P. Richard Schuurman

Subthalamic nucleus versus globus pallidus bilateral deep brain stimulation for advanced Parkinson's disease (NSTAPS study): a randomised controlled trial

BACKGROUND Patients with advanced Parkinsons disease often have rapid swings between mobility and immobility, and many respond unsatisfactorily to adjustments in pharmacological treatment. We assessed whether globus pallidus pars interna (GPi) deep brain stimulation (DBS) gives greater functional improvement than does subthalamic nucleus (STN) DBS. METHODS We recruited patients from five centres in the Netherlands who were aged 18 years or older, had idiopathic Parkinsons disease, and had, despite optimum pharmacological treatment, at least one of the following symptoms: severe response fluctuations, dyskinesias, painful dystonias, or bradykinesia. By use of a computer-generated randomisation sequence, we randomly assigned patients to receive either GPi DBS or STN DBS (1:1), applying a minimisation procedure according to drug use (levodopa equivalent dose <1000 mg vs ≥1000 mg) and treatment centre. Patients and study assessors (but not those who assessed adverse events) were masked to treatment allocation. We had two primary outcomes: functional health as measured by the weighted Academic Medical Center Linear Disability Scale (ALDS; weighted by time spent in the off phase and on phase) and a composite score for cognitive, mood, and behavioural effects up to 1 year after surgery. Secondary outcomes were symptom scales, activities of daily living scales, a quality-of-life questionnaire, the occurrence of adverse events, and drug use. We used the intention-to-treat principle for all analyses. This trial is registered with www.controlled-trials.com, number ISRCTN85542074. FINDINGS Between Feb 1, 2007, and March 29, 2011, we enrolled 128 patients, assigning 65 to GPi DBS and 63 to STN DBS. We found no statistically significant difference in either of our primary outcomes: mean change in weighted ALDS (3·0 [SD 14·5] in the GPi group vs 7·7 [23·2] in the STN group; p=0·28) and the number of patients with cognitive, mood, and behavioural side-effects (36 [58%] of 62 patients in the GPi group vs 35 [56%] of 63 patients in the STN group; p=0·94). Secondary outcomes showed larger improvements in off-drug phase in the STN group compared with the GPi group in the mean change in unified Parkinsons disease rating scale motor examination scores (20·3 [16·3] vs 11·4 [16·1]; p=0·03), the mean change in ALDS scores (20·3 [27·1] vs 11·8 [18·9]; p=0·04), and medication (mean levodopa equivalent drug reduction: 546 [SD 561] vs 208 [521]; p=0·01). We recorded no difference in the occurrence of adverse events between the two groups. Other secondary endpoints showed no difference between the groups. INTERPRETATION Although there was no difference in our primary outcomes, our findings suggest that STN could be the preferred target for DBS in patients with advanced Parkinsons disease. FUNDING Stichting Internationaal Parkinson Fonds, Prinses Beatrix Fonds, and Parkinson Vereniging.

Deep brain stimulation restores frontostriatal network activity in obsessive-compulsive disorder

Little is known about the underlying neural mechanism of deep brain stimulation (DBS). We found that DBS targeted at the nucleus accumbens (NAc) normalized NAc activity, reduced excessive connectivity between the NAc and prefrontal cortex, and decreased frontal low-frequency oscillations during symptom provocation in patients with obsessive-compulsive disorder. Our findings suggest that DBS is able to reduce maladaptive activity and connectivity of the stimulated region.

Smoking cessation and weight loss after chronic deep brain stimulation of the nucleus accumbens: therapeutic and research implications: case report.

OBJECTIVESmoking 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. CLINICAL PRESENTATIONA 47-year-old woman presented with chronic treatment-refractory obsessive-compulsive disorder, nicotine dependence, and obesity. INTERVENTIONThe 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. CONCLUSIONThis 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.

Vagus nerve stimulation inhibits cytokine production and attenuates disease severity in rheumatoid arthritis

Significance Rheumatoid arthritis (RA) is a chronic, prevalent, and disabling autoimmune disease that occurs when inflammation damages joints. Recent advances in neuroscience and immunology have mapped neural circuits that regulate the onset and resolution of inflammation. In one circuit, termed “the inflammatory reflex,” action potentials transmitted in the vagus nerve inhibit the production of tumor necrosis factor (TNF), an inflammatory molecule that is a major therapeutic target in RA. Although studied in animal models of arthritis and other inflammatory diseases, whether electrical stimulation of the vagus nerve can inhibit TNF production in humans has remained unknown. The positive mechanistic results reported here extend the preclinical data to the clinic and reveal that vagus nerve stimulation inhibits TNF and attenuates disease severity in RA patients. Rheumatoid arthritis (RA) is a heterogeneous, prevalent, chronic autoimmune disease characterized by painful swollen joints and significant disabilities. Symptomatic relief can be achieved in up to 50% of patients using biological agents that inhibit tumor necrosis factor (TNF) or other mechanisms of action, but there are no universally effective therapies. Recent advances in basic and preclinical science reveal that reflex neural circuits inhibit the production of cytokines and inflammation in animal models. One well-characterized cytokine-inhibiting mechanism, termed the “inflammatory reflex,” is dependent upon vagus nerve signals that inhibit cytokine production and attenuate experimental arthritis severity in mice and rats. It previously was unknown whether directly stimulating the inflammatory reflex in humans inhibits TNF production. Here we show that an implantable vagus nerve-stimulating device in epilepsy patients inhibits peripheral blood production of TNF, IL-1β, and IL-6. Vagus nerve stimulation (up to four times daily) in RA patients significantly inhibited TNF production for up to 84 d. Moreover, RA disease severity, as measured by standardized clinical composite scores, improved significantly. Together, these results establish that vagus nerve stimulation targeting the inflammatory reflex modulates TNF production and reduces inflammation in humans. These findings suggest that it is possible to use mechanism-based neuromodulating devices in the experimental therapy of RA and possibly other autoimmune and autoinflammatory diseases.

Unilateral pallidotomy in Parkinson's disease: a randomised, single-blind, multicentre trial

BACKGROUND The results of several cohort studies suggest that patients with advanced Parkinsons disease would benefit from unilateral pallidotomy. We have assessed the efficacy of unilateral pallidotomy in a randomised, single-blind, multicentre trial. METHODS We enrolled 37 patients with advanced Parkinsons disease who had, despite optimum pharmacological treatment, at least one of the following symptoms: severe response fluctuations, dyskinesias, painful dystonias, or bradykinesia. Patients were randomly assigned to unilateral pallidotomy within 1 month or to pallidotomy after the primary outcome assessment (6 months later). The primary outcome was the difference between the groups in median changes on the motor examination section of the unified Parkinsons disease rating scale (UPDRS 3) score done in the off phase. Secondary outcome measures included levodopa-induced dyskinesias (dyskinesia rating scale [DRS]) and extent of disability (UPDRS 2). FINDINGS The median UPDRS 3 off score of the pallidotomy patients improved from 47 to 32.5, whereas that of control patients slightly worsened from 52.5 to 56.5 (p<0.001). In the on phase the median DRS score improved 50% in pallidotomy patients compared with no change in controls. The UPDRS 2 off score improved with a median of 7 in the pallidotomy group. Two treated patients had major adverse effects. INTERPRETATION Unilateral pallidotomy is an effective treatment in patients with advanced Parkinsons disease, who have an unsatisfactory response to pharmacological treatment.

Current Status of Deep Brain Stimulation for Obsessive-Compulsive Disorder: A Clinical Review of Different Targets

Obsessive-compulsive disorder (OCD) is a chronic psychiatric disorder that affects 2% of the general population. Despite optimal cognitive-behavioral and pharmacologic therapy, approximately 10% of patients remain treatment resistant. Currently, deep brain stimulation (DBS) is being investigated as an experimental therapy for treatment-refractory OCD. This review focuses on the efficacy and adverse events of all published DBS targets for OCD: anterior limb of the internal capsule, ventral striatum/ventral capsule, nucleus accumbens, nucleus subthalamicus, and inferior thalamic peduncle. Small studies with various designs indicate an overall average Yale-Brown Obsessive Compulsive Scale score decrease ranging from 6.8 to 31 points. The average overall responder rate is ±50%. The frequency of adverse events seems to be limited. Larger prospective studies including neuroimaging are needed to estimate adequately the true potential of DBS in treatment of OCD and to elucidate its underlying mechanism of action and optimal brain target. We conclude that DBS may be a promising and safe therapy for treatment-resistant OCD.

DYT6 dystonia: Mutation screening, phenotype, and response to deep brain stimulation†

Mutations in THAP1, a gene encoding a nuclear pro‐apoptotic protein, have been associated with DYT6 dystonia. First reports on the phenotype of DYT6 dystonia show an early onset dystonia with predominant cranio‐cervical and laryngeal involvement. Here we assessed the frequency and phenotype of THAP1 mutation carriers in a large Dutch cohort of adult‐onset (≥26 years) dystonia (n = 388) and early‐onset dystonia (n = 67) patients. We describe the phenotype of DYT6 dystonia patients and their response on GPi DBS. Overall, 3 nonsynonymous heterozygous mutations were detected in the early‐onset group (4.5%). Two DYT6 families were identified, showing a heterozygous phenotype. All patients had segmental or generalized dystonia, often associated with profound oromandibular and laryngeal involvement. No nonsynonymous mutations were found in patients with adult‐onset focal dystonia. Rare synonymous variants were identified in conserved regions of THAP1, two in the adult‐onset cervical dystonia group and one in the control group. Four DYT6 dystonia patients were treated with GPi DBS with moderate to good response on motor function but marginal benefit on speech.

Top-down-directed synchrony from medial frontal cortex to nucleus accumbens during reward anticipation

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. Hum Brain Mapp, 2012.

Bilateral pallidotomy in Parkinson's disease: A retrospective study

We evaluated the effects of bilateral pallidotomy in patients with advanced Parkinsons disease. Thirteen patients with Parkinsons disease had a staged bilateral pallidotomy if they had severe response fluctuations, dyskinesias, painful dystonia, or bradykinesia despite optimum pharmacological treatment. Assessment scales were the Unified Parkinsons Disease Rating scale (UPDRS), the Schwab and England scale, and a questionnaire on the effects of disability in activities of daily living and adverse effects. Postoperative magnetic resonance imaging was evaluated for lesion location and extension. The median off‐phase UPDRS motor score was reduced from 43.5 to 29 after the first pallidotomy, and it was further reduced to 23.5 after the second pallidotomy (n = 8). The UPDRS activities of daily living off‐phase score improved from 28.5 to 20.5 after the first pallidotomy and to 19 after the second pallidotomy (n = 6). The Schwab and England scale off‐phase score showed an improvement after both procedures, first from 40 to 60, and thereafter to 90 (n = 8). On‐phase dyskinesias were reduced substantially. Eight patients had adverse effects, of whom five had problems with speech. One patient became hemiplegic due to a delayed infarction. Ten patients experienced further benefit from the second procedure. Bilateral pallidotomy reduces dyskinesias. A second contralateral pallidotomy may reduce parkinsonism, although to a lesser degree compared with the first pallidotomy and with an increased risk for adverse effects.

Deep brain stimulation for obsessive–compulsive disorders: long-term analysis of quality of life

Objective To evaluate the long-term effects of deep brain stimulation (DBS) on quality of life (QOL) in therapy-refractory obsessive–compulsive disorder (OCD) patients. Design 16 patients who met Diagnostic and Statistical Manual of Mental Disorders (4th ed) (DSM-IV) criteria for OCD and were considered therapy-refractory were treated with DBS. Patients were assessed 1 month before device implantation (T0), at 8 months of active stimulation (T1) and at 3–5 years of active stimulation (T2). QOL was measured with the WHO Quality of Life Scale-Brief Version (WHOQOL-BREF) that covers physical, psychological, social and environmental domains. The study was conducted between April 2005 and January 2011 at the Academic Medical Center, Amsterdam, The Netherlands. Results At T1 and T2, we found significant improvement (p<0.05) in the general score and in the physical, psychological and environmental domains of WHOQOL-BREF. Between T1 and T2, the physical and psychological domains improved further (p<0.05). At T2, the general score improved by a total of 90%, the physical and psychological domains both improved by 39.5% and the environmental domain improved by 16%. The social domain did not change between baseline and follow-up assessments. Conclusions In line with symptom improvement, patients QOL improved in the general score and in three of the four WHOQOL-BREF domains. This suggests that the improvement caused by DBS is not limited to symptom reduction alone, but also has a positive influence on patients’ perception of their physical, psychological, environmental and global QOL. Clinical trial registration http://isrctn.org identifier: ISRCTN23255677.