Voor sommige patiënten is alleen medicatie niet echt effectief en dit zorgt ervoor dat zij nog verschillende symptomen hebben. Verschillende biologische factoren spelen een rol in zulke casussen, zoals genen, het endocriene systeem (zoals hormonen), het immuun systeem (een depressie kan een negatieve invloed hebben op het immuunsysteem) en andere neurobiologische factoren (zoals veranderingen in het hersennetwerk). Het is noodzakelijk om een multi-dimensionele interventie te gebruiken omdat er een interactie is tussen verschillende factoren. De blootstelling vanuit de omgeving (zowel fysiek als psychosociaal) leidt tot de interactie tussen deze processen. Uiteindelijk beïnvloed deze interactie gezondheid en ziekte. Fenotype kan worden beschreven als iemands observeerbare karakteristieken. Enkele voorbeelden zijn uiterlijk, bloedtype, persoonlijkheidstrekken en gedrag. Nature (of erfelijkheid): ons fenotype wordt veroorzaakt door onze genen. Onze karakteristieken zijn aangeboren en kunnen gezien worden als een predispositie.Nurture (of omgeving): ons fenotype wordt beïnvloed door de omgeving. Onze omgeving beïnvloed de ontwikkeling van een persoon.Nature en nurture zijn allebei erg belangrijk en de combinatie van beide maakt ze onafscheidelijk. De interactie kan worden gezien aan de hand van een voorbeeld...

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Lecture notes Pharmacological and Biological Approaches to Clinical and Health Psychology - UL, B2/3

Lecture notes Pharmacological and Biological Approaches to Clinical and Health Psychology - UL, B2/3


Lecture 1: General introduction genetics

In some patients just medication is not very effective and they still have different symptoms. Different biological factors can play a role in such a case, like genes, endocrine system (like hormones), immune system (depression can have a negative influence on the immune system) and neurobiological factors (changes in the brain network). It is necessary to use a multi-dimensional intervention because of the interaction between all the different factors.

The exposure from the environment (physical and psychosocial) leads to the interaction between these processes. In the end this interaction influences health and disease.

Genetics

Why should we understand genetics?

Phenotype can be described as the observable characteristics of someone. Some examples are appearance, blood type, personality traits and behaviour.

Nature versus nurture

Nature (or heredity): our phenotype is caused by genetics. So our characteristics are congenital and can be seen as a predisposition.

Nurture (or environment): our phenotype is influenced by the environment. The surroundings affect the development of someone.

Nurture and nature are both very important and the combination makes them inseparable. The interaction is shown by the example that certain kind of genes not always lead to a certain type of pathology. These genes can be seen as a risk factor that can lead to pathology if some environmental factors cross a threshold.

Usefulness of the study of genes

The study of genetics leads to knowledge about development and mechanisms of diseases, the possibility to improve treatments and to the individualisation of (risk) prediction, therapy and prognosis (this can be tailored).

Genetics & Psychobiology: Mechanisms

Our DNA is located in the nucleus of our cells, DNA is formed by chromosomes. The entire set of the human DNA is called a genome. In total we have 23 pairs of chromosomes (one from our father and one from our mother). Our DNA is winded by the histones, because otherwise it would be too long. DNA is constituted by bases (four types), namely: A, T, G and C. A gene is a part of the DNA that encodes for one protein. Two processes play a role in de encoding from genes to proteins:

  1. DNA is transcribed into mRNA;

  2. mRNA is transcribed into a protein.

Variance across humans

Genetic variation

The genotype contains all the genes someone has. It contains the specific genes but also the general genetic constitution. A big part of our genes is fixed, this can be shown by the example that 99% of DNA is the same for every human, only 1% differs. This difference is due to mutations and polymorphisms.

Mutations

Mutations in DNA provoke permanent changes, like duplication of base segments or base change. This mutations can lead to changes in the proteins if the mutations are not repaired.

Polymorphisms

Multiple variants of a gene in the population are called polymorphisms. An example is a copy number variation (CNV), like deletions of stretch of the DNA. A single nucleotide polymorphism (SNP) is the change of one letter of the DNA, these changes are very common.

From genotype to phenotype

The Mendelian inheritance theory makes a distinction between dominant versus recessive alleles and between homozygous versus heterozygous alleles. Someone’s DNA is stable over time, but not encoding of DNA into proteins is not always necessary. This encoding process is constantly influenced by different environmental factors, like interaction of genes and the regulation of gene expression. The encoding process is also dynamic.

Epistasis

This is the interaction of genes: allele for one characteristic interferes or hides an allele for another characteristics. Illustrated image on slide 21.

Epigenetics

The environment influences whether a gene switches off or on. So there is no modification of the DNA sequence. The environmental factors can be either internal or external. External factors or for example diet, smoking and stress. The conclusion is that someone’s phenotype is the result of a gene-environment interaction (G x E).

Application of genetics and psychobiology

Gene-environment interactions can be studied through the comparison of cases and controls, like twin or family (pedigree) studies. Family studies are especially useful in the case of a rare disease that is caused by a mutation in the genes.

Genetic association studies

These kind of studies are possible in two situations:

  • Candidate gene association study: knowing the biological mechanisms (beforehand selecting genes that play a role in the disease mechanisms) or in the case of;

  • Genome-wide association study: not exactly knowing the genes, but knowing the environmental risk factors (for example smokers, alcohol users etc.) and testing many genetic variants. It is necessary to use a big sample.

Environmental influences

It is important to take both into account:

  • Trigger or enhance expression of genetic predisposition (maltreatment, negative live events, early life stress etc.)

  • Compensate for or control expression of genetic predisposition (low stress levels, social support, so protecting variables).

What is the influence of genes and environment in the clinical phenotype?

The gene-environment interaction can be shown on a genetic-environment scale. Down syndrome is totally on the genetic side of the scale: these patients have a 3rd copy of chromosome 21. In most diseases multiple genes play a role in the development.

Allergy

Allergy is an example of a complex gene-environment interaction. It is considered as a Classic psychosomatic disorder, because the G x E interaction is very important. Allergies are very prevalent and increasing. Some examples of common allergies are: eczema, food allergy or asthma. An allergy is an early manifestation of immune dysregulation. 30% of Western people suffer from allergies and the prevalence is still increasing. Allergies are influenced by different psychological factors, like stress. These factors can increase the incidence and severity of the disease.

Indications for a gene-environment interaction are:

  • Genes: Within families or twins there is a higher allergy rate (approximately 36-75% is explained by genes).

  • Environment: It is impossible to explain the high incidence increase genetically, because it is too fast. The fact that allergies are more prevalent in high developed countries gives evidence for the hygiene hypothesis. This hypothesis states that better hygiene leads to allergies because of the higher immune reaction.

Risk genes: It has been shown that encoding for immune reactions plays a role. Some environmental factors, like having pets, living on a farm or smoking influence the development of allergies. These environmental factors change the DNA transcription and the translation from DNA to mRNA through epistasis processes.

Heterogeneous diseases are diseases that are developed through multiple genes and factors from the environment. The dose (is the exposure chronic or just a single episode?) and the time of the exposure (during childhood or in adulthood?) influences the exposure of risk factors in the environment. Not every environmental factor can be measured, this is also true for the protective environmental factors.

Gene-environment interaction and psychopathology

In research about the G x E in psychopathology there is a heritability gap. Because twins also share their environment there is an overestimation of the genetic component.

Studies concluded that the genetic component of schizophrenia and major depressive disorder is 20-25%. But in schizophrenia 80% of the variance is explained by genetics. There is a much lower heritability component if you approach it via Molecular SNP.

Risk factors for the development of schizophrenia are: season of birth (while pregnant in the winter mothers are more vulnerable for certain types of viruses), cannabis use during adolescence (specifically: cannabis & COMT polymorphisms. This is a gene encoding enzyme that metabolizes dopamine).
The target of treatment for patients suffering from schizophrenia is anti-psychotic drugs, because they supress the dopamine receptors.

Risk factors for the development of major depression are: childhood maltreatment, early stressful life events (in combination with specific SLC6A4 polymorphism). Treatment consists of anti-depressant drugs, because they increase the levels of monoamines.

Environmental risk factors for alcohol dependence are: low parental monitoring, high availability of alcohol and influence of peers. In the genes there are also some risk factors found, like the genes that encode for the GABA-receptor. This because the GABA-receptor binds with alcohol, so treatment focuses on the GABA-receptor antagonist.

Goals of interventions

The human DNA can’t be changed easily, but it biological products can. It is possible to change the environmental factors, like quit smoking and eat more healthy.
 

Lecture 2: Neuro-endocrinology

The brain serves as a source and target of hormones. We will talk about the effects of hormones on the brain, behaviour and especially focus on cortisol.

Glands produce hormones

The brain controls the activity of peripheral glands. The brain itself is also a gland. The hypothalamus decides about hormones (based on information from many brain regions) and is also the outcome of the brain. The hypothalamus emits signals through the blood to the pituitary and to the brain etc. For a visual illustration see slide 3.

Receptors are hormone recognizers. The locations of these receptors depends on the hormones they bind with. To see where the cortisol receptors are, you have to look at the location of the effect of cortisol, this is where the receptors are.

Glands make hormones and hormones coordinate processes

So the hypothalamus is in contact with the pituitary through the blood. There is variation in cortisol ACTH levels in the human body, see slide 3. You can see that there is an increase in ACTH level at 03:20 o’clock and some minutes later a cortisol increase. So you can conclude that first ACTH levels increase and then (somewhat slower) an cortisol increase. So if the pituitary puts out his hormone (ACTH), this travels through the blood to the kidney and 10 minutes later cortisol level is increased. Hormones influence a lot of different processes in the body, for example metabolism, immunity and cardio-vascular function. If you are chronically stressed, this supresses your immune system. Cortisol ensures that immune function goes down, this makes it easier for bacteria to infect us, for example in the case of a stomach ulcer.

Hypothalamus (bottom of the brain)

The production of cortisol (in the adrenal gland) is stimulated by the pituitary (through ACTH) and also by the hypothalamus (through CRH). CRH is an abbreviation for corticotropin-releasing hormone. All these processes influence each other: the production of CRH moves the pituitary to produce ACTH and as a result of this the adrenal gland produces cortisol in response to the ACTH. The hormone CRH is always waiting for stress to occur so that in can initiate the processes. In a stressful situation CRH is released because of the stressor (slide 5). Novelty can be very stressful for a mouse.

CRH production in the hypothalamus

Inflammation, memories and fear influence the working of the hypothalamus. Stress occurs in the brain and you measure the hormonal response to stress.

The limbic-hypothalamus-pituitary-adrenal-axis

How do you know where cortisol acts? Look for the receptors. You find CRH receptors in the pituitary, hippocampus, striatum, cortex and the amygdala (because CRH is used as a neurotransmitter). ACTH receptors are located on the adrenal gland, but also on fat tissue for example. On the website www.brain-map.org you can explore the brain (processes). So in for example the amygdala CRH acts as a neurotransmitter (outside the hypothalamus).

Research about the CRH response in the amygdala

Amygdala CRH response to (non) escapable forelimb shock in sheep. They implanted a chip in the amygdala of sheep’s. CRH increases and decreases over time. In the non-escape group CRH level was higher than in the escape-group. So not being able to escape in a threatening situation is much worse. CRH is a biological indication for how stressed the brain is. Blocking CRH in animals leads them to become less fearful and more curious. Fear or pain is very useful and stress is adaptive. Hormones are a nice way to coordinate organization of different brain parts.

Other releasing hormones

Gonadotropic releasing hormone (GnRH) is made in a region of the hypothalamus. Release of GnRH is responsible for the production of FSH (follicle stimulating hormone) and LH (Luteinizing Hormone). In the case of a high GnRH production this leads particularly to the production of LH. In the case of a low GnRH production this leads to FSH production. LH is produced in the pituitary. In women an increase in LH leads to stimulation of the ovulation. In men LH leads to production of testosterone. The receptors of GnRH are located at the pituitary.

Posterior pituitary hormones direct connection from hypothalamus

The pituitary consists of two parts: posterior pituitary ( or neurohypophysis) and the anterior pituitary ( or adenohypophysis). The posterior pituitary is connected to the hypothalamus and the anterior pituitary is the part of the pituitary that regulates several different physiological processes.

Oxytocin is very important for women in labour: not just for the delivery but also to help bonding the mother and child. Oxytocin is made in the hypothalamus. Oxytocin neuron can also release their product from the dendrites, into the brain, and not only via the axon (as a normal neuron would). It is possible to give birth without having oxytocin released in the brain. But this leads to monogamous pair bonding (release oxytocin into the brain). Bonding in men depends on vasopressin and in women on oxytocin.

Hormone action on the brain: how cortisol affects neurotransmission

Stress is about adaptation to a certain situation. Stress is a good thing because it makes it possible for us to adapt to difficult situations. Novelty and adaptation to novelty is good. But there is a cost, sometimes the stress response may be too much. If you are adapted to one stressor all your adaptive capacity is used. If something else happens you can’t deal with that, this is the moment when stress becomes too much. Chronic stress is stress that is just too much to cope with. In contrast to acute stress (which is a good, adaptable and healthy thing).

Stress response: sheep sees dog

The CRH levels in the amygdala immediately go up and after a while the cortisol levels also go up. There are different time domains: immediate (freeze behaviour: fight/ flight) or lasting. Cortisol is slower activated and stays longer in the blood.

Trier Social Stress Test

The TSST is a social stress test inducing test in which a speaker sees a judgemental audience. This increases stress in humans because of the social exclusion by the audience. An increase in heart rate (the fast stress response, adrenaline) and ACTH and somewhat later cortisol can be found.

The effects of cortisol on the brain

Cortisol determine the initial stress response. It also dampens the stress response or support or specify this response. Cortisol supports adaptation to possible future events or chronic stressor(s). When you are stressed it is possible to experience flashbulb memories (place and time are remembered very well, located in the hippocampus).

Cortisol receptors

Glucocorticoid receptor is located everywhere in the brain, it has a lower affinity because more cortisol is needed to stimulate this stress receptor, it is very insensitive. So a lot of stress is needed to stimulate the glucocorticoid receptor.

Mineralocorticoid receptor is mainly in the limbic (emotional) brain, has a higher affinity. The mineralocorticoid receptor is the sensitive cortisol receptor.

The initial stress response is determined by cortisol level (basal levels). To determine the initial response, the sensitive receptor is used. Less-sensitive cortisol: measure how much cortisol increase has taken place. Processes like recovery, coping and memory depend on the glucocorticoid receptor.

Cortisol is slow and his effects are even slower. Cortisol receptors are located inside the cell. Once cortisol is located on the DNA it effects the activity of the DNA. Another example of an effect of cortisol is that there are more receptors for dopamine, which influence other receptors.

Cortisol can change sensitivity for neurotransmitters

Whether or not there is an effect of serotonin (5-HT) depends on prior exposure to cortisol. If you are exposed to stress levels of cortisol , this responds on the serotonin production. So high levels of cortisol influence other receptors. They change the way brain regions response to other substances. Vulnerability can lead to different psychopathologies. Psychosis depends on dopamine because there is lots of dopamine activity in the brain. Cortisol acts on the active parts in the brain and works as a greaser.

Cortisol, cognition & psychopathology

Cushing’s disease is a result of extreme exposure to cortisol. A tumour leads to too high levels of cortisol (without having stress). This has many effects on the body, like metabolic disturbance, immune suppression, muscle wasting (breaks down muscles to get energy), thrombosis, psychosis and depression.

Acute versus long term changes

Cortisol has long lasting effects on mental health. It leads to less grey matter volume and also to damage of white matter. Cortisol can cause psychopathology and is long lasting.

Synthetic steroids: lowered cortisol after anti-cancer anti-inflammatory pharmacotherapy.
Leukaemia patients get dexamethasone, this inhibits secretion of cortisol. This inhibition in cortisol has extreme psychological effects. But for this patients it is of course very important to continue the treatment, despite the extreme side effects.

In PTSD cortisol has an enhancing effect on memory (these patients engrave to deeply).

The HPA-axis

Cortisol stimulates memory consolidation: object-location-recognition. Cortisol effects memory, because without cortisol a novel task does not produce curiosity and explorative behaviour. Cortisol effects brain regions. Stress and cortisol can change relative dominance of brain circuits.

Read more