Chapter 7. The biological implications of psychotherapy. Patrícia Polgár, János Réthelyi, Zsolt Unoka. 1. Introduction

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1 Chapter 7 The biological implications of psychotherapy Patrícia Polgár, János Réthelyi, Zsolt Unoka 1. Introduction Research in neuroscience is finding more and more of the workings of the mind in the workings of the brain, refuting the idea of separation of mind and body. Hippocrates located thoughts and feelings to the brain in 400 BCE, while early Christian thinking treated the mind and the body as two separable, independent entities. One major thinker of the modern age, René Descartes, introduced the concept of Cartesian dualism, the existence of mind and body as separate substances working together. In this view, the emotions, language, memory and conscious thinking are independent of the body and brain, indeed intellectual and spiritual phenomena are not tied to any material phenomena. Dualism dominated continental European thinking for centuries. It is difficult for us to break from the basic idea that mental phenomena stand apart from the material substrate. Scientific findings over the recent period, however, tell us that we must relinquish the strict dualist interpretation if we want to understand human operation in its entirety. The 20th century witnessed a series of insights into the workings of the mind. Golgi and Cajal received the Nobel Prize in 1906 for their work on the structure of the nervous system. In 1937, Papez described how certain anatomical structures in the brain were responsible for regulating feelings. In 1949, Donald Hebb proposed the idea of neuroplasticity, the mechanism by which long term memory is created in the nervous system through interactions with the environment: frequently activated synapses connections between nerve cells become stronger and thus store information (Grosjean, 2005). Hebb s idea was at first rejected by the scientific community, but research into the neurobiological foundations of learning and memory in the second half of the century bore him out. Learning was found to involve changes at cellular level in the nervous system: environmental factors led to changes in the size and excitability of synaptic connections, the number of dendrite branches, and the thickness of the cortex and each of its layers. This phenomenon is called experience-dependent neuroplasticity. The Nobel prize-winner Eric Kandel formulated five principles governing the interaction of the environment with nerve-cell operation. He incidentally mentioned psychotherapy as one form of learning. Kandel s principles (Kandel, 1998) are: 1 All mental processes, even the most complex psychological phenomena, derive from operations of the brain. 2. Genes and their protein products are important determinants of both the patterns of interconnections between neurons in the brain and the details of their functioning. 3. Altered genes do not, by themselves, explain the variant of a given major mental illness. Social or developmental factors also contribute very importantly. Learning, including learning that results in dysfunctional behaviour, produces alterations in gene expression. 4. Alterations in gene expression induced by learning give rise to changes in patterns of neuronal connections. 5. Insofar as psychotherapy or counselling is effective and produces long-term changes in behaviours, it does so through learning by producing changes in gene expression that alter the strength of synaptic connections, and structural changes that alter the anatomical pattern of interconnections between nerve cells of the brain. This chapter looks at the neurobiological, endocrinological and immunological effects on the experiences we obtain in the course of human relationships, i.e. how relationships affect the body. In the first part, we look at the effects of everyday human relationships and upbringing, and in the

2 second, we describe the biological effects of the specific human relationship involved in psychotherapy. Human relationships and other environmental factors take their effect via the genetic make-up and vulnerabilities of the individual, by what is known as the gene-environment interaction. 2. Environmental and genetic roles 2.1 Gene-environment interactions in the cause of psychiatric disorders The gene-environment interaction responsible for a certain character, phenotype or disease is the combined effect of a specific genetic variation and the environmental effect during a critical period. It takes effect through the processes of biological development, and research over the last ten years has discovered its significance in the development of psychiatric conditions. Neither genetic nor environmental effects are enough individually to determine the occurrence of a psychiatric disease in any individual and only explain percentage probabilities even of variations common to a group (a phenotype). Models embracing the interaction of genetic and environmental effects have much higher predictive power. The most influential researchers in the field are Caspi and Moffitt (2006), who have demonstrated the involvement of genetic and environmental effects in psychiatric conditions. The genetic risks are being related to an individual with a psychiatric disease, and carrying a specific risk-allele of a gene. The environmental factors are very numerous and exert their effects at various ages. They include perinatal complications, child abuse, adolescent drug use and negative life events. Gene-environment interactions are traditionally investigated by cohort studies. The best known of these is the Dunedin study, which has continuously followed the somatic and mental health of a cohort born in the city on the south island of New Zealand in Caspi et al showed the interaction of genetic and environment factors in three psychiatric diseases. They found that if a child carrying the variation of the lower MAO-A activation variant of the regulatory polymorphism of the MAO-A gene promoter was maltreated, the symptoms of adolescent behavioural disorder and adult anti-social personality disorder (aggression) were significantly more likely to develop. Neither possession of the genetic polymorphism nor maltreatment was in itself associated with higher occurrence of the behavioural disorder. A similar gene-environment interaction has been observed in schizophrenia-like psychosis. Individuals regularly using marihuana were more likely to display psychotic symptoms in early adulthood if they carried the Val-Val genotype of the catechol-o-methyltransferase (COMT) gene val158met polymorphism. Both MAO-A and COMT have important functions in breaking down monoamine neurotransmitters. There have also been remarkable observations of the occurrence of depression, with implications for the question of why negative life events lead to depression in only some people. Like the first two studies, this made use of data from the Dunedin study. The conclusion from the longitudinal study was that negative life events experienced by adults such as job dismissal or the break-up of a couple relationship only led to depression if the individuals carried the short variant of 5-hydroxy-triptamin linked polymorphic region (5-HTTLPR) of the serotonin transporter promoter. This genetic polymorphism influences the expression of serotonin transporter and thus of serotonerg neurotransmission, which plays an important role in regulating mood and anxiety symptoms (Caspi et al, 2003; Caspi and Moffitt, 2006 Figure 7/1). Behavioural disorder, antisocial disorder MAO-A low activity Childhood maltreatment Schizophreniform psychosis COMT VAL158Met Adolescent cannabis use Depression, suicidal thoughts 5-HTTLPR Negative life events Further modulating these phenomena is the effect of epigenetics. Epigenetics concern the variations not coded in DNA, but effected by the packaging or accessibility of genes, for example the influence on the expression of a particular gene by methylation of the promoter region. As we

3 shall see, it is not only through interaction with variations at DNA level that environmental factors can give rise to a psychiatric disease. They can also permanently modify the patterns of expression of certain genes in nerve cells. 2.2 Stress as an environmental factor Psychosocial stress Stress is what occurs in situations when people cannot solve their problems with the resources available to them. Stressful situations set off many biological changes in the central nervous system and elsewhere in the body, mediated by the vegetative nervous system, the endocrine system and the immune system. The body s stress response is triggered by physical threat and by psychological burden. Psychosocial stress strongly activates the hypothalamus-pituitary-adrenal (HPA) axis in both laboratory conditions and real life. The psychosocial stress situations are often modelled using the Trier Social Stress Test (TSST), which examines neuroendocrine and cardiovascular stress responses, including cortisol levels and breathing and pulse rates (Kirschbaum, 1993). In the TSST, subjects are put in a situation similar to a job interview. They are asked to stand in front of an audience sitting behind a table and talk about themselves for five minutes without a break. The person is told that the experts present will be observing their nonverbal behaviour and will make further analyses of a video recording. Then the committee asks the person to count a large prime number backwards thirteen at a time. The real purpose of the test (which is not the observation of nonverbal communication but comparison of components of the stress response before and after the test) is only revealed to the subject afterwards. The TSST which only consists of psychosocial stress factors results in significant neuroendocrine and cardiovascular stress response in 70 80% of subjects (Kirschbaum, 1993). The social environment is also the most common source of stress in everyday life. Events with high stress-arousing scores are death of a close relative, break-up of a relationship, and disputes and failures in marriage, in other relationships, and at work. When the system experiences stress, the following biological changes occur: 1. In the hypothalamus, the corticotropin releasing hormone (CRH) gene goes into action, producing CRH. 2. CRH stimulates the release of adenocorticotropic hormone (ACTH) in the hypophysis. 3. ACTH releases cortisol in the pituitary gland. 4. The production of noradrenaline and adrenaline in the adrenergic neurons of the brainstem increases, leading to increased pulse rate, vasoconstriction and increased breathing rate. These changes are transitory in the case of acute stress, but chronic stress causes long-term changes in the operation of the stress axis. Initially, sustained stress causes hyperactivity of the stress axis, through permanently elevated cortisol level. Subsequently, the sustained hyperactivity leads to down-regulation of various levels of the stress axis, eventually lowering the cortisol level (Friese, 2005). In addition, the normally high level of cortisol in the morning evens out, and so the diurnal fluctuation of cortisol level ceases. Severe chronic stress causes functional disorders and even structural changes in the brain, including atrophy of the neurons of the hippocampus (Sapolsky, 2003) Effect of early stress on the nervous system The idea that traumatic events in early childhood influence our behaviour in adulthood emerged in psychology more than a hundred years ago. Epidemiological studies have confirmed the link between early traumatic events and certain psychiatric and even somatic diseases. Deprivation or relationship stress in early life causes long-term changes in the nervous system via the mechanism of gene expression.

4 Animal experiments Exposure to stress in childhood has a long-term influence on stress response levels later in life. The stress which leads to HPA axis dysfunction seems to have a connection with maternal care. Monkeys which were suddenly separated from their mothers at inconsistent intervals when young showed changes in stress-axis functioning when older: a decrease in morning cortisol secretion dampens daily fluctuation. Baby rats which were regularly licked and cleaned by their mothers later reacted to stress with less ACTH release, i.e. lower stress-axis activation, than those not treated the same way by their mothers (Meaney, 2005). Animals abandoned or traumatized when young are less bold and more anxious (and more susceptible to self-administration of ethanol). The effect of mistreatment on mice also depends on their genotype, and so is the result of gene-environment interaction (Holmes, 2005) Human data It is known from epidemiological surveys that persons who suffer childhood maltreatment are more often fall victim to depression, anxiety disorders and cardiovascular disease. As with animals, people who have been traumatized as children display increased stress-axis responsiveness in later life. Abnormal HPA-axis activity is displayed by children who lost a parent at an early age or were maltreated or severely neglected. This abnormality shows up in a large proportion of children who grow up in children s homes and to an extent that is linked with the extent of neglect (Fisher, 2007). The characteristic abnormality observed in such children is a change in the daily rhythm of cortisol production. In the normal case, cortisol release is higher in the morning and lower in afternoon and evening. Children who have suffered early trauma have a much lower difference between morning and evening cortisol levels, if any Neurochemical mechanisms The biochemical mechanism by which stress in early life leads to abnormal operation of the stress axis is only partly understood. We know that it involves changes in gene expression and includes epigenetic effects, but other mechanisms also influence gene expression. Animal experiments suggest that the phenomenon is partly due to epigenetic regulation of the glucocorticoid receptor. The density of glucocorticoid receptors in the hippocampus neurons influence the responsiveness to stress. Young rats neglected by their mothers have been shown to have abnormalities in the methylation promoter region of the Nr3c1 (nuclear receptor 3, group C, member 1) gene, i.e. the glucocorticoid receptor gene. A high proportion of the bonding sites for NGFI-A (a transcription factor) on the Nr3c1 gene was methylated in neglected rats, but not in well cared-for rats. This means that in neglected rats, the transcription factor cannot connect to its bonding site and so cannot influence the operation of the Nr3c1 gene. In well cared for rats, this bonding site is free and the transcription factor can attach and regulate gene operation. This phenomenon leads to a higher density of glucocorticoid receptors in the hippocampus cells of well cared for rats, a difference that remains in adulthood. As we mentioned, the density of glucocorticoid receptors affects responsiveness to stress: higher receptor density means a lower stress response. DNA methylation patterns tend to remain relatively stable during life, although they can change up to a certain age: if rat babies are exchanged in time, and the previously neglected animals are gradually transferred to caring mothers, the methylation pattern changes (Weaver, 2004). Researchers have confirmed these abnormalities in humans. McGowan et al (2009) measured glucocorticoid gene methylation in hippocampus tissue during post mortem examinations of people who had died from suicide. In persons who had died from suicide and had a history of being abused in childhood, the promoter region of the glucocorticoid receptor gene was more highly methylated. There was a lower level of methylation in people who had not been maltreated. The effect of early

5 childcare on epigenetic regulation is not confined to the level of glucocorticoid receptor levels. Other experiments have found similar epigenetic regulation in oxytocin receptor genes and the BDNF growth factor gene (Miller, 2010). Overall, these results show that maltreatment in early childhood is capable of raising stress sensitivity via epigenetic effects exerted on the glucocorticoid receptor gene. Changes in gene expression remain in later life, long after the stress which caused them, and affect the risk of both mental disorders and cardiovascular diseases, and the ability to recover from them Stress and the immune system There is a clearly established two-way link between the central nervous system and the immune system. The central nervous system influences the operation of the immune system and vice versa. The link operates via neurotransmitters, neuropeptides (e.g. CRH), cytocenes, growth factors and low molecular weight signalling agents (e.g. nitric oxide). In the 1970s, the immune response was found to alter the operation of the hypothalamus s noradrenergic neurons and raise the level of plasma corticosteroid. The adrenergic innervation of the lymphoid organs, i.e. the spleen, the thymus and the lymph glands has been anatomically demonstrated. Adrenergic nervous system effects change the operation of certain elements of the immune response. In mice, a stress-arousing stimulus can trigger immune suppression. In animal experiments, susceptibility to autoimmune diseases is linked to stress axis activity (Ziemssen, 2007). The central nervous system influences the operation of the immune system in two ways: Directly, through the extensive sympathetic and parasympathetic innervation of the lymphoid system Via the HPA axis, which regulates the production of cytocines and interleucines (e.g. IL1). Deeper investigations into the link between the central nervous system and the immune system have thrown light on how emotional states (stress, anxiety, depression, grieving) influence the ability to recover from certain somatic diseases. Environmental stress influences the operation of the immune system via neuroendocrine and vegetative effects, increasing the likelihood of certain diseases (such a mechanism has been described for psoriasis, for example). Conversely, psychosocial interventions aimed at reducing anxiety and stress can reduce the level or duration of the neuroendocrine stress response, thus improving the immune function and ability to recover from certain somatic diseases (Ziemssen, 2007). The effect of relationship stress on the immune system was first studied on HIV positive patients. (Observations of HIV/AIDS patients, who are under close immunological control, have yielded much data on immune system interactions.) Depressive symptoms and stress were associated with rapid progression of the basic disease, and positive psychological states and expression of benefits were independent predictors of slowed progression. Higher cortisol levels were associated with faster disease progression and higher rates of mortality (Carrico, 2008). 3. Biological effects of psychotherapy 3.1 The effect of psychotherapy on somatic diseases Effect of psychotherapy on the stress axis Supportive human relationships are to some extent capable of compensating for the adverse effects of early or chronic stress. In the wider sense, the psychotherapeutic relationship may be seen as such a supportive relationship. The change in stress axis operation caused by early trauma or chronic stress can be corrected by psychotherapy. The changed operation of the stress axis is present in patients with post-traumatic stress disorder (PTSD). These patients suffer from mental symptoms deriving from a trauma (natural

6 catastrophe, war, serious car accident, serious mistreatment, rape) even after the event has passed, and they display lower cortisol levels and reduced diurnal fluctuation of cortisol. Olf (2007) found that when the condition of PTSD sufferers improved in response to psychotherapy, these hormone levels were restored. The same is true for the effects of early stress: children who were adopted after living their early lives in children s homes had low levels of morning cortisol and reduced diurnal fluctuation at the time of adoption, but their diurnal cortisol rhythm was restored after adoption (by a supportive family) and complex family therapy (Fisher, 2007). Psychotherapy is thus capable of normalizing the operation of the stress axis in people exposed to chronic stress or early traumatization. Psychotherapeutic interventions achieve these neuroendocrine effects by reducing responsiveness to stress. There is some variation among psychotherapeutic interventions in the mechanism by which the change occurs. The essential character of each of the psychotherapeutic techniques discussed here is summarized in Table 7/1. Table 7/1 Methods covered in the chapter Method Cognitive behavioural therapy Relaxation methods (e.g. autogenic training, progressive muscle relaxation) Hypnosis Mindfulness Problem-solving training Psychoanalytic therapies The effect of psychotherapy on the immune system Description Identifies and corrects negative automatic thoughts, reassesses situations and changes behaviour. Reduces stress and achieves a relaxed state through regulation of muscle tension, breathing and heart rate. An altered state of consciousness in which the therapist gives suggestions to the patient. With relaxation hypnosis, the suggestion is directed at achieving the relaxed state. A kind of attention training directed at externally sensing and accepting present states of body and mind. Practising more adaptive solutions to problem situations. Explores unconscious conflicts and develops more adaptive relationship patterns. The previous section mentioned that stress-arousing life events act via the immune system to influence the ability to recover from some somatic diseases. It is thus reasonable to suppose that reducing stress sensitivity by psychotherapy or other means can also influence the immune system. Certain somatic diseases have already been proved susceptible to this effect. The most extensive studies of how psychotherapy takes effect on immunological markers have been conducted among HIV/AIDS patients. Positive results were achieved most of all with cognitive-behavioural therapy and relaxation methods. These methods reduced HIV virus count, raised CD4 lymphocyte count and through changes to other immunological markers such as improved lymphocyte PHA [phytohaemagglutinin] response and CD8 lymphocyte count improved the operation of the immune system (Carrico, 2008). Psychological states have a well-known effect on the symptoms of asthma bronchiale, and psychotherapy can reduce asthmatic symptoms. The symptom-reducing effect of psychotherapy on asthmatic symptoms has been found in recent years to be frequently accompanied by immunological changes. One project studied a controlled psychotherapeutic programme. In the group receiving psychotherapy, the specific IgE response decreased, the B-lymphocyte count decreased, the allergyspecific CD23+ lymphocyte count decreased, and the low NK (CD56+) and CD24 T-lymphocyte counts returned to normal. In the control group (subjects who did not receive psychotherapy), these changes could not be observed, or only to a significantly smaller extent (Castes, 1999). Other, similar studies have borne out the symptom-reducing effect of psychotherapeutic interventions in asthma.

7 For some tumour patients, stress-reducing psychosocial interventions improve quality of life. From patients reports (self-completed questionnaires), psychotherapy alleviated some of the fatigue, lymphoedema and feelings of pain accompanying chemotherapy. A study of breast cancer patients investigated the extent to which psychotherapeutic interventions can reduce emotional distress and enhance functional immunity and whether the two forms of improvement are related (Andersen, 2007). Patients who attended psychotherapy showed greater improvement than those in the control group, and their PHA-induced T-cell response, i.e. the effectiveness of the immune response, improved or stagnated (and that of the control group deteriorated). For breast cancer patients, improvement of health and reduction of emotional distress were accompanied by measurable immunological changes. Overall, the complex interaction between the central nervous system and the immune system is a scientifically proven fact. Whether situational stress also disrupts the operation of the immune system beyond the homeostatic boundaries and causes diseases is not proven, but relationship stress does influence the ability to recover from existing diseases. Psychosocial and psychotherapeutic interventions have been demonstrated to have an effect on immunological markers and hormones in several chronic diseases and on healthy samples. 3.2 Effect of psychotherapy on brain structure Taking the argument further, if psychotherapeutic interventions are associated with sustained behavioural changes, then there should also be sustained changes to the brain activity responsible for organizing these behaviours. In other words, psychotherapeutic activity acting on mental processes must cause changes in the biological workings of the brain. Here we will present the results of psychotherapeutic research into the changes in brain function correlated with symptomatic changes caused by psychotherapy. We will concentrate on studies of anxiety disorder and depressive disorder, but there are other conditions for which psychotherapy has been found to change brain function The effect on brain function of psychotherapy for anxiety disorders For patients suffering from anxiety disorders, functional changes are expected in the brain s fear circuitry. This involves the operation of the amygdala, the hypothalamus, the brain stem, the ventromedial prefrontal cortex and the hippocampus Panic disorder In the brain of a person who suffers from panic attacks, the amygdala is hypersensitive to slight or unconscious sensory-organ or visceral stimuli, and this sensitivity sets off the fear response. There is also an absence of the top-down brain cortex regulation by which the prefrontal cortex controls the level of fear response. Gorman et al (2000) found that psychotherapy and medication work through different mechanisms to cause the same change of symptoms. Medication relieves the panic attack by reducing the activity of the amygdala and inhibiting the circuitry of the hypothalamus and the brainstem. Effective psychotherapy takes took effect by changing the activity of the circuitry leading in the opposite direction from the amygdala: they reduce phobic avoidance by weakening the effect of environmental fear stimuli in the areas of the brain responsible for memory (hippocampus) and reduce false cognitive evaluation and abnormal emotional reactions by strengthening the activity of the prefrontal cortex structures that inhibit the amygdala. Sakai et al (2006) found that in the brains of patients who had been successfully treated by 10-session cognitive therapy, activity decreased in the areas which control the fear reaction (the right hippocampus, the left anterior cingulum, the left cerebellum and the pons), and increased in the medial prefrontal cortex on both sides, which controls the fear network. The effect is not confined to cognitive-behavioural therapy. Four-week

8 panic-focused psychodynamic treatment led to considerable improvement in participants panic symptoms and normalization of fronto-limbic activation patterns observed when patients processed panic-specific words. These changes were similar to those produced by cognitive-behavioural therapy (Beutel et al, 2010) Obsessive-compulsive disorder Brain imaging of patients with obsessive-compulsive disorder found heightened activity of the orbitofrontal cortex and the nucleus caudatus in the rest state, which was joined by heightened activity of the thalamus and anterior cingulum in situations provoking compulsions. A comparison of states after behavioural therapy, cognitive-behavioural therapy and SSRI mood improvers found that activity in the orbitofrontal cortex, the nucleus caudatus and the thalamus decreased in proportion with the alleviation of symptoms (e.g. Nakau et al, 2005) Phobias In social phobia patients, psychotherapy has been found to cause a change in fronto-limbic regulation. Before and after therapy, patients were subjected to a test where they had to make a speech in front of 6 8 strangers. Following cognitive therapy, patients displayed improved selfcontrol during the speech, and this change in behaviour correlated with a decrease of activity in certain areas of the limbic system triggered by the phobic stimulus (Furmark, 2003). In an MRI study of spider-phobic patients, the activity of the limbic system and the prefrontal cortex in response to the phobic stimulus decreased following cognitive-behavioural therapy (Paquette, 2003) Changes in the brain following psychotherapeutic treatment of depression Functional imaging has found significant changes in the brain activity of depressed patients after they received interpersonal psychotherapy, cognitive-behavioural therapy and psychodynamic therapy. There are partial overlaps of the changes caused by medication and psychotherapy, and major differences. One major study in which sufferers of major depression received either cognitivebehavioural therapy or paroxetin treatment found that the symptoms diminished via different routes. PET tests conducted before and after therapy looked for the specific neural structures affected by each therapy. In patients who received cognitive-behavioural therapy, changes were observed mainly in the medial and cingular cortexes, while in those treated with paroxetin, the main changes were in the limbic and subcortical areas. Ultimately, both forms of treatment contribute to critical changes in the prefrontal-hippocampal networks. This study points to the possibility of different mechanisms being involved in improvements to depressive condition. Although medication and psychotherapy intervene in different neural structures, they both cause changes in the complex regulation system involved in maintaining the depressive state that lead to improvement at the level of symptoms (Goldapple, 2004). Finally, a study by Karlsson (2009) comparing 16-week brief dynamic psychotherapy with fluoxetin treatment for major depression investigated changes in gene expression by measuring the serotonin 5-HT1A receptor density, which is known to decrease in major depression. Both forms of treatment were found to be effective in treating the depression, but only the psychotherapeutic treatment led to an increase in receptor density. This result bears out Kandel s hypothesis that psychotherapy leads to changes in gene expression by means of learning, and induces morphological changes in the neurons (Kandel, 1996). Summary

9 There are several possible links between environmental effects and information coded in the genes. Gene-environment interaction is the phenomenon whereby a specific genotype and environmental factors jointly determine the occurrence of a certain traits. Epigenetics comprises genetic variations outside the DNA which affect the expression of specific genes. It is probably via epigenetic effects that stress in early life influences adult operation of the stress axis. Relationship stress changes the ability to recover from certain somatic diseases through the complex interaction of the central nervous system and the immune system. The effect of psychotherapy on immunological markers has been demonstrated for several chronic diseases. Permanent symptomatic changes caused by psychotherapy are associated with specific functional and structural changes in the brain. Neural changes caused by medication in some cases correspond to those caused by psychotherapy, but there are also differences. Questions 1. What is experience-dependent neuroplasticity? 2. Give an example of gene-environment interactions. 3. Define the concept of epigenetics. What epigenetic change can early stress cause? 4. Give an example of the link between psychosocial factors and the immune system. 5. What changes in the workings of the brain can psychotherapy cause in specific conditions?