Neuropsychological aspects of depression

Abstracts

Este artigo objetiva rever os principais achados neuropsicológicos na depressão, procurando diferenciar o tipo unipolar do bipolar, com ou sem psicose, tanto nos períodos de fase aguda quanto nos períodos intercríticos. Procurou-se, ainda, correlacionar os achados neuropsicológicos descritos na literatura consultada com os seus correlatos neuroanatômicos e neurofuncionais, ressaltando-se as áreas frontais e seus principais circuitos. Considerando-se estudos neuropsicológicos dos transtornos afetivos, algumas alterações têm se mostrado mais consistentes, sendo descritas disfunções importantes nas fases críticas, mas também no paciente assintomático. Nestas, interessam principalmente os aspectos atentivos e mnêmicos e o funcionamento executivo. Estudos desta natureza têm profundas implicações terapêuticas, apontando para a necessidade de desenvolver outras técnicas coadjuvantes, tais como reabilitação cognitiva e intervenções psicossociais, tornando o tratamento mais abrangente e incisivo nestes casos.

Neuropsicologia; depressão; lobo frontal

REVIEW ARTICLE

Neuropsychological aspects of depression

Aspectos neuropsicológicos de la depresión

Marcia Rozenthal^I; Jerson Laks^II; Eliasz Engelhardt^III

^IPhD in Psychiatry and Mental Health (IPUB/UFRJ) and Coordinator of the Schizophrenia and Cognition Program (IPUB/UFRJ), Brazil

^IICoordinator of the Center for Alzheimer Disease and Other Age-Related Mental Disorders, Psychiatric Institute, UFRJ, and Professor at the School of Medicine, UERJ, Brazil

^IIICoordinator of the Cognitive Neurology and Behavior Department, Neurology Institute Deolindo Couto, UFRJ, Brazil

^{Correspondence}

ABSTRACT

This study aims at reviewing the main neuropsychological findings in depression and the differences between the unipolar and bipolar forms, with or without psychosis, during the acute and intercritical phases. Moreover, the study intends to correlate the neuropsychological findings described in the literature with neuroanatomic and neurofunctional aspects, emphasizing frontal areas and their main circuits. Considering neuropsychological studies carried out in the field of affective disorders, some alterations have shown to be more consistent, with important dysfunctions in critical phases but also in asymptomatic patients. Of these, attentive and mnemic aspects, in addition to executive functioning, are of special interest. Studies of this nature have important therapeutical implications, suggesting the need for the development of other supporting therapeutical techniques, such as cognitive rehabilitation and psychosocial interventions, making the treatment broader and more incisive.

Keywords: Neuropsychology, depression, frontal lobe.

RESUMEN

Este artículo tiene por objetivo revisar los principales hallazgos neuropsicológicos en la depresión, procurando diferenciar sus formas de presentación unipolar y bipolar, con o sin sintomatología psicótica, tanto en el cuadro agudo como en los periodos inter-críticos. Busca, además, correlacionar los hallazgos neuropsicológicos descritos en la literatura consultada con los aspectos neuroanatómicos y neurofuncionales, destacando el área cortical frontal y sus circuitos principales. Considerándose estudios neuropsicológicos en trastornos afectivos, algunas alteraciones de atención, memoria y de funciones ejecutivas se han presentado más frecuentemente, siendo descritas en los periodos de crisis y también en el paciente asintomático. Estudios de esa naturaleza tienen profundas implicaciones terapéuticas, señalando además la necesidad de desarrollar otras técnicas terapéuticas coadyuvantes, tales como la rehabilitación cognitiva y las intervenciones psicosociales, haciendo el tratamiento más completo y eficaz.

Palabras clave: Neuropsicología, depresión, lóbulo frontal.

INTRODUCTION

The arrival of a range of more modern examination techniques to investigate the central nervous system (CNS) has had an extreme influence on psychiatry in general. To an ever greater extent, scientific research developed in this area now takes into account neuroanatomic and neurofunctional substrates (neuropsychology, neurobiology), in addition to strictly mental aspects (as in cognitive psychology).^1-4 This being the case, psychiatry can be included in the vast field that is cognitive neuroscience, taking advantage of models that explain cognitive dysfunction based on understanding of the normal relationship between brain and mind.^2,5

Neuropsychology, which can be defined as an applied science that studies the repercussions of cerebral dysfunction for behavior and cognition,⁶ is currently attaining an important place in the study of psychiatric disorders. Using tests, it not only provides information on a patient's global cognitive function, but also, and primarily, attempts to qualify the functional nature of deficits observed by means of comparative and quantitative analysis of the results obtained, allowing for refined anatomofunctional correlation. Thus neuropsychology enriches clinical diagnosis and allows correlation with information obtained from other examinations that measure eletrogenic and metabolic activity and from neuroimaging studies, thus bridging the gap between these and the patient's clinical status.⁷

Depression is an affective mental disorder; according to the classification coined by Kraepelin, this group would classically have remission from symptoms during the periods between phases, in contrast with the chronic character of schizophrenia. However, it is nowadays estimated that between 30 and 50% of depressed patients do not recover completely.⁸ Furthermore, according to Trichard et al.,⁹ there is consensus that certain depressive cognitive deficits remain after clinical remission. Neuropsychological and neurobiological studies of depression are performed with the objective of tracing clinicopathological correlations in order to better understand the disorder.¹⁰ To this end, efforts have been centered on certain anatomic regions where the correlation between findings and psychopathological manifestations of the disorder shows greater consistency. Certain methodological issues, however, should be taken into account since, in psychiatry, there is no definitive gold standard for the majority of disorders. The design of a study that, a priori, takes depression to be a single disease should look for dysfunctions that are present in a group of depressed patients and absent in those not suffering from the disorder (control group). If, on the other hand, depression is taken to be a diagnostic construct that is potentially heterogeneous in terms of neurobiological abnormalities, its study should compare a number of different pre-defined subgroups (e.g. bipolar, unipolar, geriatric, pediatric), in a desire for comparative study. This being the case, and if the numerous different official classifications are added to those resulting from research, the result is a large number of studies using distinct samples that are not, therefore, comparable. Even factors related to the clinical course of individual cases, such as, for example, age at onset, duration of the condition, presence or absence of detectable structural abnormalities, also appear to have a relationship with the severity of neuropsychological findings.¹¹ Another question relates to the verification and qualification of possible neurofunctional abnormalities that may be present during a depressive episode. Permanent abnormalities that are present before and after remission of acute conditions constitute traces of, or vulnerabilities to, the disorder. It is also important to differentiate between findings (even those that are most consistent in the literature) that are primary to the disorder under study and those that are secondary or adaptive.¹² These issues, which are far from being resolved, are increasingly becoming a part of the studies consulted. Some of the most relevant results are presented below. The articles consulted for this study were found by searching the MEDLINE and Lilacs databases using the following keywords: depression, neuropsychology, neuroanatomy, neurobiology and frontal lobe.

NEUROBIOLOGICAL ASPECTS OF DEPRESSION

The regions that have been most studied are the frontal areas and their connections and also the temporal areas. The main findings are reported below.

Frontal area

Localized abnormalities. Several different authors have pointed out the importance of frontal abnormalities in depressive states,^13-20 covering clinical findings related to attention, psychomotricity, executive function and decision-making found in typical cases. One important function of the frontal and striatal areas is to modulate the function of limbic structures and of the brain stem, which are physically involved in the mediation of emotional behavior; this being so, dysfunctions in these circuits should play a part in the pathogenesis of depressive symptoms.²¹

Anatomic and functional neuroimaging studies have revealed abnormalities in the fontal areas of distinct samples of depressed patients (geriatric, pediatric, unipolar, bipolar). Bilateral abnormalities of the orbital cortex were described in depressed geriatric patients using cerebral magnetic resonance imaging (MRM),²² in addition to reduced blood flow and low prefrontal cortex metabolism in both unipolar and bipolar depressed patients.²³

Studies using positron emission tomography (PET scans) relate similarities between unipolar and bipolar patients, suggesting that there is a common nucleus linked to the emotional component. There would be a reduction in prefrontal cortical metabolism, along the medial line, which would be related to an anatomic abnormality in this region, involving a reduction in its size.^24-25 While the anatomic abnormality is of a constant nature, the metabolic factors, in contrast, would fluctuate, according the patient's clinical condition and treatment with antidepressants.

The subgenual prefrontal cortical region was examined in depressed patients, manic patients in remission and patients in a manic phase. It was shown that manic and depressed patients exhibited a reduction in activity in this area when moods returned to normal. This area would have a reduced anatomic volume in such patients, becoming hyperactive during manic or depressive phases and returning to base level function when moods return to normal. This region is normally associated with the generation of words by association and is activated in normal subjects when they are asked to generate sad thoughts — an experimental means of inducing a depressed mood in the laboratory. What may be happening in depressed patients is that when they experience incessant negative thoughts there is an associated hyperactivity. There is disagreement over the origin of this region's reduction in size as observed by PET scan, which could be a delayed consequence of tissue damage resulting from chronic hyperactivity in these areas of the brain.^21,24-26

Principal pathway abnormalities. Areas associated with the attention network and with orientation have become much studied in the field of depression, based on the idea that, in major depression, the neural system involved in processing external information and in maintaining a state of vigilance might be suppressed in favor of systems involved in the internal information generation processes, such as thoughts and emotions.²⁷

Thase,¹¹ in a review on the anatomic aspects of depression, describes abnormalities in the subcortical white matter, particularly in the periventricular area, basal ganglia and thalamus. These abnormalities are most common with bipolar disorder I and among the geriatric and appear to represent the deleterious neurodegenerative effects of recurrent affective episodes. Ventricular widening, cortical atrophy and accentuation of the sulci have also been described in patients with affective disorders when compared with controls. Furthermore, depression would also involve reductions in both blood flow and metabolism in dopaminergic tracts of the mesocortical and mesolimbic system. There is evidence that antidepressants partially normalize these alterations.

Sweeney et al.¹⁵ and also Soares & Mann^23,28 describe functional abnormalities of the frontostriatal system, reduced blood flow and metabolism in basal ganglia in both unipolar and bipolar depressives. In unipolar patients, these authors observed increase proportion of white matter, in particular in the periventricular area, and a reduction in caudate and putamen nuclei. In bipolar patients there was enlargement of the third ventricle.

The prefrontal cortex maintains intimate connections with the paralimbic networks, widely related with emotional aspects. The cingulate appears to play an important role in separation reactions in animals, which can be provoked by electrical stimulation of this area. Microstructural alterations to the white matter lateral to the anterior cingular area appear to be related to the low rates of remission observed from depression among geriatric patients.¹⁸ Frontostriatal and limbic abnormalities have been identified among pediatric and geriatric depressed patient subgroups, with their presence apparently related to worse progress over both the short and long term.¹⁸ This being so, the identification of this abnormality is important, not just to complement understanding of the overall clinical picture, but also because of the therapeutic implications which will be described below.

The amygdala has also been widely studied with respect of affective disorders because it is intimately related to emotional learning.¹⁰ The central nucleus of the amygdala appears to be of crucial importance to the relationship between emotion and behavior. In studies with animals the neuronal activity in this region has been observed to increase when the animal is faced with emotionally loaded stimuli and stimulation of the central amygdala results in emotional responses (fear) in the absence of external stimuli. In this manner, Kennedy¹⁰ refers to consistent abnormalities in PET scan studies in the pre frontal and cingular regions and in the amygdala. Other authors^22,25,29 also describe abnormalities in these regions with depression.

In depression, there appears to be a global reduction in anterior cerebral metabolism and an increase in glucose metabolism in a number of different limbic regions, with emphasis on the amygdala. The best evidence for this abnormality comes from studies on patients with relatively severe and recurrent depression and where there is a family history of affective disorder. During episodes of depression, the increase in glucose metabolism would be related to intrusive ruminations. This hypermetabolism of the amygdala would act as an emotional amplifier that would help to distort relatively small stress signals in vulnerable people.²⁷ According to Thase,¹¹ this abnormality would be reversible with effective pharmacotherapy.

Temporal cortex

Specific abnormalities in temporal areas have been studied both in unipolar and bipolar depression, a large proportion related to the correlation between depression and abnormalities in the regulation of the hypothalamus-pituitary-adrenal axis, leading to the adverse effects of stress hormones on the hippocampus and amygdala,^{15,23,28,30-33} which regions are widely related with the prefrontal area, as seen earlier.

Special issues - Depression with psychosis

The CID-10 and DSM-IV classify major depression as a construct and allow for fourth and fifth digits to specify the presence or absence of psychosis. Arguments for maintaining psychotic depression as a distinct subtype prove to be flawed, although some evidence exists that there are neurofunctional and neuropsychological differences between delusional and non-delusional forms of depression.^34-35 Clinically, psychotic depression is distinguished as having a worse prognosis, worse acute response to antidepressants, higher remission rate, more serious depressive symptoms, greater neuropsychological compromise and a positive family history.

Simpson et al.,³⁶ in a study performed on depressed patients with psychosis, found certain anatomic alterations that were predictors of delusions: diencephalic atrophy, injuries to the ascending reticular activating system and left frontotemporal atrophy, suggesting that primary cerebral atrophy could be a significant to vulnerability to delusions. Anatomic abnormalities affecting the pontine reticular formation prove to be more prevalent among psychotic patients.^34,36-39 This evidence suggests there is a genetic predisposition to neurodevelopmental paralimbic abnormalities, that increase the vulnerability of the patient to psychosis during depression. Those patients that have normal paralimbic function have a better capacity for rationalizing the processes of morbid ideation with self-referring, non-delusional solutions. The paralimbic region appears to be important to this process of rationalization of sensory information. Brain stem and reticular activating system atrophy may predispose patients with diencephalic and frontotemporal atrophy to have a limbic system that is worse at processing their experiences, resulting in vulnerability to the development of delusions. Furthermore, the loss of inhibitions that is characteristic of frontal lobe disorders may also facilitate delusions.

NEUROPSYCHOLOGICAL FINDINGS

There are many neurocognitive complaints present during the depressive state, including reduced attention and memory abilities and slow thinking.⁴⁰ Taking account of the complexity of these functions, and also the greater depth of knowledge about the neurofunctional abnormalities subjacent to them, neuropsychology is refining itself more and more in terms of separating the functions being studied in order to then identify neuropsychological factors or patterns that could be fundamental to depression. It should be pointed out that the neuropsychological findings described with depression cannot be entirely attributed to motivational aspects.⁴¹

Studies suggest that certain cognitive abnormalities may be present with unipolar depression, being independent of the depressive state. In recurring depression with melancholy, the improvement in mood at night is not accompanied by cognitive improvement.⁴²

The main domains studied with depression are described below.

Attention

Some neuroanatomic abnormalities remain after the condition improves and suggest that certain domain-specific cognitive alterations are permanent, as is regional cerebral dysfunction.⁷

Symptomatic bipolar patients would have abnormalities in sustained attention, inhibitory control6,^15,43,44 and the capacity to alternate the attention focus,^15,43 which alterations do not appear to go into remission along with the symptoms.

Unipolar patients would present alterations in visuospatial sequencing, immediate memory and attention when compared with normal subjects. These alterations would also be present during asymptomatic phases and male patients with chronic conditions would have greater chances of this profile of deficiencies being sustained.⁴² Purcel et al.⁴⁰ also described unipolar depressed patients with compromised capacity to sustain cognitive and motor activity and to alternate the attention focus, in addition to slowed motor and cognitive function. These deficiencies would be related to the severity of the case, being more intense in patients requiring hospitalization.

Memory

Memory abnormalities would be related to a dysregulation of the hypothalamus-pituitary-adrenal axis, leading to the adverse effects of stress hormones on the hippocampus.^15,24,31-33 The main findings found in the literature consulted are related below by the phases of the memorization process.

Short-term memory. Depressed patients complain of poor concentration and difficulty in memorizing, which is a pattern that is different from that of patients who exhibit primary memory fixation process abnormalities. However, the majority of studies did not demonstrate altered short-term memory in depressed patients,^44-47 although Purcel et al.40 did observe failures of associative learning in geriatric depressives.

Long-term memory. A majority of the studies found evidence of compromise of the recall and recognition of both verbal and non-verbal material.

Episodic memory. Sweeney et al.¹⁵ describe episodic memory abnormalities during mixed or manic phases and also in both unipolar and bipolar depression.

Semantic memory. McKenna⁴⁸ relates that depressed patients with com psychosis appear to exhibit a specific impairment in the recall of information organized by meaning in semantic categories, making a link between the dysfunction and clinical symptomology, where false beliefs are described (delusions or delusional ideas).

Implicit memory. Depressed patients did not present specific alterations to this function.

Recall. Depressed patients are described as having greater selectivity when recalling negative material.^49-50 Williams et al.⁵¹ suggests that that cognitive processing occurs at two periods: one pre attentive (which follows the attentive capture of information and is demonstrated in tests of implicit memory) and the other elaborative (which involves the association of target information with information in memory and is demonstrated in explicit tests). If implicit memory were not compromised, then mood congruent memory would be revealed in explicit memory tests. Denny & Hunt⁵² show that depressed patients recall more negative than positive material, which is not repeated with implicit tests. Even so, in terms of degree of significance, these findings remain inconclusive.

Depressed patients exhibit recall deficiencies in tasks that require the spontaneous use of strategies, which is the opposite to what is observed with subjects that control the use of strategies or do not need them, indicating that the deficiencies experienced in depression occur during the cognitive initiative. Depressives have impaired recall of material that is "wearing" to process, as a results of a reduced capacity to execute these operations, but not because of a reduction in the quantity of material remembered, seen in tasks dependent on more automatic processing.⁵³

Verbal and visual memory. Compromised verbal memory has been described in bipolar patients even when they are euthymic, while visuospatial memory does not exhibit consistent alterations.^{6,40,43,54,55} In bipolar patients, the length of time in a crisis state (mania or depression) appears to have a negative correlation with verbal memory performance and with executive functioning. These findings suggest the presence of persistent neurocognitive difficulties in patients with long-term bipolar disorders and the existence of a build-up of negative effects directly related to the duration of the bipolar condition on verbal memory and the executive system.

Processing speed

Slow cognitive processing is described in bipolar patients,^6,43 pediatric and geriatric unipolar patients^40,42 and in psychotic patients.³⁶

Executive function

With a view to the dysfunctions that relate to the prefrontal region in depression, a number of different neuropsychological studies have dealt with the executive function of these patients. Depression-executive dysfunction syndrome^18,19 is being studied and, given its direct interference with daily life and the prognosis of these cases, its identification essential. Certain relevant findings follow.

Mental flexibility. This has been shown to be impaired in a number of different studies of unipolar and bipolar depressives,^6,22,40 with persistent inappropriate strategies, which could, in part, explain the depressive ruminations, which, while recognized as strange and undesirable are not rejected.

Construction of planning strategies. Abnormalities are observed in both unipolar and bipolar patients.^6,36

Initiation and supervisory processes. Depressives appear to have executive impairment related to the initiation of a task, while their supervisory capacity remains normal.⁵⁶

Emotion and decision making

A new approach to the study of the decision-making process takes into account the fact that, in normal individuals, emotions facilitate the decision-making process, guiding cognition.^22,57,58 This process has great clinical relevance to depressed patients, considering that they generally have difficulty in making decisions. Similarly, individuals who experience manic episodes tend to invest excessive effort in pleasurable activities, with a greater potential for harmful consequences and therefore lose the entirety of possibilities to be considered in the decision-making process.

Studies conducted in this area¹⁶ demonstrate that depressed patients are slower at the deliberative process and when asked to "bet" on their decisions (in order to evaluate how sure they are), they use abnormal strategies (more conservative ones), with less confidence. These patients also present a distorted perception of environmental feedback, responding abnormally when this is negative, suggesting a dysregulation of reinforcement systems. In depressives, this abnormal behavioral response to performance feedback is associated with an abnormal neural response in the regions involved with compensatory mechanisms — the medial caudate and the ventromedial orbitofrontal cortex. These areas would be at the base of cognitive processes that require affective information, related to the processing of meanings related to emotions and are extensively connected with the limbic structures involved, from a behavioral point of view, in the processes of motivation, encouragement and reinforcement.

According to Murphy et al.,¹⁶ there appears to be a failure in behavior inhibition processes in mood disorders. Both manic and depressive patients appear to exhibit impulsivity, which factor, when evident during the depressive phase, would be linked with suicide attempts.

THERAPEUTIC IMPLICATIONS

The study of neurofunctional and neuropsychological abnormalities is a long way from discovering the causal factors relating to mental processes. Furthermore, genetic and constitutional factors can interfere with the structure of the CNS and, thus, in the origin of mental disorders. The demonstration that learning is accompanied by changes in the efficacy of neural connections has provoked a rethinking of concepts about the relationship between social and biological processes in defining behavioral patterns. It is known that day-to-day events can provoke an effective weakening of the synaptic connections under certain conditions and strengthening under others. This could be of great relevance to the search for non-pharmaceutical therapeutic techniques aimed at stimulating the clinical dysfunctions seen in tests.⁵⁹ This being so, neuropsychology should be considered as an important instrument for the understanding of mental disorders, being of great utility in the process of constructing therapeutic interventions that are more specifically directed at the deficiencies observed.

In the specific case of depression in geriatric patients, and also in adult patients, there can be significantly altered executive function as the condition progresses and the presence of these deficiencies correlates with functional impairment, worse response to treatment, remissions and re-occurrences.¹⁹ The identification of those patients worst affected is shown to be essential since day-to-day activity can be improved by means of compensatory strategies and that its preservation has a direct impact on the prognosis of these cases.⁶⁰ Preliminary studies suggest that the use of therapies aimed at problem resolution proves itself effective at reducing depressive symptoms and improving performance in day-to-day activities and may be an important therapeutic alternative for populations that remain symptomatic.⁶¹

CONCLUSIONS

Studies of the neuropsychological aspects of mental disorders and, in the specific case of this review, depression, are of great importance to the extent that they allow the field of neuroscience to be brought closer to that of psychiatry. A certain critical dimension must be preserved with relation to the results, there being a number of issues and controversies that remain to be cleared up. However, without doubt, the various factors are becoming better understood by clinicians, enabling a better understanding of critical and inter-critical states in affective disorders and opening new paths for the search for more effective techniques for diagnosis, treatment and preventions of possible cognitive sequelae in these patients.

REFERENCES

Received on February 9, 2004.

Revised on April 23, 2004.

Approved on June 15, 2004.

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Publication Dates

• Publication in this collection
  13 Sept 2005
• Date of issue
  Aug 2004

History

• Accepted
  15 June 2004
• Received
  19 Feb 2004
• Reviewed
  23 Apr 2004