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Neurobiology and functional brain circuits in mood disorders
Mood disorders involve biological abnormalities in brain circuits and neurotransmitter systems. Key circuits include the prefrontal cortex, orbitofrontal cortex, amygdala, hippocampus, striatum, and hypothalamus-pituitary-adrenal axis. In depression, these circuits demonstrate reduced activity of serotonin, norepinephrine, and dopamine which impacts mood, motivation, and emotional processing. Mania involves hyperactivity in the nucleus accumbens and prefrontal regions due to elevated serotonin and dopamine levels, leading to symptoms like grandiosity, risk-taking, and pressured speech. Neuroimaging supports changes in these brain regions and circuits in mood disorders.
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Neurobiology and functional brain circuits in mood disorders
- 1. Mood disorders Neurobiology &functional brain circuits Resource Person: Dr. Devrat Joshi Presenter: Dr. Suman Prasad Adhikari 2nd year Resident Department of Psychiatry NAMS
- 2. Biological considerations • Biologicalabnormalities are reported in patients with mood disorders • May be of developmental in origin • Episodes may produce neurobiological effects of scarring---worsening subsequent prognosis.
- 3. Martinowich et al,J Clin Invest, 2009; 119: 726-736. Monoamine systems
- 4. Monoamine systems SEROTONIN Learning, reinforcement Hedoniccapacity Motivation, concentration Goal directed activity Regulation of appetite, body T, libido, metabolism Regulation of Circadian rhythm, sleep
- 5. Emotional memory Behavioral sensitizationto stress MFB Goal directed & reward seeking NOR ADRENALINE Interactwithsympatheticnervoussystemandadrenalmedulla Hypothalamus
- 6. Nor epinephrine regulationof 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
- 7. Classic monoamine hypothesisof 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
- 8. Monoamine receptor hypothesisof 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
- 9. Monoamine system Changesin 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 libido Dopamine Hypoactive D1 receptor Increased binding of D2/D3 receptors in striatal regions Consistently low CSF level of homovanilic acid(HVA)
- 12. acetylcholine • Cholinergic neuronshave 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
- 13. Other neurotransmitters • GABAhave 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
- 14. Endocrine systems • HPAActivity • Thyroid Axis Activity • Growth Hormone • Prolactin
- 15. Decreased inhibitory 5-HTtone 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 Alterednegativefeedback
- 16. PATHOPHYSIOLOGICAL BASIS OFMOOD DISORDERS --2006 Elsevier Glucocorticoid receptor theory of mood disorders Increases LC activity Decreased BDNF
- 18. HPA activity isfound 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
- 20. 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
- 21. Other hormones Growth hormoneCharacteristic 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
- 22. Decreased lymphocyte proliferationin response to mitogens Decreased natural cell killer activity Increased positive acute phase reactants Increased cytokines levels(IL-1,IL-6) Immune system
- 23. Impaired sleep continuityand 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
- 24. OFC Brain circuits inMood Disorders DMPFC VMPFC DLPFC
- 25. Brain circuits inMood 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)
- 26. 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
- 27. 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
- 28. • Lesions toOFC 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
- 29. 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
- 30. prefrontal cortex inhibitsthe 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
- 31. OFC AC mPFC A Anticipatory anxiety Fear, panic Sym. Arousal Altered NE, 5-HT, DA,Ach release Increased CRH, cortisol BNST Hypothalamus NB, LC, VTA PAG Amygdala
- 32. Cortical and limbicconnections 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 excitatory inhibitory Amygdala Hippocampus
- 33. OFC AC mPFC A Anticipatory anxiety Fear, panic Sym. Arousal Altered NE, 5-HT, DA,Ach release Increased CRH, cortisol BNST Hypothalamus NB, LC, VTA PAG Amygdala Hippocampus
- 34. Cortical and limbicconnections: role of monoamines
- 35. Dorsomedial/DL Prefrontal Cortex (DM/DLPFC) (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
- 36. Kindling effect • Firstdiscovered 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
- 37. DSM-IV symptoms ofdepression.
- 38. Matching depression symptomsto circuits Functionality in each brain region is hypothetically 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.
- 39. diffuse DA reduction NEdysfunction Diffuse 5-HT reduction NE dysfunction
- 40. Diffuse DA reduction Diffuse5-HT reduction NE dysfunction
- 41. Diffuse DA reduction Diffuse5-HT reduction NE dysfunction Dysfunction of subcortical circuits Thalamus, BG, striatum
- 42. Diffuse DA reduction Diffuse5-HT reduction NE dysfunction Decreased neuro- transmission in MFB
- 43. Diffuse DA reduction Diffuse5-HT reduction NE dysfunction
- 44. Diffuse DA reduction Diffuse5-HT reduction NE dysfunction
- 45. Symptoms & circuitsin mania
- 46. DSM-IV symptoms ofmania.
- 47. Functionality in eachbrain 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.
- 49. Note:- Grandiosity, Flight ofIdeas, 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
- 50.
- 51. uses of Neuroimagingin mood disorders MRI Reduced 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
- 52. uses of Neuroimagingin mood disorders Postmortem 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)
- 53. Summary • Neuroimaging, lesionanalysis, 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
- 55. references Kaplan andSadock’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
Editor's Notes
- #7 Cell bodies of all ne neurons lies in locus ceruleus. Cell bodies of 5ht neurons lie in raphe nucleus.
- #40 This may explain the MoA if atypical antipsychotics in depression.. 5HT2A inhibit DA release in the PFC. So atypical antipsychotics having full antagonistic activity of 5HT2A receptor will disinhibit DA release so ultimately DA is increased in PFC leading to improvement of negative affect symptoms of depression..!!!
- #43 Fatigue MENTAL fatigue—due to deficient NT functioning in PFC PHYSICAL fatigue—due to deficient NT in rest areas(spinal cord, striatum.nucleus accumbens)