Deep brain stimulation for severe obsessive compulsive disorder: efficacy and mechanisms of ventral striatum and subthalamic nucleus targets

Obsessive compulsive disorder (OCD) affects 1-2 % of the population. It is characterised by intrusive unwanted thoughts and compulsive behaviours that vary in intensity, frequency and character. The standard treatment is cognitive behaviour therapy (CBT) aimed at enabling patients to gain better control of their obsessive thoughts and compulsive acts and therefore spend less time being distracted by them and function more normally in everyday life. Patients may also benefit from medication (serotonin re-uptake inhibitors) which is thought to act on the brain circuitry that is considered abnormal in OCD. However, these treatments are ineffective in up to 40% and symptoms in this subgroup can be sufficiently severe that patients are unable to perform activities of daily living, sustain work or maintain relationships. The English NHS National Specialised Commissioning Group funds services to provide assessment and intensive CBT and pharmacotherapy for such patients. Although these have good results there remains a truly refractory subgroup with significant disability.

Deep brain stimulation (DBS) is a technique which has proved safe and very successful in helping people with movement disorders such as Parkinson's disease and dystonia. It is thought to act by modifying abnormal processing in particular brain circuits which are functioning abnormally. DBS has the advantage that stimulation can be adjusted to optimise benefits and minimise adverse effects and it is also reversible in that stimulation can be switched off if the response is unsatisfactory and electrodes can be removed. DBS is now being studied in other disorders such as medically-refractory chronic, severe headache and severe depression.

There have been several studies of DBS for OCD and the results suggest that two thirds are helped, although patients remain symptomatic. More research is required to determine the best brain target for DBS and to understand more about the mechanisms of action as this might help us improve upon the current response rate and reduce symptom severity even further. Although CBT will not have previously been effective in these treatment-refractory patients, DBS may reduce symptoms enough to enable them to use CBT more effectively and the combination may result in a better outcome than DBS alone. To address these gaps in our knowledge we have brought together a network of specialist OCD clinicians, leading OCD cognitive neuroscientists and expert DBS clinicians to undertake the first UK study of DBS for severe, medically intractable OCD.

We propose to study 6 patients with severe, treatment refractory OCD who will be recruited through the specialised service for severe OCD and who will already have undergone the treatments involved in that care pathway. The study will fully comply with UK clinical governance procedures. The overarching aim is to compare the effects of DBS in two brain areas previously found to reduce OCD symptoms - the ventral striatum /ventral capsule (VS/VC) and the subthalamic nucleus (STN) - in the same patients. We will test the hypothesis, grounded in evidence from cognitive neuroscience, that DBS at both sites is better than either site alone for treating the symptom dimensions of OCD. Specifically, we will employ novel cognitive paradigms and neurophysiological measures of cortical synaptic function to test the hypothesis that VS/VC and STN DBS have different mechanisms of action and that alleviation of OCD symptoms is mediated by improvement in mood/anxiety with VS/VC DBS and by directly interrupting obsessions and compulsions with STN DBS. We will additionally determine whether adjunctive CBT enhances the response to DBS because it provides the cognitive and behavioural skills to optimise their symptom management and thereby improve daily function. At the end of the study the patients will remain on the optimum DBS treatment parameters and will continue to be monitored by our team.

The study aim is to establish the potential of deep brain stimulation (DBS) for people with obsessive compulsive disorder (OCD) who have failed to respond to the best medical treatment and who are significantly disabled by their symptoms.
Previous studies indicate that DBS of the ventral striatum/ventral capsule (VS/VC) and the subthalamic nucleus (STN) are effective for OCD. About two-thirds showed clear improvement but remained moderately symptomatic. The objectives of this study are to investigate whether this efficacy can be improved by determining: i) whether DBS at both sites is more efficacious than DBS at either site alone; ii) the mechanisms of action of DBS at these two brain sites; and iii) whether adjunctive cognitive behavioural therapy improves DBS-mediated clinical outcomes.
We will test the hypothesis that DBS alleviates OCD symptoms by improving mood/anxiety with VS/VC DBS and by directly affecting obsessions and compulsions with STN DBS. We plan to study DBS at these sites in the same patients and compare the effects of DBS at each site and in combination.
Studies of the cognitive and neurobiological phenotypes of OCD allow us to additionally hypothesise that the VS/VC DBS effects are secondary to improvement in reinforcement learning and that of STN are due to the direct inhibition of ongoing thought and motor acts. To test this we will employ novel cognitive paradigms and predict different patterns of results from DBS at each of these sites.
We will also investigate mechanisms of action at the synaptic level by using transmagnetic stimulation to examine the hypothesis that OCD symptoms are mediated by abnormal cortical excitability due to aberrant long term depression synaptic plasticity and/or reduced GABA-mediated intracortical inhibition and that these are improved by DBS.
Understanding more completely the effects of DBS on OCD symptoms has the potential of providing an effective treatment for a severely disabled group of patients.

Obsessive compulsive disorder is a common mental illness and has a lifetime prevalence of 1-2 %. This is similar in magnitude to schizophrenia and bipolar disorder. Up to 40% of people with OCD do not respond to standard treatments and symptoms in this treatment-refractory subgroup can be sufficiently severe that patients are unable to perform activities of daily living, sustain work or maintain relationships. In recognition of the unmet need for better interventions for OCD, the NHS Specialised Commissioning Group (SCG) has recently introduced a care pathway for people with persistent OCD symptoms. This involves intensive CBT and pharmacotherapy and is delivered by specialists in the field. Even with this specialist input there remains a subgroup of patients who are truly treatment refractory. Ablation of the anterior cingulate cortex is an option and is provided by the Advanced Interventions Service Ninewells Hospital, Dundee. Prospective longitudinal studies of cingulotomy suggest a sustained 2-year response rate of 32% with few adverse events and a concomitant improvement in quality of life. However this option is not readily taken up by OCD sufferers.

Deep brain stimulation (DBS) may be more acceptable because it has the advantage of reversibility in that stimulation can be switched off if the response is unsatisfactory and electrodes can be removed. In addition evidence suggests that DBS may improve upon the success rate of cingulotomy - the response can be modified following surgery and stimulation can be adjusted to optimise benefits and minimise adverse effects. If DBS proves to be a feasible intervention for people with severe and enduring OCD, there will be a highly significant impact on the quality of life in this significant subgroup.

The non-academic beneficiaries of the research will therefore be:

1. Patients with severe OCD because the research may lead to a new NHS service.
2. The carers of patients with severe OCD will also benefit. If DBS is a feasible NHS intervention for severe OCD, the improvement in symptoms are anticipated to lead to better everyday function and less reliance on family carers and social and medical services.
3. The government agency, the NHS Specialised Commissioning Group for OCD will benefit because they will be able to commission this intervention for patients who have not responded to the other treatments offered by this service and who ordinarily will be left with persistent and significant disability.
4. The manufacturers of commercially available DBS hardware, i.e. electrodes, batteries and associated products. If this research leads to a new treatment for OCD available on the NHS, it will be of benefit because this will be a new indication for their product.

Through involvement in this study a junior psychiatrist will be trained in experimental medicine for mental health.