neurobiology and functional brain circuits in mood disorders

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

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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