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The Neurobiology of Mood Disorders

The Neurobiology of Mood Disorders. Professor Keith Matthews October 2013. Learning Outcomes. to gain an understanding of what may be altered in the brain (and elsewhere) during disordered mood states to be aware of some of the key neurobiological findings in depression

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The Neurobiology of Mood Disorders

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  1. The Neurobiology of Mood Disorders Professor Keith Matthews October 2013

  2. Learning Outcomes to gain an understanding of what may be altered in the brain (and elsewhere) during disordered mood states to be aware of some of the key neurobiological findings in depression to appreciate the potential for such findings to inform prediction, prevention, and treatment

  3. Core Clinical Problems Altered Mood Anxiety Arrested Intellectual Development Behavioural Problems in Adults Deliberate Self Harm Eating Disorders Medically Unexplained Symptoms Memory Problems Misusing Drugs or Alcohol Psychological Responses to Trauma Psychosis

  4. Synopsis • a brief review of the neural substrates for emotional behaviour. • how altered functioning might generate symptoms • a brief review of research identifying substrates differentiating the MDD brain from non-MDD brain. • overview of major neurobiological findings in patients with mood disorders

  5. food warmth water sex defense / safety

  6. What do I need to enable me to survive (& reproduce)? to identify stimuli predicting appetitive or aversive consequences to generate behavioural and other physiological responses to such stimuli (emotions!) to integrate behavioural and other physiological responses to such stimuli

  7. Appetitive / Approach Systems function to mediate seeking and approach behaviours (incl. pleasure) ascending dopamine systems – mesolimbic/cortical projection ventral striatum dorsal striatum (movement) amygdala (conditioning / learning) anterior cingulate (attention / conflict / response selection) orbitofrontal cortex (relative reward preference / rule learning) Aversive / Defensive Systems function to promote survival in event of threat (fear / pain) ascending serotonin systems NA / CRF / peptide transmitters central nucleus of amygdala hippocampus ventroanterior and medial hypothalamus periaqueductal gray matter Functional Differentiation in the Brain

  8. Functional Differentiation in the Brain • Appetitive/ Approach Systems • Aversive/ Defensive Systems

  9. similar to many other syndromes…

  10. Core symptoms of Major Depression • Low mood • Anhedonia • Anergia

  11. Other symptoms (ICD-10) • reduced concentration and attention • reduced self esteem and self confidence • ideas of guilt and unworthiness • bleak and pessimistic views of the future • ideas or acts of self harm or suicide • disturbed sleep • diminished appetite

  12. difficulty identifying “rewarding” stimuli reduced contact with previously rewarding stimuli increased contact with aversive stimuli overall reduction of behaviour move less, eat less, lose weight(?), less sexual… dysphoric mood?? Disordered “Appetitive Functioning” From Biology to Prediction of Symptoms - Depression • attention / concentration ? • loss of interest? • avoidance? • inactivity, anhedonia, weight change, loss of sexual drive

  13. previously neutral stimuli become “rewarding” increased exploration / overall activity increased “appetite” for food, activity, sex etc…. intolerant of “aversion” / boredom intolerant of frustration elevated / elated mood?? Disordered “Appetitive Functioning” From Biology to Prediction of Symptoms – Mania / Hypomania • increased interest / distractibility • overactive / loss of need for sleep? • disinhibition / risk taking / poor judgement • irritability / dysphoria

  14. clinical observations epidemiology and genetics endocrinology post-mortem studies brain imaging inference from therapeutic efficacy monoamine theories antidepressant drug actions – see Lecture CAS electroconvulsive therapy – see ‘Mx’ session neurosurgical therapies - see ‘Horizons’ session Neurobiology of Depression: Overview

  15. Epidemiology • increased risk in 1st0 relatives where proband has MDD (3x) or BPD (2x) • twin studies: MZ ‘v’ DZ = 27% ‘v’ 12% • heritability (proportion of variance) of Major Depression around 70% (shared with anxiety) • onset of depression (first episode) associated with excess of adverse life events • ‘exit events’ - separations, losses • adverse early experience (neglect) increases risk of MDD

  16. Childbirth… • 7x increased risk of psychiatric admission in the 30 days following childbirth (risk for 24m) • 75% of women experience ‘blues’ within 2 weeks • 10% of women develop MDD within 3-6 months • ‘puerperal psychosis’ - 1 in 500 deliveries with a risk of recurrence of 1-3 with subsequent deliveries • despite intuitive appeal - no association with hormonal changes has ever been demonstrated

  17. Genetic Epidemiology Gelder, M., Harrison, P. & Cowen, P. (eds) (2006) Shorter Oxford Textbook of Psychiatry. Oxford: Oxford University Press.

  18. Effect of Life Stress on Depression Moderated by 5-HTT Gene s/s = short allele homozygous s/l = heterozygous l/l = long allele homozygous Caspi, A., Sugden, K., Moffitt, T. E., et al (2003) Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science, 301, 386-389.

  19. Effect of Maltreatment in Childhood on liability to Depression Moderated by 5-HTT Gene s/s = short allele homozygous s/l = heterozygous l/l = long allele homozygous Caspi, A., Sugden, K., Moffitt, T. E., et al (2003) Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science, 301, 386-389.

  20. HPA axis (cortisol) increased secretion of ACTH increased secretion of CORT elevated CORT in urine, saliva increased CRH in CSF blunted ACTH to CRH enlarged adrenal glands 50-70% fail to suppress CORT production following DEX ? chronic hypersecretion of CRF in hypothalamus HPT axis (thyroid T3 & T4 ) 20-30% MD populations show some dysfunction increased TRH in CSF TSH response to TRH blunted in 20-25% despite normal basal TSH, T3 and T4 ? chronic hypersecretion of TRH in hypothalamus Endocrine changes in Major Depression

  21. Hippocampal Neurons The effects of stress…

  22. Cytoarchitectural Changes in MDD

  23. Structural and Functional Neuroimaging

  24. Key regions implicated in mood disorders • Orbital prefrontal cortex and Ventromedial prefrontal cortex • Dorsolateral prefrontal cortex • Hippocampus and Amygdala • Anterior cingulate cortex • Davidson et al, 2002, Annu. Rev. Psychol.

  25. Structural imaging with MRI - the hippocampus hippocampus

  26. MRI: effects of MD on hippocampal volume

  27. MRI: effects of duration of MD on hippocampal volume

  28. Cognitive Function & MDD Delay-dependent deficit in visual memory function for both depression and dementia of the Alzheimer-type. Recovered depressives were still impaired relative to controls. Abas et al, Psychol Med, 1990

  29. Anterior Insular Cortex • dense connectivity with Anterior Cingulate Cortex • long considered visceral sensory region • co-activation of AIC and ACC during almost all studies of emotion • Parallel descending projections to sensory and motor nuclei in brainstem • Proposed as limbic motor (ACC) and sensory (AIC) cortices that engender the feeling (awareness) and motivation (agency) associated with emotion

  30. implicated neural substrates supporting diagnostic prediction supporting severity prediction medial temporal lobe – hippocampus and amygdala medial frontal cortex – anterior cingulate superior temporal gyrus (language comprehension & social cognition) • orbitofrontal cortex • dorsolateral prefrontal cortex • medial frontal cortex (anterior cingulate) • insular cortex

  31. Bipolar Disorder • Structural imaging : reduced grey matter volume - Brodmann Area 24 (Ant Cingulate) • functional neuroimaging : increased metabolism in amygdala (L), correlates with outcome. Reduced metabolism OfC and Medial Ventral pfC, decreased FA of DTI in anterior cingulum. • Post mortem studies : reduced glial cell numbers with NORMAL neuronal numbers Brodmann Area 24 and OfC • NB- none are specific for BPD relative to MD • Neurochemistry – signal transduction mechanisms, gene expression studies, PKA, PKC, cytoprotective protein bcl-2.

  32. changes in reward sensitivity changes in cognitive ‘attunement’ changes in reward processing changes in strength of functional connectivity changes in micro & macroarchitecture

  33. Learning Outcomes to gain an understanding of what may be altered in the brain (and elsewhere) during disordered mood states to be aware of some of the key neurobiological findings in depression to appreciate the potential for such findings to inform prediction, prevention, and treatment

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