Industrial Psychiatry Journal

: 2010  |  Volume : 19  |  Issue : 2  |  Page : 82--89

Neuropsychophysiological correlates of depression

Kalpana Srivastava1, V.S.S.R Ryali1, J Prakash1, PS Bhat1, R Shashikumar1, Shahbaz Khan2,  
1 Department of Psychiatry, Armed Forces Medical College, Pune, Maharashtra, India
2 Graded Specialist Psychiatry Military Hospital, Danapur, India

Correspondence Address:
Kalpana Srivastava
Department of Psychiatry, Scientist «SQ»F«SQ», Armed Forces Medical College, Pune, Maharashtra


The neuropsychiatric and cognitive deficits have been shown to exist in various psychiatric disorders. An attempt has been made by authors to evaluate the evidence pertaining to electrophysiological, structural and neuropsychological domains in depression. Renewal of interest in testing patients with depression on a broad range of neuropsychological tasks has revealed distinct pattern of cognitive impairment in cases with depression. The review focuses on structural and neuropsychological evidence of deficit in cases of depression.

How to cite this article:
Srivastava K, Ryali V, Prakash J, Bhat P S, Shashikumar R, Khan S. Neuropsychophysiological correlates of depression.Ind Psychiatry J 2010;19:82-89

How to cite this URL:
Srivastava K, Ryali V, Prakash J, Bhat P S, Shashikumar R, Khan S. Neuropsychophysiological correlates of depression. Ind Psychiatry J [serial online] 2010 [cited 2020 Apr 5 ];19:82-89
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Full Text

Global burden of disease lists depression as the fourth leading cause of disability in terms of its physical, social and mental impact. The world health organization predicts it to be the second only cause of morbidity worldwide by the year 2020 and the leading disorder in females. [1] Surveys suggest that most cases of depression are either unrecognized or inappropriately treated, and this leads to a social burden on the family, functional decline and increased mortality with a lifetime prevalence of 10-20%. [2] In primary health care services in India, the estimated prevalence of depression was noted to be 20%. The prevalence of depressive disorder in Psychiatric departments of general hospital has ranged from 6 [3] to 34.7%. [4] In India, a metaanalysis of epidemiological studies performed in rural and urban areas since 1960 reported a median prevalence of 3.4% for mood disorders. [5]

There has been extensive research exploring the biopsychosocial model of depression over the years. Galen ascribed depression to the various humors, which was a departure from the approaches of early researchers, who looked into the domains of unresolved conflicts, faulty parenting and other psychological and social causation. In the post-1950 era, the concept of depression as a biological disorder emerged. Although a large range of existing neuropsychological, neuropsychiatric and, lately, neuroimaging investigations throw some light toward neurobiology of this malady, a consistent picture is yet to emerge, and the issue is far from settled. [6]

 Neurobiological Correlates

Biological research in affective disorders has focused primarily on the neurochemical basis of the disorder. Recently, there has been interest in the neuroanatomical basis of these disorders. [7] Radiological techniques that allow investigation of the living brain in health and disease have become widely available. Structural abnormalities in affective disorders were initially investigated with computerized tomographic scans. Later, the more precise methodology of magnetic resonance imaging (MRI) was applied with the ultimate aim of describing the structural and functional neuroanatomy in mood disorder. [8],[9],[10] Although still controversial, convergence of MRI and other findings from studies utilizing post-stroke depression and patients with primary mood disorder have led to attempts at detailed exploration of the neuroanatomical basis of mood disorders. [11] Studies using high-resolution MRI are now available to examine smaller brain structures with precision, and they have reported brain changes associated with major depression in the hippocampus (HC), amygdala, caudate nucleus, putamen and frontal cortex. [12]

Interestingly, neurobiological substrate for this disorder has not reached finality. The circuitry underlying the representation and regulation of normal emotion and mood involves the prefrontal cortex, anterior cingulate, HC and amygdala. The abnormalities in the structure and function of these different regions are implicated in depression. [13] The clinical manifestations of depressive disorder are considered to be mediated through changes in brain neurochemistry and structural/functional connectivity, irrespective of the etiology.

 Electroencephalographic Correlates of Depression

Apart from the newer modalities of research like MRI, evidence from electroencephalographic (EEG) as well has unequivocally established that "mental disorder" has definite correlates with brain dysfunction. Pathophysiological concomitants of psychiatric and developmental disorders have been provided by EEG and quantitative electroencephalography (QEEG). [14] The exclusion of neurological conditions for confirmation of psychiatric disorder has led to the application of EEG and QEEG investigation. [15] The percentage is as high as 64-68% of EEGs in psychiatric patients providing evidence of pathophysiology, and these results have additional utility beyond simply ruling out organic brain lesions. [16],[17] Such EEG studies may also aid in differential diagnosis, treatment patient selection and evaluation.

 Conventional Versus Quantitative Eeg in Depression

A voluminous literature attests to the robustness of conventional EEG studies and their clinical utility in disorders of brain function, which includes depressive disorders. [18],[19] The conventional EEG has contributed valuable information for the psychiatrist; however, this method is essentially based on visual pattern recognition. QEEG is now being increasingly used to decipher the neurobiological correlates in mood disorder. [20],[21]

These two EEG approaches complement each other. While conventional EEG provides reliable diagnostic information especially sensitive to "organic" or neurological disorders, detecting features of wave shapes, frequency relationships and transitions of state seldom encountered in the healthy individual, QEEG, in addition, enables precise comparison of the individual patient's record with normative and psychopathologic patient databases. Across both EEG and QEEG studies, a broad consensus exists on the high proportion of abnormalities found in different psychiatric disorders and often on their electrophysiological profiles. However, the generalization of these findings and application in clinical practice is limited by the non-specific nature of the detected abnormalities found in psychiatric patients. Also, there has been considerable controversy about the clinical utility of QEEG in psychiatric practice. [22],[23]

The incidence of abnormal conventional EEG findings in mood disorders appears to be substantial, ranging from 20% to 40%. [24],[25] Specific patterns noted in mood disorder patients include the controversial small sharp spikes (SSS), 6/s spike and wave complexes, and positive spikes, seen especially in patients with suicidal ideation. [26],[27] Evidence that the EEG is abnormal in depression has been coming of late from QEEG studies, and these have been in the form of increased alfa and/or theta power in a high percentage of depressed patients. [28] Interhemispheric asymmetry, especially in anterior regions, has been reported repeatedly. [29] Hence, both EEG and QEEG studies report that a high proportion of patients with mood disorders display abnormal brain electrical activity. EEG studies report that SSS and paroxysmal events are often found, especially on the right hemisphere, and that abnormal sleep studies are common.

EEG findings in studies of genetic unipolar depressives show that depressed persons display a disorganized atypical sleep pattern that skips a "level" of deep sleep and prominent delta and theta waves (which are sleep waves) in the waking state. [29] Therefore, we may conclude that the depressed person's brainwave activity in sleep is invaded by "waking" waves, and the reverse in the waking state.

 Neuroimaging in Depression

Although biochemical, pharmacologic and brain imaging techniques have all been used to shed light on the neurobiology of mood disorders, knowledge of the underlying pathobiology remains sketchy. Overall, brain imaging changes in mood disorders exhibit some putatively specific findings. [30] Studies using high-resolution MRI have reported brain changes associated with major depression in the HC, amygdala, caudate nucleus, putamen and frontal region, [31] structures that are extensively interconnected and comprise a neuroanatomic circuit that has been termed the limbic-cortical-striatal-pallidal-thalamic tract .

Using MRI, Schaefer demonstrated gray matter volume differences in the dorsolateral prefrontal cortex, a region consistently implicated in functional neuroimaging studies of affective disorders. [32] Volume reductions has been seen in the frontal cortex ranging from 7% overall reduction in the frontal lobe volume to 48% in the subgenual prefrontal cortex. [9],[33] In some ways, the most provocative data linking the HC to major depressive disorder (MDD) have been from MRI studies of the volume of the HC in patients with MDD. Volume loss in the HC is the most robust finding and the only change consistently observed to persist past the resolution of the depression. The importance of the HC in the pathophysiology of MDD has also been supported by a substantial body of evidence from basic and clinical studies. [34] Post-mortem studies have shown moderate apoptosis in the dentate gyrus and the CA1 and CA4 regions of the HC of patients with MDD. [35] In most of the studies that assessed depression in unipolar subjects and used high-resolution MRI techniques, depression was associated with hippocampal volume loss, ranging from 8 to 19%. [36]

Sheline and colleagues reported bilateral HC volume reductions in women with MDD. [37] Other studies have reported that patients with depression have smaller left HC volumes than control subjects. [38] At the same time, at least one research also found reduction of right HC volume in depression as compared with controls [39] [Table 1]. Hippocampal volume in depressed subjects appears to be predicted by the length of the illness and other variables associated with past burden of illness. Investigations of patients with recurrent episodes have consistently indicated that there are structural changes in the hippocampal formation. [35] Moreover, Sheline et al., [37] in a study of middle-aged depressed women, found that hippocampal volume reduction was related to total lifetime duration of depression. This finding was recently replicated in a larger sample of patients, where they reported that past illness predicted HC volume reduction; others reported that volumetric reductions were greatest in patients with a chronic course and large number of weeks ill than in those who recovered fully with shorter overall illness duration. [40] In one study, hippocampal atrophy was found in patients with chronic depression but not in patients with remitted depression. [41] Studies analyzed in the comprehensive review [42] have yielded conflicting evidence. Some studies have reported no changes when depressed patients are compared with healthy controls. [43],[44],[45],[46],[47] Predominantly, evidence is suggestive of bilateral reduction in HC volume, [48],[49],[50],[51],[52],[53] and it is negatively correlated with duration of depression [Table 1].{Table 1}

 Mechanism of Hippocampal Atrophy in Depression

In the studies of depression in which hippocampal atrophy has been found, the implication is that excessively high levels of cortisol associated with the stress-related disorder cause hippocampal cell death and result in the hippocampal atrophy seen on MRI. Cellular studies of the HC in depression have revealed that volume reductions of the HC might be the result of remodeling of key cellular elements, involving retraction of dendrites, decreased neurogenesis in the dentate gyrus and loss of glial cells. [54],[55] This dysregulation of glucocorticoid secretion with increased activity of excitatory amino acid neurotransmitters could result in both potentially reversible remodelling and irreversible cell death in the HC of patients with MDD. [56]

It has, therefore, been proposed that raised cortisol levels during depression might be associated with cognitive impairments, [57] especially in functions subserved by medial temporal lobe structures. [58] A large body of evidence has also established a link between stressful life events and development or exacerbation of depression. At the cellular level, evidence has emerged indicating neuronal atrophy and cell loss in response to stress and in depression. At the molecular level, it has been suggested that these cellular deficiencies, mostly detected in the HC, result from a decrease in the expression of brain-derived neurotrophic factor associated with elevation of glucocorticoids. [59]

 Cognitive Dysfunction in Depression

Cognitive deficits in mood disorders have been addressed in different function domains, some of them being attention, executive function (EF) and memory. It is interesting to observe that cognitive deficits are noted even during the euthymic/remitted states, which indicates that certain cognitive deficits may be associated with trait characteristics. Impairment of working memory (WM), sustained attention, abstract reasoning and visuomotor skills, [60],[61] verbal memory, [62] verbal fluency [63] and visuospatial ability [64] have all been reported, even in the euthymic phase of the illness. The deficits have been shown to correlate with both the number of affective episodes and the overall duration of illness. [65]

EF is commonly seen in major depression. [66] The types of executive deficits seen in depression include problems with planning, completing goal-directed activities, organizing, initiating, sequencing, shifting, information processing speed, inhibiting context-inappropriate responses and maintaining information in the working memory. [67],[68],[69] The presence of EF in depression is associated with vocational disability and possibly poorer treatment response. Studies have documented EF in depression using the wisconsin card sorting test (WCST) as well as other such tests of cognitive dysfunction. [70]

Lesion studies in animals and neuropathological reports in humans have shown that defects in the medial temporal lobe region, including the hippocampal formation, are associated with a severe and global amnesia. Aside from its well-documented contribution to learning and memory, the hippocampal formation plays a critical role in the regulation of motivation and emotion. [71] This contribution of the HC to emotion and affective style has only recently begun to be gleaned from the available corpus of animal studies on its role in context-dependent memory. [72] Other studies have attempted novel emotional modification of the Wisconsin Card Sorting Test [73] and brought out a possible role of HC in context-dependant memory. The WCST may actually check this context-dependant memory, with its substrate in the medial temporal lobe, and show the impairments in depression. The causes and associations of impaired cognitive function during depression remain uncertain. Some authors have proposed that hypercortisolemia during depression may be important. Studies in animals and humans, involving both exogenous steroid administration and conditions such as Cushing's syndrome and stress, which raise endogenous levels, have shown a relationship between raised cortisol levels and neuropsychological dysfunction, especially memory impairment. [74] Both glucocorticoid and mineralocorticoid steroid receptors are present in high concentrations in the HC, and prolonged and raised cortisol levels can produce neuronal dysfunction. [75] It has been proposed that raised cortisol levels during depression might be associated with cognitive impairments, especially in functions subserved by medial temporal lobe structures, and that persisting hypercortisolemia might cause hippocampal damage, explaining why impairments persist in depressed subjects, even when affective symptoms have resolved. [76]

 Relationship of Cognitive Dysfunction with Severity of Illness

Although executive deficits have been reported in more severely depressed subjects with melancholic or psychotic features, scores may be affected even with relatively mild depression and EF may vary as a function of the severity of depression. significant association between depressive symptoms and magnitude of Wisconsin Card Sorting Test deficits in major depression have been seen. A few studies have shown higher cognitive impairment in psychotic depression. [77]

Merriam et al. [78] studied Wisconsin Card Sorting performance in a large group of patients with major depression who had been without medication for at least 28 days. They found significant deficits on various indices of the Wisconsin Card Sorting task in these patients in comparison with controls. [79] In patients with major depression, Hamilton depression scale scores were moderately correlated with the number of categories achieved, number of perseverative errors, number of perseverative responses and the percentage of conceptual-level responses. Patients with major depression made more perseverative and non-perseverative errors, took longer to reach the first category, completed fewer categories overall and had fewer conceptual-level responses and lower learning-to-learn scores than healthy subjects. Moreover, patients with more severe depression performed more poorly. Other authors have also described a positive correlation with duration of illness as well as with recurrent episodes of depression. The investigation in patients with euthymic status have also revealed impairment in cognitive domain. [80] The speed of information processing and response latency is another area of concern in patients of depression. [81] A study done by Taj [82] on patients of bipolar disorder in remission noted significant impairments in attention, executive function and memory in the study group compared with a matched control group of normal subjects. In fact, memory deficit pattern also did not differ in both unipolar and bipolar cases of depression [83]

[Table 2]. However, cognitive deficits did present in both types of depression. [84],[85] Interestingly, severity of depression was not associated with cognitive deficits. [86] Further patients with somatic syndrome had slower psychomotor speed and less mental flexibility compared with the non-somatic syndrome group. [87] There appears to be internal consistency in the findings in the domain of cognition and depression. Patients with depression are noted to be having various types of cognitive deficits; primarily, the affected area may be executive functioning and memory.{Table 2}


Major depression is a mood disorder that is often accompanied by the impairment of cognitive function. The severity of illness, duration of illness and other structural changes appear to be natural concomitants influencing the outcome of depression. The large range of existing neuropsychological, electrophysiological and, lately, neuroimaging investigations have provided evidence of structural changes and cognitive deficits in cases of depression. The severity and type of depression in respect of cognitive changes and anatomical substrate have not yielded very consistent findings. The evidence is suggestive of common tenet of derangement of cognitive functions in depression irrespective of the type of depression. Similarly, reduction in hippocampal volume is another indication. However, much more exhaustive, explicit and specific data analysis is required to yield a definite conclusion on structural changes leading to cognitive deficits in the cases of depression.


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