Neural response to pleasant stimuli in anhedonia: an fMRI study MartinaT. Mitterschi¡thaler,Veena Kumari, 1,2 Gin S. Malhi, 3 Richard G. Brown, 2 Vincent P. Giampietro, 4 Michael J. Brammer, 4 John Suckling, 5 Lucia Poon, 6 Andrew Simmons, Christopher Andrew and Tonmoy Sharma 7,CA Neuroimaging Research, Department of Neurology; 1 Section of Cognitive Psychopharmacology; 2 DepartmentofPsychology; 4 Brain Image Analysis Unit, Institute of Psychiatry,King’s College,London,UK; 3 School of Psychiatry,University of New SouthWales, Sydney, Australia; 5 Brain Mapping Unit, University of Cambridge,Department of Psychiatry, Addenbrooke’s Hospital,Cambridge; 6 South London and Maudsley NHS Trust,London; 7 Clinical Neuroscience Research Centre, 7 Twisleton Court, Priory Hill, Dartford, Kent, DA12EN,UK CA Corresponding Author: t.sharma@psychmed.org.uk Received 8 November 2002; accepted11December 2002 DOI:10.1097/01.wnr.0000053758.76853.cc The aim of this study was to investigate the neural correlates of a¡ectprocessingindepressedanhedonicpatients andhealthy con- trols. Whole brain functional magnetic resonance imaging scans were obtained from seven females with a diagnosis of chronic uni- polar major depression and high levels of anhedonia, and seven healthy females, while they were presented with positive valence and neutral images. Patients, compared to controls, showed decreased activation in medial frontal cortex, and increased activation in inferior frontal cortex, anterior cingulate, thalamus, putamen and insula. Reduced activation in medial frontal cortex may underlie abnormal positive a¡ect processing in patients. In- creases in neural activation in putamen and thalamus, previously found in transient sadness, and anterior cingulate could point to an involvement of these structures in anhedonia. NeuroReport 14:177^182  c 2003 Lippincott Williams & Wilkins. Key words: A¡ectprocessing; Anhedonia; Anterior cingulate; Depression; fMRI; Medial frontalgyrus;Thalamus INTRODUCTION Anhedonia, a core symptom of major depression, describes diminished ability to derive pleasure from universally pleasant sensory stimuli [1]. Dysfunction of the dopamin- ergic brain system, associated with the experience of positive emotions or reward, may contribute to the symptoms of anhedonia [2,3]. Neuroanatomically, the relationship between the normal experience of pleasure and the clinical phenomenon of anhedonia in depression has not yet received formal investigation. It is unclear whether anhedonia is associated with a simple lack of activation in brain regions normally associated with generation of pleasure, or with additional abnormal activity in brain regions not found in normal subjects. Attempts to elucidate neural substrates of positive affect processing have focused on healthy subjects [4,5], whereas research into depression has mainly investigated processing of negative affective information. Brain regions associated with processing of positive affective stimuli in healthy subjects include left caudate, medial prefrontal cortex, thalamus, hypothalamus, midbrain, right and left insula, right inferior frontal gyrus, left splenium, and left precuneus [4–6]. This study investigates affect processing in female patients with a diagnosis of chronic unipolar major depression and high levels of anhedonia, and healthy females. The emotion–activation paradigm required subjects to view positive valence and neutral pictures (International Affective Picture System (IAPS)) [7] while scans were performed. We expected to find medial frontal activation during positive valence stimuli in controls, which has been consistently reported in studies using different means of emotional stimuli, and altered activation in depressed patients in brain regions associated with processing of positive compared to neutral pictures. MATERIALS AND METHODS Subjects: Seven right-handed females (mean (7 s.d.) age 46.3 7 8.1 years); with a DSM-IV [8] diagnosis of chronic (treatment-resistant) unipolar major depression were re- cruited from the South London and Maudsley NHS Trust, London. For this diagnosis, full criteria for a major depressive episode have to be met over a period of Z 2 years. Patients received adequate and stable doses of antidepressants (monoamine-oxidase inhibitors, selective serotonin reuptake inhibitors, tricyclic antidepressants). 0959-4965  c Lippincott Williams & Wilkins Vol 14 No 2 10 February 2003 177 BRAIN IMAGING NEUROREPORT Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.