The mechanism of anhedonia

Размещено на http://www.allbest.ru/

The mechanism of anhedonia

Lecture

Anton J.M. Loonen. Department of Pharmacy. The University of Groningen; Svetlana A. Ivanova, Mental Health Research Institute SB RAMSci

Механизм ангедонии.

Лекция

Лунен Антон Дж.М., Отделение фармации Гронигенский университет; Иванова Светлана А. ФГБУ «НИИ психического здоровья» СО РАМН

В лекции авторы представляют модель нейробиологии эмоционального ответа. Эта модель предложена для постулирования механизмов двух взаимодействующих типов большого депрессивного расстройства: ажитированной депрессии и меланхолической депрессии. Первый тип может быть, по нашему мнению, связан с гиперфункцией эмоционального вентрального кортико-стриато-таламо-кортикального круга (КСТК или экстрапирамидный путь), а второй тип - с гипофункцией мотивационной части данного круга. Первым звеном этих путей являются скорлупа и ядерная часть nucleus accumbens соответственно. Ангедония является следствием гипофункции мотивационной части КСТК пути.

In this opinion paper the authors present a model for the neurobiology of the emotional response. This model is applied for postulating the mechanism of two mutually interacting types of major depressive disorder: the worrying type and the lust type. The first type can be believed to be related to a hyper-function of the emotional ventral cortico-striato-thalamo-cortical circuit (CSTC or extrapyramidal circuit), and the second type to a hypo-function of the motivational CSTC circuit. The first stations in these circuits are the shell and core parts, respectively, of the nucleus accumbens. Anhedonia is a consequence of the hypo-function of this motivational CSTC circuit.

neurobiology emotional depression anhedonia

Introduction

In psychiatry the term anhedonia (Greek: ?н- an-, «without» + ?дпнЮ hзdonз, «pleasure») stands for the inability to experience pleasure from activities usually found enjoyable, e. g. exercise, hobbies, sexual activities or social interactions. In the 1970s anhedonia was considered a core symptom of endogenous depression. It was also included as a main criterion for the diagnosis of Major Depressive Disorder (MDD) with Melancholia according to the third edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-III) of 1980. This MDD with Melancholia was considered to be a specific subtype known to respond preferentially to biological treatment, what in those days included tricyclic antidepressant drug (TCA) and electroconvulsive therapy (ECT).

Shortly after the publication of the DSM-III, selective serotonin reuptake inhibitors were marketed and this changed the borders of the disease class MDD. SSRIs appear to be therapeutically active in certain anxiety disorders, like panic disorder and obsessive compulsive disorder. This indicates that the serotonin systems has much to do with stress and worrying, or more accurate: that drugs that interfere with the activity of the serotonergic system can be used to treat disorders which are accompanied by stress reactions and cognitive anxious depressed symptoms. The fact that SSRs were indicated in MDD and anxiety disorders resulted in a widening of the depression concept and induced considerable heterogeneity within the class of disorders that are nowadays referred to as MDD.

However, it is still possible to cluster these disorders in two groups. Depression can be considered as a worrying disorder, characterized by many cognitive symptoms like feelings of hopelessness and negatice expectations, and depression can be considered a lust disorder, characterized by loss of energy and motivation. Anhedonia is mainly a symptoms of this second type of depression. It should be emphasized that these two types of depression cannot be considered separate entities. Both are components of a single category of disorders that is referred to as major depressive disorders according to DSM-IVTM.

The emotional response system

Evolution. The origin of all currently living animal species can be found in primitive creatures living in the oceans. These very ancient invertebrates are believed to have evolved three separate brain parts: a brain stem (with a motor function), a mid-brain (with a visual function, originally intended for identifying partners for reproduction), and a fore-brain (with an olfactory function for the detection of food). ¹ About 550 million years ago the mid-brain and brain stem fused together and about 500 million year ago the fore-brain joined with the combined caudal part.

In order to be able to survive as an individual and as a species these primitive animals should be capable of feeding themselves, fighting, hiding and mating. Therefore, the capability to regulate these processes should be displayed by their primitive brains. After the development of a skeleton and limbs, these primitive animals invaded the continents and this living off sea required numerous new skills. This resulted in the development of a large forebrain with its neocortex, basal ganglia and hippocampus in order to enable the individual to adequately deal with the complex input and to generate adequate (and also far more complex) output, which was required to survive. Nevertheless, the original instinctive functions were still necessary and these were largely retained in the phylogenetic older primitive brain structures. For simplicity this `older' part of the brain is considered to be represented by the amygdala. This is of course an oversimplification, because other parts of the limbic cortex and limbic sub-cortex belong to this primitive brain as well.

Three components of the emotional response

With the primitive brain thought to be concentrated in the amygdaloid complex, the system which is regulating the emotional response can be represented in figure 1.

Figure 1. Model for the regulation of the emotional response

According to this model the control centre for the emotional response is the hypothalamus. ² The output of the hypothalamus proceeds along three channels. The first route projects via the thalamus to the cortex, including a projection to the mesial PFC that contributes to the perception of the emotion, and a projection to the dorsolateral PFC that contributes to the initiation and planning of cognitive and motor responses.

The second output of the emotional response pathway from the hypothalamus is a projection via the periaqueductal grey (PAG) to several brainstem nuclei, including nuclei that regulate the endocrine and autonomic components of the emotional response. The projections from the PAG also activates the functions of the serotonergic raphe nuclei, the adrenergic locus coeruleus complex, and the dopaminergic ventral tegmental nuclei in the brainstem. From these nuclei, projections pass through the medial forebrain bundle to the forebrain. This results in adaptation of the activity of the frontal cortex (e. g. attention). The activation these and other adrenergic and serotonergic nuclei results in activation of the necessary autonomic functions (e. g. increased circulation and respiration). It should be noticed that the PAG also constitutes an important input generating structure of the emotional forebrain.

Apart from the hormone release mediated through various brain stem nuclei a direct hypothalamic projection system regulates the endocrine component of the emotional response. This results in adaptation of the milieu interne or correction of a possible misbalance. The hypothalamus also contains a receptor function for various substances in circulating blood. This endocrine component is mediated through the secretion of hormones by the eminentia medialis in the primary hypophyseal portal circulation and by the neurohypophysis. This results in activation of for example the adrenal glands.

The functional activity of the hypothalamus, control centre of the emotional (non-behavioural) output, is influenced by several routes. As explained above the hypothalamus itself receives an emotional input function that comes from the amygdala, among other regions. It is the amygdala which, on the basis of provisional analysis of environmental stimuli, gives input to the hypothalamus to initiate the emotional response. In this process of analysing, the amygdala is inhibited by the medial PFC.

Seven emotional response types

Based on their neurobiological studies Liotti and Panksepp proposed seven emotional systems; following are descriptions of these systems.³

The Appetitive Motivation SEEKING System stimulates the organism to go for the many things needed for survival. This motivation is coupled to a reward feeling that can, but not necessary does, result from these activities. The nature of the specific rewards is of lesser importance; the system works equally well in seeking food, water, warmth, illicit drugs as well as social goals like sexual gratification, maternal engagement, and playful entertainment. It is essential for motivating behaviour that, with respect to its consequence (reward), the behaviour also holds a certain degree of uncertainty about the reward and therefore risk. The value of that risk is determined in the posterior cingular cortex (pCG). This value is compared with the needs for things such as food, water, warmth, and social acceptance. Important neural substrates for this system are dopaminergic mesolimbic and mesocortical projections coming from the ventral tegmental area.

The Anger-Promoting RAGE system is associated with irritation and frustration. In this system the emotional circuit is stimulated by reciprocal projections between the medial amygdala and medial hypothalamus via the stria terminalis. Neurons also project reciprocally between specific parts of the PAG in the mesencephalon and the medial hypothalamus. The neurotransmitters acetylcholine and glutamate are important components to the RAGE system.

The FEAR system has a parallel organization as to the RAGE system, in which both the amygdala and the PAG project reciprocally to the medial hypothalamus. Activity within this system can lead to freezing or flight behaviour. Glutamate and various neuropeptides play an important role in this system. In addition, activation of the FEAR system parallels activation of the stress systems by the release of corticotropin-releasing hormone (CRH).

The Separation Distress (PANIC) and Social Bonding (Affiliative-Love) systems are based on projections of the PAG via the medial part of the thalamus to several more rostral subcortical areas (preoptical, septal, and bed nucleus of the stria terminalis) and the anterior part of the cingular cortex. Opoidergic neuropeptides and oxytocin are the most important neurotransmitters in this system.

The Nurturant CARE system promotes motherly feelings of care, devotion, and empathy. In women, this oxytocinergic system is closely related to the LUST (Sexual-Love) system. The main role of this the LUST system is sexual motivation. Decades ago it was found that subcortical hormonal control of sexuality in both men and women is situated in the frontal hypothalamic preoptic areas that project medially to the PAG. However, the LUST systems in men and women partially overlap but also differ in an important manner. In women, sexuality is related to oxytocinergic activity, and in men it is related to vasopressinergic activity. In both sexes, orgasm coincides with intensely enhanced opioid and oxytocinergic activity.

The Rough-and-Tumble PLAY-Joy system mediates playful activities that are possibly responsible for feelings of joy. The emotional effects of tickling are connected to this system. Opioid neuropeptides, glutamate, and acetylcholine are some of the neurotransmitters in this system.

Amygdala

Integrating Sewards and Sewards' ideas with those of Liotti and Panksepp leads to the model as represented in figure 1. The hypothalamus is the controller of seven possible emotional programs (seeking, rage, fear, panic, care, lust, play), which are executed by activation of the PAG, the endocrine hypothalamus and the thalamus. Activation of these hypothalamic programs is regulated by the primitive brain structures, which are represented in this paper by the amygdala. The amygdala consists of a cortical (basolateral) and ganglionic (centromedial) part and receives input from various structures. The basolateral part receives much input from thalamus (sensory information), mesial temporal memory system and the prefrontal cortex. The centromedial part receives much input from the basolateral complex and also reciprocal information from hypothalamus and (the upper part of the) brain stem. According to this model the basolateral amygdala integrates all emotionally relevant sensory information and project the results to the centromedial amygdala, which initiates a proper emotional response type.

As indicated before, this model is an oversimplification. Other parts of the limbic cortex take a similar position as the basolateral amygdala and the centromedial amygdala represents only part of the ganglionic primitive brain. The extended amygdala, bed nucleus of the stria terminalis and the shell part of the nucleus accumbens are together forming the limbic basal ganglia with a similar function (Figure 2).

Figure 2. Position of the limbic basal ganglia (centromedial amygdala, extended amygdala, bed nucleus of the stria terminalis and nucleus accumbens shell) relative to the extrapyramidal basal ganglia and hippocampus

Control of behavioural response type

Behaviour can be considered an adaptive reaction of the organism to stimuli from the environment. In humans, the neuro-system - as intermediary between perception of the environment and reaction to that environment - is very well developed. In the brain perception of the environment takes place via input from the senses. The output of the brain forms the reaction to the environment partly in the form of behaviour. How the brain of an individual gets to observe and assess the environment so as to produce the most adaptive behavioural response is determined by learning experiences and by what the machinery of the individual's brain makes instrumentally possible. From perception to action the neuro-anatomical and neuro-functional process runs as follows; Sensory stimuli from the periphery are first screened in the thalamus after which they conveyed to the posterior part of the cerebral cortex.

After analysis this information is amongst others projected to the mesial temporal memory system (necessary for identification of episodic/sematic information), amygdala, striatum and frontal cortical areas. Regarding output, several responses can be identified: reflexes, emotional (instinctive) responses, and rational (cognitively constructed) behavioural responses. The circuits regulating the latter two response types influence each other; both inhibiting and activating, as the relevant situation demands. Thus a threat can be so serious that the cognitive circuit has to be stemmed in order to prevent awareness of fear. On the other hand, activation of the circuit could be necessary precisely so as to take conscious action to counter the dangerous situation. In control of this response type selection is the prefrontal cortex (PFC). The dorsolateral part is especially important for controlling the rational response type and the medial PFC controls the emotional response. Within this latter structure the orbitofrontal cortex (OFC) plays a particular noteworthy role, because it is essential for the regulation of the direction of motivation.

Three stages of behavioural motivation can be distinguished: general motivation, initiative, and selective precedence-conveying (via inhibition). General motivation into the active search for improvement and reward (dopaminergic), and passive reaction with protective responses arising from fear, aversion and repellence (dopaminergic, adrenergic and serotonergic). Initiative - as an active, conscious and planned process (dopaminergic) - runs via the motor cortices. Initiative as a reactive, autonomous process comes about via the amygdala. The latter can be an instinctive (dopaminergic, adrenergic, serotonergic and GABA-ergic) reaction or a conditioned (dopaminergic, adrenergic, serotonergic, GABA-ergic and glutaminergic) reaction. By delivering input to the ventral striatum the OFC plays an significant role in regulating these processes. Selective precedence-conveying (as selective inhibition) is a glutaminergic function of the PFC in reaction to the reciprocal projection of the OFC and amygdala. The amygdala - in this regard - functions as the emotional memory, the OFC as the short-term working memory.⁴

A neurobiological model of depression

A major contribution of our understanding of the regulation of the emotional and rational response type in major depressive disorders came from Helen S. Mayberg and co-workers in Toronto. ⁵ She used neuroimaging techniques to develop a limbic-cortical dysregulation model. She suggests that sadness and depressive illness is associated with decreased activity in certain sensory-cognitive brain structures (PF9, P40, pCg) and relative increase in ventral limbic and paralimbic areas (Cg25, anterior insula). Integration of these activities takes place in prefrontal areas such as the orbitofrontal (oF11), rostral anterior cingulate (aCg) and medial prefrontal cortex (mF9/10). The numbers refer to Brodmann areas. Empirical data suggests that behavioural cognitive therapy (CBT) is magnifying the influence of sensory-cognitive areas and that pharmacotherapy decreases the activity of the ventral limbic and paralimbic structures. A key structure in her model is the infralimbic subgenual anterior cingulate cortex (sACC, Cg25). Activity in this area was noted to increase with sad mood and a decrease in activity was a consistent finding associated with the antidepressant response to several biological treatments.

An important limitation to the work of Mayberg and collaborators is the usage of DSM-IV criteria to characterize depression, which results in pathological heterogeneity within their patient sample. Based on the integration of five current theories, which can explain how dysfunction of neurobiological processes might result in the development of a depressive mood disorder, we have developed a different model. ⁶ Integrating amine, biorhythm, neuro-endocrine, neuro-immunological and kindling hypotheses of depression, it can be deduced that two interacting depression mechanisms can be hypothesized corresponding to depression as lust disorder, characterized by lack of energy and pleasure, and as worrying disorder, characterized by feelings of uselessness and hopelessness. The first type of depression can be associated with a dysfunction of brainstem, hypothalamic and extrapyramidal structures and the second with a dysfunction of limbic cortical areas (and the hippocampal complex).

Role of the extrapyramidal system

This term extrapyramidal system was derived from the original belief that all motions were controlled by two parallel systems: one, a direct pyramidal tract running from the cerebral cortex to the brain stem and spinal cord; and the other was thought to be a parallel indirect tract, therefore called the extra pyramidal system. Currently, it is known that the extrapyramidal system is not a parallel pathway, but a circuit that starts and ends in the cerebral cortex (figure 3).

Figure 3. Simplified representation of three cortico-striato-thalamo-cortical circuits

The first station of this circuit is formed by the striatum. This striatum consist of three parts which corresponds to three parallel divisions of the extrapyramidal system; caudate nucleus (cognitive system), putamen (motor system) and ventral striatum (emotional/motivational system). This last part is formed by the accumbens nucleus, which consists of a core (NAcb_C) and a shell part (NAcb_S). As indicated above the core part belongs to the extrapyramidal basal ganglia and primarily involved in motivating the organism to exhibit rational behaviour. The shell part belongs to the limbic basal ganglia and is primarily involved in facilitating emotional behaviour.

Activation of the NAcb_C circuit results in behaviour connected to reward. The emotion that is most specifically connected to this behaviour is `lust'. A disfunctioning of this circuit can be expected to result in being demotivated to exhibit rewarding behaviour (lack of energy) and the inability to experience pleasure (anhedonia). Activation of the NAcb<sub>S</sub> circuit results in behaviour connected with trouble. The emotion that corresponds to this behaviour is `unhappyness. ' According to this hypothesis depression as a lust disorder is expected to be related to hypo-activity of the NAcb_C system and depression as a worrying disorder to hyper-activity of the NAcb_S circuit.

How does this relate to the above ideas of Mayberg et al.? Different brain prefrontal areas are involved in the activation of the two parts of the accumbens nucleus (Figure 4).

Figure 4. Selective stimulation of the core and shell parts of the nucleus accumbens

The OFC stimulates both parts, but the rostral anterior cingulate cortex (ACC, BA24) only NAcb_C and the infralimbic subgenual anterior cingulate cortex (sCg, BA25) only the NAcb_S. In most depressive patients according to criteria of DSM-IV the NAcb_S circuit is overactive. This may be due to hyperactivity of Cg25, which in turn can be induced by the non-harmonious integration of complex, analysed and validated sensory input by the prefrontal cortex. This still may be caused by long-term dysfunctional analysis and/or validation of the sensory input by posterior and hippocampal cortical areas, but also by long-term over-activity of the emotional fear response for other reasons.

According to this hypothesis lack of motivation and anhedonia is supposed to be related to under-activity of the motivational extrapyramidal circuit. This would result from improper stimulation of the NAcb_C by OFC and lack of simulation by ACC (Figure 4). As the OFC is part of a cortico-striato-thalamo-cortical re-entry circuit, chronic hypo-activation of the NAcb_C by other brain structures (like the ACC or the VTA) could result in a chronic hypoactivity of the motivational circuit.

In conclusion

In this opinion article we have presented a model for the emotional response that can also serve to explain the pathogenesis of a depressive state. We distinguish two mutually interacting types of depression; i. e. the lust type and the worrying type. The worrying type is believed to be related to overactivity of the emotional ventral extrapyramidal circuit with the shell part of the accumbens nucleus as first station. The lust type is supposed to be related to the motivational ventral extrapyramidal circuit with the core part of the nucleus accumbens as first station. Hypo-activity of the latter circuit may result from chronic under-stimulation of this striatal structure and can be believed to result in lack of energy and anhedonia.

References

1. Sewards T.V., Sewards M.A. Representations of motivational drives in mesial cortex, medial thalamus, hypothalamus and midbrain // Brain. Res. Bull. - 2003. - Jun. - V. 30, № 61. - P. 25--49.

2. Liotti M., Panksepp J. Imaging human emotions and affective feelings: implications for biological psychiatry / Ed. J. Panksepp // Textbook of biological psychiatry. - Hoboken, N.J.: Wiley-Liss, 2004. - P. 33--74.

3. Rolls E.T. The Brain and Emotion. - Oxford : Oxford University Press, 2001.

4. Seminowicz D.A., Mayberg H.S., McIntosh A.R., Goldapple K., Kennedy S., Segal Z., Rafi-Tari S. Limbic-frontal circuitry in major depression: a path modeling metanalysis // Neuroimage. - 2004. - May. - V. 22 (1). - P. 409--418.

5. Loonen A.J. The neurobiology of depression. (unpublished presentation available upon request).

6. Loonen A.J., Ivanova S.A. The mechanism of drug-induced dyskinesia // CNS Spectrums. - 2013 (in press).

Размещено на Allbest.ru