Biological Psychology

L5 - HOMEOSTASIS

Homeostasis

Maintaining a relatively stable internal environment despite a changing external environment

• body temperature

• glucose levels in the blood

• oxygen in the blood

• blood pressure

• can also involve neurotransmitters, hormones, and immune system

• careful regulation and balance of bodily processes

• requires detection, action and feedback systems

Why Do We Eat?

• maintain homeostasis

• pleasant

• social aspect

• keep us warm

• build our body, and recycle

• stock and release energy

• use for muscle power

• needed for thinking

• energy required for metabolic processes

Digestion in Gastrointestinal (GI) Tract

GI tract is the site of digestion in which food is broken does and absorbed so that the nutrients can be mobilized and delivered as sources of energy

Steps:

1. starts before eating

2. mouth: saliva contains enzymes that facilitate breakdown

→ start digestion starch (carbohydrate)

→ bolus: moist ball of chewed food

3. swallowed → enters oesophagus → food transportation [also says “digestion carbohydrates → into small sugars” but that is duodenum]

4. stomach:

→ low pH (basic) kills bacteria

→ grinds food

→ ★ start digestion of proteins into amino acids★

→ pepsin: breaks down proteins into amino acids

→ hydrochloric acid: breaks down food into smaller particles

5. pyloric sphincter → duodenum:

→ enzymes from the pancreas and gallbladder (safra kesesi) continue the metabolic degradation of proteins, and starch as well as complex sugar molecules into simple sugar molecules (glucose)

→ small enough to mix into the bloodstream → processed by the liver

→ fats are broken down (emulsified) by bile acids (made by the liver and stored in the gallbladder and then released into the duodenum)

→ fat molecules can’t pas through the wall of duodenum and are therefore carried via small ducts into the lymphatic system.

6. small intestine absorption

7. large intestine absorption

8. rectum: water and electrolytes (e.g. sodium and potassium) are absorbed from the remaining waste material that is in the large intestine → fluid absorption

9. anus: remain waste

SUM:

1. mouth → saliva enzymes

2. oesophagus → food transport (carbohydrates → simple sugars (glucose) [?]

3. stomach → low pH (basic) bacteria, (protein → amino acids)

4. duodenum → juices pancreas neutralizes, bile acids for gallbladder emulsify fats (digestion and absorption of fats)

5. small intestine absorption

6. large intestine absorption

7. rectum (fluid absorption)

Digestion

provides three forms of energy:

• lipids (fats)

• amino acids (proteins)

• glucose (carbohydrates)

NOT all of the energy is used immediately, some of it is stored (most to least) as:

• fats (main storage system, accounts for increased body fat)

• glycogen (which is converted into glucose)

• proteins

→ fat is a physiologically economical way to store energy compared to glycogen

three phases in energy metabolism:

1. cephalic / reflex phase

2. gastric / absorptive phase

3. post-absorptive / intestinal / fasting phase

Cephalic / Reflex Phase

• preparatory processes for feeding

• sensory stimulus of food activates digestive systems

• stops when nutrients are being absorbed into the bloodstream

Absorptive / Gastric Phase

• immediate needs of the body are being attended to

• nutrients are being absorbed into the bloodstream

• nutrients are broken down, absorbed from the gastro-intestinal (GI) tract into the blood, distributed and metabolized for use and storage

• lasts 3-4 hours

[Note: whereas in this lecture we contrast ‘Absorptive’ from ‘Post-absorptive’ state, the term ‘postprandially’ (=after a meal) can be used to describe the state of having just eaten. So the absorptive state is postprandially…]

• physical distension created by food in the stomach activates stretch receptors →which then stimulates the parasympathetic release of acetylcholine (ACh)

• ACh → increases the secretion of gastric juices

• a rising pH (more alkaline) stimulates the release of gastrin (a peptide hormone that stimulates hydrochloric acid (HCI))

• gastrin also activates smooth muscle contractions and the movement of food

• HCI creates an acidic (low pH) environment for protein digestion

• low pH increases firing rate of the vagus nerve

during the gastric (and cephalic) phase, insulin is released rom the pancreas for:

• conversion of glucose to glycogen and for fat storage

• conversion of amino acids to proteins for storage

• storage of glycogen in liver and muscle

• storage of fat in adipose tissue

• storage of protein in muscles

→ insulin regulates the amount of blood-borne (carried or transmitted by the blood) during different phases

Biomolecules: break it down

• protein / peptides → amino acids

• fat (lipids) → triglycerids

• carbohydrates (carbs) → glucose

Proteins

> UNIT OF A PROTEIN / PEPTIDE = AMINO ACID

amino acids are used to make new proteins

Carbohydrates

> CATABOLISM

break down of complex molecules to release its energy

for example: sucrose (table sugar) → glucose + fructose

> ANABOLISM

generating complex molecules from simple ones to store it’s energy

for example: glycogen (storage of carbs in animals) = multiple glucose molecules bonded together (polysaccharide)

[Fact: experiencing “hitting the wall ” in sports is due to glycogen depletion during long periods of exercise]

Lipids (fats)

> LIPIDS: UNITS, TRIGLYCERIDES & PHOSPHOLIPIDS

• catabolized (broken down) units: glycerol and fatty acids (long chains)

• analogized (generating) units: triglycerides (body fat) and phospholipids (membrane)

> LIPIDS: STEROIDS

cholesterol promotes cell membrane fluidity and can be synthesizes (metabolized) into steroid hormones (all of them)

> TRANSPORT OF FATTY ACIDS IN THE BLOOD

fatty acids are lipids (cholesterol, specifically), thus water insoluble (lipophilic /fat-loving: dissolves in fat, not water → hydrophobic, avoids water)

lipoproteins: 

• transport unit for lipids, secreted by the liver

• a combination of protein, triglycerides, cholesterol in a phospholipid membrane

• low density lipoprotein (LDL): deposits excess cholesterol on the artery walls, promoting plaque formation → “bad” cholesterol

• high density lipoprotein (HDL): scrapes away necessary LDL from artery walls, preventing plaque formation → “good” cholesterol

• HDL < LDL 

Absorptive phase: glucose

glucose is:

• used for energy (all cells)

• stored as glycogen (muscle and liver)

• transformed into fat (liver and fat cells)

→ Q: during the absorptive state what three things can happen to glucose?

Absorptive phase: lipids

lipogenesis: fatty acids are taken up by adipose (fat) tissue, combined with a-glycerol phosphate to form triglycerides

[Note: glucose in the form of glycerol is needed for triglyceride synthesis]

Absorptive phase: amino acids

• analogized into new proteins (protein synthesis)

• metabolized into a-ketoacids for energy

• metabolized into fatty acids for storage (lipogenesis)

→ Q: what three things happen to amino acids during the absorptive phase?

Body composition

daily food intake compromises 44-65% carbs (body comprises of only 1% carbs)

Post-absorptive / Intestinal / Fasting Phase

• occurs when nutrients no longer provide immediate energy and the boy has to mobilize previously stored nutrients, e.g. fats.

• begins after about 4 hours of fasting

• stored nutrients are mobilized, maintaining a stable blood glucose supply

    → glycogenolyse = glucose is released from stored glycogen (limited supply)

    → gluconeogenesis = new glucose made from amino acids (a-ketoacids)

    → triglycerides are converted into ketones for fuel

[Note: “lysis” → breakdown —&— “(neo)genesis” → new formation]

• high glucagon levels and low insulin levels

• Glucagon: a peptide hormone released by the pancreas when glucose levels fall

   → promotes release of fatty acids and stimulates the conversion of these fatty acids into ketones (used as energy sources by muscles)

   → it coverts stored glycogen into glucose → mobilizes glucose

• insulin: performs tasks that are opposite of glucagon, insulin stores glucose

Energy: Cellular Respiration → ATP

• metabolic process of converting biomolecules (glucose, a-ketoacids, ketones) into energy (ATP)

• requires oxygen (O₂ ) and water (H₂O)

• produces ATP + CO₂ + heat

> CAN YOU DO SOMETHING TO INCREASE THE EFFICIENCY OF MITHOCONDRIA?

→ YES, high intensity exercise!

why:

• more oxygen (O₂)

• triggers mitochondrial genesis

Control of the Absorptive & Post-absorptive States

1. What controls uptake and breakdown of protein, glycogen, and triglycerides?

2. What controls the cells to use glucose during absorptive phase and fat during postabsorptive phase?

3. What stimulates glucose uptake by the liver during the absorptive phase, but glucogenesis and glucose release during the postabsorptive phase?

→ INSULIN & GLUCAGON

[Note: many other factors contribute]

[Remember:

» insulin → glucose uptake by cells

» glucagon → glucose release to the blood]

Homeostasis: Glucose in Blood

blood glucose optimal levels:

• hypoglycemia [<0.04] → low blood sugar, excess insulin

• excellent [0.05-0.06]

• hyperglycemia [0.07] → high blood sugar, insufficient insulin

• diabetes [>0.08] → no insulin production or insulin resistance 

Insulin: storage

• Insulin is a polypeptide hormone produced and secreted (by \beta-cells) in the pancreas → lecture 2: hormones

• \beta-cells in the pancreas detect glucose in the blood

    → when glucose is high: cells secrete insulin

    → low glucose: stop insulin production

insulin stimulates:

• uptake of glucose by cells

• conversion of glucose to glycogen and fat

• conversion of amino acids to proteins

• storage of glycogen, fat and proteins

When glucose levels are low…

glucagon:

• peptide hormone secreted by pancreatic \alpha-cells

• stimulates conversion of glycogen into glucose (to use for energy) → stimulates glucogenesis

• promotes release of fatty acids and stimulates conversion into ketones → lipolysis

• low glucose: stimulate release of glucagon

Glucose and insulin during the day [some questions]

❓a food, rich in starch and fibers?

→ carbs: potato, bread, fruits, vegetables…

❓a food, rich in sucrose?

→ sugar: fruits…

compare starch-rich vs sucrose-rich food:

❓difference in glucose blood level?

→ starch-rich: slower glucose increase (better sustained energy)

→ sucrose-rich: faster glucose spike (overshoot → sugar crush/dip)

❓difference in insulin blood level?

→ starch-rich: either high or low insulin increase

→ sucrose-rich: insulin overshoot and extreme dip

»»» why?

→ digestion speed 

❓what is meant by “hyperglycaemia”?

→ high blood sugar, insufficient insulin

❓which food source (starch or sucrse) is more likely to be related to hyperglycaemia?

→ sucrose-rich

Low blood sugar: alert!

• abnormally low glucose levels (hypoglycemia) is detected by chemosensory neurons in the CNS → CNS activates the sympathetic nervous system

• result: adrenaline secretion → blood adrenalin levels rise

• adrenaline → increases release of glucose and new assembly of glucose → increases glucose in blood 

Factors Influencing Hunger

multiple and divers factors → obesity hard to treat

Body Mass Index [It’s Relative]

BMI = weight in kg / (length in cm)²

• was designed for European men based on Scottish highland soldiers and French gendarmery 

→ bias for women and non-European people

Obesity

• problem treating obesity → lack of understanding of the aetiology and pathogenesis of this behavior

    → many reasons why someone can be obese, ranging from hormonal through genetic and behavioral

• target neural systems are noradrenergic and serotonergic

!!! obesity as an addiction !!!

Obesity as an addiction

• addiction → reduced dopamine

• discrepancy between an enhanced expectation and reduced response to the food  → might trigger drive to eat more to compensate 

• however, food addiction is not a withdrawal symptom from discontinuation of treatment drug

Obesity & stress

• (chronic) stress is a risk factor

• can both increase and reduce consumption

• stress → seeking pleasure → eating high calorie foods

     → if this continues for too long, dopaminergic systems invoke compensatory downregulation

• downregulation of dopamine may lead to anhedonia (inability to derive pleasure from life) 

Obesity & Education in the NL

obese women have lower education levels than normal weight women and obese man

→ they earn less

• obesity in women → less education

!!! correlation, NOT CAUSATION

On the Side: Ozempic - Semaglutide

not exam material!

ozempic:

• mimics (because its an agonist) action of glucagon-like peptide (GLP1)

    → longer duration than produced GLP1

GLP1:

• hormone released from the gut in response to food intake

• stimulates insulin release (only when glucose levels are high) and reduces glucagon secretion → lowers blood glucose level

• slows down gastric emptying and gut motility → improves absorptive state (less “spikes” in glucose levels)

• suppresses appetite

• beneficial for diabetes and reduces obesity (but has side effects!)

how to stimulate GLP1 release naturally:

• fiber-rich foods, “lean” protein and non-saturated fat

• regular exercise, good sleep and reduce stress

Anorexia nervous [AN]

• BMI < 85% of expected BMI

• adults (20+):

    → BMI < 18.5 = underweight

    → BMI < 16 = severe underweight

• eating disorder

• extreme fear of weight gain

• distorted body image

• excessive exercise

• amenorrhea: absence of periods 

• starvation-dependent syndrome 

• eating less is initially perceived as rewarding 

• maintained through conditioning to the situations providing reward

• different insula (disgust) and cingulate cortex (motivation)

• self-loathing

• overactive prefrontal cortex → increased inhibition 

• low serotonin and dopamine →SSRIs and Prozac helps

bulimia nervosa:

• ingestion of food my reduce stress induced negative emotions → binging 

• they usually have depression

AN vs cachexia

• anorexia → symptom of poor appetite whatever the cause

• cachexia: progressive depletion of muscle and fat mass, reduced food intake, abnormal metabolism, reduced quality of life, increased physical impairement → seen in serious/lethal illnesses

AN: physiological consequences

• fatigue, memory problems, mood

• hair loss

• dental decay → purging type

• low BMI

• low/high heart rate 

• low body temperature

• loss of bone mass density (osteoporosis)

• muscle weakness

• dehydration

• amenorrhea (no period)

• gastrointestinal problems

Are these symptoms part of a biological dysregulation

• symptoms of anorexia

• symptoms of hormonal changes throughout development affecting metabolic rate and appetite

• are these connected?

• if so, can they explain symptoms in anorexia?

• can they be treated?

Step Back…Metabolic Rate

• metabolic rate = rate at which your body burns calories

• 1 calorie = the energy needed to increase the temperature of 1g of water by 1 degree

• 1000 calories = 1kcal or 1C

• average need: women 2000 kcal, men 2500 kcal per day

• of which 60-75% required for the basal metabolic rate (BMR)

Basal metabolic rate [BMR] → metabolic cost of living

BMR is the amount of energy used daily by animals at rest → includes breathing, blood circulation, maintaining body temperature, cell growth, brain and nerve function, and contraction of muscles

• requires 60-75 % of total kcal intake

• does NOT include activity (20%) or digesting food (10%)

• estimated 1200-1500 kcal for women and 1500-1875 kcal for men → for doing absolutely nothing

Factors affecting metabolic rate

• diet / starvation → slows down metabolic rate

• age → decreases with age

• gender → women lower

• MORE height, weight and body surface the MORE energy needed

• body temperature

• physical activity

• food intake → digestion requires energy

• sleep → decreases during sleep

• pregnancy, menstruation, lactation

• emotional stress

• hormone levels → adrenaline, thyroid hormone, and leptin

Hormones which affect metabolic rate and food intake [eating behavior & energy homeostasis]

leptin: “the hormone of energy expenditure” a hormone predominantly made by adipose cells that helps to regulate energy balance by inhibiting hunger

AN & Hormones that Affect BMR and Food Intake 

Leptin hormone in AN?

• leptin (full!) = hunger suppressant hormone → anorexigenic

• stimulates anorexigenic neurons & inhibits orexigenic  (hunger) pathways

• thought to reduce incentives of rewards

underweight AN patients:

• more sensitive to leptin

• levels recover when body weight recovers

Thyroid hormone & AN symptoms

• AN: regular functioning of thyroid hormone disturbed → hypothyroidism 

• because it down regulates metabolic rate → slowed heart rate…)

Adrenalin & AN symptoms

acute increase in adrenalin (prepare for action!):

• increases heart rate 

• increases breathing rate

• vasoconstriction (tight blood vessels → high blood pressure, conserves heat) and vasodilation (dilated blood vessels → low blood pressure, heat loss)

• muscle contraction 

• stimulates release of energy from glycogen (liver) and fat

not immediately related to AN, however… ⇲

Adrenalin & thyroid hormone

• adrenaline and thyroid hormone have an additive effect (1+1 → 2)

• thus in conditions with low thyroid hormone, adrenaline cannot function properly

Summary 

• homeostasis: maintaining balance

• eating and digestion

• biomolecules: carbohydrates, lipids, proteins

• absorptive state and storage

• post-absorptive state and release

• ATP as energy molecule

• insulin and glucose storage

• glucagon and glucose release

• adrenaline ad glucose

• hunger: more than lack of food

• obesity: more than overeating

• eating disorder and starvation 

• hormones involved in metabolic rate and appetite become dysregulated

• can recover when body weight is restored

Additional Information from Book

Brain mechanisms for eating behavior

digestive system is connected to neural systems in the brain via the vagus nerve, therefore the focus of feeding behavior can be redirected towards the brain 

• brain is in control of eating behavior but it responds to the general environment of the body

• the brain itself requires enormous amounts of energy in the form of glucose

> HYPOTHALAMUS

» lateral hypothalamus (LH)

• hunger center

• lesion → aphagia (stop eating)

• aphagia followed adipsia (stop drinking)

• LH is under inhibitory control of the VMH

» ventromedial hypothalamus (VMH)

• satiety center

• lesion → hyperphagia (overeating)

• glucoreceptors (glucose receptors) → glucose is a simple sugar that gives energy to cells

→ high glucose: VMH inhibits LH

→ low glucose: VMH releases LH from control

SUM:

a complex network controls feeding, mediated by the hypothalamus in order to maintain homeostatic balance of energy supplies, and connected to the mesolimbic pathway that guides motivational behavior

Evolutionary explanations of eating disorders

obesity:

• mismatch between evolutionary requirements of the past and modern-day resource excess

• scarce food → high incentive value → reinforcing / rewarding

AN / BN:

• reproductive suppression when conditions aren’t suitable

• late sexual maturation → more time t focus on improving yourself (but men and postmenopausal women can also have these eating disorder)

• escape famine

Psychological factors which influence eating

• shape and color: same shaped pasta over and over again led to a decline in pleasantness

Drinking & thirst

extracellular fluid:

• intravascular fluid: blood plasma

• interstitial fluid: between the cells

• cerebrospinal fluid (CSF)

• there are movement / transaction between extracellular and intracellular fluids that allow cells to survive

• extracellular fluid supports the cells and is controlled by the brain by promoting thirst

two types of thirst:

1. OSMOTIC THIRST

→ when solute concentration of extracellular fluid increases (it becomes more salty) and takes water from the intracellular cells which can damage the cells

→ osmoreceptors, located in the anterior hypothalamus, detect changes in he concentration of the interstitial fluid

2. HYOVOLAEIMIC THIRST

→ when the intravascular fluid decreases, a loss of blood volume is detected by baroreceptors (detects blood pressure) and receptors in kidneys

→ kidney secretes renin » production of angiotensin (increases drinking)

→ angiotensin » activates aldosterone (retains salt and water, also constricts blood vessels) and vasopressin (reduces fluid going to the bladder)

→ vasopressin conserves water, whereas aldosterone conserves salt

• median preoptic nucleus (MPN) integrates hypovolaeimic and osmotic signals

L6 - PSYCHOPHARMACOLOGY

Depression Intro

Prevalence of depression globally

women > men

Q: is there a sex difference in depression / antidepressant use

→ YES

Dutch depression facts

• one in 10 people report feeling depressed in the post four weeks

• depression declines with older age

• women about 1.5 - 2 times more likely

• inverse / negative relation with income, work, and education level

• ethnicity: Moroccan, Turkish, Surinam more

    → Dutch people with Turkish descendant receive more antidepressants

    → Antillean / Aruban descent receive less antidepressants 

CONCLUSION:

→ “normative” group (old white educated men) are better off?

But: death by suicide is twice as prevalent in men than in women 

• one in ten people reported depression in the past year 

    → 1.5 million people (NL population: 18 million)

• about half of these people receive treatment 

• over 1.200.000 people use antidepressants

    → also used for other conditions such as anxiety disorders

• in 2021: 4% (396.000) of men, 7% (667.000) of women use antidepressant 

• in the past years: increase in use of antidepressants in children and young adults

N06? = ATC classification

Anatomical Therapeutic Chemical (ATC) 

[*also known as SNRI’s = serotonin and norepinephrine uptake inhibitors, of which many are tricyclic antidepressants (TCA’s)]

Did you ever take…

Brand names: Acephen, Alagesic, Bupap, Butapap, Capacet, Doliprane, Endocet, Excedrin, Fioricet, Goody’s, Lortab, Mexalen, Midol, Norco, Ofirmev, Panadol, Pamprin, Percocet, Percogesic, Phrenilin, Premsyn , Primlev, Roxicet, Trezix, Tylenol, Ultracet, Vanquish, Vicodin, Zolben …

description: synthetic nonopiate derivative of p-aminophenol; produces analgesia and antipyretics

class: analgesics and antipyretics

ATC code: N02BE01

DDD: 3g O

• DDD = defined daily dose

• “O” stands for oral (taken orally)

active ingredient: acetaminophen 

generic name: paracetamol

ATC classification system

• active substances divided into groups according to the organ or system on which they act and their therapeutic, pharmacological and chemical properties

• drugs are classified in groups at five different levels 

Are antidepressants drugs? - definition of drugs

A) often an illegal substance that causes addiction, habituation, or a marked change in consciousness

B) a substance used as a medication or in the preparation of medication

C) formal definition according to the Food, Drug, and Cosmetic Act (FTC)

Psychopharmacology & psychopharmaca

pharmaceutical drug / medication / medicine = a substance used to treat, cure, prevent, or diagnose a disease or to promote well-being

psychopharmaca / psychoactive drug / psychopharmaceutical, psychotropic = a chemical substance that crosses the blood-brain barrier and acts primarily upon the central nervous system where it affects brain function, resulting in changes in perception, mood, consciousness, cognition, and behavior

psychopharmacology = the scientific study of the actions of drugs and their effects on mood, sensation, thinking, and behavior

Q: what about caffeine?

→ YES, psychoactive stimulant

Summary

• depression prevalence 

• gender differences

• diversity differences (SES, ethnicity, age)

• antidepressant use

• coming of medication names

• (psycho)pharmaca and drugs definitions 

Pharmacokinetics

it is about factors that influence a drug as it travels → what body does to the drug

what the body does to the drug can be summarized as ADME

• Absorption / Administration

• Distribution

• Metabolism*

• Elimination / Excertion

*something is either added to it or it’s changed in some way

Routes of administration

process by which the drug enters the bloodstream (absorption), either via:

• passing through cell membranes

• or by direct administration to the bloodstream

[Note: concentration of drug measured in blood is reference level]

> PARENTERAL ADMINISTRATION

• bypasses the gastrointestinal tract (GI)

• injections

• epidermis → dermis → subcutaneous tissue → subcutaneous adipose tissue → muscle and vein

(slide ones are also underlined):

• epidural: nerve block to relieve pain

• intradermal (ID): into the skin, usually for diagnostic tests (don’t confuse with TRANSdermal)

• subcutaneous (SC): just below the skin

• intravenous (IV): directly to the bloodstream

• intramuscular (IM): through the muscle, slower than IV

• intraperitoneal (IP): predominantly used in animals, through the abdominal wall

• intrathecal (IT): to the arachnoid space of the spinal canals that it reaches csc → spinal anesthesia (nerve block)

• intracerebroventricular (ICV): to ventricles of the brain, done to animals

> ENTERAL ADMINISTRATION

via gastrointestinal tract (GI)

(slide ones are underlined):

• oral (PO): have to be lipid soluble, absorbed across intestinal mucosa via passive diffusion

• rectal (PR): reserved for people who are vomiting, unconscious, or have difficulty swallowing (e.g. suppository → fitil)

> OTHER ROUTES OF ADMINSTRATION

• inhaled: fast, large surface area where the drug can enter the bloodstream and capillaries of the lung carry the drug directly to the heart → faster the route more addictive (smoking)

• transdermal: via skin (patches) → nicotine replacement theory (NRT), hormone replacement therapy (HRT)

• transmucosal: across mucous membranes → intranasal, sublingual / buccal (under the lounge e.g. nitroglycerine for chest pain)

Distribution of drugs

> DISTRIBUTION IN THE BODY

• need to be taken up via cells lining the stomach or intestines for oral drugs

• mostly active transport

• all blood vessels lining stomach and intestines first go to the liver (except for oral and rectum)

• liver can transform drugs

• thus a smaller amount than ingested is measurable in the blood

• blood transports drugs to target organs / cells

• needs active transport from blood to target cells (unless lipophilic / lipid soluble)

Q: what does the portal vein do?

→ instead of sending that blood straight to your heart, it first goes through the portal vein → liver.

> DISTRIBUTION IN THE BRAIN

two arteries supply oxygenated blood to the brain:

• internal carotid artery

• vertebral artery

HOWEVER, the drug still has to overcome some obstacles → body membranes:

• cell membrane: lipid-soluble (lipophilic) drugs readily pass but many drugs aren’t, the drugs ability to pass is also determined by the environmental acidity and the drug’s acidity (pH → 7 neutral)

• the small blood vessel (capillaries): capillary walls are thin and single layered, small holes that allow small molecule to be exchanged

• blood-brain barrier: composed of high-density glial-cells restricting passage of substances from the bloodstream much more than endothelial cells in capillaries in the body

• placental barrier:connectable mother and the foetus and is a point of exchange of nutrients and drugs consumed by the mother

> DISTRIBUTION: WHERE IS THE DRUG?

• transfer of a drug from one location to another within the body

• measurement of a drug is usually in blood plasma

• but drugs can be distributed among other bodily fluids → intracellular did (ICF), interstitial fluid (IF)…

Q: can drugs distribute non-fluid compartments as well?

→ YES, skin, organs, bone, fat …

> DISTRIBUTION: BODY FLUIDS

• intracellular fluid (cytoplasm)

• extracellular fluid:

→ interstitial

→ intramuscular / blood plasma

→ cerebrospinal

> DISTRIBUTION: BODY COMPARTMENTS

• metabolic tissue → muscle, connective tissue, brain, nervous system cells

• body fluids (intracellular water and extracellular water)

• bone tissue

• fat

> BODY FAT MASS: SEX DIFFERENCES

sex differences in body fat mass (women consist of more solids than fluids when compared to men) matter considering the dosage of the medication

Metabolism & excertion

> METABOLATION: THANK YOUR LIVER (and to a lesser extent kidney, lung, brain, intestine, skin and more)

• most common excretion is via kidney and intestines but liver is the one metabolizes

• circulating blood with drugs, keeps “losing” drugs via the liver, kidneys and uptake by tissues

• metabolism involves enzymes in the liver changing the drug to increase solubility

→ sometimes leads to harmful substances: paracetamol

• liver metabolizes (both active or inactive) drugs so that they become water-soluble, and therefore can be excreted via kidney (urine) or via liver-excreted bile to the intestines (feces)

• liver does this in two biotransformation phases (hepatic metabolism)

→ phase 1, oxidation: oxygen is incorporated in to the drug

→ phase 2, conjugation: combining the drug with a small molecule

> EXCRETION / ELIMINATION

• kidney - urine

• liver - bile and feces

• skin - perspiration (sweat)

• lungs - respiration

• glands - tears, saliva, sweat, milk

• hair

• nails

Q: name an example of a drug which can be detected in respiration and hair respectively?

→ alcohol and cocaine

Measuring drugs in the body

usually blood plasma without red blood cells, but other ways to detect substances are e.g. CSF, saliva, urine, breath

T_1/2 or half-life of a drug in the body: time required for the drug concentration to fall by 50%

Q: what route of administration was most likely used here?

→ intramuscular (IV), because the drug concentration starts immediately at its peak (100%) — meaning it entered the bloodstream instantly

(Complex) Example: distribution of the [cannabinoid] in the body

Summary

Pharmacokinetics = What the body does to the drug Can be summarized as ADME

• Absorption / Administration

• Distribution

• Metabolism

• Elimination / Excretion

Pharmacodynamics

what drugs does to the body, what happens when it reaches its destination

→ involves ability of a drug act upon cells or cellular components

Pharmacodynamic examples - modulation of neurotransmission by drugs

drugs can influence neurotransmission at a number of different points that can ultimately influence behavior

> PRECURSOR PRELOADING DRUGS

• enhances synthesis and increases the turnover of a neurotransmitter by acting as a precursor in the neurotransmitter's synthesis

• Parkinson’s disease therapy → provide patients with precursor to dopamine: L - DOPA

> SYNTHESIS INHIBITION

• drugs can prevent neurotransmitters from being made

• treating depression with metyrapone: a cortisol synthesis inhibitor → blocks the recall of emotional memories in healthy participants

> STORAGE PREVENTION

• drugs can prevent the neurotransmitter from being stored in the vesicles

• reserpine makes monoamine vesicles “leaky”

> ENHANCE NEUROTRANSMITTER RELEASE

• drugs can promote neurotransmitter release from synaptic terminals

• amphetamine mimics DA and enters the synaptic terminals via the dopamine transporter (DAT → uptake receptor!), therefore it has two effects:

→ 1. competes with DA for reuptake, thus less DA can be removed from the synapse

→ 2. this causes extra release of DA that is independent from action potentials ( this release of DA is via reversing the uptake processes)

• amphetamine induces symptoms similar to those seen in paranoid schizophrenia

> POSTSYNAPTIC RECEPTOR STIMULATION

• drugs can mimic the endogenous neurotransmitters, e.g. nicotine as acetylcholine (ACh)

> POSTSYNAPTIC ANTAGONISM

• drugs can block the postsynaptic receptors by binding to them, therefore preventing the endogenous neurotransmitters to bind to them

• antipsychotic haloperidol blocks DA D2 receptors and stops DA from binding to those receptors

> AUTO-RECEPTOR STIMULATION & ANTAGONISM

autoreceptor: receptors at the synaptic neuron that gives feedback

• drugs can act at the autoreceptors to provide false feedback on synaptic activity

• dopamine receptor agonist apomorphine:

→ at already low doses stimulates the DA autoreceptor to reduce the release of DA

→ at high doses stimulates DA photoreceptor to increase the release of DA

= selective stimulation, happens because dopaminergic autoreceptors are 10 times more sensitive than postsynaptic receptors therefore at low doses provides a negative feedback

• conversely, DA antagonist haloperidol increases DA at already low doses → appears counterintuitive since it’s used to treat schizophrenia

> DRUGS THAT BLOCK REUPTAKE

• drugs can prevent the neurotransmitter being removed from the synapse (blocking metabolic escape route)

• cocaine and methylphendiate (Ritalin) block the DA transporter

• SSRI’s like prozac block 5-HT transporters

> INHIBITION OF METABOLISM / BREAKDOWN OF A SUBSTANCE

• prevents the neurotransmitter from being metabolized

• MAOI: increases the monoamines by inhibiting the enzymes that degrade them.

• donezpil for Alzheimer’s blocks the metabolism of ACh

Substances need to bind…

• in order to have a certain effect

• same for psychopharmaca

• psychopharmaca act on the same sites as the bodies own substance

• usually have a stronger effect, or rather, block the effect of a bodies own substances

• a number of terms are associated with these binding properties that affect the outcome of a treatment

Drugs acting upon a receptor

• where does it bind to the receptor?

• what is the effect on the receptor?

• how does it affect the usual functioning of the receptor?

• what happens in the long run?

→ number of receptors can be downregulated or upregulated

ligand: anything that binds to a receptor

• the shape and distribution of a binding protein determine which ligands it will bind

• the amino acid sequence of a protein determines both shape and the distribution of charge

• shape and charge work together in matching up ligands with their receptors

Specificity: only cell… has the matching receptors for a specific chemical messenger, so it is the only one that responds

Affinity (Kd): how well the ligand fits in a binding cite (high affinity binding site: best fit for the ligand and low… vice versa)

Bmax (binding maximum): maximum amount of binding sites available for a ligand

• affinity (Kd) of a drug can be measured as the percentage amount of drug that binds to the receptor (Bmax) according to a concentration (steeper the curve the higher the affinity)

• strong binding needs less concentration and vice versa

saturation: occurs when ligands become so abundant that every binding site is occupied (B)

• when two proteins can bind the same ligand, saturation occurs more readily for the protein that has a higher affinity for the ligand (A)

Drug-Ligand competition

non-competitive drugs (allosteric): binds to a different site rather that the active site

competitive drugs (orthosterically): binds to the same active site as a natural ligand

Evaluation of the drug effect

to evaluate the effect of a drug, psychopharmacologists will administer different doses and a dose-response curve will be generated which describes the biological or behavioral effect of the drug

dose-response curves permit the identification of the following:

• potency: amount of drug needed to get the effect (compare ED₅₀)

• efficacy: maximum effect (ED₁₀₀)

• ED₅₀: dose that produce half the maximum effect (Effective Dose - effective in half of the population)

• TD₅₀: dose that is toxic in 50%

• LD₅₀: dose that is lethal in 50%

Biology: antagonist vs agonist

drugs can be divided into four groups depending on what they do at the synapse:

1. agonists (full efficacy → lights on): produces a response as an endogenous neurotransmitter at maximum capacity

• many effects “downstream” in the cell = cellular cascade = stepwise processes → chain of reactions

• some examples of effects:

→ release of hormone

→ DNA transcription and creation of protein

→ opening or closing of an ion channel

→ activating or inhibiting an enzyme

→ many possibilities

2. partial agonist (dimmed lights): somewhere between an agonist and and an antagonist, binds to the receptor and prevents other ligands to bind, but it only has reduced efficacy → effects are different depending on the endogenous neurotransmitter's behavior (causes agonist at low doses when there is no full agonist but antagonism when a full agonist is present)

3. antagonist (zero efficacy → lights off): inhibits activity, doesn’t make a physiological change but just stops the receptor from being activated. It can do this by either binding to the same site as the agonist (orthosterically) or by binding to a separate site and changing the conformation of the receptor (allosterically)

• beta-blocker is drug that acts as an antagonist on the beta-adrenergic receptor

• thus preventing (nor)adrenaline to bind to the beta-adrenergic receptors

• causing the heart to bat slower and with less force, and lowering blood pressure

4. inverse agonist: response that is in the opposite direction to that of an agonist (don’t confuse it with antagonist, antagonists inhibit a response) → if agonist has a positive effect, an antagonist will have no effect, but an inverse agonist will have a zero effect

Summary

• pharmacodynamics

• ligand and receptor binding

• affinity; specificity; drug-ligand competition

• agonist - antagonist

• partial - agonist

Antidepressants: An Introduction on SSRI and MAOI

Psychiatric medications

antidepressants: used to treat disparate disorders such as depression , dysthymia (persistent depressive disorder), anxiety, eating disorders, and BPD

stimulants: treat disorders such as ADHD and narcolepsy and to suppress appetite

antipsychotics: which are used to treat psychosis, schizophrenia and mania

mood stabilizers: to treat bipolar and schizoaffective disorders

anxiolytics: to treat anxiety disorders

relaxants: used as hypnotics, sedatives, and anesthetics

Serotonin pathway

trypthophan (amino acid)

⬇ENZYME 1

5-Hydroxy-L-tryptophan (5-HTP)

⬇️ENZYME 2

serotonin (5-HT)

⬇️ENZYME 3 → MAO Monoamine Oxidase: an enzyme which inactivates serotonin

5 - HIAA (no longer serotonin)

Q: where does tryptophan come from?

→ diet

Monoamine-oxidase (MAO)

• monoamine-oxidase = an enzyme that breaks down monoamines

• a drug called Monoamine-Oxidase INHIBITOR (MAOI) blocks this step…resulting in less breakdown of monoamines (e.g. serotonin)

MAOIs

• inhibit breakdown of monoamines such as serotonin, but also (nor)epinephrine, and dopamine

• used to be irreversible - takes a few weeks to wear off

• nowadays reversible

• not first OR second choice of treatment

Serotonin pathway in the cell

5 - HT = serotonin

SERT = serotonin transporter → reuptake of serotonin!

Reuptake transporters: reuptake of monoamines

• serotonin transporter: SERT

• norepinephrine transporter: NET

• dopamine transporter: DAT

Drug class: selective serotonin uptake inhibitor (SSRI)

• inhibit the reuptake of serotonin from the synaptic cleft

• selectively serotonin

• presynaptic transporters

• acts as antagonists for the reuptake transporters

• immediate effect: less reuptake, more serotonin in synaptic cleft

• antidepressants take long to work

Reuptake inhibitors

• SSRI’s

• TCA’s (non-selective reuptake inhibitors set and NET)

• SNRI’s (selective serotonin-norephinephrine reuptake inhibitor)

Summary

• one in 10

• over 1 million antidepressant users

• mostly SSRI’s

• monoamine oxidase inhibitors

• reuptake inhibitors

Additional Info From the Book

• off-label prescribing: when drugs are used for purposes for which they were not originally intended → can be useful for understanding the pathways

Drug classification

• A to C: most harmful to least

• 1 - 4: no therapeutic value to therapeutic value

Disulfiram

to treat alcoholism by main it unbearable

Nerve agents and bioterrorism

sarin: prevents metabolization of ACh → excess ACh

Clinical trials

divided into four phases:

1. small number of paid volunteers

2. small number of the target pop. → efficacy in target pop.

3. random assignment, large n → important for licensing the drug

4. after the product is in the market

L7  - EMOTIONS

Learning Goals

• being able to understand what emotions are

• being able to distinguish emotions from other affective phenomena

• understand what the main characteristics of emotions and their functions are

• insight into five major theoretical approaches of emotional the specific role of the physiology of emotions

• understand the links between emotions and psychopathology

What is Emotion?

❌emotional is nonrational ❌

❌it is better to not have negative emotions ❌

❌shame is not an emotion ❌

→ it is an self-conscious emotion

emotional responses have at least three components:

• subjective (the feeling)

• behavioral (e.g. facial expression)

• physiological (heart rate)

❗any emotion can be adaptive or maladaptive depending on contextual factors and the employed emotion regulation strategies ❗

facial feedback theory: smiling → happy

Functions of emotions

Affective phenomena

feelings are involved but these are NOT emotions:

• preferences

• attitudes

• moods: no clear stimulus/reason, lasts longer (emotions → clear reason and lasts short)

• affects predispositions: tendency to act in a certain way (grumpy)

• interpersonal stances: shyness, friendliness, anxiety

emotions:

• aesthetic emotions → no evolutionary benefit / unclear why we show it (looking at art)

• utilitarian emotions: evolutionary/survival benefits

Characteristics of emotions

• reaction to a stimulus

• appraisal: assessment of the situation (importance)

• experiental and expression component: may or may not show when angry

• limited duration of a state

• motivates us to display certain specific behaviors: tendency to show certain behaviors

• capacity to regulate emotions: we are not defenseless victims of our emotions

• effect on self and others: seeing someone’s emotional section gives us information about them

Evolution

Reacting to our emotions

• man causes a car accident and then threatens the other driver and tries to flee - not adaptive, body reacts to emotions

Instinctive behavior (NOT emotion)

pulling your hand away from a candle:

• reflex - instinctive behavior, not an emotion

• people who don’t experience pain live less because they don’t retract their hands from the flames - adaptive

taxis: moths are attracted to light:

• survival value

• instinctive emotion (not an emotion!)

fixed action pattern: when eggs fall out of the nests swans pulls them back with their beaks, and she continues doing that movement even if you remove the egg

imprinting: baby ducks immediately start following their mother

How to cope with external threats?

our central and peripheral nervous system and our immune system have these functions:

• perception → five senses

• evaluation → brain / memory !!!

• action → muscles, autonomic nervous system , endocrine system, immune system

[NOTE: the functioning of the immune system is influenced by the central and peripheral nervous system!]

Benefits of emotions

we have infinite possible situation - if we fail to recognize a threat, we might choose to react in an incorrect way - infinite possible reactions

⬇️

optimal tuning: picking the best fitting reactions by using our emotions as a guide

behavioral immunity: we get disgusted from rotten food

Five Theoretical Approaches

• Evolutionary Emotion Theories (Darwin / Ekman)

→ emotions are universal and have adaptive value

• James-Lange Theory / Canon-Bard Theory / Schachter’s Cognitive Labelling Theory

→ emotions are essentially the perception of bodily responses to stimuli

• Cognitive Emotion Model (Arnold / Lazarus)

→ emotions are based on appraisals (cognitive point of view)

• Emotions & Our Brain (Ledoux / Damasio / Roll)

→ brain and emotions - the link between emotion and cognition

• New Approaches (Barrett)

Evolutionary Emotion Theories (Darwin / Ekman)

Darwin

• emotional expression evolved in order to signal what behavior an animal might engage in

• expression of emotions serves as an effective means of communication about intention and possible behavior

• also provides additional information to verbal communication (supported by the six primary emotions)

• being unable to recognize facial expressions, and therefore understand other people, → leads to difficulties in prosocial behavior (autism and alcoholism)

Paul Ekman

default face: everyone has different resting faces

• he measured facial expressions to identify emotions

> BASIC EMOTIONS

• 6/8 primary (innate) emotions: happiness, sadness, fear, disgust, anger, surprise (contempt and embarrassment / shame)

• these primary emotions can make up the core of other more subtle emotions

• located in a specific, innately determined neural substrate

• a characteristic facial expression or neuro-muscular expressive pattern

• a distinct subjective or phenomenological quality → we know the difference between being anxious or sad

• independent of language and culture → universal

• also displayed by blind and deaf children

> UPDATE

expansion of his theory to a neuro-cultural theory of emotion

• the neuro-part: keeping the original idea that each (basic) emotion is associated with a fixed facial expression and peripheral physiological reaction pattern

• the cultural addition: acknowledged that culture might impose rules and guidelines as to when and how an emotion is expressed → display rules

> SELF-CONSCIOUS EMOTIONS

• shame, guilt, regret, pride…

• occur at a later stage in development

• more doubt about the universal character; greater influence of culture

• occur first when an organism has the capacity to recognize itself in the mirror

James-Lange Theory / Canon-Bard Theory / Schachter’s cognitive Labelling Theory

James-Lange theory

emotion is the result of your physiological response, not the cause of it.

1. emotionally salient stimulus is perceived (bear)

2. this leads to a set of physiological responses (increased heart rate)

⭐ there are different / specific physiological responses for every different emotion⭐

3. that then determines the emotion experienced (fear)

→ eat bad food - stomach upset - feel disgust

Canon-Bard theory

1. emotionally salient stimulus is perceived by THALAMUS → site of sensory integration

2. both physiological reaction and an emotional reaction occur instantly and SIMULTANEOUSLY

⭐evolutionary advantage - faster response⭐

⭐physiological responses have NO INFLUENCE on the emotion being expressed (unlike James-Lange)⭐

3. physiological change can ADJUST THE INTENSITY of emotion felt (but not the affect)

criticized James-Lange because:

• interruption of physiological feedback (e.g. spinal injury) does not prevent emotions being expressed

• different emotions can have the same physiological reactions

• this theory is too slow, dos not make evolutionary sense

• artificial induction of physiological changes does not produce emotions

Schacter’s cognitive labelling theory

1. stimulus is perceived

2. stimulus causes a physiological reaction + COGNITIVE INTERPRETATION of CONTEXT determines the emotion felt ⭐increased heart rate because of spider → fear / increased heart rate before a date → excitation⭐

3. feedback is sent to use in the future

> EXPERIMENT: ARTIFICAL PHYSIOLOGICAL AROUSAL

• groups who were informed about the drug → attributed their reactions to treatment

• those who were NOT informed → attributed their reactions to the collaborator who acted like an asshole

• placebo conditions → intensity of emotion was related to physiological reaction

! emotion experienced is a product of the interpretation of the environment

! there is a cognitive attribution of emotion in which the context is critical and physiological arousal increased the intensity of the emotion experienced

> EXPERIMENT: BRIDGE

arousal from the bridge were misattributed to the female

> EXPERIMENT: WHETHER THE LABELLING OF EMOTIONAL STIMULI WOULD BE AFFECTED BY BIOFEEDBACK?

participants viewed naked women whilst hearing their own heart beat. However, the experiment manipulated heart rates to provide false feedback

• false feedback (increased heart rate): rated the females as more attractive

  • false arousal can also be attributed

Cognitive Emotion Model (Arnold / Lazarus)

appraisal: evaluation, how some one interprets the situation

basis of cognitive therapies - you can’t change the event but you can change how the person how a person thinks about the situation

Emotions & Our Brain (Ledoux / Damasio / Roll)

Ledoux

> PAPEZ NEURAL CIRCUIT

two routes of information flow:

1. cortical circuit: represents the thinking or perception of the emotion

2. thalamic circuit: feeling

Klüver-Bucy syndrome: medial temporal lobe lesion (Papez circuit) → monkeys showed hypersexuality, coprophagia, unresponsive to humans

visceral brain (striatal regions and basal ganglia): enhances primitive emotions → limbic system = emotional brain

> AMYGDALA

• unconscious emotional responses

• integrates cortical and subcortical info

• also involved in the preparation of the fight / flight mode

two pathways:

• unconscious subcortical pathway - directly activate body systems based on sensory info from thalamus

• conscious cortical pathway - slower - thalamus to cortex to amygdala

> HIPPOCAMPUS

• hippocampus is responsible for the conditioning of contextual fear

  • lesions prevent conditioning

• learning principle that something evokes fear

• info from memory of the stimulus

Damasio: somatic marker hypothesis

! physiological responses directly affect areas of the brain involved in decision-making !

decision making: not an entirely cognitive process, emotions play a role too

• distinguishes between emotions and feeling of emotions:

  • feelings: should only be used for subjective experiences of emotions → introspective

  • emotion: should refer to all the processes involved such as physiological state → measurable

→ thus, emotional decision making is influenced by peripheral feedback from the body (re-emergence of James-Lange theory)

Roll’s emotional model

emotion as a product of reinforcement / punishment

• different emotions will arise from different primary reinforces (effects of sex is different from the effects of food)

• environmental conditions can determine the emotion experienced (losing → anger if allowed, sadness, if anger is not allowed)

• orbitofrontal cortex, amygdala, and cingulate cortex

  • orbitofrontal cortex: permits flexibility of emotional behavior and is sensitive to changes in reinforcement

  • cingulate cortex: receives input about reward expectations from the orbitofrontal cortex and amygdala

  • amygdala: less prioritized 

New Approaches - Conceptual Act Model of Emotion (Barrett)

• evolution produced multipurpose set of mechanisms that work together to produce a variety of emotional responses that are tailored to each situation

• moves away from the Darwinian evolutionary account of specific emotions…

• … to a view that says emotions as defined by words such as “anger” correspond to mental events emerging from the interaction of basic psychological constructs

• emotions are mental events constructed, instantaneously, from psychological processes producing variations in “core effect” 

core effect: feeling of positive or negative affective states (pleasant / unpleasant)

→ mental representations of bodily sensations that inform the organism that something in the environment is important

• primitive psychological processes are not specific to emotion but are rather general processes for mental life

• non-emotional factors such as concepts and languages have an important role in determining emotion

  • categorizing emotions provides meaning

  • adaptive because understanding how other people see the world gives rise to our understanding of their intentions

  • emotions are not discrete but are collection of concepts for the emotion that can be combined in a number of diverse and flexible ways (different types of anger)

Short version it is 👇

⭐Barrett therefore sees emotion as the physiological changes brought about by stimuli along a dimension of pleasantness that are subsequently conceptualized as specific categorical emotions⭐

> HER CRITICISM ON THE EVOLUTIONARY EKMAN

• not all instances of an emotion referred to by the same (e.g. anger) look alike, feel alike, or have the same neurophysiological signature (angry at the world and angry at your partner can be experienced differently)

• cross-cultural variation in the recognition of emotional expression is greater than Ekman asserts (doubt about universality)

• how an emotion is experienced differs from culture to culture, even from person to person (sadness for some is fatigue for another)

• the “typical” posed emotional expressions are rather symbols than real expressions (real life has more variation)

→ fear can be experienced differently (inconsistent with Ekman)

→ Ekman was too optimistic some emotions aren’t well recognized as he thought it was in non-western cultures

Emotions & Psychopathology

• one single emotion can become very prominent, e.g. fear or sadness

  • anxiety disorders

• one reacts to events with deviant emotional responses

  • agression

• emotions are not properly regulated - emotions are more intense, last longer or interfere strongly with daily activities

  • antisocial p.d., bipolar, borderline

• deviant behavior is used to regulate emotions

  • OCD

• a more general incapacity to experience (and express) emotions

  • depersonalization-derealization disorder

• incapacity to experience certain very specific emotions (e.g., empathy, love, guilt, remorse)

• emotions of others are not recognized

  • autism

Summary

• emotions have evolved to solve important adaptational problems (survival / reproduction, social, and moral functioning)

• a distinction is made between basic emotions and self-conscious emotions

• emotions can be defined based on some specific criteria

• there are different theoretical approaches

• there is currently much discussion about emotions

Additional Information from the Book

Emotions as dimensions

The view of emotions as a dimension stems from early work by Wundt, who suggested that emotional experience could be described along an effective continuum (e.g. pleasantness/unpleasantness, subdued/excited and relaxation/strain)

In a similar manner, Russell's circumplex model of affect viewed emotion on dimensions of pleasant/unpleasant and aroused/not aroused

Plutchik provides a similar account but this view is one of emotions being on a continuum with extremes at either end

→ eight basic emotions that represent opposite-paired dimensions (e.g. joy being the opposite of sadness)

Physiology of facial expressions

there are two types of facial muscles:

• deep facial muscles: attach to bone to enable large movements like chewing

• superficial facial muscles: attach only to skin and provide emotional expressions

muscles of the face are innervated by two cranial nerves:

• facial nerve: innervates the superficial muscles

• trigeminal nerve: innervates the deep facial muscles such as the temporalis

Emotion: what’s love got to do with it?

when looking at their loved ones:

• increased activity in the anterior cingulate cortex and the striatum

• reduction of activity in amygdala

→ amygdala is associated with negative emotions

• activation of brain reward mechanisms like ventral tegmental area and the nucleus accumbens

• cortisol levels rise → oxytocin and vasopressin are released

• testosterone in males decrease and increase in females → reduce polarity of sexes

• endorphins and enkephalins are also involved in the love response, as is dopamine

> LOVE IS THE DRUG

similarities between addiction and love:

• people in love feel protective of the one they love and will do anything for them. Addicts will do anything to get a drug

• motivation is centered around that person at the expense of other responsibilities

• obsessive thoughts concerning the loved one are common

• the lover becomes salient in everyday occurrences

• stimuli that one ordinarily would not attend to suddenly make one think of the loved one (e.g. a scent). Stimuli associated with the drug are powerful mediators of the addiction process

• when one love is in love, the pleasure parts of the brain are activated → dopamine are seen within the mesolimbic system

• the longer a couple are together, the more their brains become tolerant to the hormones being released, which causes the euphoric feeling not to be felt as strongly

• breaking up with a loved one can lead to a withdrawal phase characterized by depression, anxiety, and possibly suicide

love and hate, common areas: putamen and insula

Neural mechanisms of aggression

• amygdala and hypothalamus influence defence behaviors and attack behaviors

• amygdala was activated in the brains of convicted murderers whose crime was impulsive and premediated, whereas those who were guilty of premediated murder exhibited greater prefrontal activity

• research suggests that the job of the prefrontal cortex is inhibiting the amygdala’s response

Emotion and music: evolutionary adaptation

music activates large neural networks related to attention, semantic processing, memory, motor functions and emotional processing

⭐ somatosensory pathways that mediate the visceral feelings of the bass⭐

• Increased activity levels in the ventral striatum have been recorded in response to music

• inferior frontal gyrus, anterior superior insula, ventral striatum, Heschel's gyrus and rolandic operculum → PLEASANT MUSIC

• activation of the amygdala, hippocampus, parahippocampal gyrus and temporal lobes was increased (all of which are areas associated with negative emotions) → UNPLEASANT MUSIC

⭐nucleus accumbens increased activity during the experience and the caudate nucleus was more active during anticipation⭐

• reduced or increased cortisol depending on the style of music (relaxing versus stimulating)

• reduced beta-endorphins

• increased immunoglobulin A (an antibody enhancing immune response)

• increased oxytocin when singing.

L8 - SEX

Why & Relevance

difference:

• biological

• sociocultural

issues:

• biological issues

• sociocultural / psychological issues

Reproduction

Definitions

• sex refers to a set of biological attributes in humans and animals

• it is primarily associated with physical and physiological features including chromosomes, gene expression, hormone levels and function, and reproductive anatomy

• reproduction, ensuring survival of your DNA

• sex as a pleasurable activity

Asexual reproduction

single parent cloning itself

(A)sexual reproduction

asexual reproduction: multiply as you are

sexual reproduction:

• conjugation: exchange of genetic material

• creates genetic diversity

• increases chance of better adapted organism

Sex: chromosomes and genetic sex

x sperm + x egg = xx embryo (female)

y sperm + x egg = xy embryo (male)

→ more variations

Male and Female Genitals

Biology of sex

factors present at birth, including:

• the number and type of sex chromosomes

• the type of gonads - ovaries or testicles

• the sex hormones

• the internal reproductive anatomy (such as the uterus)

• the external genitalia

(Sex) Hormones

Sex hormones

• cholesterol at the basis:

  • synthesized to testosetrone by enzymes

  • which then synthesizes into oestradiol or oestrone by aromataste enzyme !!!!!!!!

⭐oestrogen is synthesized from testosterone⭐

Other relevant hormones

• oxytocin (“cuddling hormone”, breastfeeding, orgasm, muscle contractions at giving birth)

• prolactin

• GnRH (FSH → sperm & egg /// LH → menstruation)

Menstruational Cycle & Ovulation

Uterus & endometrium

know: where the uterus, vagina, ovaries, uterine (fallopian) tube is, and what the uterus wall consists of

• ovary: eggs

• uterine tube: carries egg from ovaries into the uterus

• uterus → cervix → vagina

• uterus contains three layers and thickness of the endometrium is important for the nesting of an fertilized embryo

        →endometrium gets broken down during menstruation !!!!

• different phases driven by hormones

• GNRH in hypothalamus

• FSH and LH in anterior pituitary

• follicle growth

• 14th day follicle pops and the egg is released which is the ovulation (caused by the steep peak of LH hormone)

• the membrane that the egg was in shrinks to corpus luteum (yellow body)

• follicle produces estrogen / estradiol → uterus starts to thicken

• corpus luteum produces both estrogen and progesterone which impacts uterus (further thickness of endometrium to welcome the egg)

• 4 phases

  • follicular

  • ovulation

  • luteal

  • menstrual

Ovarian cycle

• corpus luteum → progesterone → endometrium

• determined number of follicles and eggs

  • one each month

  • two a month - heterozygotic twins

Hormonal control of the female reproductive cycle

the ovarian and menstrual cycles of female reproduction are regulated by hormones produced by the hypothalamus, pituitary, and ovaries

the pattern of activation and inhibition of these hormones varies between phases of the reproductive cycle

⭐3. luteal phase: double break (both hypothalamus AND anterior pituitary gland) → to further thicken the endometrium⭐

Menstrual cycle

• follicular phase, starts with menstruation (photo: follicular covers menstruation)

• gradual increase in estrogen

• growth of follicles

• peak LH at ovulation

• luteal phase: progesterone level increases then decreases

• repeat 28 days

Female issues

> PMS

• slow increasing estrogen levels makes you feel relaxed, good, perfect (after menstruation)

• ovulation and fertile phase

• enter PMS: drop in estrogen and progesterone can induce irritability, anger or sadness (PMS)

• pain sensitivity, acne, and cramps (PMS)

• start of menstruation

• repeat

⭐if abnormal: premenstrual dysphoric disorder (PMDD)⭐

> PCOS

slightly higher amount of testosterone:

• irregular periods

• more (facial) hair

• large number of ovaries which look like cysts

• often difficulties with reproduction

> MENOPAUSE

signs:

• decreased estrogen production by the ovaries

• low levels of testosterone

• erratic levels of estrogen and progesterone

• low levels of estrogen

• thinner vaginal walls

common symptoms:

• hot flashes

• night sweats

• decreased libido 

• irregular periods

• mood swings

• vaginal dryness

Sexual Development

• virilization or masculinization is the biological development of sex differences

• most of the changes of virilization are produced by androgens 

⭐both sex differences are caused by male hormones⭐

Puberty

physiological changes:

• fertility

• breast development (thelarche)

• pubic hair (pubarche)

• ovulation and first menstruation (menarche)

• growth spurt

• enlargement of scrotum and penis

• facial hair

Age of menarche

> DECREASE IN AGE OF MENARCHE IN WESTERN EUROPEAN & AMERICAN GIRLS

• higher the education level earlier the menarche age, why?

• women get their periods earlier each year, why?

    → SES status, well nourished = readiness

> DETERMINANTS OF MENARCHE ONSET

primary factors:

• a girl’s age

• weight - BMI - fat mass

• SES status

• age of menarche onset of the mother (in part genetic)

• environmental factors / toxins

• psychosocial stress (can postpone it)

> AGE OF MENARCHE DEPENDENT ON BMI

large BMI (overweight) = earlier onset !!!!

> FOOD & DIET

• puberty onset and reproductive hormone axis activity require an adequate nutritional status

  • China: higher education > adequate nutrition available > earlier onset menarche

• intake of animal foods has been associated with earlier sexual development, whereas vegetable protein intake is related to delayed maturation

• childhood obesity is related to the earlier onset of puberty in girls

  • nowadays: abundance of nutrition, obesity related to lower SES 

Cultural issues in sexual development

> FEMALE GENITAL MUTILATION

• female genital mutilation comprises all procedures that involve partial or total removal of the external female genitalia, or other injury to the female genital organs for non-medical reasons

• an attempt to control women’s sexuality, ideas about purity, modesty and beauty

• usually initiated and carried out by women, who see it as a source of honor, and who fear that failing to have their daughters and granddaughters cut will expose the girls to social exclusion

• more than 200 million girls and women alive today have been cut in 30 countries in Africa, the middle east and Asia

• the procedure has no health benefits

• procedures can cause severe bleeding and problems urinating, and later cysts, infections, as well as complications in childbirth and increased risk of newborn deaths

> AESTHETIC VAGINAL SURGERY: CULTURE AGAIN

gynoplasty: reparative or plastic surgery of the female genital organs

labiaplasty: is a plastic surgery procedure for altering the labia minora (inner labia) and the labia majora (outer labia), the folds of skin surrounding the human vulva

process:

• pathologization of genital diversity: create a normal vs abnormal

• portraying female genitals as important to wellbeing and sex life

• portraying female body as degenerative and improvable through surgery

• portraying surgery as safe, easy, and effective

Genotype vs phenotype

Male & Female Brain

Sex development in the brain

male:

• testosterone converted into estradiol which masculinizes the neurons of the brain

female:

• protected from masculinizing effects of estradiol

• the protein “alpha-fetoprotein” binds to estrogens and stops it entering the brain

⭐estradiol masculinizes the brain ⭐

Gender

• gender is usually conceptualized as a binary (woman or man) yet there is considerable diversity in how individuals and groups understand, experience, and express it

• sex and gender differences can be used in research: examining biological (sex) vs sociocultural (gender) factors

• gender refers to the socially constructed roles, behaviors, expressions and identities of girls, women, boys, men, and gender diverse people

• it influences how people perceive themselves and each other, how they act and interact, and the distribution of power and resources in society

Nurture

• parents

• teachers

• peers

• the world in general - books, literature, movies, newspaper, social media

⭐gender roles are influenced by nurturing⭐

Make vs female

brain:

• differences in volume

• differences in connectivity - women have more connections

research:

• cardiovascular studies on men doesn2t work on women

started to change

transgender brain?

transgender brain is more similar to the brain it is transferring to

L9 - PERSONALITY

Definition

Smith paper: Sullivan’s definition of personality  “the relatively enduring pattern of interpersonal situations which characterize a human life”

Personality: particular combination of emotional, attitudinal, and behavioral response patterns of an individual

Personality Types

Type A 

• hostility

• competitive

• time urgent

Big Five

• neuroticism (emotionally unstable and easily anxious)

• extraversion (outgoing)

• conscientiousness (efficient and organized)

• agreeableness (friendly and compassioned)

• openness to experience (inventive and curious)

Questionnaire: Revised Neuroticism-Extroversion-Openness (NEO) Personality Inventory NEO-PI-R

Type D

• negative affectivity

• social inhibition

Personality & Health

Coronary heart disease (CHD)

hostility: tendency to experience anger, to be cynical or to have suspicious beliefs

→ related to atherosclerosis, incidence of CHD and mortality

Neuroticism

• high neuroticism increased risk of mortality

• high neuroticism is related to adverse cardiac events among cardiac patients and poorer cardiac functioning

• high neuroticism is related to experiencing more somatic symptoms → students with high neuroticism had more somatic symptoms during exam period

Optimism

• better health

• less complications, less atherosclerosis

How do you know about these relations? (prevalence & incidence)

prevalence: how often does it occur?

• examine whether a personality trait is more prevalent in persons with a disease compared to a group without a disease

• case-control study: compare between group differences

incidence: how often will it occur in the future?

• examine whether a personality trait is related to the incidence of people who will develop the disease

• prospective cohort study: start with a group without the disease and examine the incidence over time

> PREVALENCE OF HOSTILITY

• 478 heart failure

• 298 post-infarction

• 131 post bypass

• 260 healthy elders

• use cut-off score to detect percentage “high” hostility in each group

• examine differences between groups

> HOSTILITY & INCIDENCE

• hostility in quartiles (1-4 → low to high)

• highest hostile group related to more “all cause mortality” and “any event”

Summary

• several personality types and constructs

• topic of discussion

• confirmed association with health outcomes (incidence, prevalence)

Type D Personality

Definition

combination of high scores on (have to have both)

negative affectivity (NA): tendency to experience negative emotions across time/situations

• I am often in a bad mood

• I often find myself worrying about something

• I often make a fuss about unimportant things

social inhibition (SI): tendency to inhibit expression of emotions/behaviors in social interaction

• I am a closed kind of person

• I find it hard to start a conversation

• I often feel inhibited in social interactions

Prevalence

general pop: 13-25%

cardiac pop: 25-30%

other patient pop: +-20%

⭐NOT PSYCHOPATHOLOGICAL TRAIT: normal variations among individuals⭐

Genetic basis

stable set of genes: type D personality is genetically determined and stable over time

variable set of environmental set of factors: different unique

Links with psychological constructs

> TYPE D & BIG FIVE

• NA correlates with positively with neuroticism

• SI correlates negatively with extraversion

→ related but similar

> TYPE D & SELF-ESEEM & ATTACHMENT

• lower self esteem 

• inferior body image

• diminished sense of personal accomplishment

• type D’s more often have a preoccupied or fearful attachment style, while they are less likely to have a secure attachment style

> TYPE D & DEPRESSION

Type D & CVD

Behavioral

> METABOLIC SYNDROME

a clustering of metabolic (biochemical) risk factors for CVD:

• overweight, especially abdominally (large waistline)

• high triglycerides and low HDL cholesterol

• high blood pressure (or taking medication for hypertension)

• high fasting glucose levels (or taking medication for diabetes)

• type D individuals were twice as likely to have metabolic syndrome, irrespective of age, social situation presence of heart disease and other traditional risk factors (e.g. smoking)

conclusion: increased risk of incident CAD but not through traditional risk factors !!!!

> BEHAVIORAL MECHANISMS? (EXERCISE & DIET)

type D individuals adhered less often to the Dutch healthy activity norm (52% vs 62%) as well as to the Dutch fit norm (25% vs 35%)

> SO FAR…, ROLE OF BEHAVIORAL MECHANISMS

• type D has been associated with future heart disease

• metabolic syndrome may mediate this increased risk

• type D’s unhealthy lifestyle did not completely explain the association with metabolic syndrome in our study (health behavior model)

• this leaves room for other mechanisms, that still need to be elucidated (e.g. shared genes) → new research questions

Pathophysiological - possible pathophysiological mechanisms

[Note: resembles the “interactional stress moderation model” by Smith, but does not include appraisal or coping]

mediating biological mechanisms, potential pathways:

• cortisol (HPA axis)

• immune system

• norepinephrine (SAM axis)

• oxidative stress

• cellular aging

> CORTISOL (HPA - AXIS)

» HPA - axis

Hypothalamus Pituitary Adrenal axis

• hypothalamus —(CRH)→ pituitary —(ACTH)→ adrenal cortex → cortisol ↺

• example of a regulatory negative feedback loop

• activated in stress situations

• cortisol → many effects → energy balance

» Cortisol

hyper-activity: increased awakening response throughout the day

hypo-activity: decreased awakening response

» Cortisol as measure of stress reactivity

stress reactivity in response to trier social stress task (public speaking)

> IMMUNE SYSTEM

» Inflammation

• cells (leukocytes = white blood cells):

  • nonspecific: macrophage, dendritic cell (eating cells), monocyte (undifferentiated macrophage)

  • specific: T-cells, B-cells

• substances (messenger molecules):

  • nonspecific: C-reactive protein (CRP) = marker of inflammation

  • specific: cytokines such as interleukin 6 (IL-6), tumor necrosis factor a (TNF- \alpha), soluble TNF receptors (sTNFr1/'2)

⭐involved in atherosclerosis⭐

» Inflammation in atherosclerosis

• inflammation is involved in the gradual accumulation of cholesterol, fat and calcium in the walls of the coronary arteries

• thrombi (blood clots) from ruptured plaques may cause a heart attack

• asymptomatic (not necessarily related to symptoms)

» Inflammation predicts incident heart disease

• analysis of 52 studies (246.669 patients)

• CRP (a marker of inflammation) predicted the development of heart disease over a period of 10 years

• same effect size as standard risk factors (BMI, family history)

• especially obvious in men and patients who smoke

» Inflammation predicts long-term outcome

• 20 studies, total of 17.422 participants (2789 events)

• patients with a higher CRP values after a heart attack had a larger chance of poor outcome (MACE major adverse cardiovascular events or death)

> NOREPINEPHRINE (SAM - AXIS)

» Heart rate control

• intrinsic pacemaker capacity of the heart

• sympathetic: activation of sympathetic nerves 

• increases heart rate (gas)

  • adrenaline and noradrenaline

• parasympathetic: inhibitory, activation of vagus nerve decreases heart rate (brake)

  • acetylcholine

» Heart rate variability (HRV)

• HRV is a measure of cardiac autonomic activity

• measuring the time between to heartbeats = interbeat interval

• HRV is the variation in these intervals

» Autonomic dysfunction in heart disease

• altered cardiac autonomic activity, especially lower parasympathetic activity, is associated with the risk of developing a coronary heart disease

• lower HRV after MI predicts both fatal and nonfatal cardiovascular events

⭐

• high HRV: flexible and adaptive, balance between sympathetic and parasympathetic

• low HRV: rigid and stressed out

⭐

» Type D & autonomic function

• type D seems to be associated with an imbalance in the cardiac autonomic regulation

  • balance seems to tip towards higher activity (gas) during rest

  • decreased parasympathetic control

> OXIDATIVE STRESS

• “rusting process”

• occurs when there is an excess of free radicals (oxidants), a decrease in antioxidants, or both

• damage to cell walls, DNA, cell contents, etc.

• involved in artery and heart muscle damage

• unhealthy lifestyle contributes to oxidative stress

> CELLULAR AGING

telomere shortening: as cells divide over time telomeres shorten, and eventually cell division stops → biological age of cells

» Exposome paradigm

» Type D & cellular aging

Summary

Clinical Implications

• should we screen for type D personality in cardiologic (somatic) practice?

• primary and secondary prevention are relevant (how?)

• tailored health care, taking into account type D characteristics

Hypercortisolemia & Coronary Arteries

Theories

L10 - HEART & BRAIN

Terms

Cardiovascular diseases (CVDs): any diseases involving the heart or the blood vessels

• Acute coronary syndrome (ACS): umbrella term for any situation where blood flow to the heart muscle is suddenly reduced or blocked

  • myocardial infarction (MI): heart attack - blood flow is blocked long enough to cause damage or death of heart muscle

• Atrial Fibrillation (AF): atria start quivering or “fibrillating” instead of contracting properly

Cardiovascular Physiology is Important to Biological Psychology

cardiovascular diseases (CVDs):

• are the leading cause of death globally

• was responsible for 17.9 million deaths in 2019

• that is 32% of all global deaths

in the NL:

• cardiovascular disease is still the leading cause of death in women

• cancer is the overall leading cause of death

in the USA:

• CVDs are the leading cause of death

Anger as trigger of acute MI

Sir John Hunter: angry and rude, died of a heart attack after an argument

MI patients were interviewed at an average of 4 days after MI admission:

• Anger occurred in 39 patients in the 2 hours preceding the MI

• 130 participants reported anger in 24 hours prior to MI

• N = 1623, RR = 2.3 (95%CI = 1.7-3.2)

• results may be influenced by retrospective bias (i.e. patients reporting emotional triggers as part of “seeking meaning” for their cardiac event)

Overview of Cardiovascular Disease

artery (red / oxygenated / fresh):  away from heart, high pressure, narrow

vein (blue / deoxygenated / used): toward heart, low pressure, wide

the cardiovascular system consists of:

• the heart (pump)

• the blood vessels (to supply all tissues of the body with oxygen and nutrients)

• systematic circulation: sends oxygenated blood to the whole body

• pulmonary circulation: oxygen refill trip (just between heart and lungs)

• coronary arteries: feed the heart muscle itself (myocardium)

Inside of the heart

the heart is a pump:

• it pumps oxygenated blood out of the left ventricle (LV)

• it pumps used blood through the lungs via the right ventricle (RV)

• it needs blood supply from coronary arteries to function (contract) properly

Heart from the outside

coronary arteries lie on top of the heart muscle: 

• left coronari artery (LCA)

  • left anterior descending (LAD) artery

  • circumflex artery (LCx)

• right coronari artery (RCA)

  • right marginal artery

  • posterior descending artery (PDA)

Main types of cardiovascular diseases (CVD)

1. coronary heart disease (CHD): a broad term for diseases that affect the heart itself due to the narrowing or blockage

• coronary artery disease (CAD): the specific problem where the coronary arteries are narrowed are blocked by plaque build up (CAD is the main cause of CHD)

• myocardial infarction (MI): the event - heart attack where part of the heart muscle actually dies due to complete blockage of a coronary artery

symptoms: chest pain (angina pectoris), shortness of breath, fatigue

2. Heart failure (HF): when the heart can’t pump blood effectively (still beating, just struggling)

caused by:

• CAD / CHD

• MI

• valve diseases

3. valve disease

4. arrhythmias / sudden cardiac death (SCD): severe abnormal heart beats

5. stroke / CVA & TIA

6. other (e.g., endocarditis - inflammation of the inner lining of the heart)

Coronary atherosclerosis & myocardial infarction

coronary atherosclerosis: build up of plaque inside the coronary arteries

• tissue damage develops  “behind” a complete narrowing

⭐non-atherosclerotic artery → healthy⭐

Atherosclerotic coronary heart disease: pathology, manifestations, and timeline

Risk factors for coronary artery disease

modifiable:

• hypertension

• diabetes mellitus

• elevated lipid levels (cholesterol, LDL, low HDL)

• smoke

• overweight

• psychological factors

non-modifiable:

• age

• sex (male)

• genetic factors / family history of CVD

Myocardial ischemia

ischemia = insufficient blood supply to tissue or muscle

→ results in shortage of oxygen in places where it’s needed

myocardial ischemia is typically transient (temporary) in patients with stable coronary disease because:

• there is reduced supply because of coronary narrowing, combined with

• transient (temporary) increases in cardiac demand (e.g., by exercise, anger)

• typical symptoms are chest pain / pressure and shortness of breath

• if ischemia is severe and prolonged, permanent damage to the heart muscle can occur → myocardial INFARCTION (MI)

Treatment of coronary artery disease

• percutaneous coronary intervention (PCI: coronary angioplasty: used to re-open narrowed coronary arteries) → stent

• coronary artery bypass graft (CABG) surgery (used to “bypass” a narrowed segment(s) in one or more coronary arteries) → creates another road

• thrombolysis (used to re-open a (nearly) completely blocked coronary artery in the setting of myocardial infarction)

Psychological Factors and Heart Disease

1. ACUTE FACTORS (triggers)

• within an hour

• anger, mental arousal, etc

2. EPISODIC FACTORS

• transient (2 weeks - 2 years)

• recurring

• major depressive disorder, exhaustion

3. CHRONIC FACTORS (traits)

• gradual

• trait anxiety, hostility, type D / negative effectivity, low SES

⭐associations with disease progression depend on severity of underlying coronary disease⭐

⭐most psychological risk factors for CVD are “sub-threshold” → not meeting diagnostic criteria for psychological or psychiatric disorder⭐

Prevalence of depression in patients with medical conditions

Stress

psychological distress: a negative internal state of the individual that is dependent on interpretation or appraisal of threat, harm, or demand

> WHAT IS STRESS?

there is a wide range of theories and models about stress

• process that unfolds over time and involves the whole person

• “stress” can refer to: a stressor, feeling, or consequence

• distress response (what we typically mean by “stress”): how environmental events (stressors) threaten us, how they are interpreted, and how they make us feel

→ 2 types of distress response:

• eustress: stress evoked by positive emotions or events (this term is not very common anymore)

• distress: stress evoked by negative feelings or events

> VARIABLES AFFECTING STRESS RESPONSE

• time 

• control

• individual vulnerability

> YERKES - DODSON LAW

EXAM!

⭐chronic risk factors already play a role in early stages, but acute risk factors don’t ⭐

⭐REMEBER FOR EXAM⭐

Acute Psychological Risk Factors for Cardiac Events

• anger - disaster (coronary patients increase after an eq)

• anxiety - acts of war /violence / aggression

• acute distress - major public events (sports, elections)

Going back - anger as trigger of acute MI

why there was only 39 people that scored 2h?

anger scale:

1. calm

2. busy but not hassled

3. mildly angry, irritated, and hassled, but does not show

4. moderately angry - so hassled, it shows in your face

5. very angry, body tense, clenching fists or teeth

6. furious, almost out of control, very angry, pound table, slam door

7. enraged! lost control, throwing objects, hurting yourself or others

→ because these are rare

Myocardial ischemia

chest pain is the tip of the iceberg

cardiac event - clinical test:

• chest pain — history

• ST-T wave changes — ECG

• systolic function: heart’s pumping ability — RVG, echo

• diastolic function: amount of pressure in the arteries when the heart is at rest — RVG, echo

• metabolic changes — PET scan

• reduced perfusion — perfusion scintography, PET scan (contrast echo)

> MENTAL STRESS ISCHEMIA: MECHANISMS

• decreased cardiac supply (narrowing coronary arteries)

• increased cardiac demand ( hemodymanic reactivity)

    → blood pressure, heart rate, contractility

> THE ECG - THE RECORDING OF A MOVING CURRENT

measure of the changes in electrical loading of extracellular fluid due to electrical changes that occur in all cardiac muscle cells together

⭐the ECG represents all phases of the conduction pathway

what does the ECG provide you with?

heart rate: net effect of cardiac parasympathetic and sympathetic NS activation

→ R-R interval = time between two beats

⭐60 / R-R = heart rate

< 60 beats per minute: bradycardia

> 100 betas per minute: tachycardia

ST - segment: depression / elevation

> FIELD STUDIES

patients with documented CAD → ambulatory ECG monitoring → detect ST depression → correlate with patient diaries

» DAILY LIFE ACTIVITIES AS TRIGGERS OF MYOCARDIAL ISCHEMIA

ambulatory ischemia: episodes of reduced blood flow to the heart that happens while a person is going on about their daily lives

examples of physical activity:

1. sleep

2. rest, reclining

3. eating, talking

4. washing, dressing

5. shopping

6. climbing stairs, heavy physical work

examples of mental activity:

1. sleep

2. rest, reading

3. talking, clerical work

4. waiting, driving

5. concentrating

6. anger or anxiety

»» CIRCADIAN VARIATION IN TRIGGERING AMBULATORY ISCHEMIA BY PHYSICAL ACTIVITY & MENTAL STRESS

»» AMBULATORY MONITORING STUDY OF PRE-ISCHEMIC REDUCED PARASYPATHETIC ACIVITY

Summary

• the heart is a muscle that pups oxygenated blood throughout the body (systematic circulation)

• the heart also pumps “used” blood through the lungs for re-oxygenation

• like any muscle, the heart muscle also needs supply of oxygenated blood, this occurs via the coronary arteries (this is a different process than the heart’s pump function)

• myocardial infarction (MI) and sudden cardiac d. are the end-stage of progressive coronary artery disease

• psychological stressors play a different role in the development of heart disease: acute, episodic, and chronic risk factors

• acute mental stress can trigger MI and myocardial ischemia during daily life - partially mediated by changes in autonomic nervous system activity!!!!!!!

Need for the Study of Myocardial Ischemia (Lab Studies)

multiple mental stress stimuli + exercise = provocation

measure various markers of myocardial ischemia:

• wall motion

• perfusion

• ECG

• chest pain

Assessment of wall motion

> ECHOCARDIOGRAPY & RADIONUCLIDE VENTRICULOGRAPHY

end diastole (ED): fully relaxed, filled with blood, largest

end systole (ES): contracted inward, pumping out blood, smallest

hypokinesis: moves less than normal

akinesis: doesn’t move

dyskinesis: moves outward instead of inward - very dangerous!

> CASE STUDY: EFFECT OF STRESSFUL IMAGERY ON ISCHEMIC LV WALL MOTION

patient with PTSD and angina equivalent (cough) → thinking of trauma —→ ischemic

> ISCHEMIA WITH SPECT (moderate / severe)

Clinical issues - panic disorder and inducible ischemia based on perfusion defects

1 vital capacity inhalation of a gas mixture containing 35% carbon dioxide and 65% oxygen

→ elicited panic in 26 / 35 participants who had CAD and panic disorder (PD)

→ and elicited panic in only 2 / 30 participants who had just CAD

Transient coronary occlusion in response to acute mental arousal

coronary construction common with acute mental stress (reduced supply) - this is an extreme case (1 in 200)

Relation between blood pressure response to mental stress and coronary constriction

• 59 CAD patients (age 60 to 80, only 8 women)

• repeated angiograms

  • baseline control

  • 3 minute mental arithmetic

  • 200 micro g intracoronary NTG

• 18.6 % coronary constriction

• blood pressure (BP) responses associated with constriction in diseased segments (not in nonstenotic / not-narrowed segments)

Mental stress-induced ischemia characteristic features

⭐observed in 30-70% of patients with coronary artery disease

• rarely detectable with ECG in the lab

• requires myocardial functional or perfusion imaging (echocardiography, SPECT, PET, cardiac MR)

• often asymptomatic (silent ischemia)

• more common in patients with exercise-inducible ischemia than in patients without

• effects in the lab vary in reproducibility

• associated with ambulatory ischemia

• occurs at lower heart rate (i.e., lower cardiac demand than with exercise)

⭐reduced coronary supply plays an important role

⭐mental stress-induced ischemia is associated with poor prognosis and increased risk of mortality

Tako-tsubo cardiomyopathy (TTC) 

also known as: Apical ballooning syndrome (ABS)

• transient left ventricular (LV) apical ballooning

• broken heart syndrome

• stress cardiomyopathy

• ampulla cardiomyopathy

• neurogenic stunning

• contrast enhanced ventriculography during diastole and systole

• demonstrates apical and midventricular akinesis, with relative sparing of the base of the heart (arrow)

characteristic features:

• ECG suggesting acute myocardial infarction

• apical ballooning or other major ventricular dysfunction

• chest pain/dyspnea, pulmonary edema, cardiogenic shock

• short-term recovery of LV function typically fast

• long-term prognosis similar to myocardial infarction

but also:

⭐minimal coronary artery disease

⭐often triggered by emotional or physical distress (50% each)

⭐high (supraphysiologic) circulating catecholamines on admission

⭐80% female, mostly post-menopausal

59 year old women - trigger: family member died in a car accident

coronary angiography ejection fraction 10-20% (anterolateral, apical, inferior, and posterobasal akinesia) but only moderate non-obstructive disease in the left anterior descending artery. peak  (regulates cardiac muscle contraction) 29.9

history: MI, AF, mitral valve repair, restless leg syndrome, idiopathic joint disease

Episodic Factors: Depression and CVD (Epidemiological Studies)

examples:

• major depressive disorder (vital) exhaustion

• burnt-out

features:

• transient (2 weeks - 2 years)

• recurring

INTERHEART study

aim: examine psychosocial factors as risk indicators for non-fatal MI

design:

• case-control 11,119 MI and 13,648 controls

• 52 countries, 262 sites

measures:

• stress at work

• stress at home

• financial s.

• stressful life events

• depression

• loss of control

response options:

• never, sometimes, several times, permanent

• little to none, moderate, high severe

> REPORTED STRESS DURING THE LAST YEAR & RISK OF MI

• MI higher prevalence of all 4 stress factors

• adjusted for age, sex, geographic region, and smoking

CVD ←→ depression (BIDIRECTIONAL)

factors associated with depression onset:

• life stressors (particularly in mild-moderate depressive episodes)

• negative cognitive bias

• maladaptive response to loss (of a significant other or “object”)

• genetic vulnerability

previous studies focused on depression as a risk factor for CVD

But, CVD can also increase the likelihood of developing depression:

• symptoms (chest pain, shortness of breath, fatigue)

• functional capacity (exercise tolerance)

• biological consequences (inflammation, CNS changes)

• existential questions related to a life-threatening disease (heart structure and function per se do not strongly predict depression)

> DEPRESSION IN PATIENTS WITH CVD

• prevalence 15-40%

• associated with biological risk factors (e.g., inflammation) and adverse health behaviors (e.g., physical inactivity, poor diet, smoking, alcohol overconsumption, medication non-adherence)

• somatic depressive symptoms (fatigue, sleep problems) and irritability more common than typical depressive symptoms (depressed mood & anhedonia)

• depression is not a direct byproduct of underlying coronary artery disease or poor heart function

> DEPRESSION & CARDIOVASCULAR EVENTS

> META-ANALYSIS FOR PREDICTIVE VALUE OF DEPRESSION FOR INCIDENT CARDIOVASCULAR DISEASE (CHD & MI)

Mechanisms: Inflammation & ANS Dysregulation

• central nervous system (SAM, HPA)

• autonomic nervous system (parasympathetic & sympathetic)

• blood clot formation (coagulation & reduced fibrinolysis)

• inflammation and immune dysregulation

Multidisciplinary studies on PNI in cardiovascular disease

Atherosclerosis and infection: a first clue from Virchow

presence of leukocytes in artherosklerotic lesions → infectious agent?

The most common type of vulnerable plaque

thin-cap fibroatheroma:

• lots of inflammatory cells (monocyte/macrophages, t-cells, etc.)

• large lipid core

• thin fibrous cap

Cardiovascular event-free survival among healthy individual according to baseline CRP

• gradual

• more CRP protein = more mortality risk

Elevated markers of chronic inflammation in depressive disorders

• 50 adults with depression

• 50 adults with clean mental health history

• case-matched on age, gender, ethnicity

• group differences significant

The Biopsychological Approach in Cardiovascular Health

Conclusion

• acute mental stress can induce myocardial ischemia in patients with CAD and is a significant precipitant (trigger?) of cardiac events

• acute mental stress and depression are associated with elevated inflammation markers

  • acute stress reactivity elevated in CAD patients

  • results depression-inflammation inconsistent in CAD patients

  • effect sizes are small

• depression is associated with increased cardiovascular risk

• associations of depression with cardiovascular are bi-directional

• pathways linking depression to adverse CVD outcomes may require inflammation and ANS dysregulation as co-factors

• future studies are needed to:

  • develop models of mutually reinforcing risk factors: i.e., psychosocial, health behavior, biological processes and disease outcomes

  • identify high-risk subgroups and targeted interventions based on these dynamic models

L11 - DEPRESSION

Prevalence

• mood disorders including MDD: 44 million in Europe

• 54% of patients recover from MDD within 6 months

• 81% of patients recover from MDD within 2 years

• incidence is increasing over time

Definition & Subtypes

• important is the distinction between

  • depressive symptoms (questionnaires)

  • depressive disorders (clinical assessment)

• depressive disorder

  • unipolar

  • bipolar

  • endogenous: biological, internal, genetic

  • reactive: exogenous, event/situational related 

Causes (Genetics & evolution)

• 94 possible genes related to depression

• why is it taking so long to figure out?

• different aspects of depression

Theory of Depression

Stress

disturbed HPA-axis regulation in:

• depressive patients

• those with latent vulnerability (such as childhood trauma)

• those with treatment resistant depression

⭐if a mother experiences stress during pregnancy, it changes the babies HPA - axis which is related to stress⭐

Noradrenergic (monoamines)

two types of monoamines associated with depression:

• catacholamines: variants of the amino acid tyrosine

  • dopamine

  • norepinephrine⭐

  • epinephrine

• indoleamines/tryptamines: variants of the amino acid tryptophan

  • serotonin

  • melatonin

> MONOAMINE THEORY OF DEPRESSION: NORADRENERGIC HYPOTHESIS

» Point of Action 1

• norepinephrine is synthesized from tyrosine

• if there is enough norepinephrine they can attach to the adrenergic receptors

• α-Methyl-Para-Tyrosine (AMPT): reduces norepinephrine and therefore is a short term depression inducer

» Point of Action 2

• MonoAmine Oxidase (MAO): breaks down norepinephrine → induces depression (👎🏻)

• MonoAmine Oxidase Inhibitor (MAOI): inhibits break down of norepinephrine → treatment for depression (👍🏻)

» Point of Action 3

• granules: vesicles that store and protect norepinephrine from MAO

• reserpine drug: makes granules leaky → MAO eats more norepinephrine → less norepinephrine → depression

» Point of Action 4

• tricyclic antidepressants (TCA) → selective norepinephrine uptake inhibitor (SNRI)

» Point of Action 5

autoreceptors: signals that there should be less norepinephrine when norepinephrine attaches to them

Serotonin (monoamines)

two types of monoamines associated with depression:

• catacholamines: variants of the amino acid tyrosine

  • dopamine

  • norepinephrine

  • epinephrine

• indoleamines/tryptamines: variants of the amino acid tryptophan

  • serotonin⭐

  • melatonin

> SEROTONINE HYPOTHESIS

only differences with noradrenergic hypothesis are the red circles

Inflammation

Cytokines: e.g. IL-1, IL-6, TNF-α, INF-α

The brain has cytokine-receptors and when pro inflammatory levels are elevated you develop ‘sickness behavior’: that is…

• Apathy

• Irritable

• Fatigue and

• disturbed sleep

• Increased pain sensitivity

• Social isolation

• Anorexia

    → Sickness behavior has overlap with depression

> EVIDENCE

• creating inflammation or administration of cytokines leads to symptoms of depression

• cytokine-induced depression responds to anti-depressants

• depressive patients show inflammatory activation

• severity of symptoms is related to blood cytokine levels

Neuroplasticity

increases in monoamines:

• leads to an increase in neuroplasticity

  • via the expression of growth factor (Brain-Derived Neurotrophic Factor BDNF → fertilizer for neurons)

> EVIDENCE

• depression lowers BDNF in specific brain regions (humans and animals)

  • risk factors for depression (stress and somatic illness) also decrease BDNF

  • recovery from depression (by antidepressants, ECT, physical activity) increases BDNF

• it is mechanically plausible, as decreases in BDNF levels cause:

  • neuroplasticity decrease

  • increased responsiveness of stress hormones

• injection of BDNF into the brain improves depression

> OTHER MECHANISMS INVOLVED

• gut-brain axis

  • contributor to immune dysregulation

  • HPA-axis, increases in cortisol

• Kynurenine pathway 

  • HPA-axis regulation (breaks down tryptophan)

  • reinforced by chronic inflammation

Treatments

Pharmaceutical

> TRYCICLIC ANTIDEPRESSANTS (TCAs)

• “dirty drugs”: drugs with non-specific effects

  • besides reuptake inhibition of norepinephrine it also impacts unrelated processes because it binds to other receptors as well

• higher number of side effects than SSRIs and in case of an overdose cardiac complications 

> SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRIs)

• are selective, but equally effective compared to TCAs

• less side effects and lower risk in case of overdoses

• better with other medications than TCAs

• indication not only for depression: OCD, eating disorders, PMS

» Side effects

multifunctionality: has a selective effect on the same process, but this process has different functions in different cells

→ 5HT (serotonin) in the digestive system

Non-pharmaceutical

• ECT (electroconvulsive therapy)

• physical activity

• light therapy

• Saint John’s wort herb

Depression & Somatic

Co-occurrence

• approximately 40-60% of depressed patients have a somatic condition

• depression reduces medical treatment effectivity and increases mortality 

• a very high number (85% mild depression and 60% severe depression) depressed patients are not recognized by doctors

• reversed: many somatic complaints of depressed patients are not taken seriously by their doctor

Depressogenic aspects of somatic conditions

• psychosocial

  • dealing with loss and trauma

  • being limited with respect to self care, work, social and family life

  • the underpredictability or life threatening aspects of an illness

  • undergoing painful and intervening treatments

• psychobiologic

  • neurological damage

  • effects of hormonal disturbance

  • effects of medications

> SOMATIC CONDITIONS WITH ELEVATED CYTOKINE LEVELS

• autoimmune diseases:

  • rheumatoid arthritis (joints)    

  • Crohn’s disease (inflammatory bowel disease)

  • multiple sclerosis (myelin)

  • systematic lupus erythematous (non-specific, all cells)

• chronical viral and bacterial infections

• being obese

• diabetes mellitus

• cardiovascular disease

Depression - medication

⭐25% of depression in the elderly is the effect of medication use⭐

• pharmaceutical treatment for hypertension

  • beta blockers (e.g. propandol)

  • calcium receptor blockers

• hormone treatment

• glucocorticoids (reducing inflammation, e.g. prednisone)

• alpha-interferon (INF-a ), for treating hepatitis C: 33% develops a depression <12 weeks

L12 - STRESS & ANXIETY

Cathy, 4 years:

• mother of two

• has rheumatoid arthritis (RA) since 31

• RA has been stable, yet a few months ago she experienced more symptoms

• currently getting a divorce

John, 24 years:

• has eczema since he was 10

• symptoms fluctuate over time

• current outbreak

• in a few days he has an exam

what do Cathy and John have in common?

→ STRESS

Why Stress Has Physiological Effects

• the cognitive representation of a threat causes a “fight-or-flight” response

• followed by a cascade of biological events:

  • starting in the brain

  • inducing peripheral stress responses such as increases in heart rate, blood pressure, and stress hormones (cortisol)

The reactivity hypothesis

• classical theoretical understanding: stressful events are accompanied by physiological responses, which, if frequent and intense, may cause bodily harm

  • however, mostly weak and inconsistent support

  • does not account for prolonged physiological activity

From reactivity to prolonged activation model

prolonged activation model: physiological activity during stressful events (stress reactivity) will only become a critical health threat when it is sustained long after these events, or when physiological activity is already present in anticipation of these events, sometimes even far before them

Prolonged activation model

worry, rumination, perseverative thinking

= anticipation + slow recovery

The role of continuing stressful thoughts: perseverative cognition

to explain prolonged activity, the perseverative cognition hypothesis is formulated. Two core arguments:

1. recovery of the autonomic nervous system after a physical stressor (running upstairs) is much faster than from most psychological stressors

2. human brain looks backwards and forwards: ruminating about the past and worrying about the future

   • unique to humans

   • humans make mental representations of stressors long before, and long after these events occur or are believed to occur → perseverative cognition (PC)

Physiological & psychological profile of perseverative cognition

Input of stress response

• internal stressors (vagus nerve)

• somatosensory stressors (skin and muscles)

• painful stressors

• emotional stressors

• cognitive input

Complex Network of Signaling

Sympathetic nervous system (SNS)

flight or flight → via vagus nerve:

• dilate pupil

• inhibit salivation

• increase heartbeat

• relax airways

• inhibit activity of stomach

• stimulate release of glucose, inhibit gallbladder

• inhibit activity of intestines

• secrete epinephrine and norepinephrine

• relax bladder

• promote ejaculation and vaginal contraction

Endocrine system

> HPA - AXIS

hypothalamus —CRH→ anterior pituitary —ACTH→ adrenal cortex → CORTISOL!!!!

grow and appetite, metabolism, glucose storage, learning and memory

> SCHEMATIC HPA - AXIS

Immune system

> EFFECT OF STRESS HORMONES

cortisol:

• stimulates lymphocyte maturation

• regulates inflammatory responses

• promotes catecholamine release

✅physiological response when life is actually in danger✅

❌when survival is not threatened it can lead to a poor immune functioning❌

Homeostasis vs Allostasis

homeostasis: if you are in north pole in a bikini your body has to work a little bit harder for maintaining 36C

allostasis: every thursday you drink, so your liver has to work harder in thursdays then it starts to remember that and your liver gets activated before u start drinking → anticipation, learning memory, prediction

Maladaptive or Adaptive

does stress has an effect on our health?

And if so, how?

Why is the duration of a stressor important when it comes to the effect of the stressor on one’s health?

real danger:

• upregulates (+) natural immunity, rises in the number of neutrophils and NK cells → preparation for injury

chronic stress:

• downregulates (-)

→ stress can negatively impact health through changes in immune functioning

Clinical relevance

> WOUND HEALING

a model for studying the immune function, as the immune system is involved in wound healing

» example

• 11 dental students

• 3.5mm biopsy wound was made inside their mouth

• once wounds were made during vacation, once before exams

→ wounds took longer to heal during exams than summer

exam = prolonged stress (not acute)

how are positive psychological factors related to health?

→ social support and optimism!!!!

> SOCIAL SUPPORT

• 73 HIV seropositive gay men were assessed for concealment of being gay, social support, depression and CD4 amount

CD4 → predictor of HIV:

• low CD4: bad

• high CD4: good

interaction effect: 

• low support: no effect

• high support: matters if you are open or not

> OPTIMISM

• positively correlated to cellular immunity in controllable, brief and straightforward situations

• inversely correlated with cellular immunity in uncontrollable, chronic and complex aituations

• the later may derive from optimists’ over-engagement in tasks, even if it’s complex, they cannot “give up”

> SUMMARY

• studies show that stress can have negative effects on our health (wound healing, colds, infections)

• studies show that some psychological factors can be protective (social support and optimism)

Anxiety - (mal)adaptive?

can be maladaptive and adaptive

can be evolutionarily useful - being alert

• easily startled, hypersensitive to noise → response to threat easily evoked

• insomnia → constant alertness

• restlessness, increased heart rate → body prepared for action

• attention diverted to cues related to threat → notice threats earlier

• ambiguous information interpreted as threatening → reduced chance of making a false-negative assessment and missing a possible threat

• ambiguity averse → avoidance of situations where threat is uncertain

GABA

GABA-A Receptor

Anxiety and GABA

Anxiety = too much activity

GABA leads to:

• CL^- transportation into the cell

• making the inside of the cell more negative or hyperpolarized

• therefore less likely to fire an action potential

→ less activity = less anxiety

Indirect impact at the GABA receptor via the benzodiazepine binding site, by various drugs: effects can be positive (agonist) facilitating activity or negative (inverse agonist) inhibiting activity

⭐barbiturates: don’t need GABA they can pretend to be GABA

→ on its own reduce the firing

⭐benzodiazepines : need GABA to be present in order to have an effect

Agonist: benzodiazepine + GABA

• Benzodiazepine + GABA enhance inflow of CL

• Cell is more negative, action potential is less likely 

• Inhibition of neuron, anxiety is reduced

→ agonist

Antagonist: flumazenil + GABA

• Blocking the benzodiazepine binding site by flumazenil

• Solely GABA binding will result in CL- induction (less then with benzodiazepines together)

• There is no change in CL- inflow, no effect on anxiety

→ antagonist

⭐given for ODing → cancels out benzos⭐

Inverse agonist

• Another drug attaches to the benzodiazepine binding site

• GABA binding together with this inverse agonist results in a reduction in CL- induction

• Cell is less negative, action potential is more likely

• Less inhibition of neuron, anxiety is INDUCED

Response for each category

Barbiturates & benzodiazepines

⭐barbiturates are not given anymore because they do not have an antagonist (but benzos do)

Serotonin

(-) depression —— anxiety (+)

⭐given the involvement of serotonin in both disorders a partial agonist when treating anxiety is beneficial

Noradrenaline

Alpha-2 adrenoceptors:

• blockage: increases release of noradrenaline (reduces depression)

• stimulation: decreases release of noradrenaline (increases depression)

→ can do both