NEUROBIOLOGY OF EMOTIONSChaired by Dr.Ramachandrankutty & Dr. PratheeshPresented by Dr. Sherlyn E. Mammen

Overview Emotion: definition & historyTheories of emotionsNeuro-anatomical structuresLimbic system: structure and functionsFunctional circuits of emotionsOther systems in emotion regulationSymptoms and circuits in depressionSymptoms and circuits in maniaConclusion

HISTORY

ARISTOTLE: People are thinking animals

ROUSSEAU: Emotions are what makes people special and gives us a reason for living

HIPPOCRATES: Brain is the site of emotions

Emotion : Latin word EMOVERE = To stir up or get agitated

PHINEAS GAGE (Sept 13,1848)

Definitions

• Emotion is a stirred-up state caused by physiological changes occurring as a response to some event and which tends to maintain or abolish the causative event

Mood is a pervasive and sustained emotion that colors the person’s perception of the world

Affect meaning short-lived emotion, is defined as the patient’s present emotional responsiveness

OVERVIEW OF EMOTION2 COMPONENTSMENTALPHYSICAL

EMOTION INVOLVESCOGNITIONAFFECTCONATIONPHYSICAL CHANGES: HYPERTENSION,

TACHYCARDIA, SWEATING

BASIC EMOTIONSBY EKMANHAPPINESSSADNESSFEARANGERSURPRISEDISGUSTTHESE COMBINE TO YIELD OTHER

COMPLEX EMOTIONS

Theories of emotion• James-Lang theory

• Cannon-Bard theory

• Schachter-Singer theory

• Current Theory

James lange theory• An emotional event

causes response in ANS

• This response is detected by CNS to produce an emotional experience

• Different emotional stimuli produces different bodily response and lead to different emotions

Cannon-Bard Theory

• Emotional stimuli simultaneously produce a response in the ANS and in the cerebral cortex

• The emotional experience is the combination of these two systems

Schachter-Singer theory• Cognitive arousal theory

• A two-stage theory stating that for an emotion to occur, there must be (1) physiological arousal and (2) an explanation for the arousal

• Emotions are produced when autonomic arousal is noticed by the person. He/She tries to come up with an explanation for the arousal and depending on the explanation, label their emotion.

Current Theory• No single neural system produces emotions

• Different emotions may depend on different neural circuits, but many of these circuits converge in the same parts of the brain

• Emotion results from the interplay between: The amygdala, hypothalamus,

brain stem & ANS

BRAIN STRUCTURES THAT MEDIATE EMOTIONSBrain is involved in perceptions and evaluation of

situations that give rise to emotions

PFC & ACC

Hypothalamus

Limbic system

• Brainstem

VARIATIONS IN HEMISPHERE DOMINANCE IN EMOTIONS

• L : dominant for positive emotions• R : dominant for negative emotions• R : dominant for emotional expression• L : dominant for language• R : dominant for emotion related cues like

facial expression, body posture and prosody

Prefrontal CortexRepresents goals and appropriate responses to

obtain these goals

Left sided PFC activation increases goal directed activities

Right sided PFC activation causes avoidance behavior

Lesion to the right PFC: laughter, euphoria, and moria or witzelsucht, a tendency to joke and make puns

In treating depression, rTMS therapy targets the left DLPFC

Automatic & voluntary control of emotions

• Voluntary control lateral prefrontal

cortical system, DL & VL PFC

• Automatic control medial PFC ( OFC, ACC,

DM PFC)

Anterior cingulate cortexVENTRAL PART: connects

PFC with limbic system Contains N. Accumbens

of the reward system

DORSAL PART: emotional processing and appropriate responses to stimuli

HYPOTHALAMUSPart of Diencephalon which lies below the

thalamus

Forms the floor and lower parts of the lateral walls of the 3rd ventricle

Mainly acts through 3 systems ANS ,endocrine system and the limbic

system 

BOUNDARIES Anteriory: lamina terminalis ( extends

from the optic chiasma to the ant.commissure)

Posteriorly: subthalamus

Inferiorly: structures in the floor of the

3rd ventricle.ie, tuber cinereum, infundibulam and mammillary bodies

Superiorly: thalamus 

Lateral boundary: internal capsule

Medially bounded by the cavity of 3rd ventricle

Antero_posteriorly divided into

PREOPTIC region_ area adjoining the lamina terminalis

SUPRAOPTIC region __above the optic chiasma

TUBERAL region includes the tuber cinereum,infundibulam and area around it

MAMMILLARY region_ includes the mammillary bodies and area around it

Subdivisions of hypothalamus

AFFERENT CONNECTIONS OF HYPOTHALAMUS

EFFERENT CONNECTIONS

Limbic system history Paul Pierre Broca in 1878 described

The Great Limbic lobe or ‘le grand lobe limbique’

In 1937 James Papez wrote a paper called ‘proposed mechanism of emotion’ which elaborated it’s putative role in emotion

In 1952 Paul Mclean coined the term “limbic system”

Evolution of limbic system allows animals to experience and express emotions beyond stereotyped brain stem behaviors

The cortical and subcortical structures forming a ring around the brainstem

LIMBIC SYSTEMCOMPONENTSLimbic CortexCingulate gyrus Parahippocampal gyrusHippocampal Formation Dentate gyrus Hippocampus Subicular complex AmygdalaSeptal area Hypothalmus Mamillary body Ant. Nucleus of thalamus

LIMBIC LOBE

2 concentric gyri surrounding the corpus callosum

Outer larger gyrus ‘limbic gyrus- consists of isthmus of cingulate gyrus, parahippocampal gyrus and subcallosal area

Inner smaller ‘intralimbic gyrus’

Enthorhinal complex(ERC) which funnels highly processed cortical information to hippocampal formation. Major output pathway

Cerebral association area for control of behavior

Two way communication and association linkage between the neocortex and lower limbic structures

Essentially all behavioural patterns can be elicited by specific portions of the limbic cortex

Ablation of some limbic cortical areas can cause persistent changes in an animal’s behavior

Limbic lobe

HIPPOCAMPAL FORMATION

Hippocampus, dentate gyrus, subiculum and entorhinal cortex makes the hippocampal formation

Associated with long term memory

Fibers from the entorhinal area, dentate gyrus, ammon’s horn and subiculum

The three primary pathways are the perforant pathway, mossyfibers and Schaffer collaterals

The alvear pathway, has been questioned, from the entorhinal area to ammon’s horn

INTERNAL CIRCUITS

HIPPOCAMPUS Sea horse in Greek

4 fields: CA1,CA2, CA3, CA4

The thin layer of fibers adjacent to the polymorphic layer of the hippocampus is known as the alveus

These fibers coalesce to form the fimbria.

Hippocampus Learning & memory

Emotional or contextual learning

Fear conditioning

Inhibitory regulation of HPA axis activity

DENTATE GYRUS

3 layered- outer acellular molecular, granular middle and inner polymorphic layer

Formation of new episodic memories, spontaneous exploration of novel environments

High rates of neurogenesis

SUBICULAR COMPLEXMost inferior component

Lies between the entorhinal cortex and CA1 subfield of the hippocampus

Believed to play a role in human epilepsy

Also implicated in working memory and drug addiction

Suggested that dorsal subiculum is involved in spatial relations and ventral subiculum regulates the HPA axis

AMYGDALA Almond shaped structure

deep within temporal lobe

Lies at the ant. end of the hippocampal formation and ant. Tip of inferior horn of the lateral ventricle

Consists of 14 nuclei

Window of the limbic system

Functions of amygdala

 Behavioral awareness

Project into the limbic system one's current status in relation to both surroundings and thoughts

Make the person’s behavioral response appropriate for each occasion

Bilateral amygdalectomy reduces fear and aggression in all animals

Electrical stimulation of amygdala: increased vigilance or attention

Fearful faces produce greater amygdala activity than happy faces

Case S.M S.M., is a female patient first described in 1994

Had exclusive and complete bilateral amygdala destruction since late childhood as a consequence of

an extremely rare genetic condition known as Urbach–Wiethe disease

She has little to no capacity to experience fear in her life, "woman with no fear"

S.M. has been studied extensively in scientific research, and has helped researchers to elucidate

the function of the amygdala

MAMMILLARY BODIESAct as a relay for impulses

coming from the amygdalae and hippocampi via the mamillo-thalamic tract to the thalamus

They are involved with the processing of memory & add the element of smell to memories.

ANTERIOR THALAMIC NUCLEUSCollection of nuclei at rostral end of the

dorsal thalamus

Receive afferents from mammillary bodies and subiculum

Project to the cingulate gyrus

Play a role in modulation of alertness, learning and memory

FUNCTIONAL CIRCUITS OF EMOTION

PAPEZ CIRCUIT

 James Papez’s delineation of a circuit unravelled the basis of cortical control of emotion

Recent studies show that it has a more significant role in memory functions than in emotions

Papez circuit was later modified by American neuroscientist and physician Paul D

He proposed that emotional expression is organized in the hippocampusexperienced in the cingulate gyrus and expressed via the mammillary bodies

The hypothalamus was considered to be the site where hippocampal processes gain access to the autonomic outflow that controls the peripheral expression of emotional states

The original circuit proposed by Papez is shown by thick lines and more recent connections as proposed by Paul D Mac Lean are shown by thin lines

Cerebral cortex and limbic system

Basal ganglia and limbic system

Amygdala, hypothalamus and cortex

EMOTIONAL RESPONSES FEAR: fear responses are produced by the

stimulation of the hypothalamus and amygala. Amygdala is also involved in fear learning. Amygdala destruction abolishes fear and its autonomic and endocrine responses. 

RAGE AND PLACIDITY: Rage reponses to minor stimuli are observed after removal of the neocortex. Destruction of the the ventromedial hypothalamic nuclei and septal nuclei also induces rage.

AUTONOMIC AND ENDOCRINE RESPONSES TO EMOTION

The stimulation of the cingulate gyrus and hypothalamus can elicit autonomic responses

The fear and rage responses mediated by the limbic system cause stimulation of various parts of the hypothalamus, produce diffuse sympathetic discharge; fight or fright response

Stress via cortical and limbic connections causes release of CRH from the paraventricular nuclei of the hypothalamus

Emotional memory

• Emotion has powerful influence on learning and memory

• Amygdala, in conjunction with prefrontal cortex &medial temporal lobe, is involved in consolidation and retrieval of emotional memories

• Amygdala, prefrontal cortex and hippocampus are also involved in the acquisition, extinction and recovery of fears to cues and contexts

Neurotransmitters in emotions

Monoamine neurotansmitters – Norepinephrine, Serotonine, Dopamine

Aminoacid transmitters – GABA, Glutamate

Peptide neurotransmitters – CRH, Neuropeptide Y, Substance P, Opioids

SEROTONIN DOPAMINE

NOR ADRENALINE

ACETYLCHOLINE

GABA

• 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

GLUTAMATE

• Excess glutamate- neurotoxic effects

• Drugs antagonizing NMDA receptors (ketamine) may have antidepressant effects

• Abnormalities in G-protein signalling/ second messenger system dysregulation

NEUROPEPTIDESOpioids :• Placebo controlled studies – No significant

antidepressant efficacy• Continued interest in use of opioid

antagonists in Rx of refractory depression

Neuropeptide Y• Dec CSF level in major depression• Neg correlation b/w levels of NPY and rating

of anxiety in depressed pts.• NPY levels in cortex increased by

imipramine & ECT.

Endocrine systems

• HPA activity

• Thyroid axis activity

• Growth hormone

• Prolactin

HPA AXIS

1. Pts with MDD have cortisol in plasma, CSF & urine

2. Pts with MDD show resistance to normal suppression of cortisol and corticotropin secretion by dexamethasone

3. Depressed pts have CSF CRH

4. Adrenal gland hypertrophy and increased sensitivity to CRH may be a reversible state marker of depression.

Dexamethasone suppression test• Detects resistance to glucocorticoid mediated

feedback

• Diagnostic marker of MDD

• 1mg of dexa at 11pm, blood drawn at 4pm & 11pm next day

• High plasma cortisol level(5gm/dl) assoc with MDD

• Degree of nonsuppression correlated with severity of depression

HPA axis• Increased activity in the HPA axis in depression

is viewed as the “most venerable finding in all of biological psychiatry” (Nemeroff , 1998)

• CRH is hypersecreted in depression (Nemeroff,

1992, 1998) • HPA normalization precedes clinical recovery

and return to abnormal HPA precedes clinical relapse – suggest that HPA dysregulation is not a result of depression

Thyroid axis activity• Depression : low levels of circulating thyroid

hormone, elevated basal TSH level, increased TSH response to TRH, 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

IMMUNOLOGICAL HYPOTHESIS

BDNF HYPOTHESIS

NEURONAL PLASTICITY• Brain mechanisms for adaptation to stress

plays fundamental role in the pathophysiology of mood disorders

• Antidepressants & mood stabilizers act by targeting these processes

• In mammalian hippocampus neuronal arborization & formation of new neurons are decreased by stress & increased by 5HT and NE

2nd messenger system hypothesis

• Altered platelet phosphatidyl inositol

• Abnormal intracellular calcium metabolism

Electrolyte abnormalities• Intracellular sodium is increased in mania &

depression and normalizes with recovery

• Decreased sodium pump in RBCs & increased intracellular calcium in WBC and platelets

Kindling effect

• 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

Sleep changes• 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

• Decreased REM latency may persist & indicate a vulnerability to relapse

CIRCUITS IN DEPRESSION

CIRCUITS IN MANIA

PET SCAN IMAGES

OVERVIEW OF NEUROBIOLOGY OF EMOTIONS

REFERENCES

• Kaplan and Saddock’s Comprehensive text book of psychiatry 9th edition

• Stephen M. Stahl’s Essential psychopharmacology 4th edition

• Shorter oxford text book of psychiatry 6th edition

• Allan Tassman’s Psychiatry 4th edition