- Email: [email protected]
The neuropsychological profile in unipolar depression
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Arnsten – Catecholamine modulation of PFC function
63 Foote, S.L., Bloom, F.E. and Aston-Jones, G. (1983) Nucleus locus
receptor-mediated facilitation of somatosensory cortical neuronal
coeruleus: new evidence of anatomical and physiological specificity
responses to excitatory synaptic inputs and iontophoretically applied
Physiol. Rev. 63, 844–914
acetylcholine Neuropharmacology 20, 907–920
64 Arnsten, A.F.T. and Goldman-Rakic, P.S. (1984) Selective prefrontal
71 Kasamatsu, T. and Heggelund, P. (1982) Single-cell responses in cat
cortical projections to the region of the locus coeruleus and raphe
visual
nuclei in the rhesus monkey Brain Res. 306, 9–18
noradrenaline Exp. Brain Res. 45, 317–327
65 Sara, S.J. and Herve-Minvielle, A. (1995) Inhibitory influence of frontal cortex on locus coeruleus Proc. Natl. Acad. Sci. U. S. A. 92, 6032–6036 66 Jodo, E., Chiang, C. and Aston-Jones, G. (1998) Potent excitatory influence of prefrontal cortex activity on noradrenergic locus 67 Rajkowski, J. et al. (1998) State-related activity, reactivity of locus coeruleus neurons in behaving monkeys Adv. Pharmacol. 42, 740–744 68 Foote, S.L., Freedman, F.E. and Oliver, A.P. (1975) Effects of putative neurotransmitters on neuronal activity in monkey auditory cortex Moises,
H.C.
and
to
visual
stimulation
during
iontophoresis
of
72 Darracq, L. et al. (1998) Importance of the noradrenaline–dopamine coupling in the locomotor activating effects of
D-amphetamine
J. Neurosci. 18, 2729–2739 73 Arnsten, A.F.T. and Goldman-Rakic, P.S. (1990) Analysis of alpha-2 performance of aged rhesus monkeys Neurobiol. Aging 11, 583–590 74 Sirviö, J. et al. (1991) The effects of guanfacine, alpha-2 agonist, on the performance of young and aged rats in spatial navigation task Behav. Neural Biol. 56, 101–107 75 Witte,
Brain Res. 86, 229–242 B.D.,
cortex
adrenergic agonist effects on the delayed nonmatch-to-sample
coeruleus neurons Neuroscience 83, 63–79
69 Waterhouse,
Review
Woodward,
D.J.
(1980)
E.A.
and
Marrocco,
R.T.
(1997)
Alterations
of
brain
noradrenergic activity in rhesus monkeys affects the alerting
Noradrenergic modulation of somatosensory cortical neuronal
component of covert orienting Psychopharmacology 132, 315–323
responses to iontophoretically applied putative transmitters Exp.
76 Arnsten, A.F.T. and Jentsch, J.D. (1997) The alpha-1 adrenergic agonist, cirazoline, impairs spatial working memory performance in aged
Neurol. 69, 30–49 70 Waterhouse, B.D., Moises, H.C. and Woodward, D.J. (1981) Alpha-
monkeys Pharmacol. Biochem. Behav. 57, 1–5
The neuropsychological profile in unipolar depression Rebecca Elliott There is a wealth of empirical data pertaining to the issue of neuropsychological impairment in depression. However, a coherent and comprehensive framework for understanding the disorder remains elusive. This review will briefly consider some of the important issues on which recent research has focused. It would be premature to derive firm conclusions in an area characterized by considerable confusion, so the aim of this review is to highlight the key areas that must be addressed. Three distinct questions are considered. The first concerns the neuropsychological specificity of the deficits associated with depression; whether they represent selective deficits or a more general profile of impairment. The second question is to determine how cognitive deficits might relate to clinical and demographic factors, including symptom severity, hospitalization, medication and ageing. Finally, a comprehensive theory of depression must also relate impairments to neuropathology, and evidence is now available from imaging studies that have attempted to elucidate neural substrates of neuropsychological deficits.
M
ajor depression is a common disorder, affecting approximately one in ten of the population at some time in their lives. The core symptoms involve disturbances of mood and affect but there is substantial evidence that cognitive function is also impaired. An understanding of these cognitive deficits has a number of important implications, both practical and theoretical, for the study of depression. On a practical level, impaired cognition can com-
promise social function. It also has diagnostic implications, particularly in elderly patients whose cognitive deficits are often pronounced, meaning that differential diagnosis of depression and dementia can prove problematic. In more theoretical terms, understanding cognitive deficits, their interaction with disordered mood and their relation to neuropathology is essential to a comprehensive understanding of the disorder.
1364-6613/98/$ – see front matter © 1998 Elsevier Science. All rights reserved.
PII: S1364-6613(98)01235-2
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Rebecca Elliott is at the Wellcome Department of Cognitive Neurology, 12 Queen Square, London, UK WC1N 3BG. tel: +44 171 833 7485 fax: +44 171 813 1420 e-mail: r.elliott@fil. ion.ucl.ac.uk
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Box 1. Neuropsychological functions Memory and memory tests It is now widely accepted that memory is not a unitary concept but can be divided into a number of different subtypes. A simple taxonomy of memory can be outlined as follows:
Memory Long-term
Declarative (explicit)
Episodic (memory for events)
Short-term
Procedural (implicit)
Semantic (memory for facts)
in memory; for example, using free recall (subjects simply asked to remember), cued recall (subjects provided with partial information as a prompt) or recognition (subjects presented with information and asked whether they have seen it before). These separable aspects of memory have been dissociated in neuropsychological and, to some extent, functional-anatomical terms and they can be tested separately in patient groups.
e.g. Skill learning, priming
However, there are many further distinctions and dissociations that can be considered. For example, within short-term memory, there is a clear distinction between memory for visuospatial information and memory for auditory–verbal information. There are also different ways to access items stored
Executive function Executive function is a term that has been coined to describe a family of processes thought to depend on the intact function of the prefrontal cortex, whereby cognitive subprocesses are coordinated for the successful performance of complex cognitive tasks. These processes are important in the planning and execution of complex behaviours, in the generation of a strategic approach to cognitive problems, in the monitoring of performance and in the revision of strategies and behaviours that cease to be appropriate. Tests that have been used to tap aspects of executive function include: • Tower of Hanoi/Tower of London task (see Fig. 1) • Wisconsin Card Sort test (see Fig. 1) • Cognitive estimates test • Hayling sentence-completion test • Trail making A and B
An important issue in the study of depression is the existence of various subtypes of the disorder with different symptom profiles. Some of the key distinctions are between unipolar (depression alone) and bipolar depression (depression with mania), between dysthymia (a mild form) and depression itself and between primary depression and that which is secondary to another brain disease. These different subtypes may be associated with distinct cognitive profiles. While this is an interesting debate, it is beyond the scope of the present review, which will focus on primary, unipolar depression. Until the last 20 years, the prevailing opinion was that even severe depression was associated with only minor neuropsychological impairments1. An influential review of the evidence by Miller2 challenged this position, concluding that patients showed deficits in a wide range of cognitive domains, a view that is now widely accepted. Current debate centres around the exact nature of these neuropsychological deficits and their relation to other dimensions of the disorder. There are many complex issues involved, some of which are considered briefly here. Broadly the review is divided into three sections: (1) a discussion of the actual nature of the neuropsychological profile in depression; (2) a consideration of the interaction between cognitive deficits and clinical features which might account for some of the confusion in the neuropsychological literature; and (3) a review of the neuroimaging evidence relating neuropsychology to neuropathology that may help point to a resolution of the issues. The area of neuropsychology and depression is a particularly confused one and the aim of this review is to highlight some of the debates and issues involved, which need to be resolved before the disorder can be fully understood. General or specific deficits? The consideration of whether depression is associated with selective deficits in particular domains or whether the profile
is more general is a hotly debated question. The debate has historically taken a number of different forms but for the purposes of this review, I will focus on three illustrative questions. Do patients show selective impairments in memory or executive function? In recent years it has become popular to consider questions of specificity in terms of these two different aspects of function (Box 1), which have been experimentally dissociated in patients with neurological and neurosurgical damage. Patients with the posterior cortical dementia, Alzheimer’s disease, show selective deficits in visual short-term-memory tests with relative sparing of executive function (see, for example, Ref. 3). In contrast, patients with the fronto-subcortical dementia, Parkinson’s disease, show the reverse pattern (e.g. Ref. 4). A similar dissociation has been identified for patients with focal brain lesions in prefrontal cortex (executive deficits) and temporal lobes (memory deficits; e.g. Refs 5,6). Thus, if selective impairments could be demonstrated in depressed patients, it would have implications for neurobiological, as well as neuropsychological theories. Depressed patients have been studied using tasks that sample aspects of memory and learning (visual and verbal, short-term and long-term) as well as different tests of executive function, for example the Tower of London and Wisconsin Card Sort tests (Fig. 1). It has been reported that patients show deficits in both memory7–9 and executive function10–12. Although the exact pattern of deficits reported in individual studies varies, depending on the specific tests used and the populations studied, impairment is typically seen across a broad range of cognitive domains8–10,13,14. In a recent meta-analysis of all studies published since 1975, Veiel15 concluded that the neuropsychological deficits seen in patients with major depression are ‘consistent with global-diffuse impairment in brain functions’. However,
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two recent comprehensive reviews15,16 have suggested that while deficits are seen in many cognitive domains, executive deficits associated with frontal lobe dysfunction may be particularly prominent in depression. As will be discussed below, more marked executive deficits are consistent with the neuroimaging evidence for frontal lobe pathology. Effortful versus automatic processing A different approach to determining the selectivity of neuropsychological deficits is to consider the importance of underlying cognitive factors which cut across demarcated neuropsychological domains, accounting for a generalized profile of impairment. An influential hypothesis, based on this approach, is that depressed patients are more impaired on effortful than on automatic tasks17. Thus, more demanding tasks, whatever function they assess, will be differentially sensitive to depression. For example, one prediction of the hypothesis is that explicit memory (relatively effortful) will be more impaired in depressed patients than implicit memory (relatively automatic). Although there is empirical support for this prediction18–20, there is also contradictory evidence21,22. Another clear prediction is that executive tasks, which are almost by definition effortful, will be particularly sensitive to depression. This prediction is borne out by some of the evidence reviewed above. Overall, the jury is still out on the cognitive effort hypothesis; recent accounts continue to support the idea23 but further research is needed in order to clarify whether cognitive effort is a useful concept for explaining neuropsychological impairments in depression. Mood-congruent biases in information processing One very specific form of deficit that has been widely studied in depression is whether the affective or emotional tone of material being processed in cognitive tasks influences the efficiency of performance. The most reliably reported bias is in memory studies, in which depressed patients show a facilitation of recall of unpleasant compared to pleasant material (see Ref. 24 for review). There is also evidence that moodcongruent memory bias is evident in implicit contexts, such as priming, when subjects are not actively attempting to remember information. For example Watkins et al.25 showed that depressed patients showed greater priming of negative than positive words while non-depressed controls showed the reverse pattern. Although not all studies have demonstrated implicit biases in depression (e.g. Ref. 26), the balance of evidence suggests that mood-congruent information-processing biases are an important influence on cognition in depressed patients. This line of enquiry has the advantage of explicitly linking mood and cognition and can be related to cognitivebehavioural theories of depression, on which treatment strategies have been based27. It is clearly important that the relation between neuropsychological deficits and clinical features, such as depressed mood, be more thoroughly understood. The next portion of this review considers some of the issues which need to be addressed. Clinical factors influencing neuropsychological performance It is clear from the above discussion that there is some inconsistency across studies as to the nature and extent of
Review
A
B
Fig. 1 Executive tasks. (A) The Tower of London task. Subjects are given the instruction: ‘Rearrange the balls on the right-hand set of rods so that the arrangement is the same as that on the left-hand set of rods’. (B) The Wisconsin Card Sort test. Subjects are asked to: ‘Work out a rule to sort the deck of cards on the basis of colour, shape or number. At unpredictable intervals the rule will change; work out the new rule’.
neuropsychological deficits associated with depression. An often cited reason for inconsistencies of this sort is that there can be large differences in the clinical and demographic profile of patients in different studies. This raises the important question of the extent to which specific symptoms and cognitive deficits can be theoretically and empirically related. Relating neuropsychological deficits to specific symptoms Some of the clinical symptoms of depression appear to have a direct causal effect on performance. For example, subjective reports of problems with concentration and attention are common. Indeed, impaired concentration represents a standard operational criterion for a diagnosis of depression28. There are relatively few empirical studies of attention in depression although impairments have been reported29. The mood-congruent memory biases discussed above can be considered as clinical symptoms impacting directly on cognitive performance. Another example of the thin boundary between clinical symptom and neuropsychological deficit is the issue of motivation; lack of motivation is a clinical symptom which could play a causal role in neuropsychological impairments. There have been arguments assigning all the cognitive deficits of depression to motivational factors (e.g. Ref. 30), which has strong echoes of the cognitive effort hypothesis discussed above. However, a fundamental motivational cause of deficits would not explain the sparing of aspects of cognitive function which many studies have shown.
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Certain recent studies have attempted to relate the profile of neuropsychological impairment to a highly specific form of motivational deficit, namely response to performance feedback. In many cognitive tasks, subjects are given information about performance accuracy and recent evidence suggests that depression is associated with an abnormality in their response. Beats et al.10 described a ‘catastrophic response to perceived failure’ on the Tower of London task (see Fig. 1) such that once patients made an initial error, subsequent performance deteriorated rapidly. In a more explicit test of this hypothesis Elliott et al.9,31 reported abnormal response to failure on two contrasting tests and suggested that depressed patients failed to use negative feedback as a motivational boost to improve subsequent performance. In normal subjects failing a problem in a series increased the likelihood of succeeding on subsequent problems but this was not seen in depressed patients. This is consistent with a finding of Channon et al.32 in dysphoric subjects that reported an inefficient use of feedback to improve performance on a card sorting test. This finding has the advantage of being directly related to aspects of symptomatology and also to influential cognitive and psychological accounts of the disorder33–35. However, it has yet to be empirically confirmed and some attempts at replication have failed36,37. One of the reasons for this, and indeed for many other discrepancies, may be demographic differences in the patient populations. There are a number of factors which might interact with neuropsychological function, including severity of depression, hospitalization, medication and age, which are briefly considered below. Severity of depression Many studies of neuropsychological function have attempted to relate deficits to severity of depression measured on clinical rating scales. Some have reported correlations between severity and particular impairments7,38,39 while others have not8. There are several possible explanations for these differences. One important consideration is that different rating scales are used and this may lead to different results in correlational studies. Clearly, scales with specific questions about cognitive function are more likely to correlate with neuropsychological deficits. In a study by Elliott et al.9, scores on the widely used Hamilton scale40 did not correlate with any of the neuropsychological variables measured. However, scores on the Montgomery and Asperg scale41, which includes several questions related to cognitive function, were significantly correlated with measures of visual memory. State versus trait factors in depression A related issue to the severity question is whether neuropsychological deficits represent a state factor, evident only while individuals are currently depressed, or a trait factor, evident in individuals susceptible to depression even when they are not currently depressed. In empirical terms, this question has most usually been addressed by assessing patients in longitudinal studies, when depressed and again on clinical recovery. The balance of evidence suggests that there is a substantial improvement in cognitive performance on symptomatic recovery9,10,42. However, all these studies report the presence of residual impairments relative to controls.
Convergent findings have been reported in patients with seasonal affective disorder43 and with pronounced diurnal variation in mood13. It therefore seems that both state and trait factors might influence the cognitive profile in depression. Hospitalization It has recently emerged that hospitalization of patients is a significant factor in determining performance on neuropsychological tests. Depression may be managed on an inpatient or an out-patient basis and studies generally assess different proportions of these groups. In a recent study9, subgroups of in- and out-patients were compared on a range of tests. There were significant differences in performance, with the in-patients performing worse than the out-patients, although there were no significant differences in measured severity of depression. Using the same test battery44 with a group of out-patients Purcell et al.36 reported less global impairment than Elliott et al.9 and, interestingly, reported that patients with a history of in-patient episodes performed worse on some measures than those without. There are two possible explanations for these results; one is that neuropsychological impairment is an important indicator for hospitalization, the other is that factors related to hospitalization contribute to cognitive deficits. One such factor may be differences in treatment regimes, an issue that has more widespread implications. Medication An important confounding factor of many neuropsychological studies of depression is that patients are often medicated, with very different individual medication regimes and histories. Antidepressant medications might interact with cognitive function, though in a major review of studies, Thompson and Trimble45 reported that available evidence was inconclusive. Antidepressants with anti-cholinergic properties were found to impair aspects of cognitive function although the situation for other antidepressants was less clear, in that different studies reported beneficial or detrimental effects, a combination of both, or neither. A more recent review46 also highlights this complexity. However, the consensus of recent evidence suggests that while traditional tricyclic antidepressants can disrupt aspects of cognitive function (and particularly psychomotor speed), more modern antidepressants have less effect either in patients or controls. This is true both of selective serotonin-reuptake inhibitors (SSRIs) (Refs 47–51) and of monoamine oxidase inhibitors (MAO-Is) (Ref. 52). Differential effects of different antidepressants suggest that medication is an important factor in determining the neuropsychological profile of depression and may contribute to discrepancies between different studies. Interaction of performance with age Another factor, which might interact with clinical features, and is emerging as an important determinant of neuropsychological deficits in depression is the age of subjects. In elderly patients, neuropsychological deficits observed have been compared with those seen in organic dementias53. Qualitative comparisons between studies suggests that depression is more reliably related to cognitive impairment in
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elderly patients8,10,14 than in patients under 40 years (Refs 54–56). This suggests that depression and age interact in causing deficits but explicit attempts to test this prediction have not necessarily confirmed it. For example, Tarbuck and Paykel57 compared depressed and recovered patients under and over the age of 60 on a battery of tests. While depression and age both significantly influenced performance, there was no interaction between the two. A recent series of studies using a computerized test battery44 have found different results in three different age groups. Patients with a mean age under 40 showed restricted deficits in tests of executive function36. Patients with a mean age around 50 showed more widespread impairments extending to tests of memory as well as executive function9. Finally, elderly patients, with a mean age over 70, showed deficits in a range of memory and executive tests, and pronounced cognitive slowing10. However, it cannot be concluded on this basis that deficits simply become more widespread with age. In the Beats et al.10 study, elderly patients showed intact performance on some measures that were impaired in the middle-aged group. This was not because the older patients performed better but because the older control group performed worse (in line with the finding of Robbins et al.44 that normal performance on these tests declines with age). It seems that the interaction between age and cognitive impairment in depression is a complex one, which needs to be clarified using more extensive, and ideally longitudinal, studies. Neural correlates of neuropsychological deficits There has been much discussion over the years concerning whether depression is associated with structural changes in the brain. Convergent evidence suggests that there may be structural abnormalities in elderly patients which are related to the degree of cognitive impairment (see Refs 16,58 for reviews). However, the evidence for structural changes in younger patients is much less clear and assessment of possible functional changes has proved more productive. In the past decade, functional neuroimaging, using positron emission tomography (PET), single-photon emission computed tomography (SPECT) and functional magnetic resonance imaging (fMRI), has been used to identify functional abnormalities associated with depression. The earlier resting-state studies have identified a number of regions that are abnormal in patients with depression. One of the most robust findings is of abnormal blood flow in prefrontal cortex, particularly involving medial regions of dorsal and ventral anterior cingulate cortex59–64. Another commonly reported abnormality is decreased striatal blood flow59,65,66 which, combined with the prefrontal abnormalities, provides support for the popular theory that depression involves abnormalities in fronto-subcortical circuitry16,58,67,68. These studies strongly suggest that functional abnormalities are a feature of the pathophysiology of depression. Recent studies have explicitly attempted to relate neuropathology to neuropsychological and clinical dimensions in depression, using correlational techniques. Bench et al.69 used factor analysis to relate regional cerebral blood flow (rCBF) to clinical features. One of the factors which emerged had high loading for cognitive performance and
Fig. 2 Brain activations associated with the performance of an executive task. Activations, shown superimposed on a standard MRI template, to the Tower of London task in (A) controls and (B) depressed patients. Note the absence of anterior cingulate activation in patients.
correlated positively with rCBF in the medial prefrontal cortex. In a follow-up study, Dolan et al.70 performed principal-components analysis on neuropsychological data and identified two factors with high loadings for memory and attention. Both factors correlated significantly with rCBF in the medial prefrontal cortex and frontal pole. In the studies discussed above, subjects were scanned during some form of resting state, most usually being asked simply to relax with eyes closed. This provides a reasonably standard baseline in functional imaging studies, but is a rather poorly controlled state because subjects might think about a range of things during scanning. Cognitive-activation studies provide a different approach, where subjects are scanned during the explicit performance of a specified cognitive task giving much greater control over their mental processes. Regions that are found to be abnormal in such activation studies are not necessarily those identified in the resting state. Berman et al.71 scanned depressed patients during performance of the Wisconsin Card Sort test and
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Fig. 3 Activations in the presence of performance feedback. Highlighted regions are those regions showing significantly reduced cerebral blood flow (significance measured by standard Z-values) in depressed patients relative to controls, in the presence compared with the absence of performance feedback on an executive task.
found no evidence of abnormal prefrontal blood flow. However, two more recent studies have shown reduced frontal blood flow, particularly in the anterior cingulate, during performance of the Stroop task72 and a version of the Tower of London task73 (Fig. 2). The focus of medial prefrontal dysfunction depends on the nature of the cognitiveactivation paradigm used. For example, a recent study74 related the highly specific response to feedback described above to focal functional abnormality in the medial orbitofrontal cortex (Fig. 3), a region that has also been implicated in recent studies of response to treatment75. This
latter study highlights the importance of neuroimaging in assessing the important issue of abnormal neurotransmitter (specifically serotonin) function in depression. What is striking in these functional imaging studies is the predominance of prefrontal abnormalities, which supports the general notion of impaired executive processing in depression. However, prefrontal dysfunction might also contribute to memory deficits, particularly on more ‘effortful’ tasks. Regions of lateral prefrontal cortex have been widely implicated in working memory (e.g. Ref. 76) and there is also evidence for a role for anterior cingulate cortex in control processes related to memory77. ‘Working memory’ and ‘control processes’ can be interpreted as ‘executive’ aspects of memory but, as discussed above, depressed patients also show deficits in simple recognition tasks. Functional neuroimaging has also demonstrated anterior cingulate activation in association with short-term visual recognition tasks78,79. In general, therefore, the functional abnormalities observed in depression are consistent with the neuropsychological deficits. The medial prefrontal cortex, which has been most reliably associated with depression, is implicated in a range of cognitive functions including general processes such as attention and also in emotional responses. The schematic diagram in Fig. 4 shows how a fundamental pathology in regions of the medial prefrontal cortex might underpin both clinical features and cognitive deficits seen in depression. This pathology may involve both functional and structural abnormalities, as suggested in a recent paper by Drevets et al.80, reporting both types of abnormality in the subgenual cingulate, a ventromedial region lying between the anterior cingulate and orbitofrontal cortices. The medial prefrontal cortex is extensively connected to other structures and is also a region where activity is crucially modulated by the neurotransmitters believed to be implicated in depression. It is therefore entirely plausible that dysfunction in this region could be fundamental to depression, characterized as it is by a complex interaction of affective and cognitive disturbance.
Implicated in:
Neuromodulatory influences (e.g. DA, 5-HT)
Primary projections to: Lateral prefrontal cortex
Executive deficits
Extended limbic system
Memory and mood
Limbic system and basal ganglia
Mood and reinforcement
Dorsal anterior cingulate
Ventral anterior cingulate
Medial orbitofrontal cortex
Fig. 4 Schematic diagram of the role of medial prefrontal cortex in depression.
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Conclusion This review has highlighted the complexity of understanding the nature of the neuropsychological profile of depression. It seems likely that depression is associated with a range of cognitive deficits, but with an emphasis on effortful executive tasks, dependent on the function of prefrontal cortex. The neuroimaging evidence suggests that it is particularly medial prefrontal cortex and the anterior cingulate that mediate these impairments in depression. Antidepressant medications act in this region and factors such as age and severity might also modulate its function. While a framework of this sort could prove an important way of thinking about depression, there are clearly many unresolved issues and questions that need to be addressed in the search for a coherent account of this challenging disorder.
Review
Outstanding questions • Can the predominance of executive deficits in depression be confirmed? • How useful is the concept of cognitive effort in understanding depression? • How important are general factors related to clinical features, such as response to feedback, in causing neuropsychological impairments? • How does the neuropsychological profile seen in depression interact with the ageing process studied in longitudinal designs? • Do the functional abnormalities of medial prefrontal cortex that have been widely reported in depression represent the fundamental neuropathology of the disorder? • Are functional abnormalities of medial prefrontal cortex state or trait markers for depression? • What are the implications of impaired cognition for patient management? • How can a better understanding of the complex interaction between neuropsychology, clinical symptomatology and neuropathology be translated into the development of effective treatments?
Acknowledgements I am grateful to Dr Barbara Sahakian for many invaluable discussions and to Professor Raymond Dolan for his helpful comments on this manuscript.
memory J. Exp. Psychol. Gen. 108, 356–388 18 Danion, J-M. et al. (1991) Explicit memory and repetition priming in depression Arch. Gen. Psychiatry 48, 707–711 19 Denny, E.B. and Hunt, R. (1992) Affective valence and memory in
References 1 Friedman, A.S. (1964) Minimal effects of severe depression on cognitive functioning J. Abnorm. Soc. Psychol. 69, 237–243 2 Miller, W.R. (1975) Psychological deficit in depression Psychol. Bull. 82,
Psychol. 101, 575–580 20 Bazin, N., Perruchet, P., De Bonis, M. and Feline, A. (1994) The dissociation of explicit and implicit memory in depressed patients
238–260 3 Sahakian, B.J. et al. (1990) Sparing of attentional relative to mnemonic function in a subgroup of patients with dementia of the Alzheimer
Psychol. Med. 24, 239–245 21 Elliot, C.L. and Greene, R.L. (1992) Clinical depression and implicit memory J. Abnorm. Psychol. 101, 572–574
type Neuropsychologia 28, 1197–1213 4 Owen, A.M. et al. (1992) Frontostriatal cognitive deficits at different
22 Watkins, P.C. et al. (1992) Mood-congruent memory in depression: emotional priming or elaboration J. Abnorm. Psychol. 101, 581–586
stages of Parkinson’s disease Brain 115, 1727–1751 5 Owen, A.M. et al. (1991) Extra-dimensional versus intradimensional set shifting performance following frontal lobe excisions, temporal lobe excisions or amygdalo-hippocampectomy in man Neuropsychologia
23 Hartlage, S. et
al. (1993) Automatic and effortful processing in
depression Psychol. Bull. 113, 247–278 24 Blaney, P.H. (1986) Affect and memory: a review Psychol. Bull. 99, 229–246
29, 993–1006 6 Owen, A.M. et al. (1995) Visuo-spatial short term recognition memory and learning after temporal lobe excisions, frontal lobe excisions or amygdalo-hippocampectomy in man Neuropsychologia 33, 1–24 7 Austin, M-P. et al. (1992) Cognitive function in major depression
25 Watkins, P.C. et al. (1996) Unconscious mood-congruent memory bias in depresssion J. Abnorm. Psychol. 105, 34–41 26 Isley, J.E., Moffoot, A.P.R. and O’Carroll, R.E. (1995) An analysis of memory dysfunction in major depression J. Affect. Disord. 35, 1–9 27 Teasdale, J.D. (1983) Negative thinking in depression: cause effect or
J. Affect. Disord. 25, 21–30 8 Brown, R.G. et al. (1994) Cognitive function in depression: its relationship to the presence and severity of intellectual decline
reciprocal relationship? Adv. Behav. Res. Therapy 5, 3–25 28 American Psychiatric Association (1994) Diagnostic and Statistical Manual of Mental Disorders, 4th edn (DSM-IV), American Psychiatric
Psychol. Med. 24, 829–847 9 Elliott, R. et al. (1996) Neuropsychological impairments in unipolar depression: the role of perceived failure on subsequent performance
Association 29 Mialet, J.P., Pope, H.G. and Yurgulen-Todd, D. (1996) Impaired attention in depressive states: a non-specific deficit? Psychol. Med. 26,
Psychol. Med. 26, 975–989 10 Beats, B.C., Sahakian, B.J. and Levy, R. (1996) Cognitive performance in tests sensitive to frontal lobe dysfunction in the elderly depressed
1009–1020 30 Schmand, B. et al. (1994) Cognitive disorders and negative symptoms as correlates of motivational deficits in psychotic patients Psychol.
Psychol. Med. 26, 591–603 11 Dalla Barba, G. et al. (1995) Anosognosia, intrusions and ‘frontal’ functions in Alzheimer’s disease and depression Neuropsychologia 33,
Med. 24, 869–884 31 Elliott, R. et al. (1997) Abnormal response to negative feedback in unipolar depression: evidence for a disease-specific impairment
247–259 12 Moreaud, O. et al. (1996) Frontal lobe dysfunction and depressive state: relation to endogenous character of depression Encephale 22,
J. Neurol. Neurosurg. Psychiatry 63, 74–82 32 Channon, S. (1996) Executive dysfunction in depression: the Wisconsin Card Sort test J. Affect. Disord. 9, 107–114
47–51 13 Moffoot, A.P.R. et al. (1994) Diurnal variation in mood and neuropsychological function in major depression with melancholia
33 Beck, A.T. (1967) Depression: Clinical, Experimental and Theoretical Aspects, Harper and Row 34 Teasdale, J.D. and Barnard, P.J. (1993) Affect, Cognition and Change,
J. Affect. Disord. 32, 257–269 14 Palmer, B.W. et al. (1996) Neuropsychological deficits among older depressed patients with predominantly psychological or vegetative
Erlbaum 35 Lewinsohn,
P.M.,
Youngren,
M.A.
and
Grosscup,
S.J.
(1979)
Reinforcement and depression, in The Psychobiology of Depressive
symptoms J. Affect. Disord. 41, 17–24 15 Veiel, H.O.F. (1997) A preliminary profile of neuropsychological deficits associated with major depression J. Clin. Exp. Neuropsychol.
Disorders (Depue, R.A., ed.), pp. 291–316, Academic Press 36 Purcell, R. et al. (1997) Neuropsychological function in young patients with unipolar depression Psychol. Med. 27, 1277–1285
19, 587–603 16 Goodwin,
depression: dissociation of recall and fragment completion J. Abnorm.
G.M.
(1997)
Neuropsychological
and
neuroimaging
evidence for the involvement of frontal lobes in depression
37 Shah, P. et al. Response to feedback in major depression Psychol. Med. (in press) 38 Smith, M.J. et al. (1994) Experimental evidence for two dimensions of
J. Psychopharmacol. 11, 115–122 17 Hasher, L. and Zacks, R.T. (1979) Automatic and effortful processes in
cognitive disorders in depressives J. Psychiatr. Res. 28, 401–411
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Elliott – Neuropsychological impairments in depression
39 Boone, K.B. et al. (1995) Cognitive functioning in older depressed outpatients: relationship of presence and severity of depression to neuropsychological test scores Neuropsychology 9, 390–398
depression J. Neurosci. 12, 3628–3641 61 George, M.S., Ketter, T.A. and Post, R.M. (1993) SPECT and PET in mood disorder J. Clin. Psychiatry 54 (Suppl.), 6–13
40 Hamilton, M. (1960) A rating scale for depression J. Neurol. Neurosurg. Psychiatry 23, 56–62
62 Goodwin, G.M. et al. (1993) State changes in brain activity shown by the uptake of 99mTc-exametazime with single photon emission
41 Montgomery, S.A. and Asberg, M. (1979) A new depression scale designed to be sensitive to change Br. J. Psychiatry 134, 382–389
tomography in major depression before and after treatment J. Affect. Disord. 29, 243–253
42 Abas, M., Sahakian, B.J. and Levy, R. (1990) Neuropsychological deficits and CT scan changes in elderly depressives Psychol. Med. 20, 507–520 43 O’Brien, J.T., Sahakian, B.J. and Checkley, S.A. (1993) Cognitive impairment in patients with seasonal affective disorder Br. J. Psychiatry 163, 338–343
63 Ebert, D. and Ebmeier, K.P. (1996) The role of the cingulate gyrus in depression: from functional anatomy to neurochemistry Biol. Psychiatry 39, 1044–1050 64 Drevets, W.C. et al. (1997) Subgenual prefrontal cortex abnormalities in mood disorders Nature 386, 824–827
44 Robbins, T.W. et al. (1994) Cambridge Neuropsychological Battery
65 Buchsbaum, M. et al. (1986) Frontal cortex and basal ganglia metabolic
(CANTAB): a factor analytic study of a large sample of normal elderly
rates assessed by positron emission tomography with [18F]2-
volunteers Dementia 5, 266–281
deoxyglucose in affective illness J. Affect. Disord. 10, 137–152
45 Thompson, P.J. and Trimble, M.R. (1982) Non-MAOI antidepressants and cognitive functions: a review Psychol. Med. 12, 539–548
glucose metabolism in major affective disorders and schizophrenia
46 Amado-Boccara, I. et al. (1995) Effects of antidepressants on cognitive functions: a review Neurosci. Biobehav. Rev. 19, 479–493 general practice: a double-blind comparison of paroxetine and lofepramine Br. J. Clin Practice 50, 240–244 J.S.
and
Hindmarch,
I.
(1996)
Neuropsychopharmacology 2, 241–254 67 Mega, M.S. and Cummings, J.L. (1994) Fronto-subcortical circuits
47 Moon, C.A.L. and Vince, M. (1996) Treatment of major depression in
48 Kerr,
66 Cohen, R. et al. (1989) Evidence for common alterations in cerebral
and neuropsychiatric disorders J. Neuropsychiatry Clin. Neurosci. 6, 358–370 68 Cummings, J.L. (1995) Anatomic and behavioral aspects of fronto-
Citalopram
and
other
antidepressants: comparative effects on cognitive function and psychomotor performance J. Serotonin Res. 3, 123–129
subcortical circuits Ann. New York Acad. Sci. 769, 1–13 69 Bench, C.J. et al. (1993) Regional cerebral blood flow in depression measured by positron emission tomography: the relationship with
49 Kerr, J.S. and Hindmarch, I. (1996) The effects of reboxetine and amitryptaline, with and without alcohol on cognitive function and psychomotor performance Br. J. Clin. Pharmacol. 42, 239–241
clinical dimensions Psychol. Med. 23, 579–590 70 Dolan, R.J. et al. (1994) Neuropsychological dysfunction in depression: the relationship to regional cerebral blood flow Psychol. Med. 24,
50 Fairweather, D.B. et al. (1997) Citalopram compared to Dothiepin and placebo: effects on cognitive function and psychomotor performance Hum. Psychopharmacol. 12, 119–126
849–857 71 Berman, K.F. et al. (1993) Is the mechanism of prefrontal hypometabolism in depression the same as in schizophrenia? Regional
51 Orengo, C.A. et al. (1996) The use and tolerability of fluoxetine in geripsychiatric inpatients J. Clin. Psychiatry 57, 12–16
cerebral blood flow during cognitve activation Br. J. Psychiatry 162, 183–192
52 Roth, M. et al. (1997) Moclobemide in elderly patients with cognitive
72 George, M.S. et al. (1997) Blunted left cingulate activation in mood
decline and depression: an international, double-blind placebo-
disorder subjects during a response interference task (the Stroop)
controlled trial Br. J. Psychiatry 168, 149–157
J. Neuropsychiatry Clin. Neurosci. 9, 55–63
53 Robbins, T.W., Elliott, R. and Sahakian, B.J. (1996) Neuropsychology: dementia and affective disorders Br. Med. Bull. 52, 627–643
73 Elliott, R. et al. (1997) Prefrontal dysfunction in depressed patients performing a planning task: a study using positron emission
54 Martin, D.J., Oren, Z. and Boone, K. (1991) Major depressives’ and dysthymics’ performance on the Wisconsin card sorting test J. Clin. Psychol. 47, 684–690
tomography Psychol. Med. 27, 931–942 74 Elliott, R. et al. (1998) Abnormal response to feedback on planning and guessing tasks in patients with unipolar depression Psychol. Med. 28,
55 DeLuca, J. et al. (1995) Neuropsychological impairments in chronic fatigue syndrome, multiple sclerosis and depression J. Neurol. Neurosurg. Psychiatry 58, 38–43
559–571 75 Mayberg, H.S. et al. (1997) Cingulate function in depression: a potential predictor of treatment response NeuroReport 8, 1057–1061
56 Albus, M. et al. (1996) Contrasts in neuropsychological test profile
76 Dolan, R.J., Paulesu, E. and Fletcher, P.C. (1997) Human memory
between patients with first episode schizophrenia and first episode
systems, in Human Brain Function (Frackowiak, R.S.J. et al., eds),
affective disorder Acta Psychiatr. Scand. 94, 87–93
pp. 367–404, Academic Press
57 Tarbuck, A.F. and Paykel, E.S. (1995) Effects of major depression on the
77 Fletcher, P.C. et al. (1995) Brain systems for encoding and retrieval of
cognitive function of younger and older subjects Psychol. Med. 25,
auditory-verbal memory: an in vivo study in humans Brain 118,
285–296
401–416
58 Robbins, T.W., Joyce, E.M. and Sahakian, B.J. (1992) Neuropsychology and neuroimaging of affective disorders, in Handbook of Affective Disorders (Paykel, E.S., ed.), pp. 289–310, Churchill Livingstone
78 Paulesu, E. et al. (1993) Functional anatomy of working memory: the visuospatial ‘sketchpad’ J. Cereb. Blood Flow Metab. 13, S551 79 Elliott, R. and Dolan, R.J. (1998) The neural response in short-term
59 Bench, C.J. et al. (1992) The anatomy of melancholia: focal abnormalities of cerebral blood flow in major depression Psychol. Med. 22, 607–615
visual recognition memory for perceptual conjunctions Neuroimage 7, 14–22 80 Drevets, W.C. et al. (1997) Subgenual prefrontal cortex abnormalities
60 Drevets, W.C. et al. (1992) A functional anatomical study of unipolar
in mood disorders Nature 382, 824–827
Articles of interest in the other Trends journals On brain lesions, the milkman and Sigmunda, by I. Izquierdo and J.H. Medina Trends in Neurosciences 21, 423–426 Protein precipitation: a common etiology in neuro-degenerative disorders? by A. Kakizuka Trends in Genetics 14, 394–400 Tan protein pathology in neuro-degenerative diseases, by M.G. Spillantini and M. Goedert Trends in Neurosciences 21, 428–433 Sensory ecology, receiver biases and sexual selection, by J.A. Endler and A.L. Basolo Trends in Ecology & Evolution 13, 415–420
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Arnsten – Catecholamine modulation of PFC function
63 Foote, S.L., Bloom, F.E. and Aston-Jones, G. (1983) Nucleus locus
receptor-mediated facilitation of somatosensory cortical neuronal
coeruleus: new evidence of anatomical and physiological specificity
responses to excitatory synaptic inputs and iontophoretically applied
Physiol. Rev. 63, 844–914
acetylcholine Neuropharmacology 20, 907–920
64 Arnsten, A.F.T. and Goldman-Rakic, P.S. (1984) Selective prefrontal
71 Kasamatsu, T. and Heggelund, P. (1982) Single-cell responses in cat
cortical projections to the region of the locus coeruleus and raphe
visual
nuclei in the rhesus monkey Brain Res. 306, 9–18
noradrenaline Exp. Brain Res. 45, 317–327
65 Sara, S.J. and Herve-Minvielle, A. (1995) Inhibitory influence of frontal cortex on locus coeruleus Proc. Natl. Acad. Sci. U. S. A. 92, 6032–6036 66 Jodo, E., Chiang, C. and Aston-Jones, G. (1998) Potent excitatory influence of prefrontal cortex activity on noradrenergic locus 67 Rajkowski, J. et al. (1998) State-related activity, reactivity of locus coeruleus neurons in behaving monkeys Adv. Pharmacol. 42, 740–744 68 Foote, S.L., Freedman, F.E. and Oliver, A.P. (1975) Effects of putative neurotransmitters on neuronal activity in monkey auditory cortex Moises,
H.C.
and
to
visual
stimulation
during
iontophoresis
of
72 Darracq, L. et al. (1998) Importance of the noradrenaline–dopamine coupling in the locomotor activating effects of
D-amphetamine
J. Neurosci. 18, 2729–2739 73 Arnsten, A.F.T. and Goldman-Rakic, P.S. (1990) Analysis of alpha-2 performance of aged rhesus monkeys Neurobiol. Aging 11, 583–590 74 Sirviö, J. et al. (1991) The effects of guanfacine, alpha-2 agonist, on the performance of young and aged rats in spatial navigation task Behav. Neural Biol. 56, 101–107 75 Witte,
Brain Res. 86, 229–242 B.D.,
cortex
adrenergic agonist effects on the delayed nonmatch-to-sample
coeruleus neurons Neuroscience 83, 63–79
69 Waterhouse,
Review
Woodward,
D.J.
(1980)
E.A.
and
Marrocco,
R.T.
(1997)
Alterations
of
brain
noradrenergic activity in rhesus monkeys affects the alerting
Noradrenergic modulation of somatosensory cortical neuronal
component of covert orienting Psychopharmacology 132, 315–323
responses to iontophoretically applied putative transmitters Exp.
76 Arnsten, A.F.T. and Jentsch, J.D. (1997) The alpha-1 adrenergic agonist, cirazoline, impairs spatial working memory performance in aged
Neurol. 69, 30–49 70 Waterhouse, B.D., Moises, H.C. and Woodward, D.J. (1981) Alpha-
monkeys Pharmacol. Biochem. Behav. 57, 1–5
The neuropsychological profile in unipolar depression Rebecca Elliott There is a wealth of empirical data pertaining to the issue of neuropsychological impairment in depression. However, a coherent and comprehensive framework for understanding the disorder remains elusive. This review will briefly consider some of the important issues on which recent research has focused. It would be premature to derive firm conclusions in an area characterized by considerable confusion, so the aim of this review is to highlight the key areas that must be addressed. Three distinct questions are considered. The first concerns the neuropsychological specificity of the deficits associated with depression; whether they represent selective deficits or a more general profile of impairment. The second question is to determine how cognitive deficits might relate to clinical and demographic factors, including symptom severity, hospitalization, medication and ageing. Finally, a comprehensive theory of depression must also relate impairments to neuropathology, and evidence is now available from imaging studies that have attempted to elucidate neural substrates of neuropsychological deficits.
M
ajor depression is a common disorder, affecting approximately one in ten of the population at some time in their lives. The core symptoms involve disturbances of mood and affect but there is substantial evidence that cognitive function is also impaired. An understanding of these cognitive deficits has a number of important implications, both practical and theoretical, for the study of depression. On a practical level, impaired cognition can com-
promise social function. It also has diagnostic implications, particularly in elderly patients whose cognitive deficits are often pronounced, meaning that differential diagnosis of depression and dementia can prove problematic. In more theoretical terms, understanding cognitive deficits, their interaction with disordered mood and their relation to neuropathology is essential to a comprehensive understanding of the disorder.
1364-6613/98/$ – see front matter © 1998 Elsevier Science. All rights reserved.
PII: S1364-6613(98)01235-2
Trends in Cognitive Sciences – Vol. 2, No. 11,
November 1998
Rebecca Elliott is at the Wellcome Department of Cognitive Neurology, 12 Queen Square, London, UK WC1N 3BG. tel: +44 171 833 7485 fax: +44 171 813 1420 e-mail: r.elliott@fil. ion.ucl.ac.uk
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Box 1. Neuropsychological functions Memory and memory tests It is now widely accepted that memory is not a unitary concept but can be divided into a number of different subtypes. A simple taxonomy of memory can be outlined as follows:
Memory Long-term
Declarative (explicit)
Episodic (memory for events)
Short-term
Procedural (implicit)
Semantic (memory for facts)
in memory; for example, using free recall (subjects simply asked to remember), cued recall (subjects provided with partial information as a prompt) or recognition (subjects presented with information and asked whether they have seen it before). These separable aspects of memory have been dissociated in neuropsychological and, to some extent, functional-anatomical terms and they can be tested separately in patient groups.
e.g. Skill learning, priming
However, there are many further distinctions and dissociations that can be considered. For example, within short-term memory, there is a clear distinction between memory for visuospatial information and memory for auditory–verbal information. There are also different ways to access items stored
Executive function Executive function is a term that has been coined to describe a family of processes thought to depend on the intact function of the prefrontal cortex, whereby cognitive subprocesses are coordinated for the successful performance of complex cognitive tasks. These processes are important in the planning and execution of complex behaviours, in the generation of a strategic approach to cognitive problems, in the monitoring of performance and in the revision of strategies and behaviours that cease to be appropriate. Tests that have been used to tap aspects of executive function include: • Tower of Hanoi/Tower of London task (see Fig. 1) • Wisconsin Card Sort test (see Fig. 1) • Cognitive estimates test • Hayling sentence-completion test • Trail making A and B
An important issue in the study of depression is the existence of various subtypes of the disorder with different symptom profiles. Some of the key distinctions are between unipolar (depression alone) and bipolar depression (depression with mania), between dysthymia (a mild form) and depression itself and between primary depression and that which is secondary to another brain disease. These different subtypes may be associated with distinct cognitive profiles. While this is an interesting debate, it is beyond the scope of the present review, which will focus on primary, unipolar depression. Until the last 20 years, the prevailing opinion was that even severe depression was associated with only minor neuropsychological impairments1. An influential review of the evidence by Miller2 challenged this position, concluding that patients showed deficits in a wide range of cognitive domains, a view that is now widely accepted. Current debate centres around the exact nature of these neuropsychological deficits and their relation to other dimensions of the disorder. There are many complex issues involved, some of which are considered briefly here. Broadly the review is divided into three sections: (1) a discussion of the actual nature of the neuropsychological profile in depression; (2) a consideration of the interaction between cognitive deficits and clinical features which might account for some of the confusion in the neuropsychological literature; and (3) a review of the neuroimaging evidence relating neuropsychology to neuropathology that may help point to a resolution of the issues. The area of neuropsychology and depression is a particularly confused one and the aim of this review is to highlight some of the debates and issues involved, which need to be resolved before the disorder can be fully understood. General or specific deficits? The consideration of whether depression is associated with selective deficits in particular domains or whether the profile
is more general is a hotly debated question. The debate has historically taken a number of different forms but for the purposes of this review, I will focus on three illustrative questions. Do patients show selective impairments in memory or executive function? In recent years it has become popular to consider questions of specificity in terms of these two different aspects of function (Box 1), which have been experimentally dissociated in patients with neurological and neurosurgical damage. Patients with the posterior cortical dementia, Alzheimer’s disease, show selective deficits in visual short-term-memory tests with relative sparing of executive function (see, for example, Ref. 3). In contrast, patients with the fronto-subcortical dementia, Parkinson’s disease, show the reverse pattern (e.g. Ref. 4). A similar dissociation has been identified for patients with focal brain lesions in prefrontal cortex (executive deficits) and temporal lobes (memory deficits; e.g. Refs 5,6). Thus, if selective impairments could be demonstrated in depressed patients, it would have implications for neurobiological, as well as neuropsychological theories. Depressed patients have been studied using tasks that sample aspects of memory and learning (visual and verbal, short-term and long-term) as well as different tests of executive function, for example the Tower of London and Wisconsin Card Sort tests (Fig. 1). It has been reported that patients show deficits in both memory7–9 and executive function10–12. Although the exact pattern of deficits reported in individual studies varies, depending on the specific tests used and the populations studied, impairment is typically seen across a broad range of cognitive domains8–10,13,14. In a recent meta-analysis of all studies published since 1975, Veiel15 concluded that the neuropsychological deficits seen in patients with major depression are ‘consistent with global-diffuse impairment in brain functions’. However,
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two recent comprehensive reviews15,16 have suggested that while deficits are seen in many cognitive domains, executive deficits associated with frontal lobe dysfunction may be particularly prominent in depression. As will be discussed below, more marked executive deficits are consistent with the neuroimaging evidence for frontal lobe pathology. Effortful versus automatic processing A different approach to determining the selectivity of neuropsychological deficits is to consider the importance of underlying cognitive factors which cut across demarcated neuropsychological domains, accounting for a generalized profile of impairment. An influential hypothesis, based on this approach, is that depressed patients are more impaired on effortful than on automatic tasks17. Thus, more demanding tasks, whatever function they assess, will be differentially sensitive to depression. For example, one prediction of the hypothesis is that explicit memory (relatively effortful) will be more impaired in depressed patients than implicit memory (relatively automatic). Although there is empirical support for this prediction18–20, there is also contradictory evidence21,22. Another clear prediction is that executive tasks, which are almost by definition effortful, will be particularly sensitive to depression. This prediction is borne out by some of the evidence reviewed above. Overall, the jury is still out on the cognitive effort hypothesis; recent accounts continue to support the idea23 but further research is needed in order to clarify whether cognitive effort is a useful concept for explaining neuropsychological impairments in depression. Mood-congruent biases in information processing One very specific form of deficit that has been widely studied in depression is whether the affective or emotional tone of material being processed in cognitive tasks influences the efficiency of performance. The most reliably reported bias is in memory studies, in which depressed patients show a facilitation of recall of unpleasant compared to pleasant material (see Ref. 24 for review). There is also evidence that moodcongruent memory bias is evident in implicit contexts, such as priming, when subjects are not actively attempting to remember information. For example Watkins et al.25 showed that depressed patients showed greater priming of negative than positive words while non-depressed controls showed the reverse pattern. Although not all studies have demonstrated implicit biases in depression (e.g. Ref. 26), the balance of evidence suggests that mood-congruent information-processing biases are an important influence on cognition in depressed patients. This line of enquiry has the advantage of explicitly linking mood and cognition and can be related to cognitivebehavioural theories of depression, on which treatment strategies have been based27. It is clearly important that the relation between neuropsychological deficits and clinical features, such as depressed mood, be more thoroughly understood. The next portion of this review considers some of the issues which need to be addressed. Clinical factors influencing neuropsychological performance It is clear from the above discussion that there is some inconsistency across studies as to the nature and extent of
Review
A
B
Fig. 1 Executive tasks. (A) The Tower of London task. Subjects are given the instruction: ‘Rearrange the balls on the right-hand set of rods so that the arrangement is the same as that on the left-hand set of rods’. (B) The Wisconsin Card Sort test. Subjects are asked to: ‘Work out a rule to sort the deck of cards on the basis of colour, shape or number. At unpredictable intervals the rule will change; work out the new rule’.
neuropsychological deficits associated with depression. An often cited reason for inconsistencies of this sort is that there can be large differences in the clinical and demographic profile of patients in different studies. This raises the important question of the extent to which specific symptoms and cognitive deficits can be theoretically and empirically related. Relating neuropsychological deficits to specific symptoms Some of the clinical symptoms of depression appear to have a direct causal effect on performance. For example, subjective reports of problems with concentration and attention are common. Indeed, impaired concentration represents a standard operational criterion for a diagnosis of depression28. There are relatively few empirical studies of attention in depression although impairments have been reported29. The mood-congruent memory biases discussed above can be considered as clinical symptoms impacting directly on cognitive performance. Another example of the thin boundary between clinical symptom and neuropsychological deficit is the issue of motivation; lack of motivation is a clinical symptom which could play a causal role in neuropsychological impairments. There have been arguments assigning all the cognitive deficits of depression to motivational factors (e.g. Ref. 30), which has strong echoes of the cognitive effort hypothesis discussed above. However, a fundamental motivational cause of deficits would not explain the sparing of aspects of cognitive function which many studies have shown.
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Certain recent studies have attempted to relate the profile of neuropsychological impairment to a highly specific form of motivational deficit, namely response to performance feedback. In many cognitive tasks, subjects are given information about performance accuracy and recent evidence suggests that depression is associated with an abnormality in their response. Beats et al.10 described a ‘catastrophic response to perceived failure’ on the Tower of London task (see Fig. 1) such that once patients made an initial error, subsequent performance deteriorated rapidly. In a more explicit test of this hypothesis Elliott et al.9,31 reported abnormal response to failure on two contrasting tests and suggested that depressed patients failed to use negative feedback as a motivational boost to improve subsequent performance. In normal subjects failing a problem in a series increased the likelihood of succeeding on subsequent problems but this was not seen in depressed patients. This is consistent with a finding of Channon et al.32 in dysphoric subjects that reported an inefficient use of feedback to improve performance on a card sorting test. This finding has the advantage of being directly related to aspects of symptomatology and also to influential cognitive and psychological accounts of the disorder33–35. However, it has yet to be empirically confirmed and some attempts at replication have failed36,37. One of the reasons for this, and indeed for many other discrepancies, may be demographic differences in the patient populations. There are a number of factors which might interact with neuropsychological function, including severity of depression, hospitalization, medication and age, which are briefly considered below. Severity of depression Many studies of neuropsychological function have attempted to relate deficits to severity of depression measured on clinical rating scales. Some have reported correlations between severity and particular impairments7,38,39 while others have not8. There are several possible explanations for these differences. One important consideration is that different rating scales are used and this may lead to different results in correlational studies. Clearly, scales with specific questions about cognitive function are more likely to correlate with neuropsychological deficits. In a study by Elliott et al.9, scores on the widely used Hamilton scale40 did not correlate with any of the neuropsychological variables measured. However, scores on the Montgomery and Asperg scale41, which includes several questions related to cognitive function, were significantly correlated with measures of visual memory. State versus trait factors in depression A related issue to the severity question is whether neuropsychological deficits represent a state factor, evident only while individuals are currently depressed, or a trait factor, evident in individuals susceptible to depression even when they are not currently depressed. In empirical terms, this question has most usually been addressed by assessing patients in longitudinal studies, when depressed and again on clinical recovery. The balance of evidence suggests that there is a substantial improvement in cognitive performance on symptomatic recovery9,10,42. However, all these studies report the presence of residual impairments relative to controls.
Convergent findings have been reported in patients with seasonal affective disorder43 and with pronounced diurnal variation in mood13. It therefore seems that both state and trait factors might influence the cognitive profile in depression. Hospitalization It has recently emerged that hospitalization of patients is a significant factor in determining performance on neuropsychological tests. Depression may be managed on an inpatient or an out-patient basis and studies generally assess different proportions of these groups. In a recent study9, subgroups of in- and out-patients were compared on a range of tests. There were significant differences in performance, with the in-patients performing worse than the out-patients, although there were no significant differences in measured severity of depression. Using the same test battery44 with a group of out-patients Purcell et al.36 reported less global impairment than Elliott et al.9 and, interestingly, reported that patients with a history of in-patient episodes performed worse on some measures than those without. There are two possible explanations for these results; one is that neuropsychological impairment is an important indicator for hospitalization, the other is that factors related to hospitalization contribute to cognitive deficits. One such factor may be differences in treatment regimes, an issue that has more widespread implications. Medication An important confounding factor of many neuropsychological studies of depression is that patients are often medicated, with very different individual medication regimes and histories. Antidepressant medications might interact with cognitive function, though in a major review of studies, Thompson and Trimble45 reported that available evidence was inconclusive. Antidepressants with anti-cholinergic properties were found to impair aspects of cognitive function although the situation for other antidepressants was less clear, in that different studies reported beneficial or detrimental effects, a combination of both, or neither. A more recent review46 also highlights this complexity. However, the consensus of recent evidence suggests that while traditional tricyclic antidepressants can disrupt aspects of cognitive function (and particularly psychomotor speed), more modern antidepressants have less effect either in patients or controls. This is true both of selective serotonin-reuptake inhibitors (SSRIs) (Refs 47–51) and of monoamine oxidase inhibitors (MAO-Is) (Ref. 52). Differential effects of different antidepressants suggest that medication is an important factor in determining the neuropsychological profile of depression and may contribute to discrepancies between different studies. Interaction of performance with age Another factor, which might interact with clinical features, and is emerging as an important determinant of neuropsychological deficits in depression is the age of subjects. In elderly patients, neuropsychological deficits observed have been compared with those seen in organic dementias53. Qualitative comparisons between studies suggests that depression is more reliably related to cognitive impairment in
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elderly patients8,10,14 than in patients under 40 years (Refs 54–56). This suggests that depression and age interact in causing deficits but explicit attempts to test this prediction have not necessarily confirmed it. For example, Tarbuck and Paykel57 compared depressed and recovered patients under and over the age of 60 on a battery of tests. While depression and age both significantly influenced performance, there was no interaction between the two. A recent series of studies using a computerized test battery44 have found different results in three different age groups. Patients with a mean age under 40 showed restricted deficits in tests of executive function36. Patients with a mean age around 50 showed more widespread impairments extending to tests of memory as well as executive function9. Finally, elderly patients, with a mean age over 70, showed deficits in a range of memory and executive tests, and pronounced cognitive slowing10. However, it cannot be concluded on this basis that deficits simply become more widespread with age. In the Beats et al.10 study, elderly patients showed intact performance on some measures that were impaired in the middle-aged group. This was not because the older patients performed better but because the older control group performed worse (in line with the finding of Robbins et al.44 that normal performance on these tests declines with age). It seems that the interaction between age and cognitive impairment in depression is a complex one, which needs to be clarified using more extensive, and ideally longitudinal, studies. Neural correlates of neuropsychological deficits There has been much discussion over the years concerning whether depression is associated with structural changes in the brain. Convergent evidence suggests that there may be structural abnormalities in elderly patients which are related to the degree of cognitive impairment (see Refs 16,58 for reviews). However, the evidence for structural changes in younger patients is much less clear and assessment of possible functional changes has proved more productive. In the past decade, functional neuroimaging, using positron emission tomography (PET), single-photon emission computed tomography (SPECT) and functional magnetic resonance imaging (fMRI), has been used to identify functional abnormalities associated with depression. The earlier resting-state studies have identified a number of regions that are abnormal in patients with depression. One of the most robust findings is of abnormal blood flow in prefrontal cortex, particularly involving medial regions of dorsal and ventral anterior cingulate cortex59–64. Another commonly reported abnormality is decreased striatal blood flow59,65,66 which, combined with the prefrontal abnormalities, provides support for the popular theory that depression involves abnormalities in fronto-subcortical circuitry16,58,67,68. These studies strongly suggest that functional abnormalities are a feature of the pathophysiology of depression. Recent studies have explicitly attempted to relate neuropathology to neuropsychological and clinical dimensions in depression, using correlational techniques. Bench et al.69 used factor analysis to relate regional cerebral blood flow (rCBF) to clinical features. One of the factors which emerged had high loading for cognitive performance and
Fig. 2 Brain activations associated with the performance of an executive task. Activations, shown superimposed on a standard MRI template, to the Tower of London task in (A) controls and (B) depressed patients. Note the absence of anterior cingulate activation in patients.
correlated positively with rCBF in the medial prefrontal cortex. In a follow-up study, Dolan et al.70 performed principal-components analysis on neuropsychological data and identified two factors with high loadings for memory and attention. Both factors correlated significantly with rCBF in the medial prefrontal cortex and frontal pole. In the studies discussed above, subjects were scanned during some form of resting state, most usually being asked simply to relax with eyes closed. This provides a reasonably standard baseline in functional imaging studies, but is a rather poorly controlled state because subjects might think about a range of things during scanning. Cognitive-activation studies provide a different approach, where subjects are scanned during the explicit performance of a specified cognitive task giving much greater control over their mental processes. Regions that are found to be abnormal in such activation studies are not necessarily those identified in the resting state. Berman et al.71 scanned depressed patients during performance of the Wisconsin Card Sort test and
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Fig. 3 Activations in the presence of performance feedback. Highlighted regions are those regions showing significantly reduced cerebral blood flow (significance measured by standard Z-values) in depressed patients relative to controls, in the presence compared with the absence of performance feedback on an executive task.
found no evidence of abnormal prefrontal blood flow. However, two more recent studies have shown reduced frontal blood flow, particularly in the anterior cingulate, during performance of the Stroop task72 and a version of the Tower of London task73 (Fig. 2). The focus of medial prefrontal dysfunction depends on the nature of the cognitiveactivation paradigm used. For example, a recent study74 related the highly specific response to feedback described above to focal functional abnormality in the medial orbitofrontal cortex (Fig. 3), a region that has also been implicated in recent studies of response to treatment75. This
latter study highlights the importance of neuroimaging in assessing the important issue of abnormal neurotransmitter (specifically serotonin) function in depression. What is striking in these functional imaging studies is the predominance of prefrontal abnormalities, which supports the general notion of impaired executive processing in depression. However, prefrontal dysfunction might also contribute to memory deficits, particularly on more ‘effortful’ tasks. Regions of lateral prefrontal cortex have been widely implicated in working memory (e.g. Ref. 76) and there is also evidence for a role for anterior cingulate cortex in control processes related to memory77. ‘Working memory’ and ‘control processes’ can be interpreted as ‘executive’ aspects of memory but, as discussed above, depressed patients also show deficits in simple recognition tasks. Functional neuroimaging has also demonstrated anterior cingulate activation in association with short-term visual recognition tasks78,79. In general, therefore, the functional abnormalities observed in depression are consistent with the neuropsychological deficits. The medial prefrontal cortex, which has been most reliably associated with depression, is implicated in a range of cognitive functions including general processes such as attention and also in emotional responses. The schematic diagram in Fig. 4 shows how a fundamental pathology in regions of the medial prefrontal cortex might underpin both clinical features and cognitive deficits seen in depression. This pathology may involve both functional and structural abnormalities, as suggested in a recent paper by Drevets et al.80, reporting both types of abnormality in the subgenual cingulate, a ventromedial region lying between the anterior cingulate and orbitofrontal cortices. The medial prefrontal cortex is extensively connected to other structures and is also a region where activity is crucially modulated by the neurotransmitters believed to be implicated in depression. It is therefore entirely plausible that dysfunction in this region could be fundamental to depression, characterized as it is by a complex interaction of affective and cognitive disturbance.
Implicated in:
Neuromodulatory influences (e.g. DA, 5-HT)
Primary projections to: Lateral prefrontal cortex
Executive deficits
Extended limbic system
Memory and mood
Limbic system and basal ganglia
Mood and reinforcement
Dorsal anterior cingulate
Ventral anterior cingulate
Medial orbitofrontal cortex
Fig. 4 Schematic diagram of the role of medial prefrontal cortex in depression.
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Conclusion This review has highlighted the complexity of understanding the nature of the neuropsychological profile of depression. It seems likely that depression is associated with a range of cognitive deficits, but with an emphasis on effortful executive tasks, dependent on the function of prefrontal cortex. The neuroimaging evidence suggests that it is particularly medial prefrontal cortex and the anterior cingulate that mediate these impairments in depression. Antidepressant medications act in this region and factors such as age and severity might also modulate its function. While a framework of this sort could prove an important way of thinking about depression, there are clearly many unresolved issues and questions that need to be addressed in the search for a coherent account of this challenging disorder.
Review
Outstanding questions • Can the predominance of executive deficits in depression be confirmed? • How useful is the concept of cognitive effort in understanding depression? • How important are general factors related to clinical features, such as response to feedback, in causing neuropsychological impairments? • How does the neuropsychological profile seen in depression interact with the ageing process studied in longitudinal designs? • Do the functional abnormalities of medial prefrontal cortex that have been widely reported in depression represent the fundamental neuropathology of the disorder? • Are functional abnormalities of medial prefrontal cortex state or trait markers for depression? • What are the implications of impaired cognition for patient management? • How can a better understanding of the complex interaction between neuropsychology, clinical symptomatology and neuropathology be translated into the development of effective treatments?
Acknowledgements I am grateful to Dr Barbara Sahakian for many invaluable discussions and to Professor Raymond Dolan for his helpful comments on this manuscript.
memory J. Exp. Psychol. Gen. 108, 356–388 18 Danion, J-M. et al. (1991) Explicit memory and repetition priming in depression Arch. Gen. Psychiatry 48, 707–711 19 Denny, E.B. and Hunt, R. (1992) Affective valence and memory in
References 1 Friedman, A.S. (1964) Minimal effects of severe depression on cognitive functioning J. Abnorm. Soc. Psychol. 69, 237–243 2 Miller, W.R. (1975) Psychological deficit in depression Psychol. Bull. 82,
Psychol. 101, 575–580 20 Bazin, N., Perruchet, P., De Bonis, M. and Feline, A. (1994) The dissociation of explicit and implicit memory in depressed patients
238–260 3 Sahakian, B.J. et al. (1990) Sparing of attentional relative to mnemonic function in a subgroup of patients with dementia of the Alzheimer
Psychol. Med. 24, 239–245 21 Elliot, C.L. and Greene, R.L. (1992) Clinical depression and implicit memory J. Abnorm. Psychol. 101, 572–574
type Neuropsychologia 28, 1197–1213 4 Owen, A.M. et al. (1992) Frontostriatal cognitive deficits at different
22 Watkins, P.C. et al. (1992) Mood-congruent memory in depression: emotional priming or elaboration J. Abnorm. Psychol. 101, 581–586
stages of Parkinson’s disease Brain 115, 1727–1751 5 Owen, A.M. et al. (1991) Extra-dimensional versus intradimensional set shifting performance following frontal lobe excisions, temporal lobe excisions or amygdalo-hippocampectomy in man Neuropsychologia
23 Hartlage, S. et
al. (1993) Automatic and effortful processing in
depression Psychol. Bull. 113, 247–278 24 Blaney, P.H. (1986) Affect and memory: a review Psychol. Bull. 99, 229–246
29, 993–1006 6 Owen, A.M. et al. (1995) Visuo-spatial short term recognition memory and learning after temporal lobe excisions, frontal lobe excisions or amygdalo-hippocampectomy in man Neuropsychologia 33, 1–24 7 Austin, M-P. et al. (1992) Cognitive function in major depression
25 Watkins, P.C. et al. (1996) Unconscious mood-congruent memory bias in depresssion J. Abnorm. Psychol. 105, 34–41 26 Isley, J.E., Moffoot, A.P.R. and O’Carroll, R.E. (1995) An analysis of memory dysfunction in major depression J. Affect. Disord. 35, 1–9 27 Teasdale, J.D. (1983) Negative thinking in depression: cause effect or
J. Affect. Disord. 25, 21–30 8 Brown, R.G. et al. (1994) Cognitive function in depression: its relationship to the presence and severity of intellectual decline
reciprocal relationship? Adv. Behav. Res. Therapy 5, 3–25 28 American Psychiatric Association (1994) Diagnostic and Statistical Manual of Mental Disorders, 4th edn (DSM-IV), American Psychiatric
Psychol. Med. 24, 829–847 9 Elliott, R. et al. (1996) Neuropsychological impairments in unipolar depression: the role of perceived failure on subsequent performance
Association 29 Mialet, J.P., Pope, H.G. and Yurgulen-Todd, D. (1996) Impaired attention in depressive states: a non-specific deficit? Psychol. Med. 26,
Psychol. Med. 26, 975–989 10 Beats, B.C., Sahakian, B.J. and Levy, R. (1996) Cognitive performance in tests sensitive to frontal lobe dysfunction in the elderly depressed
1009–1020 30 Schmand, B. et al. (1994) Cognitive disorders and negative symptoms as correlates of motivational deficits in psychotic patients Psychol.
Psychol. Med. 26, 591–603 11 Dalla Barba, G. et al. (1995) Anosognosia, intrusions and ‘frontal’ functions in Alzheimer’s disease and depression Neuropsychologia 33,
Med. 24, 869–884 31 Elliott, R. et al. (1997) Abnormal response to negative feedback in unipolar depression: evidence for a disease-specific impairment
247–259 12 Moreaud, O. et al. (1996) Frontal lobe dysfunction and depressive state: relation to endogenous character of depression Encephale 22,
J. Neurol. Neurosurg. Psychiatry 63, 74–82 32 Channon, S. (1996) Executive dysfunction in depression: the Wisconsin Card Sort test J. Affect. Disord. 9, 107–114
47–51 13 Moffoot, A.P.R. et al. (1994) Diurnal variation in mood and neuropsychological function in major depression with melancholia
33 Beck, A.T. (1967) Depression: Clinical, Experimental and Theoretical Aspects, Harper and Row 34 Teasdale, J.D. and Barnard, P.J. (1993) Affect, Cognition and Change,
J. Affect. Disord. 32, 257–269 14 Palmer, B.W. et al. (1996) Neuropsychological deficits among older depressed patients with predominantly psychological or vegetative
Erlbaum 35 Lewinsohn,
P.M.,
Youngren,
M.A.
and
Grosscup,
S.J.
(1979)
Reinforcement and depression, in The Psychobiology of Depressive
symptoms J. Affect. Disord. 41, 17–24 15 Veiel, H.O.F. (1997) A preliminary profile of neuropsychological deficits associated with major depression J. Clin. Exp. Neuropsychol.
Disorders (Depue, R.A., ed.), pp. 291–316, Academic Press 36 Purcell, R. et al. (1997) Neuropsychological function in young patients with unipolar depression Psychol. Med. 27, 1277–1285
19, 587–603 16 Goodwin,
depression: dissociation of recall and fragment completion J. Abnorm.
G.M.
(1997)
Neuropsychological
and
neuroimaging
evidence for the involvement of frontal lobes in depression
37 Shah, P. et al. Response to feedback in major depression Psychol. Med. (in press) 38 Smith, M.J. et al. (1994) Experimental evidence for two dimensions of
J. Psychopharmacol. 11, 115–122 17 Hasher, L. and Zacks, R.T. (1979) Automatic and effortful processes in
cognitive disorders in depressives J. Psychiatr. Res. 28, 401–411
453 Trends in Cognitive Sciences – Vol. 2, No. 11,
November 1998
TICS NOVEMBER 1998/new 19/10/98 10:53 am Page 454
Review
Elliott – Neuropsychological impairments in depression
39 Boone, K.B. et al. (1995) Cognitive functioning in older depressed outpatients: relationship of presence and severity of depression to neuropsychological test scores Neuropsychology 9, 390–398
depression J. Neurosci. 12, 3628–3641 61 George, M.S., Ketter, T.A. and Post, R.M. (1993) SPECT and PET in mood disorder J. Clin. Psychiatry 54 (Suppl.), 6–13
40 Hamilton, M. (1960) A rating scale for depression J. Neurol. Neurosurg. Psychiatry 23, 56–62
62 Goodwin, G.M. et al. (1993) State changes in brain activity shown by the uptake of 99mTc-exametazime with single photon emission
41 Montgomery, S.A. and Asberg, M. (1979) A new depression scale designed to be sensitive to change Br. J. Psychiatry 134, 382–389
tomography in major depression before and after treatment J. Affect. Disord. 29, 243–253
42 Abas, M., Sahakian, B.J. and Levy, R. (1990) Neuropsychological deficits and CT scan changes in elderly depressives Psychol. Med. 20, 507–520 43 O’Brien, J.T., Sahakian, B.J. and Checkley, S.A. (1993) Cognitive impairment in patients with seasonal affective disorder Br. J. Psychiatry 163, 338–343
63 Ebert, D. and Ebmeier, K.P. (1996) The role of the cingulate gyrus in depression: from functional anatomy to neurochemistry Biol. Psychiatry 39, 1044–1050 64 Drevets, W.C. et al. (1997) Subgenual prefrontal cortex abnormalities in mood disorders Nature 386, 824–827
44 Robbins, T.W. et al. (1994) Cambridge Neuropsychological Battery
65 Buchsbaum, M. et al. (1986) Frontal cortex and basal ganglia metabolic
(CANTAB): a factor analytic study of a large sample of normal elderly
rates assessed by positron emission tomography with [18F]2-
volunteers Dementia 5, 266–281
deoxyglucose in affective illness J. Affect. Disord. 10, 137–152
45 Thompson, P.J. and Trimble, M.R. (1982) Non-MAOI antidepressants and cognitive functions: a review Psychol. Med. 12, 539–548
glucose metabolism in major affective disorders and schizophrenia
46 Amado-Boccara, I. et al. (1995) Effects of antidepressants on cognitive functions: a review Neurosci. Biobehav. Rev. 19, 479–493 general practice: a double-blind comparison of paroxetine and lofepramine Br. J. Clin Practice 50, 240–244 J.S.
and
Hindmarch,
I.
(1996)
Neuropsychopharmacology 2, 241–254 67 Mega, M.S. and Cummings, J.L. (1994) Fronto-subcortical circuits
47 Moon, C.A.L. and Vince, M. (1996) Treatment of major depression in
48 Kerr,
66 Cohen, R. et al. (1989) Evidence for common alterations in cerebral
and neuropsychiatric disorders J. Neuropsychiatry Clin. Neurosci. 6, 358–370 68 Cummings, J.L. (1995) Anatomic and behavioral aspects of fronto-
Citalopram
and
other
antidepressants: comparative effects on cognitive function and psychomotor performance J. Serotonin Res. 3, 123–129
subcortical circuits Ann. New York Acad. Sci. 769, 1–13 69 Bench, C.J. et al. (1993) Regional cerebral blood flow in depression measured by positron emission tomography: the relationship with
49 Kerr, J.S. and Hindmarch, I. (1996) The effects of reboxetine and amitryptaline, with and without alcohol on cognitive function and psychomotor performance Br. J. Clin. Pharmacol. 42, 239–241
clinical dimensions Psychol. Med. 23, 579–590 70 Dolan, R.J. et al. (1994) Neuropsychological dysfunction in depression: the relationship to regional cerebral blood flow Psychol. Med. 24,
50 Fairweather, D.B. et al. (1997) Citalopram compared to Dothiepin and placebo: effects on cognitive function and psychomotor performance Hum. Psychopharmacol. 12, 119–126
849–857 71 Berman, K.F. et al. (1993) Is the mechanism of prefrontal hypometabolism in depression the same as in schizophrenia? Regional
51 Orengo, C.A. et al. (1996) The use and tolerability of fluoxetine in geripsychiatric inpatients J. Clin. Psychiatry 57, 12–16
cerebral blood flow during cognitve activation Br. J. Psychiatry 162, 183–192
52 Roth, M. et al. (1997) Moclobemide in elderly patients with cognitive
72 George, M.S. et al. (1997) Blunted left cingulate activation in mood
decline and depression: an international, double-blind placebo-
disorder subjects during a response interference task (the Stroop)
controlled trial Br. J. Psychiatry 168, 149–157
J. Neuropsychiatry Clin. Neurosci. 9, 55–63
53 Robbins, T.W., Elliott, R. and Sahakian, B.J. (1996) Neuropsychology: dementia and affective disorders Br. Med. Bull. 52, 627–643
73 Elliott, R. et al. (1997) Prefrontal dysfunction in depressed patients performing a planning task: a study using positron emission
54 Martin, D.J., Oren, Z. and Boone, K. (1991) Major depressives’ and dysthymics’ performance on the Wisconsin card sorting test J. Clin. Psychol. 47, 684–690
tomography Psychol. Med. 27, 931–942 74 Elliott, R. et al. (1998) Abnormal response to feedback on planning and guessing tasks in patients with unipolar depression Psychol. Med. 28,
55 DeLuca, J. et al. (1995) Neuropsychological impairments in chronic fatigue syndrome, multiple sclerosis and depression J. Neurol. Neurosurg. Psychiatry 58, 38–43
559–571 75 Mayberg, H.S. et al. (1997) Cingulate function in depression: a potential predictor of treatment response NeuroReport 8, 1057–1061
56 Albus, M. et al. (1996) Contrasts in neuropsychological test profile
76 Dolan, R.J., Paulesu, E. and Fletcher, P.C. (1997) Human memory
between patients with first episode schizophrenia and first episode
systems, in Human Brain Function (Frackowiak, R.S.J. et al., eds),
affective disorder Acta Psychiatr. Scand. 94, 87–93
pp. 367–404, Academic Press
57 Tarbuck, A.F. and Paykel, E.S. (1995) Effects of major depression on the
77 Fletcher, P.C. et al. (1995) Brain systems for encoding and retrieval of
cognitive function of younger and older subjects Psychol. Med. 25,
auditory-verbal memory: an in vivo study in humans Brain 118,
285–296
401–416
58 Robbins, T.W., Joyce, E.M. and Sahakian, B.J. (1992) Neuropsychology and neuroimaging of affective disorders, in Handbook of Affective Disorders (Paykel, E.S., ed.), pp. 289–310, Churchill Livingstone
78 Paulesu, E. et al. (1993) Functional anatomy of working memory: the visuospatial ‘sketchpad’ J. Cereb. Blood Flow Metab. 13, S551 79 Elliott, R. and Dolan, R.J. (1998) The neural response in short-term
59 Bench, C.J. et al. (1992) The anatomy of melancholia: focal abnormalities of cerebral blood flow in major depression Psychol. Med. 22, 607–615
visual recognition memory for perceptual conjunctions Neuroimage 7, 14–22 80 Drevets, W.C. et al. (1997) Subgenual prefrontal cortex abnormalities
60 Drevets, W.C. et al. (1992) A functional anatomical study of unipolar
in mood disorders Nature 382, 824–827
Articles of interest in the other Trends journals On brain lesions, the milkman and Sigmunda, by I. Izquierdo and J.H. Medina Trends in Neurosciences 21, 423–426 Protein precipitation: a common etiology in neuro-degenerative disorders? by A. Kakizuka Trends in Genetics 14, 394–400 Tan protein pathology in neuro-degenerative diseases, by M.G. Spillantini and M. Goedert Trends in Neurosciences 21, 428–433 Sensory ecology, receiver biases and sexual selection, by J.A. Endler and A.L. Basolo Trends in Ecology & Evolution 13, 415–420
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