Nucleus Accumbens/anterior Limb Of Internal Capsule Stimulation Using Self-developed DBS System For The Relapse Prevention In Opioid Addicts After Drug Withdrawal

Background and objective:Relapse after withdrawal is a tricky problem for the treatment of drug addciton. Current treatment measures, such as drug substitution therapy, psychological-behavioral intervention and compulsory detoxification, can not effectively prevent relapse, leading to a high recidivism rate in a short time after withdrawal, as high as 97% within half year. The possible reason may be that the intervention measures mentioned above could only ease the physical dependence induced by addictive drug, while the psychological dependence is still not alleviated, leaving behind a strong desire for drug use. The preliminary studies indicated that the brain rewarding system, as the nucleus accumbens(NAc) being in the core, may be the anatomical basis of potential mechanisms, uncovering the psychological craving of drug addiction. Therefore, in 2000, we for the first time used the NAc ablation in treatment of drug addiction, worldwidly. The 5 year follow-up results suggest that abstinence rate is 61.5%, which is far better higher than the results treated using conservative methods. However, the ablation procedure is irreversible and destructive, hence, the normal function of NAc could also be disturbed. As the deep brain stimulation(DBS) developed recently, because of its successful application in the treatment of Parkinson’s disease(PD)(taking the place of ablation in the treatment of PD), DBS will serve as a safe method for investigating new strategy in the treatment of drug addiction. However, the results of case reports using DBS for the treatment of addiction showed deficit of the existing DBS method in the treatment of addiction talking about below. First, the results come from a small sample size; second, the existing differences between the ablation and DBS for addiction treatment may affect the efficacy of DBS; third, the deficient of Medtronic DBS(designed for the PD) system for the application in addiction treatment; forth, the comorbid OCD or depression may also affect the efficacy of DBS for addiction; and the last, craving is a kind of psychological feeling, how to obtain the treatment-feedback objectively may also disturb the effect of DBS. Therefore, multiple targets stimulation simultaneously, as the NAc being in the core, will serve as a possible method providing more clinical benefit for patients with addiction. Methods:Combing with our own previous experiences and the cutting-edge progresses in the treatment of drug addiction, we conducted this study using self-developed new DBS system. Subjects with long history of heroin use(> 3 years) trying many times(> 3) to give up but failed were enrolled. Stereotactic neurosurgery was used to implant the stimulation electrode going through the anterior limb of internal capsule(ALIC) into NAc. Simultaneous and individual stimulations were performed on these two targets. The efficacy and safety of NAc/ALIC- DBS in the prevention of relapse in opioid addicts after drug withdrawal were evaluated. This study is a prospective, observational, open-label and pilot clinical trial and is approved by the Ethics Committee of our hospital. In addition, the study has also been registered on the international Clinicaltrial website(ID, NCT01274988). Results:8 participants with long history of opioid drug use and negative tests of morphine urinalysis and naloxone challenge were recruited. All patients had tried many times to give up drugs but all relapsed. 5 took drug through intravenous injection and the other 3 by snoring. 6 got married, 1 single and 1 divorced. 7/8 patients were male and had a mean age of 34 ± 8.8(22 – 50) at the surgery. All the patients met the criteria of ICD-10 for the diagnosis of drug addiction, with an average age at onset of drug use of 21.4 ± 4.5(12 – 25), a mean duration of illness of 12.6 ± 7.4(3 – 25) years and an average number of attempt to give up drug of 6.5 ± 2.8(3 – 10) before DBS treatment. The mean education time was 10.4 ± 2.2(6 – 12) years, average RMB per drug use was 212.5 ± 64.1(100 – 300), duration of longest abstinence time was 4.75 ± 2.12(1 – 8) months and duration of current abstinence time in the last 30 days was 20.6 ± 6.9(10 – 30). Heroin was the main addictive drug before enrollment in all the patients, with ever used drugs such as methamphetamine, diphenoxylate, opium and marijuana. Comorbid depression was found in 3 patients and OCD in 5.7 patient finished 6 month follow-up, with 6 keep abstinence(according to negative test results of morphine urinalysis during the timepoints of follow-up and at least 3 random time-points), the longest duration of abstinence time was 13 months(case 1、2) and 1(case 6) was lost during 3 month follow-up. 4(case 1, 2, 5 and 7) subjects got full-time jobs and returned to the society successfully and 1(case 3) helped to do family business. 6 got weight increase during 6 month follow-up compared with baseline, with an average of 6.1 ± 2.4 kg(P = 0.002). 4(case 1, 2, 5 and 7) reported changes of libido, showing strong desire of sex than preoperatively and the frequency of sexual life increased from 1 per month to 8 – 12 per month which was a sign of normalization. No sexual dysfunction or libido decline was reported. 1(case 4) lost weight(4kg) for the reason reshaping her body figure. 1(case 3) got married and 2(case 1 and 3) patients’ wives got pregnant postoperatively, with one healthy child already delivered.DBS operation procedure and post-operative programming were well tolerated in all subjects. An intracranial hemorrhage(< 3 ml) beside the implanted electrode occurred, but no brain function damage symptoms were observed during the in-patient period. Moreover, the hemorrhage had been completely absorbed during 6 months follow-up supported by MRI scans. In addition, no long-term complications were observed at the same time. There were some adverse events related to the stimulation parameter, including 1 memory decline, 2 paresthesia, 3 transient hypomania, 2 agitation and 1 sweeting. All the stimulation-related adverse events were reversible and disappeared when decreasing the voltages or turning off the DBS. 1 patient got weight loss which was unrelated to the DBS.The results of postoperative MRI indicated that the new DBS electrodes could be implanted successfully and accurately going through ALIC into NAc, leaving the ventral 2 contacts located in the NAc and 2 dorsal contacts located within the ALIC. The Arc Angle confirmed by postoperative MRI was about 29(22.6 – 32.4) degrees apart from the midline plane and the Ring Angle was 68(59.5 – 75.6) degrees designed preoperatively. The self-developed programming-feedback measure – a daily adjustment of programming parameter in a week – in the initial programming section was proved that the relative objective feedback(such as decreased craving for drug use, increased mood and energy, going to bed later than normal) during programming could be obtained successfully. The stimulation parameters were set as below: NAc, 2.2 – 2.8 V, 180/210/240 μs, 145 Hz; ALIC, 1.5 – 2.4V, 150/180/210/240μs, 185 Hz.During the 6 month follow-up, the scores of visual analog scale(VAS) decreased from 7.57 preoperatively to 0.71(P < 0.001), the total amount time of craving for drug use rated by self-developed Subject Diary also declined from 5.07 h(21.1 %) to 0.29 h(1.2 %)(P < 0.001), the results of Medical Outcomes Study 36-Item Short-Form Health Survey(SF – 36)(RP、BP、GH、RE) indicated that DBS improved the overall quality of life. In addition, the results of self-developed Addictive Scale dropped a hint that DBS normalized the family-relationships, daily activities, sex life and sleep of the patients. The scores of Hamilton Depression Scale(HAMD) decreased from 16.57 ± 9.22(8 – 32)to 5.43 ± 3.82(1 – 11)(P = 0.008) and the scores of Yale-Brown Obsessive Compulsive Scale(Y – BOCS) declined from 22.43 ± 9.25(6 – 33)to 8.0 ± 4.83(0 – 15)(P = 0.021). The scores of So, Oc, De, An, Ps(subdivisions of Symptom Checklist-90, SCL – 90) and the total score of SCL – 90 decreased significantly compared with that preoperatively. There were no changes of ratting scores evaluating memory function using Wechsler Memory Scale(WMS) pre and post-operatively(P = 0.133), however, subjects self-reported memory decline of episodic memory related to drug-using. Eysenck Personality Questionnaire(EPQ) data suggested that DBS had no effect on personality. PET analysis showed that after 6 month stimulation the increased glucose metabolism of brain regions were left cerebellum anterior lobe, left angular, both sides of middle temporal gyrus, left inferior frontal gyrus, both sides of inferior frontal partes opercularis, right supramarginal gyrus and right precuneus, while the decreased was right corpus callosum. Conclusions:1. Nucleus accumbens/anterior limb of internal capsule deep brain stimulation using self-developed DBS system for the treatment of opioid drug addiction was efficacy and safe. The stimulation-related adverse events were reversible. There were no long-term complications during 6 months follow-up.2. The new programming pattern – daily adjustment of programming parameter in a week – was proved that the relative objective feedback during programming could be obtained successfully. The stimulation parameters were set as below: NAc, 2.2 – 2.8 V, 180/210/240 μs, 145 Hz; ALIC, 1.5 – 2.4V, 150/180/210/240μs, 185 Hz.3. During 6 month follow-up, 7 patients kept abstinence, DBS could decrease the extent of craving for drug use and decline the total amount and proportion of craving time in each 24 h. DBS also improved the general psychological state of spirit, the comorbid depression, the comorbid obsessive behavior and the quality of life. DBS had no effect on personality and memory, although some patients reporting the decline of episodic memory related to drug-using.4. After 6 month stimulation, the glucose metabolism of specific brain regions were regulated by DBS in a two-way method. In addition, DBS seemed to have a remote and networking adjustment function on the brain activity.