Basic definition and Classification of Anhedonia. Preclinical and Clinical assessment of anhedonia.

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3 Basic definition and Classification of Anhedonia. Preclinical and Clinical assessment of anhedonia. Neurobiological basis and pathways involved in anhedonia. Objective characterization and computational models. TRANSLATIONAL NEUROMODELING AND COMPUTATIONAL NEUROECONOMICS SEMINAR HS 2013

4 Anhedonia as a psychopathological symptom was first noted in the early 19th century. Haslam, who documented the first complete study of a psychiatric patient in 1809, noted a neglect *of+ those objects and pursuits which formerly proved sources of delight and instruction. The term anhedonie was later introduced by the French psychologist Ribot in 1896 to describe the counterpart to analgesia in his patients, for whom it was impossible to find the least pleasure. Nonetheless, the term anhedonia was subsequently seldom used to describe general signs of apathy and lack of interest. TRANSLATIONAL NEUROMODELING AND COMPUTATIONAL NEUROECONOMICS SEMINAR HS 2013

5 Anhedonia is a core symptom of Major Depressive Disorder (MDD). The DSM-IV-TR defines anhedonia as diminished interest or pleasure in response to stimuli that previously perceived as rewarding. Along with depressed mood, anhedonia is one of two required symptoms for a diagnosis of MDD. Anhedonia is a particularly difficult symptom to treat because of its enormous heterogeneity, like: i) Diagnostic heterogeneity. ii) Etiological heterogeneity. iii) Symptom heterogeneity. Translation research approach is necessary to tease apart these multiple form of heterogeneity, which is critical for elucidating the neurobiological pathways involved in anhedonia and improving the treatment quality. TRANSLATIONAL NEUROMODELING AND COMPUTATIONAL NEUROECONOMICS SEMINAR HS 2013

6 Beats et al. asked depressed patients and control subjects to perform the Tower of London planning task. Depressed patients performance deteriorated with the number of mistakes. Other studies also confirmed the abnormal processing of negative feedback in depressed patients which could explain learned helplessness. In addition to maladaptive reactions to aversive stimuli, depressed individuals exhibit blunted responses to rewarding information, possibly representing a deficit in the approach related or appetitive system. These studies emphasized the role of reward related processing & reinforcement learning in anhedonia. TRANSLATIONAL NEUROMODELING AND COMPUTATIONAL NEUROECONOMICS SEMINAR HS 2013

7 Anhedonia can be broadly classified on the basis of reward processing components into Consummatory anhedonia (CA), Motivational anhedonia (MA) and Decisional anhedonia (DA). CA arises due to the dysfunction of hedonic response to reward, it reflects the basic sensitivity to reward ( How pleasant the reward is ). MA arises due to dysfunction of reinforcement learning mechanism, which may be due to following abnormalities: i) Associating the relative values & costs with rewards. ii) Determining the effort required to obtain the reward & integrating it with the previous outcomes. DA arises due to impaired decision making capability in a goal directed actions for reward. TRANSLATIONAL NEUROMODELING AND COMPUTATIONAL NEUROECONOMICS SEMINAR HS 2013

8 Neural Circuits sub-serving these reward related process involve Ventral Straitum, Prefrontal Cortex (PFC), Orbitofrontal Cortex (OFC), Anterior Cingulate Cortex (ACC). Prediction, anticipation and motivation are mediated by ventral tegmental area, amygdala and ventral striatum. Ventral Straitum and OFC Contribute to experiences of pleasure. In particular, opioid and endocannabinoid receptors in the nucleus accumbens (NAc) and ventral pallidum mediate hedonic perception of rewards. ACC receives input from the OFC, determines the effort required to obtain rewards. Dorsal ACC neurons encode previous reward outcomes that guide future decisions. Reward value and effort information is then integrated in vmprc and dlpfc to make decision on goal directed action. TRANSLATIONAL NEUROMODELING AND COMPUTATIONAL NEUROECONOMICS SEMINAR HS 2013

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10 Monoamines are linked to reinforcement learning and reward related process. In particular, three monoamine subgroups have shown to play a crucial role in depression, namely: i) Seretonin. ii) Dopamine. iii) Norepinephrine. Manipulating serotonin levels through either tryptophan depletion or selective serotonin reuptake inhibitor (SSRI) administration changes how healthy individuals respond to rewards and punishments. Intracranial self-stimulation in rats to single-cell recording in monkeys and neuroimaging in humans have demonstrated a role for dopamine in reward and motivation TRANSLATIONAL NEUROMODELING AND COMPUTATIONAL NEUROECONOMICS SEMINAR HS 2013

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31 Anhedonia is not just about perception of the reward. Detailed analysis of various reward related process with computational modeling and animal models can unearth the neurobiological underpinnings. Targeting specific neural pathways would help in better diagnosis & treatment of anhedonia. TRANSLATIONAL NEUROMODELING AND COMPUTATIONAL NEUROECONOMICS SEMINAR HS 2013

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33 To test the role of VTA dopamine neurons in depression in real time with bidirectional manipulation of dopamaine neurons. Optogentic manipulation of specific dopaminergic pathways to elucidate their effect on specific depression like phenotype. Expressing enhanced halorhodopsin (enphr3.0) in VTA tyrosine hydroxylase (TH)- expressing dopamine neurons. enphr was fused with eyfp. In the context of depressive phenotypes, motivation is assayed by presenting rats with Tail Suspention Test (TST) & Forced Swim Test (FST), and quantifying the proportion of time spent immobile. TRANSLATIONAL NEUROMODELING AND COMPUTATIONAL NEUROECONOMICS SEMINAR HS 2013

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