), right anodal/left cathodal tDCS of DLPFC (n=9), or sham stimulation (n=8); results on Risk Task during sham/active tDCS were compared to healthy volunteers from a previously published dataset. Chronic marijuana users demonstrated more conservative (i.e. less risky) decision-making during sham stimulation. While right anodal stimulation of the DLPFC enhanced conservative decision-making in healthy volunteers, both right anodal and left anodal DLPFC stimulation increased the propensity for risk-taking in marijuana users. These findings reveal alterations in the decision-making neural networks among chronic marijuana users. Finally, we also assessed the effects of tDCS on marijuana craving and observed that right anodal/left cathodal tDCS of DLPFC is significantly associated with a diminished craving for marijuana.
The lateral habenula (LHb) is critical for modulation of negative reinforcement, punishment and aversive responses. In light of the success of deep-brain-stimulation (DBS) in the treatment of neurological disorders, we explored the use of LHb DBS as a method of intervention in cocaine self-administration, extinction, and reinstatement in rats. An electrode was implanted into the LHb and rats were trained to self-administer cocaine (21 days; 0.25-1 mg/kg) until they achieved at least three days of stable performance (as measured by daily recordings of active lever presses in self-administration cages). Thereafter, rats received DBS in the presence or absence of cocaine. DBS reduced cocaine seeking behavior during both self-administration and extinction training. DBS also attenuated the rats' lever presses following cocaine reinstatement (5-20 mg/kg) in comparison to sham-operated rats. These results were also controlled by the assessment of physical performance as measured by water self-administration and an open field test, and by evaluation of depressive-like manifestations as measured by the swim and two-bottles-choice tests. In contrast, LHb lesioned rats demonstrated increased cocaine seeking behavior as demonstrated by a delayed extinction response. In the ventral tegmental area, cocaine self-administration elevated glutamatergic receptor subunits NR1 and GluR1 and scaffolding protein PSD95, but not GABA(A)β, protein levels. Following DBS treatment, levels of these subunits returned to control values. We postulate that the effect of both LHb modulation and LHb DBS on cocaine reinforcement may be via attenuation of the cocaine-induced increase in glutaminergic input to the VTA.
The use of deep brain stimulation (DBS) has recently been expanded to the investigational treatment of specific psychiatric disorders. Much like movement disorders, the targets selected for DBS are based on past experience with stereotactic lesions. A literature review of past studies incorporating stereotactic lesions for psychiatric disorders was performed to provide historical context and possible guidance for current and future attempts at treating psychiatric disorders with DBS.
Original copies of the proceedings of the second, third, fourth, and fifth World Congresses of Psychiatric Surgery meetings were reviewed, and a Medline search was conducted for studies with the word "psychosurgery" and each of 14 highly prevalent psychiatric conditions identified by the National Institute of Mental Health. Postoperative results for 1145 patients with stereotactic brain lesions targeting various anatomical foci were standardized using a 5-point scale (3 [free of symptoms] to -1 [worse]). Each patient was entered into a database as a unique data point and used for this literature review.
General anxiety disorder and obsessive-compulsive disorder had the greatest reported improvements from anterior capsulotomy, and bipolar disorder, depression, and schizoaffective disorder had the greatest reported improvements from anterior cingulotomy, supporting these areas for DBS investigation. Addiction and schizophrenia showed the least improvement from surgery. Therefore, pursuing the treatment of these disorders with DBS using the targets in these studies may be ineffective.
This study provides retrospective data that suggest which anatomical focus may be effective to lesion or stimulate for the treatment of each of several psychiatric disorders.
Nicotine is the principal component of tobacco smoke, resulting in addiction, and recent evidence suggests that damage to the insular cortex (insula) disrupts tobacco addiction in human smokers. However, the effect of an inactivation of this structure in an animal model of nicotine addiction has yet to be evaluated.
To study this question, we investigated the effects of reversible inactivation of the granular insula by local injection of a gamma-aminobutyric acid agonists mixture (baclofen/muscimol) on nicotine self-administration (SA) under fixed and progressive ratio and on reinstatement of nicotine seeking induced by nicotine priming or nicotine-associated cues in rats. We also evaluated the effects of granular insula inactivation on food SA and relapse as a control.
The inactivation of the granular insula decreased nicotine SA under both fixed and progressive ratios without affecting the SA of food under the same schedules of reinforcement. This inactivation also prevented the reinstatement, after extinction, of nicotine seeking induced by nicotine-associated cues or nicotine priming without modifying the reinstatement of food seeking.
Our study indicates that the integrity of the granular insula is necessary for exhibiting motivation to take nicotine and to relapse to nicotine seeking but not for consuming food pellets or to relapse for food seeking. Indeed, it might be interesting to study the effect of methods that are able to modulate the activity of the insula--such as repetitive transcranial magnetic stimulation or deep brain stimulation--on tobacco addiction and relapse in humans.
We studied the effect of stereotactic surgery in cases of alcohol dependence. Twelve patients with a psychological dependence on alcohol (treated systematically with medication for detoxification 3-8 times in various rehabilitation centers before, but had relapsed within 2 weeks after withdrawal) were treated by ablating the nucleus accumbens (NA(C)) bilaterally using stereotactic surgery. The therapeutic effect and safety evaluation index of the surgery were analyzed. The timing of the conducted evaluations was preoperatively and in the sixth postoperative month. Currently, relapse has not occurred in 9 cases. Relapse occurred in 3 cases after surgery. The prevalence of relapse was 16.7% within 6 months, and 25% within 12 months. Non-specific complications of this type of surgery (e.g., intracranial hematoma, infection) were not observed. One case in 12 patients suffered dysosmia, but he recovered completely 4 months later after surgery. The full-scale intelligence quotient (FSIQ) and memory quotient (MQ) of these patients were significantly improved 6 months postoperatively compared with preoperatively. The severity of alcohol dependence scale and a scale measuring alcohol craving in these patients were significantly decreased. There were also significant changes over time in the Minnesota multiphasic personality inventory (MMPI) profile, suggesting a decrease in depression, irritability, and psychopathy. Ablating specified targets (NA(C)) using stereotactic surgery is a safe method to alleviate alcohol craving, reduce relapse rates and improve quality-of-life in patients with psychological dependence on alcohol.
To study the anticraving efficacy of high-frequency repetitive transcranial magnetic stimulation (rTMS) of the right dorsolateral pre-frontal cortex (DLPFC) in patients with alcohol dependence.
We performed a prospective, single-blind, sham-controlled study involving 45 patients with alcohol dependence syndrome (according to ICD-10 DCR), with Clinical Institute of Withdrawal Assessment in Alcohol Withdrawal (CIWA-Ar) scores <or=10. Patients were allocated to active and sham rTMS in a 2 : 1 ratio, such that 30 patients received active and 15 patients sham rTMS to the right DLPFC (10 Hz frequency, 4.9 seconds per train, inter-train interval of 30 seconds, 20 trains per session, total 10 sessions). The Alcohol Craving Questionnaire (ACQ-NOW) was administered to measure the severity of alcohol craving at baseline, after the last rTMS session and after 1 month of the last rTMS session.
Two-way repeated-measures analysis of variance (ANOVA) showed significant reduction in the post-rTMS ACQ-NOW total score and factor scores in the group allocated active rTMS compared to the sham stimulation. The effect size for treatment with time interaction was moderate (eta(2) = 0.401).
Right dorsolateral pre-frontal high-frequency rTMS was found to have significant anticraving effects in alcohol dependence. The results highlight the potential of rTMS which, combined with other anticraving drugs, can act as an effective strategy in reducing craving and subsequent relapse in alcohol dependence.
Smoking and overeating are compulsory habits that are difficult to stop. Several studies have shown involvement of the nucleus accumbens in these and other addictive behaviors. In this case report, we describe a patient who quit smoking and lost weight without any effort, and we review the underlying mechanisms of action.
A 47-year-old woman presented with chronic treatment-refractory obsessive-compulsive disorder, nicotine dependence, and obesity.
The patient was treated with deep brain stimulation of the nucleus accumbens for obsessive-compulsive disorder. Unintended, effortless, and simultaneous smoking cessation and weight loss were observed.
This study supports the idea of compulsivity with common circuitry in the processing of diverse rewards and suggests that deep brain stimulation of the nucleus accumbens could be a possible treatment of patients with a dependency not responding to currently available treatments.
We explore whether clinical research on deep brain stimulation (DBS) of the nucleus accumbens (NAc) to treat addiction is justified besides theoretical speculation.
Since 2004, 10 patients who were also smokers were treated at the University of Cologne for Tourette's syndrome (TS), obsessive-compulsive disorders (OCD) or anxiety disorders (AD) by DBS of the NAc. We assessed their smoking behavior after DBS and (in retrospection) before by the Fagerstrom Test for Nicotine Dependence (FTND) and additional items.
Three male patients were able to quit smoking after DBS. They were less dependent and higher motivated compared to the rest of the sample. They are stimulated with a higher voltage. During 1-year, 2-year, and 30-month follow-ups, we found a higher rate of successful smoking cessation (20, 30 and 30%) compared to unaided smoking cessation in the general population (13, 19 and 8.7%).
Albeit the results of the study are severely limited by the method of retrospective self-assessment of psychiatric patients, further research of DBS of the NAc to treat addiction seems justified. In addition to biological mediators, psychosocial factors should be assessed in further prospective studies.
Smoking cue-provoked craving is an intricate behavior associated with strong changes in neural networks. Craving is one of the main reasons subjects continue to smoke; therefore interventions that can modify activity in neural networks associated with craving can be useful tools in future research investigating novel treatments for smoking cessation. The goal of this study was to use a neuromodulatory technique associated with a powerful effect on spontaneous neuronal firing - transcranial direct current stimulation (tDCS) - to modify cue-provoked smoking craving. Based on preliminary data showing that craving can be modified after a single tDCS session, here we investigated the effects of repeated tDCS sessions on craving behavior. Twenty-seven subjects were randomized to receive sham or active tDCS (anodal tDCS of the left DLPFC). Our results show a significant cumulative effect of tDCS on modifying smoking cue-provoked craving. In fact, in the group of active stimulation, smoking cues had an opposite effect on craving after stimulation - it decreased craving - as compared to sham stimulation in which there was a small decrease or increase on craving. In addition, during these 5 days of stimulation there was a small but significant decrease in the number of cigarettes smoked in the active as compared to sham tDCS group. Our findings extend the results of our previous study as they confirm the notion that tDCS has a specific effect on craving behavior and that the effects of several sessions can increase the magnitude of its effect. These results open avenues for the exploration of this method as a therapeutic alternative for smoking cessation and also as a mean to change stimulus-induced behavior.
Alcohol consumption has been identified as an important risk factor for chronic disease and injury. In the first paper in this Series, we quantify the burden of mortality and disease attributable to alcohol, both globally and for ten large countries. We assess alcohol exposure and prevalence of alcohol-use disorders on the basis of reviews of published work. After identification of other major disease categories causally linked to alcohol, we estimate attributable fractions by sex, age, and WHO region. Additionally, we compare social costs of alcohol in selected countries. The net effect of alcohol consumption on health is detrimental, with an estimated 3.8% of all global deaths and 4.6% of global disability-adjusted life-years attributable to alcohol. Disease burden is closely related to average volume of alcohol consumption, and, for every unit of exposure, is strongest in poor people and in those who are marginalised from society. The costs associated with alcohol amount to more than 1% of the gross national product in high-income and middle-income countries, with the costs of social harm constituting a major proportion in addition to health costs. Overall, we conclude that alcohol consumption is one of the major avoidable risk factors, and actions to reduce burden and costs associated with alcohol should be urgently increased.
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 microA. ETOH consumption was significantly reduced from baseline levels at the 150 microA 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.
2 or 3 years follow-up of 13 hypothalamotomy patients with alcohol and drug addiction reveals that the addicted patients regained their self-control, the severe preoperative social deterioration was removed, and the tendency to social stabilisation was clearly in evidence.
The treatment of 198 psychiatrically disabled patients with stereotactic cingulotomy was evaluated prospectively for a mean follow-up of 8.6 years. Patients with major affective disorders and anxiety disorders fared the best, with a return to normal functioning in the majority. Patients with obsessive-compulsive disorders, schizophrenia, and personality disorders improved less predictably, with an uneven improvement in functioning that required active ongoing psychiatric treatment. Low mortality and morbidity, a reduction of violent behavior, a possible reduction of suicidal risk, and a lessening of the intractable suffering of chronic psychiatric illness all indicate that cingulotomy can be an effective, safe treatment for patients with affective disorders that are unresponsive to all other forms of therapy.
Chronic electrical stimulation instead of bilateral capsulotomy was done in four selected patients with long-standing treatment-resistant obsessive-compulsive disorder. In three of them beneficial effects were observed.
Drug addiction can take control of the brain and behavior, activating behavioral patterns that are directed excessively and compulsively toward drug usage. Such patterns often involve the development of repetitive and nearly automatic behaviors that we call habits. The striatum, a subcortical brain region important for proper motor function as well as for the formation of behavioral habits, is a major target for drugs of abuse. Here, we review recent studies of long-term synaptic plasticity in the striatum, emphasizing that drugs of abuse can exert pronounced influences on these processes, both in the striatum and in the dopaminergic midbrain. Synaptic plasticity in the ventral striatum appears to play a prominent role in early stages of drug use, whereas dopamine- and endocannabinoid-dependent synaptic plasticity in the dorsal striatum could contribute to the formation of persistent drug-related habits when casual drug use progresses towards compulsive drug use and addiction.
Cingulotomy can be helpful in certain patients with severe, disabling, and treatment-refractory major affective disorders, OCD, and chronic anxiety states. This form of psychosurgical treatment should only be carried out by an expert multidisciplinary team with experience in these disorders. Cingulotomy should be considered as one part of an entire treatment plan and must be followed by an appropriate psychiatric rehabilitation program. Many patients are greatly improved after cingulotomy, and the complications or side effects are few. Cingulotomy remains an important therapeutic option for disabling psychiatric disease and is probably underutilized.
To compare data from the general population on intentionally reduced smoking and smoking cessation.
Longitudinal observation study.
Northern German region.
Randomly sampled residents aged 18-64 (T1; n = 4075, response rate 70%). Daily cigarette smokers (n = 1520) were followed up after 30 (T2; n = 913) and 36 months (T3; n = 786).
Self-reported smoking-related and socioeconomic variables. Participants were explicitly asked for reduction attempts (reducing cigarettes per day) and maintenance of reduction, which was defined independently of consumption measures.
Between T1 and T2, reduction attempts (39%) were more frequent than quit attempts (33%), and according to self-report, reduction was more likely to be maintained for up to 12 months. Smokers maintaining reduction for up to 6 months had reduced their consumption at T3 by 34% compared with T2. Between T1 and T2, the occurrence of both a reduction and a quit attempt was most frequent (22%), followed by subjects exclusively trying to reduce (17%) and subjects exclusively trying to quit (4%). Subjects who exclusively tried to reduce had a significantly increased probability of further reduction attempts at T3 (OR = 4.4, 95% CI 2.0-10.1), while the probability of quit attempts was equal compared with subjects not attempting to reduce or quit (OR = 1.1, 95% CI 0.3-3.2). DSM-IV nicotine dependence was less common in subjects who exclusively tried to reduce. Other smoking-related and socioeconomic variables did not predict whether individuals attempted to reduce or attempted to quit.
A considerable proportion of general population smokers attempt to reduce, and are able to maintain reduction of, cigarette consumption over time. Reduction attempts did not reduce the probability of a subsequent cessation attempt.
It is now generally believed that psychological dependence in drug addicts is determined not only socially, but also physiologically. At the Institute of the Human Brain (Russian Academy of Sciences), bilateral stereotactic cryocingulotomy has been used for treatment of drug addiction since 1998. To date, the surgery has been performed on 348 patients, which has made it possible to study long-term consequences of the surgery, perform the necessary psychological studies, and summarize the results. Interviewing of 187 patients with catamneses of more than two years has shown that 45% of them have entirely abstained from addictive drugs after the surgery and 17% have entirely abstained from drugs for more than two years after one or two instances of drug-taking within the first two months after the surgery; there are no data on 13% of the patients. The remaining patients exhibit either a partial improvement (they have found at least temporary work and have decreased the drug dosage and the frequency of intake) or show no change (13 and 12% of the cases, respectively). The results of catamnestic study have demonstrated that the surgery is effective against heroinism and rarely causes complications. Apparently, the physiological mechanism of the therapeutic effect is the suppression of the mechanism of error detection. The duration of the resultant destabilization may vary depending on the individual characteristics of the patient and environmental factors. Therefore, this period should be included in the duration of treatment and patients must follow the rehabilitation regimen.
The aim of this study was to explore a new way of treating drug addiction by ablating the nucleus accumbens (NAC), which has a close relationship with drug-induced psychological dependence, using stereotactic surgery, blocking the mesocorticolimbic dopamine circuit, alleviating craving for drugs and lowering the relapse rate after detoxification. On the basis of animal experiments, stereotactic surgery was performed in 28 patients by making a lesion in the NAC bilaterally to treat opiate drug dependence. Indications, the criterion of therapeutic effect, treatment process and the therapeutic and safety evaluation index of the surgery were formulated particularly. The mean follow-up period was 15 months. Relapse has not occurred in 11 cases up till now. Drug-free time in these patients has been more than half a year in 4 cases (more than a year in 3 cases), and less than half a year in 7 cases. Relapse occurred in 15 cases after surgery. Drug-free time in these patients was more than half a year in 3 cases, between 1 month and half a year in 10 cases and less than 1 month in 2 cases. The therapeutic effect was excellent in 7 cases (26.9%), good in 10 cases (38.5%) and poor in 2 cases (7.7%). Another 7 cases were still under investigation at the time of writing. Relapse rates after surgery were 7.7, 38.5 and 57.5% within 1 month, between 1 month and half a year and after more than half a year, respectively. There were no common complications of surgery such as intracranial hematoma or infection in these patients after operation. Character type was changed slightly in 2 cases, and 4 cases suffered temporary memory loss, which did not affect their daily lives and learning function. They all recovered within 1 month. There were different degrees of effectiveness of treating drug addicts' psychological dependence by making lesions in the NAC bilaterally with stereotactic surgery. No particular complications occurred. The operation is safe and feasible. The mean follow-up time in this study was 15 months. The effectiveness was satisfactory. The relapse rate of drug addicts after detoxification was clearly reduced.