neurobiology and functional brain circuits in mood disorders
TRANSCRIPT
Mood disordersNeurobiology & functional brain circuits
Resource Person: Dr. Devrat JoshiPresenter: Dr. Suman Prasad Adhikari
2nd year ResidentDepartment of Psychiatry
NAMS
Biological considerations
• Biological abnormalities are reported in patients with mood disorders
• May be of developmental in origin
• Episodes may produce neurobiological effects of scarring---worsening subsequent prognosis.
Martinowich et al, J Clin Invest, 2009; 119: 726-736.
Monoamine systems
Monoamine systems
SEROTONIN
Learning, reinforcementHedonic capacity
Motivation, concentrationGoal directed activity
Regulation of appetite, body T, libido, metabolism
Regulation of Circadian rhythm, sleep
Emotional memoryBehavioral sensitization to stress
MFBGoal directed & reward seeking
NOR ADRENALINE
Inte
ract
with
sym
path
etic
nerv
ous s
yste
m a
nd a
dren
al m
edul
la
Hypothalamus
Nor epinephrine regulation of serotonin
Regulates serotonin by acting as a brake on serotonin release at alpha 2 receptors on axon terminals and as an accelerator of serotonin release at alpha 1 receptors at the somatodendritic area
5HT2A
Classic monoamine hypothesis of depression
The monoamine hypothesis of depression states that if the "normal" amount of monoamine neurotransmitter activity becomes reduced, depleted, or dysfunctional for some reason, depression may ensue
Deficient monoamine--> depression
Monoamine receptor hypothesis of depression
Extends the classic monoamine hypothesis of depression, stating that deficient activity of monoamine neurotransmitters causes up regulation of postsynaptic monoamine neurotransmitter receptors, and that this leads to depression
Monoamine system Changes in depression
Serotonin Decrease in 5-HT1A receptor binding throughout cortical and subcortical regions
Reduction in 5-HT reuptake sites
5-HT mediated endocrine responses blunted
Nor epinephrine Decreased MFB neurotransmission
Leading to:
anergia, anhedonia, and diminished libidoDopamine Hypoactive D1 receptor
Increased binding of D2/D3 receptors in striatal regions
Consistently low CSF level of homovanilic acid(HVA)
acetylcholine
• Cholinergic neurons have reciprocal relationship with all 3 monoamine systems
• Abnormal levels of choline, found in autopsy of brain of some depressed patients
• Cholinergic agonist can exacerbate symptoms in depression and reduce symptoms in mania
Other neurotransmitters
• GABA have inhibitory effect on ascending monoamine pathways
• Reductions in GABA observed in plasma, CSF and brain areas in depression
• GABA receptors up regulated by antidepressants
• Some GABAergic medications have weak antidepressant effects
• Excess glutamate- neurotoxic effects
• Drugs antagonizing NMDA receptors (ketamine) may have antidepressant effects
• Abnormalities in G-protein signalling/ second messenger system dysregulation
Endocrine systems
• HPA Activity
• Thyroid Axis Activity
• Growth Hormone
• Prolactin
Decreased inhibitory 5-HT tone
Increased drive from NE, ACh or CRH
Decreased feedback inhibition from the hippocampus
Hypercortisolemia
HPA activity
Elevated HPA activity as stress responses has clearest links between depression and biology of chronic stress
Alte
red
nega
tive
feed
back
PATHOPHYSIOLOGICAL BASIS OF MOOD DISORDERS --2006 Elsevier
Glucocorticoid receptor theory of mood disorders
Increases LC activityDecreased BDNF
HPA activity is found to be increased apparently in 20 to 40% of depressed outpatients and 40 to 60% of inpatients
Laboratory evidence:
• Administration of dexamethasone (0.5 to 2.0 mg) : non suppression of cortisol secretion at 8:00 AM the following morning or
is -indicative of impaired feedback inhibition
• Non suppression may implicate a loss of inhibitory hippocampal glucocorticoid receptors more than increased CRH drive
Thyroid axis activity
• 5 to 10% depressed patients have previously undetected hypothyroidism
• Reflected by : low levels of circulating thyroid
hormone, elevated basal TSH level, increased TSH response to TRH
• Often associated with elevated anti-thyroid antibody levels
• 20 to 30% of depressed patients have blunted TSH response to TRH challenge
• Blunted TSH response is evidence of an increased risk of relapse
• blunted TSH response to TRH does not normalize with effective treatment
Other hormonesGrowth hormone Characteristic secretory surge during the first few hours of sleep
Blunted GH response to Clonidine, an α2-receptor agonist
Blunted response to nonselective adrenergic agonists (Desipramine)
Decreased CSF somatostatin levels
Prolactin Blunted prolactin response to various 5-HT agonists
Decreased lymphocyte proliferation in response to mitogens Decreased natural cell killer activityIncreased positive acute phase reactantsIncreased cytokines levels(IL-1,IL-6)
Immune system
Impaired sleep continuity and duration
Decreased stage 3 and 4 sleep
Decreased REM latency
Increased proportion of REM sleep in the early part of the night
Sleep changes
Decreased REM latency may persist in recovered depressed patients and indicate a vulnerability to relapse
OFC
Brain circuits in Mood DisordersDMPFC
VMPFC
DLPFC
Brain circuits in Mood Disorders
• Neuroimaging, lesion analysis and post mortem methodologies
• Extensive interconnecting neural networks are responsible
• Cortical-striatal-limbic circuits
Dorsomedial/DL Prefrontal Cortex
(DM/DL PFC)
(Cognition-decision making, planning)
VM PFC
(Emotion)
OFC
(Social)
The Dorsal “Cognitive” Circuit
• Receives input from DL and DM cortex
• DLPFC has top-down inhibitory control over amygdala and other limbic tissue
• Hypometabolism of the dorsal PFC in both unipolar and bipolar depression
• Global decreases in both GM and WM volume, including areas of the DLPFC
Orbital Frontal Circuit
• Receives inputs from the OFC
• Projects to amygdala, hypothalamus, and brainstem
• Integrates limbic data with sensory input and provides early analysis of reward or aversiveness of stimuli
• Data then processed by higher-level circuits (MPFC) to guide behavior
• Lesions to OFC region manifests as : - depression, - mood instability and - anxiety
• Has central role in self-regulation of emotion and social behavior
• Elevated metabolic activity or perfusion of the OFC in young to middle-aged Unipolar acutely depressed subjects
• Potentially elevated OFC activity and tissue loss is consistent with the operation of an excitotoxic process
Ventromedial “Emotion” Circuit
• Ventromedial prefrontal (ACC) plays a pivotal role in translating OFC-derived valenced data into behavior
• More ventral and caudal to the SGPFC (24/25), BA 32pl is also an integral part of the ventral “emotional” circuit
• Right-sided lesions produced anosognosic and manic symptomatology
• Emotional distress and depression often associated with left-hemisphere lesions
prefrontal cortex inhibits the amygdala
The mPFC, OFC, and ACC all inhibit amygdalar activity
When these structures are dysregulated, amygdalar activity is less modulated by the prefrontal cortex: anxiety and emotional responses are less controlled; fear may be more easily aroused
OFC
AC
mPFC
A
OFC
AC
mPFC
A Disinhibition Anticipatory anxiety
Fear, panicSym. Arousal
Altered NE, 5-HT, DA, Ach
release
Increased
CRH, cortis
ol
BNST
Hypothalamus
NB, LC, VTA
PAG
Amygdala
Cortical and limbic connections
When prefrontal-striatal-thalamic processing is dysregulated, prefrontal function inhibition of hippocampus/amygdala will be disconnected resulting in:
• abnormal function in the mPFC, ACC, and the OFC• autonomic arousal, hypothalamic pituitary axis (HPA) activation
OFC
AC
mPFC
GABA
excitatoryinhibitory Amygdala Hippocampus
OFC
AC
mPFC
A Disinhibition Anticipatory anxiety
Fear, panicSym. Arousal
Altered NE, 5-HT, DA, Ach
release
Increased
CRH, cortis
ol
BNST
Hypothalamus
NB, LC, VTA
PAG
Amygdala
Hippocampus
Cortical and limbic connections: role of monoamines
Dorsomedial/DL Prefrontal Cortex
(DM/DL PFC)
(Cognition-decision making, planning)
VM PFC
(Emotion)
OFC
(Social)
Striatum
Amygdala
Decreased reward/ goal directed behavior
Disinhibition of Amygdala
Bed nuclei of striae
terminalis
Hypothalamus Nucleus basalis
VTA; LC
PAG
(Periaqueductal gray)
Anticipatory anxiety
Increased CRH
Increased Cortisol
Altered
Ach, DA, 5HT, NE release
Fear, panic, social isolation
Functional hypersensitivity
Kindling effect
• First discovered in 1967 by a scientist in Nova Scotia, named Graham Goddard – somehow he had created epileptic rats
• First applied to Bipolar Disorder by Dr. Robert Post of the NIMH
• Like seizures, mood episodes can occur without obvious triggers, and have fairly abrupt beginnings and endings
• Initial stress---mood episodes----episodes beget episodes—frequency increases/ worsens
DSM-IV symptoms of depression.
Matching depression symptoms to circuitsFunctionality in each brain region is hypothetically associated with a different constellation ofsymptoms. PFC, prefrontal cortex; BF, basal forebrain; S, striatum; NA, nucleus accumbens; T, thalamus; HY, hypothalamus; A, amygdala; H, hippocampus; NT, brainstem neurotransmitter centers; SC, spinal cord; C,cerebellum.
diffuse DA reductionNE dysfunction
Diffuse 5-HT reductionNE dysfunction
Diffuse DA reductionDiffuse 5-HT reductionNE dysfunction
Diffuse DA reductionDiffuse 5-HT reductionNE dysfunction
Dysfunction of subcortical circuits
Thalamus, BG, striatum
Diffuse DA reductionDiffuse 5-HT reductionNE dysfunction
Decreased neuro-transmission in MFB
Diffuse DA reductionDiffuse 5-HT reductionNE dysfunction
Diffuse DA reductionDiffuse 5-HT reductionNE dysfunction
Symptoms & circuits in mania
DSM-IV symptoms of mania.
Functionality in each brain region may be associated with a different constellation of symptoms. PFC, prefrontal cortex; BF, basal forebrain; S, striatum; NA, nucleus accumbens; T, thalamus; HY, hypothalamus; A, amygdala; H, hippocampus; NT, brainstem neurotransmitter centers; SC, spinal cord; C, cerebellum
Matching mania symptoms to circuits.
Note:-
Grandiosity, Flight of Ideas, Racing thoughts are due to hyperactivity in the nucleus accumbens
Regulated by 5HT & DA
Risk taking, pressured speech(poor impulse control) due to hyperactivity in OFC,DLPFC,VMPFC
Regulated by 5HT, DA & NE
(Cognitive symptoms)
uses of Neuroimaging in mood disordersMRIReduced hippocampal volume in individual with MDD (Average 8% on left, 10% on right)
Reduction in grey matter volume in PFC ventral to genu of corpus callosum
Findings remain inconclusive in regard to amygdala(In adults -increased amygdala volume, reverse in children and adolescents)
MRS
Specific studies suggest that NAA may be reduced in the hippocampus of depressed patients
Elevated choline levels in the basal ganglia of mood disorder subjects
White mater changes
White matter hyperintensities (WMHs), especially of the deep frontal cortex and BG- characteristic of UPD and BD
Increased white matter hyperintensities associated with - late onset depressive disorder - greater severity and poorer treatment response - presence of vascular risk factors
uses of Neuroimaging in mood disordersPostmortem study of UPD and BD showed volumetric reductions of :
- left nucleus accumbens, - bilateral pallidum, and - right putamen
Metabolic activity/perfusion elevated in manic or hypomanic as well as depressed samples
Enlargement of the BG nuclei - antipsychotic regimens for BD patients
Ventricular enlargement (mostly of the third or lateral ventricles) in UPD: In old or chronically depressed samples with late-onset illness
Excitotoxic processes operating in medial-temporal or lateral-prefrontal cortical tissue could cause ventricular enlargement
Decreased glial cell numbers(ACC)
Decreased neuronal size and density(ACC,PFC)
Decreased synaptic markers(PFC)
Summary
• Neuroimaging, lesion analysis, post-mortem analysis, drug analysis support the role of neurobiology and brain circuitry
• Neurobiology extends further from neurotransmitters, secondary messengers to the relevant genes
• Neurohumoroendocrinal connectivity is being established
• Brain areas and circuitry forming reciprocal connectivity of limbic-cortico-striato-pallido-thalamic circuits
references
Kaplan and Sadock’s Comprehensive Textbook of Psychiatry, 9th edition
New Oxford Textbook of Psychiatry, 2nd edition
Shorter Oxford Textbook of Psychiatry, 6th edition
Stephan M. Stahl, Essential psychopharmacology; 4th edition
Other Internet sources