Effect of depression on brain

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Depression as a special mode of brain functioning: data from neuroimaging studies

Depression is a persistent negative emotional state characterized by depressed mood, decreased interest in the environment and inability to enjoy. Its characteristic manifestations are feelings of melancholy, self-abasement, indifference, tearfulness, decreased activity and fatigue, psychomotor retardation or, conversely, arousal. Sleep disturbances in the form of insomnia or, conversely, hypersomnia are typical for depression; changes in appetite with concomitant changes in body weight. nine0027

Depression is an important medical problem, since numerous studies [10, 57] have demonstrated a significant relationship between its severity, morbidity and mortality due to cardiovascular and other somatic diseases. Depression is an independent unfavorable prognostic factor during the postoperative period in surgical patients, associated with a high risk of infectious and neurological complications [28, 42]. The emotional state is one of the most important criteria for the quality of life, and therefore the concept of "health", as defined by the World Health Organization (WHO), includes the psychological well-being of a person, including the absence of depression [1]. Given the potentially curable nature of depression, understanding the mechanisms of its development, as well as the development of objective approaches to the diagnosis of this disorder, are of great scientific and practical importance. nine0027

The functioning of the central nervous system in depression has significant differences from the norm. A number of experimental studies [41, 57] have shown the tendency of depressed patients to negatively perceive neutral or even positive stimuli and/or situations. In particular, patients with depression are significantly more likely to perceive a neutral facial expression in portraits as a sign of sadness or anger [14, 31, 41]. In addition, numerous neurophysiological studies have revealed a typical asymmetry in the power of the α-rhythm in the frontal leads for patients with depression [17, 27]. Finally, studies of heart rate indicate a significant relationship between depression and a lack of power in the high- and low-frequency components of the spectrum of its variability [2, 7]. nine0027

This review discusses the results of modern neuroimaging studies in depression. It is important to note that in the overwhelming majority of the cited works, the severity of depressive disorders met the DSM-IV criteria for "major" depression. In addition to the data obtained using magnetic resonance imaging, we also cite electroencephalographic studies of depression, the results of which became the basis for the formation of modern concepts of its pathogenesis. nine0027

At the end of the review, we present a description of modern concepts of emotion regulation (the concept of the "negative brain", cognitive regulation of emotions and deficit of activation of the left frontal cortex, which consider depression as a special mode of brain functioning.

Neuroimaging and pathology studies of depression

Structural-anatomical correlates of depression

Most neuroimaging and pathological studies in patients with major depression have shown gray matter deficits in the prefrontal cortex and structures of the limbic system. nine0027

The most typical finding in such cases is a gray matter deficit in the anterior cingulate cortex located ventral to the genu corpus callosum (popliteal cingulate cortex) [49]. So, in the study by M. Ballmaier et al. [4] the volume of gray matter in the left and right cingulate gyrus in elderly patients with depression was reduced by 18 and 20%, respectively. In addition, the researchers found a decrease in the volume of white matter in the same brain structure by 14% on the left and 21% on the right. A similar white matter deficit in the left anterior cingulate cortex in elderly depressed patients was noted in a study by S. Bell-McGinty et al. [five]. K. Cullen et al. [16] found a deficit of myelinated tracts connecting the popliteal cingulate cortex to the amygdala in the right hemisphere of the brain in adolescents with depression. At the same time, M. Ries et al. [52], who found gray matter deficits in the posterior cingulate cortex and adjacent cortex in older people with moderately severe depression, did not find significant differences in the volume of the anterior cingulate cortex compared with the control group. According to some researchers [9, 35, 49], pathomorphological changes in the popliteal cingulate cortex are more likely a predisposing factor than a consequence of depression, since this anomaly was detected at the earliest stages of the disease, as well as in healthy individuals with a high family history of affective disorders. So, P. Keedwell et al. [35] revealed differences in the microstructure (decrease in fractional anisotropy) of the cingular fascicle in healthy students with a burdened family history of major depression compared with students who did not have relatives with depression. Intergroup differences were most pronounced in the popliteal area of ​​the left cingular fasciculus. Interestingly, the ability to experience pleasure (hedonia) was positively correlated with the fractional anisotropy of the left and, to a lesser extent, right cingular fasciculus. It is important that in a number of longitudinal studies [49] demonstrated a progressive decrease in the volume of the popliteal cingulate cortex in patients with psychotic depression, as well as significant correlations between the severity of depressive disorders and a deficit in the volume of the popliteal cingulate cortex.

The volume of the orbitofrontal cortex is also reduced in patients with severe depression compared with the control group [4, 49]. So, in the study by M. Ballmaier et al. [4] patients with depression showed a smaller volume of the medial parts of the orbitofrontal cortex by 19% on the left and 24% on the right and lateral sections - by 12% compared with the control group. At the same time, in some studies, an excess of normative indicators of gray matter volume in a number of areas of the orbitofrontal cortex in patients with depression was noted. So, according to J. Phillips et al. [48], in patients in remission during treatment with antidepressants, there was a general increase in brain volume, which was most pronounced in the orbitofrontal cortex and inferotemporal gyrus of the right hemisphere, although in patients who did not achieve remission in the same period, a decrease in tissue volume in the left hemisphere was recorded. . nine0027

In a number of studies [5, 49], the volume of gray and/or white matter in patients with depression was reduced in the ventrolateral prefrontal cortex, the cortex of the frontal poles, and the dorsolateral prefrontal cortex. H. Soennesyn et al. [60] found in elderly patients a significant positive correlation between the volume of hyperintense foci in the white matter of the deep parts of the frontal lobes of the brain and the severity of depression, as well as a tendency to persistence of depressive disorders. Similar data were obtained in a longitudinal 3-year study by M. Firbank et al. [22], who noted the relationship between the progression of hyperintense changes in the white matter of the brain and the onset of depression in the elderly. nine0027

Deficiency in the volume of prefrontal cortex structures has also been regularly identified in populations at high risk of developing depression. So, A. Carballedo et al. [9] found a deficit in the volume of prefrontal cortex structures in a group of healthy people with a family history of depression aggravated. J. Lagopoulos et al. [40] revealed a significant relationship between a decrease in the size of the frontal cortex and the severity of depressive disorders in young patients already at the initial stage of the disease.

In the same study, a significant relationship was found between the duration of depression and a decrease in the volume of the hippocampal-entorhinal cortex. Similar data were published by K. Sawyer et al. [58], who found a decrease in the volume of the right hippocampus during 4 years of observation of elderly patients with depression. At the same time, in the study by I. Rosso et al. [55], the volume of gray matter in the hippocampus of adolescents with depression did not differ from the control group. nine0027

According to a number of researchers, the size of the amygdala (a subcortical nucleus located in the deep parts of the temporal lobes) in patients with depression is also changed. Thus, smaller amygdala sizes compared to the control group were found in children with depression [41, 55]. For example, I. Rosso et al. [55] noted corresponding changes in adolescent girls with major depression: the tonsils in both hemispheres were 12% smaller in volume compared to the control group. At the same time, in adult patients, the size of the tonsils is sometimes slightly larger compared to the age norm [41]. A possible explanation for these discrepancies is the trend towards a decrease in gray matter volumes as the brain matures, and it is most pronounced in the subcortical nuclei. Accordingly, large volumes of gray matter in populations with mental disorders may be a correlate of delayed brain development. nine0027

It should be noted that in many neuroimaging and pathological studies in cases of severe depression, gray matter deficit was more pronounced in the left hemisphere compared to the right [49, 63]. So, in the study of P. Tu et al. [63] patients with depression had a significantly smaller volume of the left temporal, entorial and lingual cortex compared to the control group. We also note a higher incidence of depression in patients with damage to the left frontotemporal region compared with damage to the right hemisphere in patients after traumatic brain injuries [8], strokes [65], and other brain diseases. It is important to emphasize that the relationship between left hemispheric brain damage and depression is recorded mainly in cases of small lesions [18]. nine0027

Functional-anatomical correlates of depression

Dozens of studies have now been published investigating the patterns of brain activity in depressed patients using functional magnetic resonance, single photon or positron emission tomography. In most of these studies, brain activity is assessed in terms of performing functional tests with an impact on the emotional sphere. The most common test is to present the patient with portraits of faces with an expression of sadness, fear, anger or joy, as well as photographs of people in a neutral emotional state. nine0027

Most of these studies have shown that depressed patients, when presented with sad or frightened faces, tend to respond with hyperactivation of limbic structures such as the amygdala, anterior cingulate cortex, and ventromedial prefrontal cortex [41, 49]. At the same time, presentation of joyful faces to patients with depression does not cause activation of the listed brain structures in them, which is characteristic of healthy people. In addition, patients with depression are characterized by a lack of synchronization of activity between the amygdala and the medial prefrontal cortex. The listed functional disorders correlate with the intensity of depressive experiences, and the improvement of the psychological state in such patients is associated with the normalization of the functions of these brain structures. Relapses of depression are accompanied by an increase in metabolism in the popliteal region of the anterior cingulate gyrus, the ventromedial cortex of the frontal poles, and the amygdala [49].

It has been noted in many studies that anomalies in the activation of structures of the limbic system in patients with depression tend to lateralize. So, J. Almeida et al. [3] observed in patients with depression a lack of interaction between the left hemispheric ventromedial, popliteal cingulate cortex and amygdala in the process of assessing joyful faces. At the same time, the presentation of photographs with frightened faces was accompanied by an excessive expression of conjugation of the activity of the left hemispheric popliteal cortex and amygdala. Z. Mingtian et al. [43] also studied the features of activation of brain structures upon presentation of photographs with frightened faces in young patients with an early onset of depressive disorders. Researchers have observed similar overactivation of the left hemispheric structures - the amygdala, thalamus, prefrontal and temporal cortex, in combination with its insufficiency of the right prefrontal cortex in patients with depression. At the same time, in the study by G. Perlman et al. [47] found that presentation of negative emotional images to depressed adolescents was accompanied by hyperactivation of the right hemispheric amygdala with less interaction of this subcortical structure with the insular cortex and medial prefrontal cortex compared with the control group. J. Fournier et al. [24] reported hyperactivation of the right hemisphere of the amygdala in adult patients with depression upon presentation of photographs with angry faces. In a study by R. Tao et al. [61], bilateral amygdala hyperactivation in combination with hyperactivation of the popliteal cingulate and orbitofrontal cortex was reported in patients with depression upon presentation of photographs with frightened faces. nine0027

E. Rose et al. [54] observed significantly less deactivation of the popliteal cingulate cortex and adjacent medial orbitofrontal cortex in depressed patients who performed a visuospatial memory test. The authors suggested that excessive activation of the popliteal cingulate cortex in depression is directly related to negative experiences in such patients.

Lack of activation of the ventral striatum during reward is also characteristic of patients with depression [49]. So, in the study by O. Robinson et al. [53] in patients with depression, a reduced ability to learn with reward was noted against the background of normal learning indicators with punishment. In the same study, behavioral deficits in depressed patients were accompanied by deficits in activation of the ventral striatum in response to rewards.

Brain activity in depressed patients at rest is also altered. So, M. Gaffrey et al. [25] observed a lack of coordinated activity between the posterior cingulate cortex and areas of the middle temporal gyrus, inferior parietal lobule, and cerebellum in children with depression compared to the age norm. nine0027

At the same time, coordination of activity in the posterior cingulate and anterior popliteal cortex was increased in children with depression. A similar lack of conjugation of activity in the posterior cingulate cortex and adjacent cortical centers in young patients with depression was observed by X. Zhu et al. [68]. In addition, in this same patient population, excessive coordination of activity in the anterior cingulate and medial prefrontal cortex was found. M. Wu et al. [66] observed excessive synchronization of the activity of the dorsomedial prefrontal and orbitofrontal cortex in elderly depressed patients with a synchronization deficit in the popliteal cingulate cortex. The listed anomalies of brain activity at rest correlated with a number of psychopathological phenomena characteristic of depression. In particular, excessive synchronization of the activity of the anterior cingulate and medial prefrontal cortex correlated with the tendency to obsessions in a study by X. Zhu et al. [68]. In a study by S. Green et al. [29] lack of coordinated activity between the popliteal cingulate and temporal cortex correlated with ideas of self-blame and guilt.

A number of studies have revealed changes in the activity of the amygdala and prefrontal cingulate cortex in patients in remission. P. Kanske et al. [34] observed excessive activity of the amygdala in patients in remission when viewing plots with negative content. In addition, R. Elliott et al. [20] revealed in such patients insufficient activation of the frontal poles and lateral orbitofrontal cortex when presented with images with social plots, both negative and positive. Hypoactivation of the left hemispheric orbitofrontal and dorsolateral prefrontal cortex when looking at photographs with frightened faces in patients in remission was also demonstrated in a study by R. Kerestes et al. [36]. nine0027

In the same study, activation of the right hemispheric dorsolateral prefrontal cortex was positively correlated with duration of euthymia.

H. Cremers et al. [13] studied the correlation between neuroticism (in this case, it was considered as a risk factor for depression) in middle-aged healthy people and the activity of brain structures when assessing the expression of anger, fear, and sadness in portrait photographs. The authors found a significant direct correlation between neuroticism and the activity of the right hemispheric dorsomedial prefrontal cortex, while in individuals with elevated levels of neuroticism, activity in this region of the prefrontal cortex correlated with activity in the right amygdala; in the group with a high level of neuroticism, the activity of the left amygdala correlated less with the right hemispheric cingulate gyrus compared to the subjects with a low level of neuroticism. Another research group [21] found a positive relationship between neuroticism and excessive activation of the insular cortex in the decision-making process under conditions of information deficit. nine0027

Neurophysiological correlates of depression

R. Davidson [17] was the first to point out the relationship between the severity of interhemispheric asymmetry of frontal cortex activation and predisposition to severe depression. He proposed a method for measuring interhemispheric asymmetry as the difference between the power of α-activity (8-13 Hz) in the right (F4) and left (F3) frontal leads. Based on the results of his own research, the author revealed the relative nature of the hypoactivation of the left frontal cortex in patients with severe depression, demonstrating the relationship between the activation of the left frontal cortex and positive affective reactions, on the one hand, and the activation of the right frontal cortex and negative affective reactions, on the other. nine0027

Subsequently, a number of research groups confirmed the relationship between hypoactivation of the left frontal cortex and the severity of depression. So, I. Gotlib et al. [27] noted hypoactivation of the left frontal cortex not only in persons with severe depression, but also in those cases where there were episodes of depression in history (during the examination, the patients were in remission). The authors did not reveal significant correlations between the asymmetry of frontal cortex activation and the severity of unrealistic ideas about oneself or the opinions of other people, i.e. correlations with cognitive factors that reduce stress resistance. No relationship was found between hemispheric asymmetry and performance of the well-known Stroop test. The researchers concluded that hypoactivation of the left frontal area is an important predisposing factor in the pathogenesis of depression. However, hypoactivation of the left frontal area is not associated with the current state of depression or cognitive factors that reduce stress tolerance. nine0027

Although the relationship between depression and interhemispheric asymmetry of α-activity in the frontal leads has been established in many studies, it has not been found in some studies. So, S. Reid et al. [51] found no intergroup differences in the distribution of α-activity power in the frontal leads. Nevertheless, in this study, the “classic” intergroup differences in the indices of interhemispheric asymmetry of α-activity in the frontal leads were revealed by a separate analysis of data related to the first minutes of EEG recording. It is also important that, unlike other researchers, the authors used too “soft” criteria for inclusion in the study of both patients and participants in the control group, which could lead to “blurring” of intergroup differences. nine0027

Interestingly, in a study by D. Smit et al. [59], the relationship between hemispheric asymmetry and the risk of developing depressive and anxiety disorders was significant only in a subgroup of young women. In the same study, the influence of heredity on the severity of interhemispheric asymmetry in the group of both young women and young men was revealed.

At the same time, in middle-aged subjects, the severity of interhemispheric asymmetry was significantly higher compared to young people, however, the influence of heredity on interhemispheric asymmetry in this group was not revealed. nine0027

Thus, the results of neuroimaging studies point to three main features of the functioning of the brain in patients with depression: firstly, depression is characterized by excessive activity of such structures of the limbic system as the tonsils, popliteal cingulate and ventromedial prefrontal cortex, while the maximum severity of such changes is observed in exposure to negative incentives. Secondly, patients with depression are characterized by a deficiency of gray matter and abnormal functioning of the frontotemporal structures of the cerebral cortex. Thirdly, in depression there is a tendency to more pronounced anomalies in the functioning of the structures of the left hemisphere of the brain, including a typical finding of electroencephalographic studies is a deficit in activation of the left prefrontal cortex in patients with depression. These features correspond to modern concepts of emotion regulation, which we consider below. nine0027

Modern concepts of emotion regulation

The "negative brain" concept

The term "negative brain" was proposed by L. Carretié et al. [11] based on data from experimental and neuroimaging studies indicating the activation of a number of brain structures in response to negative stimuli. The fundamental function of the structures that make up the "negative brain" is to provide rapid and intense responses to dangerous, harmful and potentially destructive events. Obviously, an effective response to such stimuli has a more important adaptive value than a response to neutral or positive (attractive) stimuli. nine0027

In dangerous situations, the organism is required to urgently mobilize the appropriate resources, and the evolutionary process supported the formation of neurological mechanisms that can increase adaptive capabilities in difficult conditions. The speed of information processing in brain structures can only be ensured by reducing the number of connections between neuronal centers, i.e. relative specialization of such centers in the processing of the same type of information patterns. Thus, in the structure of the brain, a number of neuronal centers specialize primarily in processing information about threatening and destructive events. The data of modern studies indicate the relative autonomy of the "negative brain", provided with its own sensory subcortical centers, cortical analyzer and executive structures [11]. nine0027

The amygdala is the most studied structure of the "negative brain". It receives direct projections from the thalamus and sensory cortex, which makes it possible to form fast responses to negative stimuli that are independent of higher cortical centers [11, 38]. The quick response of the amygdala to negative stimuli is also ensured by direct connections of these structures with a number of executive vegetative and motor centers of the brain.

Numerous experimental studies have demonstrated the leading role of the amygdala in the formation of conditioned reflex manifestations of fear and anxiety [19]. In healthy people, activation of the tonsils is recorded mainly when looking at faces with an expression of fear or sadness, while this trend is most pronounced after the induction of a sad mood in patients [26, 64]. The studies presented in the first part of the review indicate the maximum severity of these tendencies in depression.

In addition to the amygdala, to the brain structures mainly involved in the processing of negative information, L. Carretié et al. [11] include the ventromedial prefrontal cortex and the adjacent anterior cingulate cortex, the anterior insula, and some other brain structures whose functions are less studied. Some researchers [62] suggest that the medial prefrontal cortex, including the anterior cingulate cortex, forms the subject's cognitive representation of current affective experiences. Other authors [33] point to the direct involvement of the ventromedial cortex in the formation of associations between threatening events and the context in which they occur. Finally, there is an opinion that the activation of the popliteal cingulate cortex in the process of processing negative information is aimed at finding a decision on further actions [54]. Probably, the deficit of gray matter in the popliteal cingulate cortex and the ventromedial prefrontal cortex adjacent to it reduces the computing capabilities of these brain structures in depressed patients and leads to the stereotyping of the “decisions” being formed. nine0027

The hyperactivation of the “negative brain” structures detected in patients with depression explains such clinical characteristics of depression as the persistent tendency of depressed patients to perceive neutral stimuli as negative [13, 31, 41] and a deficit in heart rate variability [2, 7]. The latter is explained by the direct involvement of the amygdala and anterior cingulate cortex in the regulation of heart rate [15, 67].

Concept of cognitive regulation of emotions

Cognitive deficit is a fairly common finding in the neuropsychological examination of patients with depression. A number of studies have found that patients with depression are characterized by a lower level of education compared with the corresponding control groups [5, 52]. The most pronounced cognitive deficit is recorded in patients with psychotic depression (with delusional ideas) [23]. In the work of K. Blankstein et al. [6], who examined students with moderate depression, it was found that they have great difficulties in resolving interpersonal conflicts, as well as in organizing their time, everyday life and the educational process. Thus, cognitive deficits can be considered a common component of depressive disorders and possibly an unfavorable prognostic factor. nine0027

J. Gross and R. Thompson [30] formulated the main postulates of the concept of cognitive regulation of emotions. In their opinion, the emotional system of the brain is capable of self-regulation, however, the “meaningfulness” of emotional processes has a significant impact on the emotional state of the subject. The ability to make the right choice, taking into account the long-term outcomes of a particular form of behavior, requires significant cognitive effort and relies on previous experience. Active transformation of the current situation, the ability to switch attention from unpleasant but inevitable moments, to see the positive in an ambiguous context are important cognitive mechanisms that allow an individual to adapt to emotionally difficult conditions. Accordingly, cognitive deficit deprives the individual of the opportunity to adapt to difficult conditions, which in many cases leads to depression. nine0027

A number of experimental studies [37, 39] have established a direct link between being in an information-enriched environment and neuroplastic changes in the “cognitive” cortex. Neuroplastic changes in the structures of the brain include thickening of the gray matter, elongation and an increase in the "branching" of dendrites, an increase in the density of dendritic spines and the density of synapses on them. At the same time, stressful situations inhibit neuroplastic processes and cause reverse changes in brain structures [50]. This can be demonstrated using the results of an experimental study by J. Radley et al. [50]: 3-week stress led to a decrease in the length and "branching" of dendrites of neurons in the medial prefrontal cortex by 20% and a decrease in the number of synapses on pyramidal neurons by 33%. The authors suggest that hypotrophic changes on the background of stress are a consequence of hypercortisolemia, which is a typical characteristic of depressive disorders. Such results of experimental studies of stress are consistent with the results of neuroimaging studies of depression, which showed a decrease in gray matter volume in a number of brain structures with an increase in the duration of the disease [5, 58]. nine0027

Thus, a vicious circle is formed in depressive disorders. Cognitive deficit reduces adaptive capabilities and contributes to the subject getting into stressful situations. At the same time, chronic stress and hypercortisolemia exacerbate hypotrophic changes in brain structures, which leads to aggravation of cognitive deficits and depression.

Left frontal cortex activation deficit concept

The concept of left frontal cortex activation deficit in depression is a special case of the concept of cognitive emotion regulation. However, modern studies point to the importance of this factor in the pathogenesis of affective disorders. So, K. Ochsner et al. [46] recorded a pronounced activation of the left convexital prefrontal cortex in the process of “rethinking” the meaning of an emotionally negative plot picture in healthy people. The main finding of this study was an inverse correlation between the degree of activation of the left hemispheric dorsolateral prefrontal cortex and the degree of activation of the right hemispheric amygdala and left orbitofrontal cortex. In other words, the researchers observed an "inhibitory" effect of activation of the left dorsolateral prefrontal cortex on the structures of the "negative" brain. At present, the inhibitory (braking) effect of the prefrontal cortex on the activity of the amygdala is a generally recognized fact, since it has been demonstrated in numerous studies, including neuroimaging studies [18, 32]. nine0027

In a number of neuroimaging and neurophysiological studies, a tendency was established for greater activation of the left frontal cortex against the background of experiencing positive emotions in healthy people and the right frontal cortex - negative ones [18, 44]. In a study by J. Coan and J. Allen [12], the predominance of activation of the left frontal cortex compared to the right hemisphere significantly correlated with the tendency to active behavior in healthy people. Thus, the deficit in activation of the left prefrontal cortex, recorded in numerous studies of patients with depression, explains the deficit of positive emotions and lethargy in a significant proportion of these patients. nine0027

Conclusion

Short-term states of depression are experienced throughout life by almost every person, since negative emotional experiences are a normal reaction of people to stressful and tragic events. Not all adverse events in the environment and especially within the body require active action from the individual. On the contrary, in many situations, adaptation is provided by the complete cessation of activity with monitoring of information about the danger. According to R. Nesse [45], depression is a natural way of adapting the body to such unfavorable conditions, when vigorous activity can worsen the situation of the individual. In such cases, pessimism, self-abasement, and loss of interest in the outside world force the individual to refrain from unnecessary and dangerous activities. In other words, depression is a special mode of brain functioning, characterized by a significant decrease in the individual's motivated activity in the environment. At the same time, the depressive type of internal experiences and behavioral manifestations is a consequence of the dominance of activity in such structures of the "negative brain" as the amygdala and the structures of the medial prefrontal cortex closely related to it. nine0027

Depression acquires a pathological character in cases where there are no real prerequisites for negative experiences in the environment surrounding the individual or the potentially solvable nature of the problems that have arisen. In such cases, prolonged depressive disorders are the result of a weakness in the mechanisms of cortical control over the excessive activity of the tonsils and other components of the “negative brain”. Long-term depressive disorders are characterized by a vicious circle. On the one hand, insufficiency of the orbitofrontal, dorsolateral prefrontal, and temporal structures of the cerebral cortex predisposes to the development of long-term depressive disorders.

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