Modelling human habenula-5-HT2C interactions with high field-strength (7T), high-resolution pharmacological FMRI

Lead Research Organisation: University of Oxford
Department Name: Psychiatry

Abstract

Depression is a serious and debilitating disease that can affect as many as 1 in 4 people at some point in their life. Despite the devastating impact of depression on individuals and society, we know very little about what happens in the brain when a person becomes clinically depressed, or how antidepressant medications work.

We do know that serotonin, one of the brain?s chemical messengers, is important in controlling our mood (how happy or sad we are) and most of the drugs used to treat depression act on serotonin. What we do not know is why it can take many weeks for a person to feel better once they start taking an antidepressant, or why some people respond very well to treatment while others respond poorly or not at all.

The principal aim of the current research proposal is to better understand what antidepressants do in the brain and how we can make them more effective. We have shown that a very small and largely ignored part of the brain called the habenula is very important in controlling the levels of serotonin in the brain, especially when people first start to take antidepressants. Part of our research will look at this control pathway using Functional Magnetic Resonance Imaging (a technique that allows us to ?see? where the brain is active) to investigate if drugs that act in a particular way on the serotonin system also change the way this pathway functions. If we can ?switch off? this control pathway we may be able to make antidepressant drugs that work more quickly.

The habenula is also involved in motivation and reward, and some depressed patients lack drive and often show reduced or blunted responses to rewarding events (psychiatrists call this anhedonia). These anhedonic patients are also sometimes the most difficult to treat. Dopamine, another of the brain?s chemical messengers, is very important for reward processing and we think that the habenula may control the release of dopamine through interactions with serotonin. Another part of our research will look at these dopamine/serotonin interactions with Functional Magnetic Resonance Imaging. If we can understand how the habenula interacts with dopamine, we may be able to better help those depressed patients who have very high levels of anhedonia.

Technical Summary

Major depressive disorder (MDD) is the most common single psychiatric disorder worldwide and is associated with a high level of functional disability and impaired quality of life. Current first-line pharmacotherapies for MDD (e.g selective serotonin reuptake inhibitors [SSRIs]), while superior to placebo, frequently fail to render patients symptom free and there is a troublesome delay between starting medication and reported improvement in mood. There is a critical need therefore to identify novel antidepressant targets and develop improved treatment strategies. One possible therapeutic target that has attracted a great deal of interest recently is the habenula complex (Hb), a small structure located at the posterior-dorsal-medial end of the thalamus. Habenula efferents project to the dopaminergic ventral tegmental area (VTA) and the 5-HTergic dorsal raphe nucleus (DRN) where they act to inhibit cell firing. The Hb, therefore, is uniquely positioned both anatomically and functionally to play an important role in the regulation of both 5-HT and dopamine and, consequently, in the aetiology and pathophysiology of MDD and the therapeutic effects of antidepressants. The pharmacology of these control pathways is not yet fully understood, however recent preclinical work indicates a key regulatory role for the 5-HT2C receptor. The aim of the current proposal, therefore, is to use high-field (7T) high-resolution (voxel size 1mm3) Functional Magnetic Resonance Imaging (FMRI) in combination with the selective 5-HT2C agonist m-chlorophenylpiperazine (mCPP) to model Hb-DRN and Hb-VTA connectivity. We will use a randomised, placebo-controlled, within-subjects design. Participants (20 right-handed healthy volunteers) will attend two sessions separated by at least one week. At the first visit participants will receive either intravenous mCPP (0.08mg/kg) or saline placebo and the other infusion at the second visit. At each session participants will undergo a resting pharmacological challenge scan (phFMRI). We predict that: 1) Following mCPP challenge, Hb blood oxygenation level-dependent (BOLD) response will inversely correlate with that of the midbrain raphe region; and 2) Following mCPP challenge, Hb BOLD response will inversely correlate with that of the midbrain DRN and VTA. It is anticipated that our results will greatly increase our current understanding of the role of the Hb in 5-HT and dopamine homeostasis and may lead to advances in antidepressant treatment strategies.

Publications

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Title Habenula 
Description Imaging the human habenula is challenging. The relatively small size of these nuclei mean that commonly used FMRI protocols have insufficient resolution and signal-to-noise ratio. Here, in our ongong project, we have combined very high-resolution FMRI with a simple reward task to first functionally localise the human habenula. In a novel step we then use these data to image habenula-dorsal raphe (Hb-DRN) and habenula- ventral tegmental area (Hb-VTA) feedback pathways with and without pharmacological manipulation. Several pharmaceutical companies have interest in, or have a program of research into, 5-HT2C receptors as potential new treatments for depression and schizophrenia. Our human model of Hb-DRN and Hb-VTA feedback would, therefore, be extremely useful in the screening and characterisation of novel investigational products prior to randomised controlled trials for these disorders. 
Type Of Material Data analysis technique 
Provided To Others? No  
Impact Our human model of Hb-DRN and Hb-VTA feedback will likely be extremely useful in the screening and characterisation of novel investigational products prior to randomised controlled trials. 
 
Description Partnership with Pharmacology 
Organisation University of Oxford
Department Department of Pharmacology
Country United Kingdom 
Sector Academic/University 
PI Contribution We have contributed our imaging expertise which has facilitated the translation of animal models of antidepressant action to work in humans
Collaborator Contribution Our partners have pioneered the development of animal models of antidepressant action and laid down some of the key anatomical pathways implicated in antidepressant response. Data that are invaluable if we are to develop new improved treatments for depression
Impact This project is ongoing (completion date February 2013). This collaboration is multi-disciplinary including Psyciatry, Pharmacology and Psychology.
Start Year 2010
 
Description Schools 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Type Of Presentation Workshop Facilitator
Geographic Reach Local
Primary Audience Schools
Results and Impact We are committed to public engagement of science. As an example we have hosted, on two occasions, 6th form pupils from local schools. The pupils attended the University of Oxford Centre for Clinical Magnetic Resonance Research (OCMR) and were were given a demonstration of the scanner in action, a 30-45 imin general presention on MagneticResonance Imaging (MRI) and an MRI data analysisdemonstraion. The pupils were also asked to work in small groups and develop their own FMRI experiment 'Which areas of the brain process colour'? The aim being to encourage the pupils to think about experimental design in general and also to think about what you can and cannot do with an MR scanner.

We have also hosted, on two seperate occasions, undergraduate psychology students from Oxford Brookes University.

Feedback provided by the teachers, lectures and pupils has been very positive. It is anticipated that similar presentations/workshops will continue and remain popular.
Year(s) Of Engagement Activity 2009