* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download The neuroscience of depression: why does it matter?
Neural oscillation wikipedia , lookup
Haemodynamic response wikipedia , lookup
Brain Rules wikipedia , lookup
Cortical cooling wikipedia , lookup
Activity-dependent plasticity wikipedia , lookup
Adult neurogenesis wikipedia , lookup
Neurophilosophy wikipedia , lookup
Human brain wikipedia , lookup
Neurobiological effects of physical exercise wikipedia , lookup
Eyeblink conditioning wikipedia , lookup
Neuroesthetics wikipedia , lookup
Development of the nervous system wikipedia , lookup
Cognitive neuroscience wikipedia , lookup
Premovement neuronal activity wikipedia , lookup
Nervous system network models wikipedia , lookup
Apical dendrite wikipedia , lookup
Neuroanatomy wikipedia , lookup
Cognitive neuroscience of music wikipedia , lookup
Executive functions wikipedia , lookup
Neuroanatomy of memory wikipedia , lookup
Channelrhodopsin wikipedia , lookup
Neuroplasticity wikipedia , lookup
Metastability in the brain wikipedia , lookup
Spike-and-wave wikipedia , lookup
Environmental enrichment wikipedia , lookup
Affective neuroscience wikipedia , lookup
Optogenetics wikipedia , lookup
Neural correlates of consciousness wikipedia , lookup
Clinical neurochemistry wikipedia , lookup
Aging brain wikipedia , lookup
Feature detection (nervous system) wikipedia , lookup
Neuroeconomics wikipedia , lookup
Molecular neuroscience wikipedia , lookup
Synaptic gating wikipedia , lookup
Emotional lateralization wikipedia , lookup
Limbic system wikipedia , lookup
Orbitofrontal cortex wikipedia , lookup
The neuroscience of depression: why does it matter? Dr Susan Mizen Exeter Mark Solms and the Freudian Brain Neuroscience and the clinical features of depression Clinical features Neural correlates and decreased drive Anhedonia Highly simplified. The SEEKING system Reduced energy The HPA axis Memory problems Hippocampus dysfunction Attention and cognitive impairment Hippocampus, prefrontal cortex and anterior cingulate Anxiety Amygdala and related regions Immune dysfunction HPA dysregulation implicated. Brain regions implicated in depression dorsolateral PFC (DLPFC) orbital PFC (OFC) ventrolateral PFC (VLPFC) anterior cingulate amygdala hippocampus from Davidson et al 2002 One overarching system ties many regional disruptions together: HPA axis and the stress response immediate response (seconds) adrenaline (norepinephrine): blood from viscera to muscles increase fuel availability increase attention decrease pain perception longer-term response (min-hr) cortisol: increase glucose formation increase cardiac contractility suppresses inflammation and other immune activity (prevents genes from being replicated) supports memory formation (sensitizes amygdala and hippocampus) Findings linking stress and depression Depressed patients have: • high levels of circulating cortisol • impaired negative feedback (suppression test) • elevated levels of CRF in CSF • increased number of CRF-secreting neurons • CRF binding sites reduced in frontal cortex • dysregulated circadian cortisol patterns • reduced hippocampal volume • increased amygdala sensitivity Dysregulation caused by early life stress Maternal separation and similar protocols (in rats) associated with: • increased CRF mRNA • sensitization of CRF neurons • hippocampal atrophy • decreased glucocorticoid receptor density in HC and PFC • increased locus coeruleus (NA) activity • decreased GABA/BZ binding • decreased oxytocin binding Early life stress and depression Dep. ELS Not all depressed people have a history of ELS Not all people with history of ELS are depressed However, HPA dysregulation is clearly linked to ELS and ELS clearly linked to depression SEEKING system • evidence that DA modulates appetitive positive affect • “High” associated with DA activity in ventral striatum • “High” attenuated by DA antagonism • DAT polymorphism associated with diminished high • Extroversion associated with DA functioning • Dysphoria of DA antagonists associated with DA binding • Drugs of abuse increase DA in Nacc • Depression associated with dysregulation of DA/SEEKING system and, of course, reduced motivation. The value cycle Amygdala = Reward encoding Overall Function: Adjusts reward/punishment expectations according to evolving contingencies Mobilizes autonomic nervous system Balleine (2006) Trends Neurosci 29 272 OFC = Improved Amygdala Learns associations between primary and secondary reinforcers. Idealization/Devaluation is likely implicated here. Primary reinforcers (taste, touch) encoded in posterior regions; more abstract (secondary) reinforcers (attachment figures) encoded in anterior regions; hierarchical processing. OFC encodes pleasure DLPFC = Control DLPFC: Control functions OFC: Reward (and punishment) encoding Euthymia: When control is on and punishment is off. Depression: When punishment is on and control is off Mayberg (1999) Reciprocal limbic-cortical function and negative mood: Converging PET findings in depression and normal sadness. Am J Psych 156:5 675-682 Both transient sadness & depression have increased ACC and decreased DLPFC activity simultaneously; this reverses in neutral mood and remission respectively. ACC = Conflict Detection ACC is itself subdivided: - Dorsal ‘Cognitive’ division (red) - Ventral ‘Affective’ division (blue); “Activated in conflict between incompatible streams of information. Following conflict detection, the lateral prefrontal cortices… are engaged to resolve the conflict.” (Van Veen and Carter, 2002) - May also be involved in post hoc error detection - Can function consciously and unconsciously ACC activation in social exclusion ACC is active -- and subjective distress reported -- when we think we have been purposely neglected by others, but not when we think their neglect is inadvertent. Eisenberger (2003) Does Rejection Hurt? An fMRI study of social exclusion. Science 302: 290-292 The PANIC system The PANIC system Putting it all together Control DLPFC OFC Reward Conflict & Advertising + ACC Amygdala Reward VTA/NA Putting it all together Anterior Cingulate DLPFC Suppression Abstract pl. / unpl./ guilt OFC + Conflict / discrepancy from ideal Pleasure/ Unpleasure Amygdala Libido Key NTs in MDD • • • • • • Nestler (2002) Neuron 34 13-25 Locus Ceruleus (LC) produces Norepinephrine (NE) Ventral Tegmental Area (VTA) produces dopamine (DA) Dorsal Raphe Nuclei (DRN) produce serotonin (5-hydroxy tryptophan or 5-HT) GABA: inhibitory interneurons Glutamate: excitatory NT from pyramidal cells GABA Major inhibitory NT in mammalian brain; 40% of all neurons produce GABA! Primarily interneurons – eg local circuits – and particularly abundant in mood-related regions Pyramidal (output) neurons: Each GABA neuron innervates ~3,000 pyramidal cells Li, Depakote, gabapentin, topirimate, lamotrigine, SSRIs all increase plasma GABA. GABA density reduced in MDD, and in plasma and CSF Source: Taylor et al (2003) Psychologocial Medicine 33 387-393 Glutamate • Major Excitatory NT of brain; caffeine works via Glu • Allows Na+ influx, hyperpolarizing cell (bringing it closer to firing) • Activates NMDA receptors (cortex, amygdala, hippocampus, BG) involved in LTP (long term potentiation) • Released by Pyramidal cells of cortex (80% of neurons of cortex!) • Reabsorbed through active transport; recycled and reused • GABAergic interneurons: 40% of all neurons in cortex! • 1 GABA: 1000 Pyramidal (permits oscillating coordination) Amygdala GABA Pyr Prefrontal Cortex Hippocampus + • Serotonin is major excitatory input to cortical, amygdala, and hippocampal GABA interneurons = dampens activity • In turn, pyramidal neurons are major excitatory input to DRN GABA interneurons = dampens the dampening Glutamate + • Negative Feedback loop 5-HT GABA Taylor et al (2003) Psychological Medicine 33 387-393 Dorsal Raphe Nuclei Overview Serotonin dampens cortical, amygdala and hippocampal activity in pyramidal cells, via GABA Medications that increase GABA and 5-HT may potentiate this inhibition If these regions are biased towards punishment encoding, they can provide relief If they help to grow more neurons (via BDNF), they can improve information processing BDNF and neurogenesis Hippocampus reduces in size in MDD, regains in treatment BDNF (brain derived neurotrophic factor) modulates hippocampal plasticity, and triggers both increased dendritic sprouting, synaptic creation, and neurogenesis ADs are known to increase BDNF and lead to increased size of hippocampus and frontal cortex Nestler (2002) Neuron 34 13-25 Overview GABA suppresses processing in amygdala, cortex Serotonin potentiates GABA, therefore suppresses processing in amygdala, cortex Both can suppress ‘punishment’, social pain and distress calculations BDNF boosts neural networks ? If the brain is biased towards calculating punishments, improving function may mitigate this bias S allele predisposes to ‘exogenous’ depression Caspi (2003) Science 301 386 S-allele Dose-dependent amygdala activity Bertonino (2005) Biol Psych 57 1517-1525 No of s alleles: 0, 1 or 2 s-alleles Activity on a negative emotion perception task Amygdala activity was predicted as a fx of No s alleles! Putting it all together Anterior Cingulate DLPFC Suppression Abstract pl. / unpl./ guilt OFC + Conflict / discrepancy from ideal Pleasure/ Unpleasure Amygdala Libido Depression Subtypes Typical Poor sleep, no appetite, low mood, (melancholic) ruminations, anhedonic Atypical Rejection sensitive, hedonic, high sleep, high appetite Alexithymic Hostile Anxious Psychotic Profuse somatic sx (pain, HA, GI) and denial of psychological sx Irritable, rage attacks + depression, often atypical MDD + GAD, often with trembling, pacing, obsessions, ‘lady MacBeth’ Loss of reality testing + MDD Therapeutic implications? Mourning and Melancholia Revisited 2008: Carhart-Harris, Mayberg, Malizia and Nutt Panksepp’s three innovations: Reducing pain and increasing pleasure Intervening with: PANIC (promoting excessive sadness and grief) SEEKING (promoting enthusiasm) PLAY (promoting social joy) To regulate depressive affect through: (a) reducing PANIC, namely, “psychic pain” with buprenorphine; (b) facilitating enthusiasm with deep brain stimulation of SEEKING (c) facilitating social joy (PLAY) GLYX-13, a partial agonist of glycine receptors) currently in successful human testing. Therapeutic perspective Centrality of loss and separation in depression How loss is grieved for (Mourning)or defended against (Melancholia) in the mind. (Freud, S. 1917) How do therapies work? Adshead and Fonagy (2012) Therapy Brain Area Cognitive Therapy Dorsal prefrontal cortex, medial prefrontal cortex. Reflective Therapy Anterior cingulate cortex, Posterior cingulate cortex, Precuneus and Insula. Amygdala Behavioural Therapy