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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

The Neurobiology of Mood Disorders

Professor Keith Matthews

October 2013


Learning outcomes

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


Core clinical problems

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


Synopsis
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


food

warmth

water

sex

defense / safety


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


Functional differentiation in the brain

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


Functional differentiation in the brain1
Functional Differentiation in the Brain

  • Appetitive/ Approach Systems

  • Aversive/ Defensive Systems



Core symptoms of major depression
Core symptoms of Major Depression

  • Low mood

  • Anhedonia

  • Anergia


Other symptoms icd 10
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


Disordered appetitive functioning

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


Disordered appetitive functioning1

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


Neurobiology of depression overview

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


Epidemiology
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


Childbirth
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


Genetic epidemiology
Genetic Epidemiology

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


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.


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.


Endocrine changes in major depression

HPA axis (cortisol) Depression Moderated by 5-HTT Gene

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


Hippocampal Depression Moderated by 5-HTT Gene Neurons

The effects of stress…


Cytoarchitectural Changes in MDD Depression Moderated by 5-HTT Gene


Structural and functional neuroimaging
Structural and Functional Neuroimaging Depression Moderated by 5-HTT Gene


Key regions implicated in mood disorders
Key regions implicated in mood disorders Depression Moderated by 5-HTT Gene

  • Orbital prefrontal cortex and Ventromedial prefrontal cortex

  • Dorsolateral prefrontal cortex

  • Hippocampus and Amygdala

  • Anterior cingulate cortex

  • Davidson et al, 2002, Annu. Rev. Psychol.


Structural imaging with MRI - the hippocampus Depression Moderated by 5-HTT Gene

hippocampus


MRI: effects of MD on hippocampal volume Depression Moderated by 5-HTT Gene


MRI: effects of duration of MD on hippocampal volume Depression Moderated by 5-HTT Gene


Cognitive function mdd
Cognitive Function & MDD Depression Moderated by 5-HTT Gene

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


Anterior insular cortex
Anterior Insular Cortex Depression Moderated by 5-HTT Gene

  • 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


Implicated neural substrates
implicated neural substrates Depression Moderated by 5-HTT Gene

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


Bipolar disorder
Bipolar Disorder Depression Moderated by 5-HTT Gene

  • 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.


changes in reward sensitivity Depression Moderated by 5-HTT Gene

changes in cognitive ‘attunement’

changes in reward processing

changes in strength of functional connectivity

changes in micro & macroarchitecture


Learning outcomes1

Learning Outcomes Depression Moderated by 5-HTT Gene

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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