Deep Brain Stimulation and Obsessive-Compulsive Disorders


Introduction

Principle Investigator: Damiaan Denys, M.D., Ph.D.

Deep brain stimulation or DBS has shown to be effective in therapy-resistant cases of a number of neurological and psychiatric diseases. However, it has not yet been fully determined which psychiatric symptoms respond best to DBS and which brain targets are optimal. Additionally, despite extensive clinical and experimental research, our knowledge of the mechanisms of action of DBS still is limited.

The research program of this group focuses on two main questions:

  1. How can DBS be used safely and efficaciously for the treatment of compulsivity, depression, addiction and eating disorders?
  2. How does successful DBS alter neurotransmission in these diseases?

As these diseases are characterized by profound behavioral alterations due to disturbances of affect, motivation and cognition, our research is focused on neurobiological substrates of motivational behavior in general.

Our approach is translational and multidisciplinary; clinical findings from DBS studies in humans are translated in relevant animal models, in which we observe effects of DBS on behavior and its underpinning neurocircuitry. Our human research tools include methods for intracerebral electrophysiological recordings, functional MRI, SPECT, neuroendocrinology and genetics in combination with neuropsychological tests.

Deep Brain Stimulation in chronic treatment-refractory drug dependence: A Pilot Study

Addiction is a highly prevalent and chronic relapsing disease with severe negative consequences for patients, their environment and society. Not all patients respond to the currently available treatments and therefore additional treatments are needed.

Deep brain stimulation (DBS) has shown to be effective in different neurological and psychiatric diseases. Both animal research and observational human studies provide compelling evidence for the potential efficacy of DBS in patients with a substance disorder. DBS of the nucleus accumbens (NAc) is compatible with our neurobiological understanding of addiction based on extensive experimental animal and human research.

This research project aims to establish the feasibility, safety, and potential efficacy of NAc DBS in patients with a chronic, treatment refractory heroin and/or cocaine addiction. Additionally the functional effects of DBS will be explored in several ways 1) we will look at changes in brain activation patterns in response to specific tasks by means of functional MRI 2) we will look at the striatal D2 binding using [123I]IBZM SPECT 3) we will look at neuropsychological functioning using cognitive tasks. Changes found in these three areas will be associated with clinical outcome parameters. 

EEG and intracranial recording of local field potential in the human Nucleus Accumbens

In this project we record EEG and intracranial LFPs from patients implanted for DBS treatment of refractory obsessive compulsive disorder, depression or drug-addiction. During the recording sessions, the patients perform a battery of clinical and basic-research psychophysics tests.

Effects of DBS in Nucleus Accumbens in OCD on brain activity and dopamine release

In this PhD-project we will investigate how deep brain stimulation (DBS) in the Nucleus Accumbens of obsessive-compulsive disorder (OCD) patients changes brain function in the cortico-striatal-thalamo-cortical (CSTC) circuits. Dopaminergic changes due to DBS will be measured with IBZM SPECT. Changes in brain activity related to DBS will be investigated using functional MRI combined with reward and reversal learning paradigms.

Effects of neuromodulation in the cortico-striatal-thalamo-cortical circuits on striatal dopamine release and motivated behaviour

Deep Brain Stimulation (DBS) in cortico-striato-thalamo-cortical (CSTC) circuits may be an effective treatment in otherwise treatment-resistant patients with obsessive compulsive disorder (OCD) and major depressive disorder (MDD). Within the CTSC circuits, stimulation of several target areas (e.g. ventral striatum, anterior cingulate, subthalamic nucleus) has resulted in reduction of clinical symptoms. Despite successful use of DBS in the clinic, the mechanism by which DBS reduces symptoms remains elusive. In addition, it is not clear which target area can best be stimulated to result in optimal clinical effects. Dysfunction in CSTC circuits and altered DA transmission are thought to be a hallmark of both OCD and MDD pathology. Under normal circumstances, CSTC circuits are important for motivated and goal-directed (e.g. reward-related) behaviour. These circuits are involved in learning and adapting associations between stimulus, response and outcome and for that depend on dopamine (DA) neurotransmission. One of the effects of DBS may therefore be that it stabilizes dysfunctional activity in the CSTC circuit, resulting in normalization of DA release and behaviour. This PhD project focuses on the effects of DBS in the CSTC circuit on motivated behaviour and DA release in the striatum.

Geographic variation in efficacy and generalizability of pharmacological treatment in schizophrenia, bipolar disorder and OCD

Placebo controlled randomised clinical trials are the accepted method for testing the efficacy of new pharmaceutical compounds. However, the internal and external validity of such trials has been disputed. On area of concern is with respect to the generalizability of the results across geographic regions. For example pharmacokinetics or cultural differences in background treatment in different countries may cause differences in efficacy across regions. Likewise, differences in training of investigators might lead to differences in accuracy of assessments, thereby also influencing efficacy estimation. In addition, placebo response may vary across regions due to inclusion of different patient populations in trials that are conducted in different regions. The concern is that conclusions regarding the benefit/risk balance that are based on trials that are conducted in one geographic region, may not be generalizable to other regions. This issue is of special importance given the increasing tendency to conduct studies in different regions.

The purpose of our study is to examine whether regional difference in efficacy exist. The different factors that may limit generalizability of efficacy across geographical regions may be captured in a theoretical frame as being due to one of the following three processes: biological, social or methodological. Furthermore, some specific efficacy aspects such as placebo response over time and relationship between efficacy and drug dose and exposure length will be examined for each disorder. The research methodology is individual patient data meta-analysis. Individual patient data from clinical trials performed with new chemical entities indicated for the three disorders is obtained from cooperating pharmaceutical companies and will be compiled into three data sets. Different meta-analytic methods will be applied to examine variability across regions.

Neuroimaging of Deep Brain Stimulation in treatment-refractory patients with major depressive disorder

The Academic Medical Centre (AMC) started 5 years ago with treating obsessive compulsive disease (OCD) patients with Deep Brain stimulation (DBS). After the first 30 patients promising results have been seen. Despite reduction of compulsive behavior these patient also had a huge reduction of co-morbid depressive symptoms during DBS. This means DBS treatment can also be effective in therapy refractory major depressive disorder (MDD).

Until now a few international research groups are performing DBS in therapy refractory MDD. Although only 50 patients are treated the results are promising. Despite clinical effects during DBS not much is known about the neurobiological effects on brain function.

From March 2010 the AMC together with St. Elisabeth Hospital Tilburg will start treating 30 therapy refractory MDD patients with DBS in the nucleus Accumbens and will research clinical and neurobiological effectiveness. The neurobiological effects will be researched with both functional MRI and SPECT imaging. The main objectives of this study are (1) to assess the effects of DBS on D2 receptors binding using SPECT imaging and (2) to assess alterations in cerebral perfusion associated with deep brain stimulation (DBS) using fMRI.

Both SPECT and fMRI will be performed before and after DBS implantation at various timepoints. With SPECT we measure dopamine D2 receptor binding with a radioactive ligand IBZM. We expect to see a decrease in receptor binding of IBZM in the caudate nucleus over time, indicative of an increase in dopaminergic neurotransmission, which is expected to be related to improvement in mood and anhedonia. Secondly, we predict that clinical response to DBS will be associated with changes in activity within the cortical-limbic-thalamic-striatal network measured with fMRI.

Neuropsychological effects of deep brain stimulation of the nucleus accumbens on treatment-refractory patients with major depressive disorder

Major depressive disorder (MDD) is a psychiatric illness characterized by a disorder of mood, but is also associated with several neuropsychological deficits. Additionally, some of the treatment options for the disorder are linked with further cognitive decline, most notably electroconvulsive therapy (ECT). At present ECT is the “treatment-of-choice” for treatment-refractory (TR) MDD patients, who have failed to respond to different therapies (medication and/or psychotherapy).

In recent years a new neurosurgical treatment option for TR MDD has emerged in the form of deep brain stimulation (DBS). Different targeting sites have proposed as a potential target, e.g. subgenual cingulate region (Brodmann area 25) and the nucleus accumbens (N.Acc.). For this project the latter has been chosen, because DBS of this site has shown to have a positive result on mood in obsessive-compulsive patients. N.Acc. DBS has also shown promising results in lifting depression in a small group of MDD patients.

However, no results have been reported on the effect of N.Acc. DBS on neuropsychological functions. Therefore this study will compare the neuropsychological outcomes of patients treated with N.Acc DBS to those treated with ECT or medication. Testing will take place before the surgery or first treatment and at several time points after. A healthy control group is included to control for learning effects of repetitive testing.

Quality of life and cost effectiveness of deep brain stimulation in psychiatric disorders

Therapy refractory obsessive compulsive disorder and depressive disorder not only have a major impact on the quality of life of patients, but it also has important consequences on the economical level. Costs are mainly generated due to the treatment and professional help patients need at home, but also as a result of unemployment and time spent on informal care.

Preliminary findings suggest that Deep Brain Stimulation (DBS) is an effective therapy for these therapy refractory patients and can alleviate the burden that patients experience. However, in these times of growing budgetary limitations medical decisions are no longer merely based on clinical efficacy, but also on cost-effectiveness. Therefore, an important consideration in the future provision of the DBS treatment in mental disorder will be the substantial medical costs involved in treatment and how we can reduce the costs without losing effectiveness.

In our research we not only see effectiveness as an improvement in clinical symptoms observed by a clinician, but also as the subjective quality of life experienced by patients.

Body Dysmorphic Disorder (BDD): Studies in imagined ugliness

Body Dysmorphic Disorder (BDD) is a chronic and debilitating psychiatric disorder. Patients with BDD have excessive concerns about one’s physical appearance. Often patients have compulsive behaviors with the primary goal of reducing negative associated feelings. Severe BDD symptoms can be described as egosyntonic and in some cases delusional beliefs about one’s appearance, extensive rituals, widespread avoidance behaviors and/or secondary severe depression with or without suicidality. Overall, patients have poor quality of life and impairments in daily, occupational and social functioning.

A CBT Group Treatment Program Currently, BDD-patients are treated with and Cognitive Behavioural Therapy (CBT) and/ or pharmacotherapy. Though guidelines prescribe individual CBT therapy, this treatment is often time consuming and expensive, with experienced therapists difficult to find and waiting lists rising. An alternative to long-lasting individual CBT can be a more intensive form of treatment: group CBT.Therefore, the primary goal of this research project is to determine whether Group CBT is an effective strategy in treating this debilitating disorder. Neuropsychological Functioning in BDDBecause of the fact that BDD has not been studied sufficient, there is limited data on neuropsychological processes underlying BDD. Consequently, the primary goal of this research project is to learn more about the cognitive impairments associated with BDD. Pharmacological enhancement of fear extinction in BDD.Recent studies in humans and rodents show that the efficacy of cognitive behavioural treatment might be augmented by D-cycloserine (DCS). DCS is a partial agonist of the N-Methyl-D-aspartate (NDMA) glutamergic receptor, which has been thought of as a putative target for enhancing memory and cognitive functioning in general. DCS might enhance the acquisition and consolidation processes that occur during associative learning and Exposure and Respons Prevention (ERP) is a form of associative learning. Fear extinction can be likened to a form of inhibitory learning.The objective for this study is threefold. First we will determine whether DCS addition to ERP may enhance fear extinction and improve symptoms in BDD. Furthermore, we will examine if DCS has an effect on learning, memory and executive tasks. Finally we will evaluate cost-effectiveness.

Deep Brain Stimulation (DBS) in patients with refractory OCD and refractory major depression: possible immunological and HPA axis changes

Background: Obsessive-compulsive disorder (OCD) and major depression, among other psychiatric disorders, are associated with altered activity of the immune system and changes in HPA axis activity.

The objective of the recent study is to investigate these changes in relation to DBS in the Nucleus Accumbens.

Patients and Method: Patients with refractory OCD and refractory major depression will be included. During the On/Off phases of DBS severity of obsessive-compulsive and depressive symptoms will be rated with the Yale-Brown Obsessive compulsive Scale (Y-BOCS) and Hamilton Depression Rating Scale (HDRS). Primary outcome measures are pro- and anti-inflammatory markers and markers of HPA activity: a.o. serum and 24 hr-urine cortisol.

Deep Brain Stimulation in Treatment-refractory patients with Anorexia Nervosa: a Pilot Study

Anorexia Nervosa (AN) is an eating disorder characterised by a relentless pursuit of thinness and a refusal to maintain body weight at 85% of the expected standard for age and weight, combined by an intense fear of gaining weight or becoming fat. Furthermore, individuals with AN exhibit disturbed perceptions of their own body shape and size.

AN is a serious psychiatric disorder and forms a major problem for public health. In about 20% of the cases the disease takes on a chronic course, and with a mortality rate of 10-15%, AN has the highest mortality of all psychiatric illnesses. Up to date, there is no evidence-based treatment for AN.

Deep Brain Stimulation (DBS) has shown to be an effective treatment in different neurological and psychiatric disorders. Data from neuroimaging studies on AN suggest that AN may be a suitable target for neuromodulatory therapy with DBS.

This research project aims to establish the feasibility, potential efficacy and safety of DBS in patients with chronic, treatment refractory anorexia nervosa. Additionally, the functional effects of DBS will be explored in different ways. In this pilot study clinical outcome measures will be associated with:

1) the changes in cerebral perfusion in response to specific tasks using functional MRI

2) EEG changes associated with DBS

3) the effects of DBS on striatal D2 receptor binding using IBZM SPECT

4) changes in neuropsychological functioning

5) immunological changes

6) endocinological changes

Feelings of Incompleteness – studies on dopamine in obsessive-compulsive disorder

Although obsessive-compulsive disorders have been subject to intense multimodal research, their pathogeneses are yet to be fully understood. However, increasing evidence from both preclinical and clinical studies support a role for dopamine in OCD. The studies in this thesis provide circumstantial evidence for the involvement of dopamine in OCD. On the one hand, first exacerbation of OCD symptoms by blocking the dopamine transporter (DAT) with bupropion in OCD patients, and second augmentation of the efficacy of citalopram by blocking the D2 receptor with quetiapine, both confirm dopamine abnormalities in OCD. On the other hand, (1) the absence of abnormal striatal D2 receptor binding at baseline in a [11C]raclopride PET study, (2) no differences in change in BP of [11C]raclopride in the striatum after amphetamine in a [11C]raclopride PET study, together with (3) similar distributions of genotypes or allele frequencies of the COMT or DRD2 receptor between responders and nonresponders to citalopram with quetiapine, challenges the evidence for dopamine alterations in OCD. However, conclusions from our PET and pharmacogenetic study are limited by small sample size. Therefore, enlargement of the sample in future studies is warranted. Heterogeneity of OCD symptoms of participants in our PET study could also be a potential confounder, since various neuroimaging studies suggest that different symptoms may be mediated by distinct neural systems.

Taken together, results from this thesis show that patients with OCD who have never been treated before, preferentially benefit from a combination of a SSRI and quetiapine, compared to monotherapy with SSRIs. Immediate augmentation increases the number of responders, though psychiatrists need to consider the increased number of dropouts due to side effects with add-on therapy. Genetic research can provide additional information which patients will respond to a combination of SSRIs and quetiapine.

Database research and genetics

In this research project we systematically collect demographics, clinical data, neuropsychological findings and genetics of all patients with obsessive-compulsive disorder (OCD) and body dysmorphic disorder (BDD). These data will be used to elaborate knowledge on the associations between genes and specific features of OCD or BDD like severity of symptoms, familial incidences and comorbidity.

The concept of obsessionality: similarities in the obsessive compulsive spectrum

Obsessionality comes form the ancient Latin ‘obsidere’ which means being taken into possession, being occupied or preoccupied. In obsessionality people are focused on a single theme and completely seized by it. For example a mother with obsessive-compulsive disorder could be obsessed with the thought that she could strangle her daughter. The mother is so focussed to this single theme that she’ll forget her surrounding; her attention is narrowed to this single theme. However, one’s obsessionality does not have to be pathological per se. A driven sportsman or politician could be obsessed as well. Where the (neurobiological) boundaries of obsessionality lay, still needs to be defined.

The purpose of this thesis is to investigate disorders in the obsessive-compulsive spectrum to come closer to the concept of obsessionality.

Body Identity Integrity Disorder (BIID)

BIID is a term that covers several conditions in which people feel their body-image does not match with their body shape. For example, some people would like to have their leg to be amputated under their knee, whereas others prefer to resemble someone who is paralysed. BIID is an infrequently described condition, is not included in DSM-IV-TR, and often not known to surgeons, neurologist and psychiatrists.

To learn more about BIID the AMC-Amsterdam Department of Psychiatry has initiated a research study in the Body Identity Integrity Disorder (BIID) and would like to inform everyone (from every country) with this entity about the study and invite them to participate. The study has two aims. The first is to make a phenomenological profile of BIID individuals using a standardized questionnaire. The second aim is to try to find a causative gene or genes in phenomenological identical BIID individuals.

For more information please contact Rianne Blom: r.m.blom@amc.uva.nl.

Inhibitory control over emotions: GABAergic regulation of the amygdala

Appropriate responding to adversity is of vital importance for survival. The key brain structure for the detection of potential threat and learning about dangerous situations is the amygdala. Large interindividual differences in amygdala responsivity exist that predict differences in vulnerability for mood and anxiety disorders. Recent animal studies suggest that GABAergic interneurons control amygdala output and fear learning. In this project, we investigate the role of the GABAergic system in the regulation of fear in humans. To this aim, we combine genetics with several neuroimaging techniques and psychophysiology. We predict that individual differences in the GABAergic system determine amygdala responsivity and the ability to learn about fear and safety. The results may help to explain why some individuals are more vulnerable for the development of mood and anxiety disorders than others.

ADHD: a disconnection between the attentional control and sensory systems of the brain?

Attention is the cognitive ability that permits us to effectively process and act upon relevant information while ignoring the irrelevant. Theories of attention have distinguished between top-down and bottom-up influences on the focusing of attention. In such a framework, the “sources” of attentional control exert influence on a “site” of action which is often the perceptual/sensory system.

Attention deficit hyperactivity disorder (ADHD) is a neurobiological disorder which has attention deficits as one of its key symptoms. In my previous work in children (8-12 years old) with ADHD I found a disconnection between the activity of the sources of attentional control and the sensory processing systems during performance on an attention task. The objective of my current research is to identify the neuronal substrate underlying this disconnection.  Specifically, my aims are to investigate if the disconnection between the activity of frontal control and sensory systems are: (1) present in different age groups of ADHD; (2) related to anatomical abnormalities in the pathways connecting frontal cortical and sensory systems, and (3) restored by using medications typically prescribed for the symptoms of ADHD.

The impact of DBS on the phenomenology of psychiatric patients

Deep Brain Stimulation (DBS) is a relatively new treatment for psychiatric patients and still in an experimental phase. At the AMC, mainly patients with treatment-resistant obsessive compulsive disorder (OCD) and major depression are treated with DBS. The effects of treatment are mostly assessed with functional and psychopathological scales. However, the effects of DBS may go beyond what is measured by these tests: DBS is a powerful intervention that may change the way in which patients experience their world. Especially the patients’ mood and motivation seem to alter.

In order to gain a broader perspective on the possible impact of DBS on the experiences of these patients, I will conduct semi-structured qualitative interviews with the focus on the phenomenological changes that have occurred as a result of DBS treatment. The main goal of this research project is to arrive at a more complete understanding of these phenomenological changes. An important practical motivation is to find out whether the success of treatment could be predicted, e.g. whether a specific type of problems may be more prone to react well to DBS than others. Related to that we can investigate what DBS treatment learns us about the validity of current psychiatric classifications. And lastly the philosophical goal of this research project is to investigate the consequences of these insights for phenomenological theories on what are considered to be normal ways of experiencing one’s world.

Apart from the interviews, I will draw on theories and insights from phenomenology, ecological psychology, emotion theory, enactivism, and cognitive neurosciences.

Global neural networks involved in Deep Brain Stimulation and reward-driven behaviour

The successful treatment of psychiatric disorders with Deep Brain Stimulation likely results from the electrical interference with neural processing in circuits of the reward system. Despite the fact that positive clinical results are currently being obtained with several different stimulation targets, it is still rather unclear which brain structures beyond the local site of stimulation are influenced by DBS of these targets. In this project we will combine DBS with simultaneous neuroimaging (fMRI) in order to map the acute brainwide consequences of local stimulation paradigms. The identified global activity patterns evoked by DBS will then be compared with the networks that are activated by a range of reward-driven behaviours. Finally, we will combine DBS and fMRI with these behavioural measures to record the simultaneous impact of DBS on neural processing and cognitive behaviour. By unraveling the interplay between neural network activity, DBS and behavioural performance, we aim to identify potentially new targets for the clinical application of DBS, refine the procedure by providing an indication of the consequences of particular sites of stimulation, and progress our understanding of the basic neuronal underpinnings of reward sensitivity, motivation, and executive control.

Stress, Habits and Attachment in OCD

People with obsessive-compulsive disorder (OCD) suffer from recurrent distress provoking thoughts (obsessions) and repetitive behaviors (compulsions) aimed at reducing the evoked distress. In severe cases compulsive behavior, like washing and checking could come to dominate daily life of OCD patients, making it a highly invalidating disorder. Although patients with OCD are well aware that their compulsions are senseless and disabling, they are unable to stop. In order to shed more light on etiology factors in OCD, in this interdisciplinary research project, combining clinical psychiatry, neuroimaging and psychoanalysis, we focus on two main questions.

First: How does pathological compulsive behavior develop in patients with OCD? Two apparent opposing theories have been postulated to explain compulsivity. The classical cognitive-behavioral theory posits that the primary function of compulsive behavior is to 'neutralize' the anxiety or distress that originates from obsessional beliefs. However, the recent habit hypothesis of OCD posits that compulsive behavior is due to a deficit in the control over goal-directed actions, leading to increased reliance on habitual behavior. In this fMRI study we aim to integrate these theories. We test the hypothesis that a stress-induced shift from goal-directed towards habitual control underlies compulsive behavior in OCD.

Second: What makes people vulnerable to develop OCD symptoms? The current dominant cognitive behavioral theory explains maintaining and recurrence factors, but does not focus on developmental factors. Attachment theory is suitable to bridge developmental and cognitive viewpoints. Cognitive theory consists of the idea that core beliefs about the self, the world and the future construct dysfunctional beliefs and evoke maladaptive reactions (e.g. OC-symptoms) to intrusions. Early attachment experiences with caregivers shape adult representations about the self and the other/world, or ‘attachment style’. Adult attachment style can be measured along two orthogonal dimensions representing attachment ‘anxiety’ (defining a strong desire for closeness and protection and intense worries about availability of important others) and attachment avoidance (defining discomfort with closeness and dependence, preference for emotional distance and self-reliance) However, the relationship between OCD and attachment, is currently insufficiently investigated. In a cohort of OCD patients we examine attachment style and the correlation with symptoms and treatment response. Furthermore we investigate if the results from the first study are associated with attachment style.

Structural and functional connectivity in attention and motor control

The main focus of my research is attention and response selection. Reacting to relevant information and ignoring irrelevant information requires different brain regions to cooperate. This functional connectivity could arise from neural synchronization of electrophysiological oscillations in brain areas involved during this task. The first objective of my study is to determine the role of oscillations and synchronization in certain frequency bands using MEG/EEG.

Attention deficit/ hyperactivity disorder (ADHD) is a neurobiological disorder which is characterized by deficits in attention and motor control. Symptoms could arise from a disconnection between sensory systems, motor areas, and frontal control regions. The second objective of my research is to investigate this possible functional disconnection using neural synchronization as measure of connectivity.

Research in disorder such as obsessive-compulsive disorder (OCD) is mainly focussed on deficits in high-level-cognitive functions. However, deficits in low-level processes, such as attention, have not been excluded. Low-level deficits could underlie the high-level cognitive deficits found in these patients. Therefore, I will also examine basic attention and response selection in this population.

Misophonia: an imaging study on the neurobiology and the efficacy of cognitive behavioural therapy

Misophonia is a currently underrecognized and uninvestigated condition in which specific sounds, commonly produced by human beings, trigger impulsive aggressiveness in apparently normal people. The intensity of the anger initiates a profound feeling of loss of self-control which causes significant avoidant behaviour that results in limited social contacts and functioning.Recently, diagnostic criteria have been formulated by Schröder, Vulink and Denys to distinguish it as a separate psychiatric disorder. Subsequently, a special group therapy consisting of cognitive behavioural therapy (CBT) and psychomotor therapy (PMT), has been developed in the AMC, which resulted in significant symptom reduction in the majority of the patients.The objective for this study is threefold. The first goal is to objectify differences in brain function between patients and normal controls, using EEG and fMRI. The second objective is to support preliminary findings that the combination of CBT/PMT is an effective treatment for misophonia. The final goal is to determine the genetic and epigenetic factors involved in misophonia and its treatment.

Methodological aspects of genetic analysis.

The influence of genetics in psychiatric diseases can be large. For example, the heritability of schizophrenia has been estimated as 80% based on twin studies.  Advances in DNA techonology make it possible to have a closer look at how genetics influence pyschiatric diseases. This project aims to study and advance methods commonly used to quantify the influence of genetics and apply those methods in the context of psychiatric disease.

Effects of DBS and developmental drug exposure on functional connectivity in rat brain circuits

DBS in CSTC circuits has proven to be an effective treatment in OCD. By conducting fMRI studies (resting state) in awake animals, Maik assesses changes in functional connectivity within CSTC circuits resulting from DBS and optogenetic stimulation in various target areas. In a second project, in collaboration with Dr. Liesbeth Reneman (Radiology, AMC), Maik measures changes in functional brain connectivity after MDMA exposure using phMRI.

Virtual reality GAME for OCD patients

The use of virtual reality (VR) for various mental health problems has grown substantially over the past decade. VR can be applied as a diagnostic or treatment tool or to help clarify the etiology of a disorder. However, to date a proper VR application for obsessive-compulsive disorder (OCD) is still lacking.

We created a VR game for OCD using video images. In this first-person game the player walks around in a family home and gets confronted with situations that could provoke anxiety or distress (for example running gas or a dirty toilet). During the game the player gets the opportunity to intervene while the desire to intervene and the level of distress, insecurity en restlessness is measured on a 0-10 scale. After intervening the player can check the situation as often as desired after which the four dimensions are scored again.

The VR game for OCD patients could have various applications:
The primary focus is to use the game as an instrument to provoke and register symptoms that could help us gain insight in the pathophysiological structure of OCD when, for instance, played in a functional MRI-scanner or during EEG registration.

Secondly, the game could also be used as an actual severity measurement of obsessive and compulsive symptoms. Current severity measurement tools, like the Y-BOCS, measure only retrospectively. This implementation would also make the game viable as an evaluation instrument to assess the effect of OCD treatment in any form.  

Finally, the game could be used in the treatment of OCD by creating an environment in which virtual exposure in vivo can take place. Exposure to situations provoking anxiety and compulsive behavior can precede or even become an alternative to actual exposure in vivo.

TRACE - TRacing genetics of Alcoholism and Comorbid disorders in Extended pedigrees

Alcohol dependence is a highly prevalent disorder that forms a major burden for society. The disease has adverse physical, psychological, and social consequences for patients and their relatives. In the Netherlands, the misuse of alcohol is associated with yearly costs of 2.6 billion euro, including costs related to treatment of alcohol dependence, treatment of health related problems caused by alcohol use, costs of lost productive work time, and costs linked to alcohol-related crimes. Alcohol dependence is a complex trait which is to a large extent influenced by genetic factors. However, despite the high heritability little is known on the specific disease-related genetic variants that contribute to the risk of developing this disorder. The identification of novel genes may therefore increase our understanding of the biological pathways which cause alcohol dependence. This will guide the development of novel treatments and may also provide insight in the efficacy of novel and existing medication. Secondly, knowledge on the disease-related genetic variants can help identification of those individuals who are at increased risk to develop alcohol dependence.

For this study a family based design is used which will allow for the investigation of co-segregation between a genetic marker and a disease within a pedigree and will therefore increase the statistical power to detect rare genetic variants. The goal is to collect data from at least 25 pedigrees in which we aim to include seven to ten first- and second degree family members. In these families we are interested in the associations between alcohol dependence and other psychiatric problems (e.g. OCD and ADHD), other addictions (e.g. gambling, smoking, drugs, eating and internet addiction) and addiction-associated traits (e.g. compulsivity).

Appraising stimulation-induced effects; deep brain stimulation parameter setting optimization in psychiatric disorders

As a chronic and invasive neuromodulatory technique, deep brain stimulation (DBS) essentially comprises two steps. First there is the imaging-guided stereotactic implantation of electrodes in deep brain structures. The second step consists of a trial and error process of optimizing parameter settings in response to the patient’s feedback and clinical scores. As the therapeutic merit of DBS comes down to direct neuromodulation, the optimization of electrical stimulation parameters (voltage, frequency etc) is at least equally important as the neurosurgical targeting of the electrodes. Curiously, this is not reflected in the amount of research presently available.

Optimization currently takes nine months, which leaves the patient at least partially symptomatic for a prolonged period of time. The fact that this is considerably longer than in movement disorders, prompts a distinct approach towards psychiatric indications, as end points are missing and latencies of effect remain unclear. Crucially, there are thousands of potential parameter settings and there is no consensus on how to appraise and anticipate stimulation-induced effects. Furthermore, recent evidence from our department showed that the phenomenology of the patient not only changes with respect to obsessions, compulsions, and fear, but that there are many more DBS-induced changes in phenomenology, including feelings of alienation and increased creativity, that need to be apprehended.

Our aim is to explicate and improve the practice of DBS-parameter setting optimization, and to develop and validate a protocol.Using qualitative methods, we will first investigate how various (inter)national experts on DBS in psychiatric disorders appraise and anticipate stimulation-induced effects. Secondly, we will integrate these findings with previous findings on the patient’s phenomenology and propose a protocol, which we will test on all new OCD-DBS patients, using a randomized controlled trial including standard scales for symptoms and quality of life. The philosophical framework we use to interpret our qualitative data is based on a the central claim of a broader VIDI-project, which holds that what is traditionally referred to as “higher-order” cognitive capacities can, at least with respect to the expert intuition of DBS-therapists, be understood along the same lines as “lower-order” skillful action, such as grasping a coffee cup or riding a bike. Both types of action can be understood in terms of responsiveness to affordances, which are perceived possibilities for action.

Schema-ECT: a novel treatment for severe depression

Hypothesis: We recently found that memories can be weakened by applying electroconvulsive therapy (ECT) shortly after reactivation of a memory (Kroes et al., 2014). This suggests that reactivation of negative schemas just prior to ECT may also weaken those schemas. According to the cognitive theory of depression this will lead to the recovery from depression and will additionally reduce the risk to relapse, but this has not yet been investigated. In this study, we aim to investigate the efficacy of “schema-ECT” and hypothesize that repeated reactivation of depressive schemas prior to ECT weakens negative schemas, increases the efficacy of the ECT course, and reduces the relapse rate after the reduction of the ECT session frequency or discontinuing ECT. In addition to our main aim, we will investigate whether the clinical response to ECT response is associated with changes in neurobiological biomarkers using neuroimaging scans and blood samples obtained from the venous catheter, and whether these biomarkers at baseline can predict treatment response.

Study design: A randomized controlled trial (RCT) is used to determine schema-ECT efficacy.

Neuromodulation and Behavior - Corticostriatal Circuits in Compulsivity

The Neuromodulation and Behavior group headed by Ingo Willuhn studies “compulsivity” and the effects of “deep-brain stimulation” on compulsive behavior. 

Compulsivity is behavior that we perform persistently and repetitively despite the unwillingness to act or despite its negative outcome. To understand its neurobiological basis, we investigate different aspects of compulsivity (i.e., habit formation, response inflexibility, loss of voluntary control, and aggravation by stress and anxiety) and measure neuronal activity in the brain simultaneously.

In therapy-resistant cases of a number of neurological and psychiatric disorders including obsessive-compulsive disorder (OCD) and addiction, deep-brain stimulation (DBS) has been shown to be effective. We study the mechanisms of action of DBS in order to better understand and improve DBS treatment. 

Our research tools include behavioral and genetic animal models as well as methods for intracerebral stimulation (e.g., DBS, optogenetics) in freely moving rodents. Furthermore, we use behavioral tests to study emotional and cognitive behavior, we collect neurochemical and electrophysiological measurements, and we apply pharmacological and functional magnetic resonance imaging (phMRI and fMRI).  

Team members:

Marianne Klanker, Maik Derksen, Isabell Ehmer, Soon-Lim Shin, Chris Klink, Ralph Hamelink, Matthijs Feenstra.

Electrophysiology & Machine Learning

Neural oscillations as can be measured with intra/extra-cranial EEG have been shown to reflect whether a brain region is engaged or inhibited during a task, and by studying them, one can find the brain signatures associated with various cognitive processes. These signatures will not only aid in the understanding of the brain network, but will also allow us to probe the deterioration of each of the networks under certain disorders. This can then in turn result in new treatment protocols that directly approach the brain mechanism underlying the disorder. To detect these brain signatures, I develop novel cognitive tasks and employ machine-learning techniques. These signatures can be used together with closed loop brain computer interfaces and brain stimulation to prevent the progress of or even to treat the disorders.

Efficacy of drug treatment for acute mania across geographic regions

Regulatory authorities are assigned with the task to decide on the market authorization of pharmaceutical products. Since pharmaceutical companies have embraced globalization as a core component of especially clinical trials, regulatory bodies are facing a problem. The globalization of clinical trials means that regulatory bodies now have to evaluate the relevance of studies from different regions and involving populations that may differ from those in their own region. The question arises whether the results of studies from one geographic region can be extrapolated to another region, bearing in mind there might be differences in patient characteristics, environment and culture related factors.

The aim of our study was to investigate whether there are differences across geographic regions in the efficacy of medications for the treatment of the acute manic episode of bipolar disorder, and to investigate whether possible regional differences in effect can be explained by regional differences in baseline characteristics, placebo response or compound distributed.

Furthermore, efficacy trials of medicines for psychiatric disorders, as acute mania, have a higher failure rate than trials of medicines for other medical disorders. One of the most frequently cited reasons for the high failure rate is the relatively high placebo response in trials of psychiatric medications. We examined this placebo response; does it predict treatment effect? What characteristics influence the placebo response and can you predict the placebo response?

We used double-blind randomized, placebo-controlled trials for the indication acute manic episode of bipolar disorder to conduct an individual patient data meta-analysis.