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Contains the following key public domain (not copyrighted) U.S. Government publication(s) on one CD-ROM in both Microsoft PowerPoint and Adobe Acrobat PDF file formats: TITLE: Defining Neurocircuits in Depression , 45 pages (slides) SLIDE TOPICS, SUBTOPICS and CONTENTS: Defining Neurocircuits in Depression CPT Gabriel Cuka MC USAR June 2006 Journal Article Mayberg HS. Defining Neurocircuits in Depression. Psychiatric Annals. 2006;36(4):259-268. April 2006 Major Depression Treatment “…no clinical or biological markers identify which patients are likely to respond to a given treatment or explain why one treatment modality or class of medication is effective when another is not.” Treatment Modalities Pharmacotherapy Cognitive-Behavior Therapy (CBT) Deep Brain Stimulation (DBS) Augmentation Combination New Somatic Therapies Repetitive transcranial magnetic stimulation (rTMS) Vagal nerve stimulation (VNS) Deep brain stimulation (DBS) Circuit Model of Depression “…a major depressive episode is defined by the pattern of dysfunctional interactions among specific cingulate, paralimbic, subcortical, and frontal regions critical to maintaining emotional homeostasis under conditions of exogenous or endogenous stress.” The Triune Brain Paul D. MacLean [1990], Neurologist Reptilian Mammalian Human Overlap Reptilian Brain Archipallium Survival, homeostasis, fear, feeding Dominance, submission Autonomic nervous system, reflexes Brainstem, caudate, putamen, globus pallidus, cerebellum, medulla, olfactory bulbs, amygdala Mammalian Brain Paleopallium Emotions, mood, feelings Limbic system: amygdala, thalamus, hypothalamus, cingulate gyrus, hippocampus Human Brain Neopallium Problem solving, ability to learn, creativity 80% of human brain Cortex of mouse is relatively small and is not convoluted Assumption “…depression is unlikely a disease of a single gene, brain region, or neurotransmitter system. Rather, it is conceptualized as a systems-level disorder affecting select cortical, subcortical, and limbic regions and their related neurotransmitter and molecular mediators.” Structure-Function Correlations 1 Acquired brain lesions and neurodegenerative disorders Frontal cortex Striatum Structure-Function Correlations 2 Structural abnormalities in primary affective disorders Amygdala Hippocampus Orbital frontal cortex Prefrontal cortex Structure-Function Correlations 3 Comparative cytoarchitectural and connectivity studies in animal models Cingulate gyrus Other limbic structures Frontal cortex Striatum Thalamus, hypothalamus Brainstem System Dysfunction “A major depressive episode is further viewed as the net result of failed regulation of this integrated system under circumstances of cognitive, emotional, or somatic stress.” Pathological Syndrome Sustained negative mood Disturbed motivation Disturbed motor performance Disturbed cognition Disturbed circadian functions Model Flexibility Contributing factors Genetic vulnerability Affective temperament Developmental insults Variability in presentation View of Treatments “…different modes of treatment modulating distinct neural targets, resulting in a variety of complementary chemical and molecular adaptations and homeostatic effects that re-establish a normal mood state.” Integrated Findings Functional neuroimaging studies of depression (in humans) Published nonhuman primate anatomical, electrophysiological, and tract-tracing experiments Included Are Data From Experiments On… (1 of 2) Specific brain lesions and neurological disorders Blood flow changes in resting state patterns of regional metabolism in patients with primary depression Changes in metabolism with various types of antidepressant treatments Included Are Data From Experiments On… (2 of 2) Studies of acute mood change and emotional processing in healthy volunteers and various patient and at-risk populations PET: resting state blood flow and glucose metabolism measures Attempting to Correlate Groups of abnormal-appearing anatomical regions Symptom clusters of depression Symptom Clusters of Depression Mood State Cognitive Processing: attention, memory, action Emotion-Cognition Integration: salience, self-reference, reinforcement Autonomic Responses: arousal, vegetative, circadian, internal milieu Cingulate Gyrus Brodmann’s Area 25 Deep Brain Stimulation Abnormalities 1 “frontal and cingulate abnormalities are most commonly reported” “most robust and best-replicated finding is that of decreased frontal lobe function, although normal frontal as well as frontal hyperactivity also has been reported” Abnormalities 2 “The best-replicated behavioral correlate of a resting state abnormality in depression is that of an inverse relationship between prefrontal activity and depression severity.” Dysregulated “Network” Activity Foci of primary dysfunction Sites of adaptive (and maladaptive) compensatory processes Failure to initiate or maintain compensatory response Pharmacotherapy “bottom-up” Aminergic reuptake inhibition and associated presynaptic autoregulatory desensitization Upregulation and downregulation of multiple post-synaptic receptor sites Receptor-mediated second messenger and neurotrophic intracellular signaling effects Paroxetine & Fluoxetine Increases in Activity Frontal (cortical, human) Parietal (cortical, human) Posterior cingulate (limbic, mammalian) Brainstem (subcortical, reptilian) Decreases in Activity Subgenual cingulate (limbic, mammalian) Hippocampus (limbic, mammalian) Thalamus (subcortical, mammalian) Striatal (subcortical, reptilian) Psychotherapy “top-down” “…focuses on modifying attention and memory functions involved in the mediation of depression-relevant explicit cognitions, affective bias, and maladaptive information processing…” Cognitive-Behavioral Therapy Decreases in Activity Frontal (cortical, human) Parietal (cortical, human) Posterior cingulate (limbic, mammalian) Increases in Activity Mid-cingulate (limbic, mammalian) Hippocampus (limbic, mammalian) Time Course “…neural adaptation in specific brain regions with chronic treatment.” SSRI: “…early brainstem and hippocampal changes and late cortical effects.” CBT/IPT: “…prefrontal changes occur early with psychotherapy.” Structural Equation Modeling Meta-analysis of baseline PET scans Predefined seven-region model structure Strength and direction of effective connections between the regions FINDING: “…significantly different baseline patterns of best fit for different subgroups of patients defined by response outcome.” References 1 Deep Brain Stimulation for Treatment-Resistant Depression: An Expert Interview with Helen S. Mayberg, M.D. Available online at http://www.narsad.org/news/press/pr2006-03-20.html (accessed 06/07/2006) References 2 Goldapple K, Segal Z, Garson C, Lau M, Bieling P, Kennedy S, Mayberg H. Modulation of cortical-limbic pathways in major depression: treatment-specific effects of cognitive behavior therapy. Arch Gen Psychiatry. 2004 Jan; 61(1):34-41. References 3 Mayberg HS, Lozano AM, Voon V, et al. Deep brain stimulation for treatment-resistant depression. Neuron. 2005;45:651-660. Available online at http://www.neuron.org/content/article/fulltext?uid=PIIS089662730500156X (accessed 06/07/2006) References 4 Mayberg HS, et al. The Functional Neuroanatomy of the Placebo Effect. Am J Psychiatry 159:728-737, May 2002. Available online at http://ajp.psychiatryonline.org/cgi/content/full/159/5/728 (accessed 06/07/2006) -->
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