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 Anhedonia and decreased drive Highly simplified. Reduced energy Memory problems Neural correlates The SEEKING system The HPA axis Hippocampus dysfunction Attention and cognitive impairment Anxiety Immune dysfunction Hippocampus, prefrontal cortex and anterior cingulate Amygdala and related regions HPA dysregulation implicated.
Brain regions implicated in depression orbital PFC (OFC) ventrolateral PFC (VLPFC) dorsolateral PFC (DLPFC) amygdala anterior cingulate 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): cortisol: blood from viscera to muscles increase fuel availability increase attention decrease pain perception longer-term response (min-hr) 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 + Conflict & Advertising ACC OFC Reward Amygdala Reward VTA/NA
Putting it all together DLPFC Suppression + Anterior Cingulate Conflict / discrepancy from ideal Abstract pl. / unpl./ guilt OFC 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) GABA + Pyr Amygdala 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 Negative Feedback loop + Glutamate 5-HT GABA Dorsal Raphe Nuclei Taylor et al (2003) Psychological Medicine 33 387-393
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 DLPFC Suppression + Anterior Cingulate Conflict / discrepancy from ideal Abstract pl. / unpl./ guilt OFC Pleasure/ Unpleasure Amygdala Libido
Depression Subtypes Typical (melancholic) Atypical Alexithymic Hostile Anxious Psychotic Poor sleep, no appetite, low mood, ruminations, anhedonic Rejection sensitive, hedonic, high sleep, high appetite 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 Cognitive Therapy Reflective Therapy Behavioural Therapy Brain Area Dorsal prefrontal cortex, medial prefrontal cortex. Anterior cingulate cortex, Posterior cingulate cortex, Precuneus and Insula. Amygdala