I. Emotion and Affect

A. Defining emotions

B. Ontogeny of emotion

C. Expression and measurement of components of emotion

II. Theories of Emotion

A. James-Lange

B. Cannon-Bard

C. Papez-MacLean

III. Theories of Stress

A. Cannon

B. Selye

C. Mason

D. A contemporary view

IV. Stress and Pathophysiology

A. Selye's general adaptation syndrome

B. Allostasis 241-5.0a

31:241 Behavioral and Cognitive Neuroscience31:241 Behavioral and Cognitive NeuroscienceProfessor A.K. JohnsonProfessor A.K. Johnson

Fall 2012Fall 2012OutlineOutline

Neurobiology of Mood, Emotion and Mental IllnessNeurobiology of Mood, Emotion and Mental Illness11/6; 11/13; 11/1511/6; 11/13; 11/15

V. Neural and Neurochemical Substrates of Fear and AnxietyA. The defense response and the conditioned emotional response (CER)

1. Neural pathwaysB. Neurochemistry

1. CRH2. GABA

C. Anxiety DisordersD. Somatic disease, stress and the defense response

VI. DepressionA. Mood disorders introductionB. Epidemiology and genetics of depressionC. Physiological and biochemical correlates of depression

1. Autonomic and cardiovascular changes2. Endocrine and cytokine3. Biological rhythms - Seasonal affective disorder

D. Theories of Depression1. Biogenic-amine2. Stress and the brain–pituitary-adrenal dysfunction3. Sickness behavior, inflammatory cytokines and depressive symptomatology4. Stress-Impaired neurogenesis

E. Antidepressant drugs and electroconvulsive shock 241-5.0b

Neurobiology of Mood, Emotion and Mental IllnessNeurobiology of Mood, Emotion and Mental Illness

(Continued)(Continued)

Key Terms and ConceptsKey Terms and Concepts

AnhedoniaAllostasisAllostatic loadAmygdalaArousalBasic emotionsBrain-deprived neurotrophic factor (BDNF)Cannon-Bard theory of emotionConditioned emotional response (CER)Corticotropic releasing hormone (CRH) or factor (CRF)Defense responseElectroconvulsive therapy (ECT)Emotional responseGeneral adaptation syndrome (GAS)Generalized anxiety disorderLeukocytesMacLean's visceral brain (limbic system) theory of emotion

Median forebrain bundleMonamine oxidase inhibitors (MAOI) antidepressantsNociceptorsNucleus accumbensPanic disorderPapez theory of emotionPeriaqueductal gray (PAG)Post-traumatic stress syndromeSimple phobiaSocial phobiaStressStress responseStressorSubjective feelingsTricyclic/polycyclic (TCA) antidepressantsWilliam James' theory of emotion

241-5 KTC

Examples of Lists of Basic EmotionsExamples of Lists of Basic Emotions

241-5.1

• Surprise • Fear• Interest • Disgust• Joy • Shame• Rage • Anguish

• Surprise • Fear• Happiness • Disgust• Anger • Sadness

A Scheme Proposed by BridgesA Scheme Proposed by Bridgesfor the Development of Emotionsfor the Development of Emotions

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Types of Emotional ResponsesTypes of Emotional Responses

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FeelingsFeelings

Emotional Emotional Subjective Action Expression Feelings

Darwin's Expression of theDarwin's Expression of theEmotions in Man and AnimalsEmotions in Man and Animals

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Commonality of Emotional ExpressionCommonality of Emotional Expressionin the Faces of Animals and Peoplein the Faces of Animals and People

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William James' Theory of EmotionWilliam James' Theory of Emotion

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Cannon-Bard Theory of EmotionCannon-Bard Theory of Emotion

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The Papez Circuit Theory of EmotionThe Papez Circuit Theory of Emotion

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MacLean's Visceral BrainMacLean's Visceral Brain(Limbic System) Theory of Emotion(Limbic System) Theory of Emotion

241-5.9

Originators and Popularizers of the Concept of StressOriginators and Popularizers of the Concept of Stress

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Cannon (1920's) used the term "stress" to characterize the physical impact of averse stimuli on an organism much as an engineer uses the term stress and strain to characterize the effect of a load placed on steel structures.

Selye (1936) used the term stress to account for the generalized physiological response to different averse insults to the body.

W.B. Cannon Hans Selye

Evolution of the Concept of StressEvolution of the Concept of Stress

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Adaptive Effects of the Stress ResponseAdaptive Effects of the Stress Response

Immediate increase of metabolic fuel

Increased oxygen intake

Optimization of blood flow to key tissues

Inhibition of digestion, growth immune function, reproduction and pain perception

Enhancement of sensory intake and memory

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Selye's General Adaptation Syndrome (GAS) Selye's General Adaptation Syndrome (GAS) and the Consequence of Another Stressorand the Consequence of Another Stressor

241-5.13

Original Stress

Normal

New Stress

Pathological State Associated with Chronic StressPathological State Associated with Chronic Stress

Fatigue, myopathy; steroid diabetes

Hypertension

Peptic ulcers

Psychosocial dwarfism

Impotence; anovulation; loss of libido

Impaired disease resistance; cancer

Accelerated neural degeneration during aging

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Allostasis and Allostatic LoadAllostasis and Allostatic Load

Idea evolved from concepts of homeostasis and stress.

P. Sterling and J. Eyer were the originators of the concept.

Allo – prefix meaning variable.

Allostasis = maintaining stability through change; the active process of maintaining a physiological function in the face of a challenge by old control systems adjusting level of function or "new" systems being activated.

Systems involved in the stress response show dramatic responses.

Allostatic load = wear and tear on the body that results from repeated or sustained activation of processes that maintain homeostasis.

241-5.15

Bruce McEwen

Popularizer of Allostasis and Allostatic Load

The Cardiovascular Defense ResponseThe Cardiovascular Defense Response

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Brain Stimulation-Induced Defense ResponseBrain Stimulation-Induced Defense Response

241-5.17

Behavioral• Piloerection• Hissing• Halloween Posture

Cardiovascular• Cardiac Output ( HR)• Blood Pressure• Skeletal Muscle Blood Flow• Renal Blood Flow• Mesenteric Blood Flow

The Conditioned Emotional Response (CER):The Conditioned Emotional Response (CER):

A Rat Undergoing Fear Conditioning

241-5.18

Neural Pathways Mediating theNeural Pathways Mediating theCardiovascular (A) and the BehavioralCardiovascular (A) and the Behavioral

(Freezing) (B) Components of the Defense Response(Freezing) (B) Components of the Defense Response

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The Amygdala and FearThe Amygdala and Fear

241-5.20

Stress Pathways and the Control of GlucocorticoidsStress Pathways and the Control of Glucocorticoids

241-5.21

The Physiological Effects of CRFThe Physiological Effects of CRF

241-5.22

Putative CRF Pathways and CRFPutative CRF Pathways and CRF1 1 (a) and(a) and

CRFCRF22 (b) Receptor Localization (b) Receptor Localization

241-5.23

Effects of Amygdala Lesions on the CRF Effects of Amygdala Lesions on the CRF Enhancement of the Startle ResponseEnhancement of the Startle Response

241-5.24

The Projections of the Amygdala That Mediate The Projections of the Amygdala That Mediate Behavioral, Physiological and Endocrine Behavioral, Physiological and Endocrine

Responses to Fear StimuliResponses to Fear Stimuli

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There is a Key Role for GABA inThere is a Key Role for GABA inControlling Activity of the AmygdalaControlling Activity of the Amygdala

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The GABA SynapseThe GABA Synapse

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GABA SynthesisGABA Synthesis

241-5.28

COOH COOH

CH2 CH2

+ CO2

CH2 CH2

H2N CH H2N CH2

COOH Glutamic Acid GABA

Glutamic Acid

Decarboxylase

The Interplay Between NeuronsThe Interplay Between Neuronsand Glia in GABA Metabolismand Glia in GABA Metabolism

241-5.29

Schematic Model of the GABASchematic Model of the GABAAA Receptor Complex Receptor Complex

241-5.30BDZ, benzodiazepine

Anxiety DisordersAnxiety Disorders

241-5.31

The Defense Response as an Inducer of The Defense Response as an Inducer of Chronic HypertensionChronic Hypertension

241-5.32

About 50 years ago, Folkow hypothesized that sustained or repeated activation of the defense response predisposes towards developing chronic hypertension.

Björn Folkow Hypothalamic StimulationProducing the Defense Response

and Chronic Hypertension

Multiple EnvironmentalMultiple EnvironmentalStressor-Induced HypertensionStressor-Induced Hypertension

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Mood DisordersMood Disorders

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Major DepressionMajor Depression

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• Major depression is the leading cause of disability in the U.S. and worldwide.

• Depressive disorders affect an estimated 9.5% of adult Americans ages 18 and over in a given year, or about 18.8 million people in 1998.

Distribution of Mood Disorders in the U.S. PopulationDistribution of Mood Disorders in the U.S. Population

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Symptoms and Signs of Major Depression*Symptoms and Signs of Major Depression*

241-5.37

• Must include either pervasive depressed mood (verbal report) or pervasive loss of ability to experience pleasure or interest in other things (anhedonia).

• Must include at least five of the following:- Depressed mood (require verbal report)

- Feelings of worthlessness or guilt (require verbal report)

- Diminished concentration (require verbal report)

- Recurrent thoughts of death or suicide (require verbal report)

- Weight change - Sleep disturbance - Psychomotor agitation or retardation - Fatigue or loss of energy- Loss of pleasure (anhedonia) or interest

*Adapted form DSM-IV-RT

DSM-IV-RT Diagnostic Criteria for Dysthymic DisorderDSM-IV-RT Diagnostic Criteria for Dysthymic Disorder

241-5.38

A. Depressed mood for most of the day, for more days than not, as indicated either by subjective account or observation by others, for at least 2 years. Note: In children and adolescents, mood can be irritable and duration must be at least 1 year.

B. Presence, while depressed, of two (or more) of the following:• Poor appetite or overeating• Insomnia or hypersomnia• Low energy or fatigue• Low self-esteem• Poor concentration or difficulty making decisions• Feelings of hopelessness

C. During the 2-year period (1 year for children or adolescents) of the disturbance, the person has never been without the symptoms in Criteria A and B for more than 2 months at a time.

D. No Major Depressive Episode has been present during the first 2 years of the disturbance (1 year for children and adolescents); i.e., the disturbance is not better accounted for by chronic Major Depressive Disorder, or Major Depressive Disorder, In Partial Remission. Note: There may have been previous Major Depressive Episode provided there was a full remission (no significant signs or symptoms for 2 months) before development of the Dysthymic Disorder. In addition, after the initial 2 years (1 year in children or adolescents) of Dysthymic Disorder, there may be superimposed episodes for Major Depressive Disorder, in which case both diagnoses may be given when the criteria are met for a Major Depressive Episode.

E. There has never been a Manic Episode, a Mixed Episode, or a Hypomanic Episode, and criteria have never been met for Cyclothymic Disorder.

F. The disturbance does not occur exclusively during the course of a chronic Psychotic Disorder, such as Schizophrenia or Delusional Disorder.

G. The symptoms are not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication) or a general medical condition (e.g., hypothyroidism).

H. The symptoms cause clinically significant distress or impairment in the social, occupational, or other important areas of functioning.

Specify if:Early Onset: if onset is before age 21 yearsLate Onset: if onset is age 21 years or older

Specify (for most recent 2 years of Dysthymic Disorder):With Atypical Features

Criteria for Manic EpisodeCriteria for Manic Episode

241-5.39

A. A distinct period of abnormally and persistently elevated, expansive, or irritable mood, lasting at least 1 week (or any duration if hospitalization is necessary).

B. During the period of mood disturbance, three (or more) of the following symptoms have persisted (four if the mood is only irritable) and have been present to a significant degree:

• Inflated self-esteem or grandiosity• Decreased need for sleep (e.g., feels rested after only 3 hours of sleep)• More talkative than usual or pressure to keep talking• Flight of ideas or subject experience that thoughts are racing• Distractibility (i.e., attention too easily drawn to unimportant or irrelevant external

stimuli)• Increase in goal-directed activity (either socially at work or school, or sexually) or psychomotor agitation• Excessive involvement in pleasurable activities that have a high potential for

painful consequences (e.g., engaging in unrestrained buying sprees, sexual indiscretions,

or foolish business investments)

C. The symptoms do not meet criteria for a Mixed Episode.

D. The mood disturbance is sufficiently severe to cause marked impairment in occupational functioning or in usual social activities or relationships with others, or to necessitate hospitalization to prevent harm to self or others, or there are psychotic features.

E. The symptoms are not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication, or other treatment) or a general medical condition (e.g., hyperthyroidism). Note: Manic-like episodes that are clearly caused by somatic antidepressant treatment (e.g., medication, electroconvulsive therapy, light therapy) should not count toward a diagnosis of Bipolar 1 Disorder.

Male/Female Prevalence of Affective DisordersMale/Female Prevalence of Affective Disorders

241-5.40

Genetic Component of Behavioral/Mental DisordersGenetic Component of Behavioral/Mental Disorders

241-5.41

Confirmed Linkages in Bipolar DisorderConfirmed Linkages in Bipolar Disorder

241-5.42

Genomic Principle IndependentLocation Report Confirmations

18p11.2 Berrettini et al., 1994 (38) Stine et al., 1995 (40); Nothen et al., 1999 (41);and 1997 (39) Turecki et al., 1999 (42)

21q22 Straub et al., 1994 (44) Detera-Wadleigh et al., 1996 (45); Smythe etal., 1996 (46); Kwok et al., 1999 (47);Morissette et al., 1999 (48)

22q11-13 Kelsoe et al., 2001 (49) Detera-Wadleigh et al., 1997 (50) and 1999 (51)

18q22 Stine et al., 1995 (40) Mcinnes et al., 1996 (52); McMahon et al., 1997 (53); De Bruyn et al., 1996 (54)

12q24 Morissette et al., 1999 (48) Ewald et al., 1998 (56); Detera-Wadleigh et al.,1999 (51)

4p15 Blackwood et al., 1996 (57) Ewald et al., 1998 (58); Nothen et al., 1997(59); Detera-Wadleigh et al., 1999 (51)

Physiological and Biochemical Signs in DepressionPhysiological and Biochemical Signs in Depression

241-5.43

Vegetative• Increased heart rate

• Decreased heart rate variability

• Increased cardiovascular reactivity to psychosocial stressors

• Increased susceptibility to heart disease

Endocrine• Increased plasma norepinephrine

• Increased cerebrospinal fluid CRF

• Increased plasma corticosterone

• Altered cytokines in depressed mood

Circadian• Altered sleep cycles

• Increased REM

• Decreased REM onset latency

• Sleep deprivation and depression

• Altered CRF cycle

• Seasonal affective disorder

Average Plasma Cortisol ConcentrationsAverage Plasma Cortisol Concentrations

241-5.44

Patterns of the Stages of Sleep of a Normal Patterns of the Stages of Sleep of a Normal Subject and of a Patient with Major DepressionSubject and of a Patient with Major Depression

241-5.45

Changes in the Depression Rating of a Depressed Patient Changes in the Depression Rating of a Depressed Patient Produced by a Single Night's Total Sleep DeprivationProduced by a Single Night's Total Sleep Deprivation

241-5.46

Mean Mood Rating of Responding and Non-Responding Patients Mean Mood Rating of Responding and Non-Responding Patients Deprived of One Night's Sleep as a Function of the Time of DayDeprived of One Night's Sleep as a Function of the Time of Day

Seasonal Affective Disorder (SAD)Seasonal Affective Disorder (SAD)

241-5.47

• Distinctive constellation of symptoms including

- Overeating- Oversleeping- Carbohydrate craving

• Triggered by light deficiency• Responds to phototherapy• Theories accounting for the antidepressant

effects of phototherapy- Melatonin hypothesis- Circadian phase shift- Circadian rhythm amplitude

Light Box Therapy May AmeliorateLight Box Therapy May AmeliorateSeasonal Affective Disorder (SAD)Seasonal Affective Disorder (SAD)

241-5.48

Biological Theories of DepressionBiological Theories of Depression

I. Monoamine Theory of Depression

241-5.49

• The monoamine theory, proposed in 1965, suggests thatdepression results from functionally deficient

monoaminergic(norepinephrine and/or 5-HT) transmission in the CNS.

• The theory was based on the ability of known antidepressant

drugs (TCA and MAOI) to facilitate monoaminergictransmission, and of drugs such as reserpine to causedepression.

• Other pharmacological evidence fails to support themonoamine hypothesis.

• Biochemical studies on depressed patients do not, in general,

support the monoamine hypothesis, except that consistently

low concentrations of 5-HIAA in the CSF are found.

• Though the monoamine hypothesis in its simple form is no

longer tenable as an explanation of depression,pharmacological manipulation of monoamine

transmissionremains the most successful therapeutic approach.

Pharmacological Evidence Relating to the Pharmacological Evidence Relating to the Monoamine Hypothesis of DepressionMonoamine Hypothesis of Depression

241-5.50

Effect in Drug Principal Action Depressed Patients

Effects consistent with the hypothesis

Reserpine Inhibits NE and 5-HT storage Mood

Tricyclic Block NE and 5-HT re-uptake Mood antidepressants

MAO inhibitors Increase stores of NE and 5-HT Mood

-methyltyrosine Inhibits NE synthesis Mood ; calming of manic patients

Methyldopa Inhibits NE synthesis Mood

Electroconvulsive Increases CNS response to Mood therapy NE and 5-HT

Pharmacological Evidence That Does Not SupportPharmacological Evidence That Does Not Supportthe Monoamine Hypothesis of Depressionthe Monoamine Hypothesis of Depression

241-5.51

Effect in Drug Principal Action Depressed Patients

Amphetamine Releases NE and blocks None. Euphoria in normal subjects re-uptake

Cocaine Inhibits NE re-uptake None. Euphoria in normal subjects

Tryptophan Increases 5-HT synthesis Mood? but only in some studies (5-hydroxytryptophan)

- and -adrenoceptor Blocks actions of NE Mood slightly ↓ with -adrenoceptor antagonists antagonists; No effect on manic

patients

Methysergide 5-HT receptor antagonist None

L-dopa Increases NE synthesis None

Iprindole No effect on amine Mood metabolism

Stahl's Hypothesis for Specific Syndromes Associated Stahl's Hypothesis for Specific Syndromes Associated with Different Kinds of Monoamine Deficiencieswith Different Kinds of Monoamine Deficiencies

241-5.52

Norepinephrine Deficiency Syndrome• Depressed mood

• Impaired attention

• Problems concentrating

• Deficiencies in working memory

• Slowness of information processing

• Psychomotor retardation

• Fatigue

Serotonin Deficiency Syndrome• Depressed mood

• Anxiety

• Panic

• Phobia

• Obsessions and compulsions

• Food craving; bulimia

Biological Theories of DepressionBiological Theories of Depression

II. Evidence for a CRF-HPA Theory of Depression

241-5.53

Corticotropin-releasing factor (CRF) in cerebrospinal fluida,b

Blunted adrenocorticotropic hormone (ACTH) -endorphin to CRF stimulationa

Density of CRF receptors in frontal cortex of patients who commit suicide

Pituitary gland enlargement in depressed patientsb

Adrenal gland enlargement in depressed patients and patients who commit suicideb

Cortisol production during depressiona

Plasma glucocorticoid, ACTH, and -endorphin non-suppression after dexamethasone administrationa

Urinary free cortisol concentrations

aState-dependent

bSignificantly correlated to post-dexamethasone cortisol concentrations

Biological Theories of DepressionBiological Theories of Depression

III. Macrophage Theory of Depression

-- R.S. Smith Medical Hypotheses 35:298-306, 1991

241-5.54

Seven Lines of Support1. Volunteers given monokines (IL-1; INF-; TNF) develop symptoms of a major depressive episode.

2. IL-1 can account for hormonal abnormalities (e.g., ACTH; GH).

3. Diseases and cohorts characterized by macrophage activation are associated with high rates of depression.

4. Brain macrophages (microglia) secrete monokines.

5. Estrogen increases IL-1 secretion by macrophages.

6. Eicosapentaenoic acid suppresses macrophages, whereas linoleic acid activates them.

7. Substantial epidemiology is consistent with this hypothesis.

Biological Theories of DepressionBiological Theories of Depression

IV. Stress-Induced Neurodegeneration

241-5.55

Drugs Used in Affective Disorders: AntidepressantsDrugs Used in Affective Disorders: Antidepressants

241-5.56

Reuptake Inhibition Drug Name Sedative Anticholinergic EliminationGeneric (Trade) Activity Activitya Half-Life (hr) NE Serotonin Dopamine

Tricyclic CompoundsImipramine (Tofranil) Moderate Moderate 10-20 ++ ++ 0Desipramine (Norpramin) Low Low 12-75 +++ + 0Trimipramine (Surmontil) High Moderate 8-20 + + 0Protriptyline (Vivactil) Low Moderate 55-125 +++ + 0Nortriptyline (Pamelor, Aventil) Moderate Low 15-35 ++ ++ 0Amitriptyline (Elavil) High High 20-35 ++ ++ 0Doxepin (Adapin, Sinequan) High High 8-24 ++ ++ 0Clomipramine (Anaframil) Low Low 19-37 ++ ++++ 0Second-Generation (Atypical) CompoundsAmoxapine (Asendin)b Low Moderate 8-10 ++ + 0Maprotiline (Ludiomil) Moderate Moderate 27-58 +++ 0 0Trazodone (Desyrel) Moderate Low 6-13 0 ++ 0Bupropion (Wellbutrin) Low Low 8-14 0/+ 0/+ ++Venlafaxine (Effexor) None None 3-11 ++ ++++ 0Serotonin-Specific Reuptake InhibitorsFluoxetine (Prozac) None None 24-96 0 ++++ 0Sertraline (Zoloft) None None 26 0 ++++ 0Paroxetine (Paxil) None None 24 + ++++ 0Citalopram (Celexa) None None 33 0 ++++ 0Fluvoramine (Luvox) None None 15 0 ++++ 0Dual-Action AntidepressantMirtazapine (Remeron) High Low 20-40 ++ ++++ 0MAO Inhibitors: IrreversiblePhenelzine (Nardil) Low None 2-4c 0 0 0Isocarboxazid (Marplan) None None 1-3c 0 0 0Tranylcypromine (Parnate) None None 1-3c 0 0 0MAO Inhibitor: ReversibleMoclobemide (Aurorix)d None Low 1-3c 0 0 0Norepinephrine-Specific Reuptake InhibitorReboxetine (Edronax) None Low 13 ++++ 0 0

aAnticholinergic side effects include dry mouth, blurred vision, tachycardia, urinary retention, and constipation. bAlso has antipsychotic effects due to blockage of dopamine receptors. cHalf-life does not correlate with clinical effects. dNot available for use in the US. 0=no effect; +=mild effect; ++=moderate effect; +++= strong effect; ++++=maximal effect.

Changes in Adrenergic Receptors and in Changes in Adrenergic Receptors and in Norepinephrine Synthesis and Release with Chronic Norepinephrine Synthesis and Release with Chronic

Antidepressant Treatment (Reuptake Inhibitors)Antidepressant Treatment (Reuptake Inhibitors)

241-5.57

Selective Serotonin Reuptake InhibitorsSelective Serotonin Reuptake Inhibitors

241-5.58

Drugs

• Fluoxetine

• Sertraline

Advantages

• Fewer anticholinergic and cardiovascular side effects

• However relatively new and long-term effects need to be evaluated

Changes Induced with Chronic Treatment withChanges Induced with Chronic Treatment withSelective Serotonin Reuptake InhibitorsSelective Serotonin Reuptake Inhibitors

241-5.59

Long-Term Adaptations to Antidepressant TreatmentLong-Term Adaptations to Antidepressant Treatment

241-5.60

Progression of Changes in the Pharmacological Progression of Changes in the Pharmacological Treatment of Major Depressive DisorderTreatment of Major Depressive Disorder

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Electroconvulsive Therapy (ECT)Electroconvulsive Therapy (ECT)

241-7.62

• 1900's observed that spontaneous seizures improved psychiatric state

• Early seizures induced with camphor and oil

• 1938 ECT

• ECT generally used on depressed patients unresponsive to pharmacotherapy

• Its efficacy is 80% to 90% which is higher than conventional therapies

• Technically difficult and expensive

• Must be administered several times a week for several weeks

• Mood changes are due to cortical seizures and not to peripheral results

• Mechanisms are not known