Deep brain stimulation for severe obsessive compulsive disorder: efficacy and mechanisms of ventral striatum and subthalamic nucleus targets
Lead Research Organisation:
University College London
Department Name: Institute of Neurology
Abstract
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.
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.
Technical Summary
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.
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.
Planned Impact
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.
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.
Publications
Dougherty DD
(2019)
Will Deep Brain Stimulation Help Move Precision Medicine to the Clinic in Psychiatry?
in Biological psychiatry
Fineberg NA
(2023)
Feasibility, acceptability and practicality of transcranial stimulation in obsessive compulsive symptoms (FEATSOCS): A randomised controlled crossover trial.
in Comprehensive psychiatry
Fineberg NA
(2016)
Compulsivity-A new trans-diagnostic research domain for the Roadmap for Mental Health Research in Europe (ROAMER) and Research Domain Criteria (RDoC) initiatives.
in European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology
Fineberg NA
(2018)
Mapping Compulsivity in the DSM-5 Obsessive Compulsive and Related Disorders: Cognitive Domains, Neural Circuitry, and Treatment.
in The international journal of neuropsychopharmacology
Li N
(2020)
A unified connectomic target for deep brain stimulation in obsessive-compulsive disorder.
in Nature communications
Li N
(2021)
A Unified Functional Network Target for Deep Brain Stimulation in Obsessive-Compulsive Disorder.
in Biological psychiatry
Tyagi H
(2017)
16 A randomised controlled trial of deep brain stimulation in obsessive compulsive disorder: a comparison of ventral capsule/ventral striatum and subthalamic nucleus targets
in Journal of Neurology, Neurosurgery & Psychiatry
Visser-Vandewalle V
(2022)
Deep brain stimulation for obsessive-compulsive disorder: a crisis of access.
in Nature medicine
Description | NICE Guidelines for Interventional Procedures; invited to provide expert opinion to the committee for DBS for OCD September 2020 |
Geographic Reach | National |
Policy Influence Type | Contribution to a national consultation/review |
URL | https://www.nice.org.uk/guidance/IPG693/chapter/1-Recommendations |
Title | New target for DBS electrodes |
Description | We are investigating the effect of deep brain stimulation of new brain targets for control of severe obsessive compulsive disorder and mood |
Type Of Material | Model of mechanisms or symptoms - human |
Provided To Others? | No |
Impact | Study ongoing |
Description | DBS for OCD shared database with USA centres |
Organisation | University of Rochester |
Department | University of Rochester Medical Centre |
Country | United States |
Sector | Academic/University |
PI Contribution | Led by Suzanne Haber, USA, we are contributing our data to a public database |
Collaborator Contribution | sharing their data |
Impact | no outputs as yet |
Start Year | 2022 |
Description | DBS for OCD shared database with USA centres |
Organisation | University of Rochester |
Department | University of Rochester Medical Centre |
Country | United States |
Sector | Academic/University |
PI Contribution | Led by Suzanne Haber, USA, we are contributing our data to a public database |
Collaborator Contribution | sharing their data |
Impact | no outputs as yet |
Start Year | 2022 |
Description | Wellcome Centre for Human Neuroimaging |
Organisation | Wellcome Trust |
Department | Wellcome Trust Cente for Neuroimaging |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | This grant has massively strengthened ties between the Unit of Functional Neurosurgery and the UCL Wellcome Centre for Human Neuroimaging (previously known as the Functional Imaging Laboratory - FIL). As a result, the UCL Wellcome Centre for Human Neuroimaging has had unprecedented access to patients undergoing deep brain stimulation and the opportunity to utilise MRI protocols in clinical practice and not just in the research setting. |
Collaborator Contribution | The the Unit of Functional Neurosurgery has benefited from strengthening ties between MR researchers and academic clinicians allowing us to implement advanced MR protocols into clinical practice to the benefit of our patients as reflected in the numerous publications listed as a result of this grant. |
Impact | The publications listed are a direct result of this collaboration. Patients have benefitted as a result with improved outcome and safety when undergoing functional neurosurgical procedures. |
Start Year | 2013 |
Description | Wellcome Centre for Integrative Neuroimaging |
Organisation | Wellcome Centre for Integrative Neuroimaging |
Country | United Kingdom |
Sector | Public |
PI Contribution | Our team provided the clinical and radiological data for project on thalamic segmentation, hyper direct pathway and subthalamic sweet spots |
Collaborator Contribution | The partners provided software, engineering expertise, support for GPU programming and supervision. |
Impact | This multidisciplinary collaboration (neurosurgery, neurology, psychiatry, neuropsychology, speech and language therapy, computer science, mathematics, MR physics) has resulted in the numerous publications listed with this grant. |
Start Year | 2013 |
Title | Using deep brain stimulation to treat severe obsessvie compulsivre disorder |
Description | We are undertaking a small trial of DBS (N=6) comparing two brain targets; we aim to have recruited and collected all feasibility data by August 2016. MRC funding until August 2015. We are now self fuding to complete the study. |
Type | Therapeutic Intervention - Surgery |
Current Stage Of Development | Early clinical assessment |
Year Development Stage Completed | 2016 |
Development Status | Under active development/distribution |
Clinical Trial? | Yes |
Impact | None yet - still under development |
URL | http://public.ukcrn.org.uk/Search/StudyDetail.aspx?StudyID=13158 |
Description | Article in OCD Charity written by an investigator and participant |
Form Of Engagement Activity | A magazine, newsletter or online publication |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | The purpose was to inform the wider patient and carer OCD community about the results our study from a clinician and a participant |
Year(s) Of Engagement Activity | 2019 |
Description | Data sharing with a European centre resulting in new findings |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | We were asked to share our unique data set which resulting in new finding about how deep brain stimulation affects neural pathways |
Year(s) Of Engagement Activity | 2020 |
Description | Guardian piece on our research paper written by science correspondent |
Form Of Engagement Activity | A magazine, newsletter or online publication |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | A Guardian science correspondent interviewed me about our project and published a piece about it. The aim was to inform the public about a relatively new intervention for severe mental illness. |
Year(s) Of Engagement Activity | 2019 |
Description | Local press release |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Professional Practitioners |
Results and Impact | To reach the UCL and associated UCLH hospital community |
Year(s) Of Engagement Activity | 2019 |
Description | Press release by Biological Psychiatry |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | The journal aimed to increase the impact of the work |
Year(s) Of Engagement Activity | 2019 |
Description | Wellcome Collection discussion group on 'Spark of Life Exhibition' |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | I was an invited speaker as part of the 'Spark of Life' exhibition to discuss brain stimulation as a medical technology |
Year(s) Of Engagement Activity | 2017 |