B R I T I S H J O U R N A L O F P S YC H I AT RY ( 2 0 0 1 ) , 1 7 8 , 2 0 0 ^ 2 0 6

Cognitive deficits in depression

Possible implications for functional neuropathology
MARIE-PAULE AUSTIN, PHILIP MITCHELL and GUY M. GOODWIN

Background While depression is

known to involve a disturbance of mood,
movement and cognition, its associated
cognitive deficits are frequently viewed as
simple epiphenomena of the disorder.
Aims To review the status of cognitive
deficits in depression and their putative
neurobiological underpinnings.
Method Selective computerised
review of the literature examining
cognitive deficits in depression and their
brain correlates.
Results Recent studies report both
mnemonic deficits and the presence of
executive impairment ^ possibly
selective for set-shifting tasks ^ in
depression.Many studies suggestthat
these occur independent of age,
depression severity and subtype, task
`difficulty', motivation and response bias:
some persist upon clinical`recovery'.
Conclusions Mnemonic and executive
deficits do not appear to be
epiphenomena of depressive disorder. A
focus on the interactions between
motivation, affect and cognitive function
may allow greater understanding of the
interplay between key aspects of the
dorsal and ventral aspects of the
prefrontal cortex in depression.
Declaration of interest This paper
was supported by an Australian National
Health and Medical Research Council
Program Grant (993208).

200

There has been a renewal of interest in testing patients with depression on a broad
range of neuropsychological tasks in the
last decade. It has promoted a growing
awareness that, like schizophrenia and
neurological disorders, mood disorders
may be associated with a distinct pattern
of cognitive impairment. Such impairments
of cognitive function are seldom measured.
This is surprising because it is easier objectively to measure memory impairment, for
example, than it is to characterise other
core features of depression such as the
severity of depressed mood or sleep disturbance. Cognitive impairment is also likely
to be a key factor affecting the subject's
ability to function occupationally and,
hence, the timing of his or her return to
work. However, also central to current interest is the effort to link theories of cognitive neuropsychology to the anatomy and
physiology of brain function. If depression
is indeed a brain disease then neuropsychological impairments may lead us to the relevant neural substrate(s). In this article we
aim to review the cognitive deficits reported
in depression and how these deficits may
reflect disruption in the anatomy and function of putative frontosubcortical neuronal
pathways.

METHOD
Computerised Medline and Psycinfo
searches were performed from January
1966 to September 1999 using the terms
NEUROPSYCHOLOGICAL
TESTING,
TESTING,
COGNITIVE FUNCTION,
FUNCTION, DEPRESSION
and DEPRESSIVE DISORDERS.
DISORDERS. Where a
large number of studies had been performed, only the most methodologically
rigorous are highlighted. Where there is a
paucity of studies (e.g. of follow-up), those
available are overviewed. This is not an allinclusive review, and the choice of articles
reflects the authors' qualitative assessment
of current themes of importance in this area
of research.

REVIEW ARTICLE

RESULTS
Cognitive deficits in depression
It is now commonly accepted that depression is associated with a number of deficits
in episodic memory and learning (see Goodwin, 1997 for a review). This finding is
consistent across most studies and appears
to involve both explicit verbal and visual
memory in patients with both melancholic
(endogenous) and non-melancholic
non-melancholic (nonendogenous) depression (Austin et al,
al,
1999). Implicit memory tasks, on the other
hand, appear to be spared (Hertel & Hardin,
1990; Denny & Hunt, 1992; Bazin et al,
al,
1994; Danion et al,
al, 1995; Ilsley et al,
al,
1995). Temporal lobe lesions typically
disrupt episodic memory; given that reductions in hippocampal volume are demonstrated in patients with major depression
(Sheline et al,
al, 1996) it may be that impaired
mnemonic function is associated with dysfunction of the hippocampus in depression.
The initial studies examining impairment in executive tasks produced conflicting
results, although, in general, significant impairment was seen in subjects with more
severe depression (Friedman, 1964; Raskin
et al,
al, 1982; Silberman et al,
al, 1983). The pattern of executive deficits described in recent
reports has been relatively consistent across
studies (Austin et al,
al, 1992a
1992a, 1999; Beats et
al,
al, 1996; Purcell et al,
al, 1997; Murphy et al,
al,
1999), with a single exception (Elliott et al,
al,
1996). Thus, Beats et al (1996), examining
a more severely depressed elderly sample
found these subjects to be most prominently impaired on verbal fluency and attentional set-shifting. Purcell et al (1997)
in a study of younger out-patients with
moderate depression reported no impairment on working memory, but did find impairment on measures of motor speed and
attentional set-shifting, with half of the depression group failing to complete all stages
of this task. The number of trials to reach
criterion on the extra-dimensional component of the task (which may indicate perseveration), was similar to that seen in the
elderly subjects with depression in the Beats
et al (1996) study. These `impaired' subjects
had a higher rate of admissions for treatment of depression, suggesting that those
with overall greater illness severity are
more impaired on set-shifting tasks. However, the studies by Channon (1996) and
Channon & Green (1999) would suggest
that impairment in executive function is
also present in younger (mean 2040 years)
patients with dysphoria, and those with less

C O G NI T I V E D E F I C I T S IIN
N D E P R E S S I ON

severe depression (mean Beck Depression

Inventory (Beck, 1963) scores of 1721).
Austin et al (1992a
(1992a, 1999) examined two
separate depression samples, both of which
were divided into endogenous and nonendogenous subsets using narrow definitions
of endogenous depression namely the
Newcastle system (Carney et al,
al, 1965), with
the Austin et al (1999) study further subdividing the samples into melancholic and
non-melancholic
non-melancholic according to the CORE
instrument (Parker et al,
al, 1994). Both studies
revealed selective executive deficits in subjects
with melancholic (endogenous) compared
with non-melancholic (non-endogenous)
depression. In the Austin et al (1999) study
subjects
with
endogenous/melancholic
depression were impaired (as in the Austin
et al,
al, 1992a
1992a study) on working memory
(digits backwards) as well as on tasks heavily reliant on set-shifting (Trails B, and digit
symbol substitution); in addition there was
an increased perseverative response on the
Wisconsin Card Sorting Task (WCST;
Heaton, 1981), while tasks of inhibitory
control (Stroop test (Golden, 1987), WCST
set initiation and maintenance) and conceptual tasks (similarities, verbal fluency), were
spared. Finally, Murphy et al (1999), in a
study comparing the performance of subjects with depression and mania on a novel
affective set-shifting task, reported that subjects with depression were impaired in their
ability to shift the focus of attention (apparently corresponding to the set-shifting component of the WCST), while patients with
mania were impaired in their ability to
inhibit behavioural responses (apparently
corresponding to the interference effect of
the Stroop test). This latter study further
confirms the earlier trend reported for
selective set-shifting deficits in depression.
The exception to this finding was the study
by Elliott et al (1996) of middle-aged subjects
with moderate, predominantly chronic
depression, who demonstrated impaired
ability on the Tower of London, verbal fluency and spatial working memory tasks,
but intact performance on a modified and
easier version of the Cambridge Neuropsychological Battery (CANTAB) set-shifting
task (Robbins et al,
al, 1994). It may be that this
version of the task was at ceiling and unable
to detect an impairment in set-shifting.

Severity of depression, depressive

subtype and impact upon cognitive
performance
The effect of severity of depression on
neurocognitive task performance has been

measured in many studies by examining the

correlation between Hamilton depression
scores (Hamilton, 1960) and neurocognitive
task scores. Findings have, however, been
conflicting. Nine studies report no correlation between task performance and depression severity (Rush et al,
al, 1983; Cornell et al,
al,
1984; Abas et al,
al, 1990; Brown et al,
al, 1994;
Ilsley et al,
al, 1995; Trichard et al,
al, 1995; Moreaud et al,
al, 1996; Palmer et al,
al, 1996; Purcell
et al,
al, 1997) while another 11 studies do report such a correlation (Stromgren, 1977;
Cohen et al,
al, 1982; Fromm & Schopflocher,
1984; Wolfe et al,
al, 1987; Sweeney et al,
al,
1989; Peselow et al,
al, 1991; Austin et al,
al,
1992a
1992a; Bazin et al,
al, 1994; Tarbuck &
Paykel, 1995; Elliott et al,
al, 1996; Austin et
al,
al, 1999), often selectively for the more
demanding tasks. Correlations may be sensitive to patient selection because Hamilton
scores may be confounded by whether
severe scores are associated with more endogenous patterns of symptoms (see below).
The finding that subjects with depression were impaired on verbal recall while
performing normally on verbal recognition
(Roy-Byrne et al,
al, 1986) led Weingartner
to suggest that patients with depression
generally had difficulty with `effortful' as
compared to `automatic' tasks (Weingartner
et al,
al, 1981; Cohen et al,
al, 1982; Roy-Byrne
et al,
al, 1986). Based on correlation findings
alone, the authors hypothesised that both
the motor and cognitive impairments seen
in depression could be secondary to an underlying motivational deficit, rather than
arising in their own right. Similarly, Bazin
et al (1994) proposed that the dissociation
between explicit (impaired) and implicit
(intact) memory tasks seen in patients with
depression (Hertel & Hardin, 1990; Denny
& Hunt, 1992; Bazin et al,
al, 1994; Danion et
al,
al, 1995; Ilsley et al,
al, 1995) was also a result
of the greater effort required for the former
and the more automatic performance of the
latter. The `effortfulautomatic' hypothesis
has been undermined by a number of studies. Frith et al (1983), Wolfe et al (1987),
Golinkoff & Sweeney (1989), Austin et al
(1992a
(1992a, 1999) and Brown et al (1994) have
all reported both impaired verbal recall (an
effortful task) and recognition (an automatic task) in subjects with depression. In
the CANTAB's Delayed Match to Sample
Task (DMST), the mnemonic encoding
deficit cannot be dependent upon effortful
processing alone because subjects with
depression showed deficits at zero delay as
well as later times (Abas et al,
al, 1990;
Moffoot et al,
al, 1994).

The impact of depressive subtype on

task performance has been explored in a
small number of studies. Byrne (1977) and
Cornell et al (1984), both using the Newcastle scale to define subjects with endogenous and non-endogenous depression, found
impairment of complex reaction time in
subjects with endogenous depression alone.
Fromm & Schopflocher (1984), also using
the Newcastle criteria, and Rush et al
(1983) using the Research Diagnostic
Criteria criteria reported that subjects with
endogenous depression were more impaired
on all cognitive tasks (Trails, Stroop test,
visual recall and complex attention) than
subjects with non-endogenous depression.
The relationship between severity and depression subtype is a further confounder.
Thus, while Austin et al (1992a
(1992a, 1999) reported frontal deficits only in their subjects
with narrowly defined (Newcastle and
CORE) endogenous or melancholic depression, these disappeared after covarying for
Hamilton scores (Austin et al,
al, 1999), indicating that this pattern of frontal deficits
was more likely to be present as a result
of depression severity rather than depressive subtype. A useful probe of the effects
of severity per se is provided by the significant diurnal variation in mood seen in
many subjects with melancholia, where depressed mood is typically worse early in the
day. It has been demonstrated that these
subjects perform less well on most cognitive
tasks (except for the DMST) in the morning
compared to evening, with the opposite
finding in controls (Moffoot et al,
al, 1994).
In summary, melancholic subtype and depression severity both appear to contribute
to the neuropsychological deficits seen in
subjects with depression. Some tests are
highly dependent on current mood severity,
others are not: differential effects of this
sort may offer clues to the mechanisms
and brain networks involved.

Impact of motivation, `response

bias' and `negative cognitive set'
on cognitive performance in
depression
The neuropsychological deficits that are
correlated with depression severity have attracted controversy. A number of researchers have applied the cognitivebehavioural
paradigms of motivation, `response bias'
and `negative cognitive set', to explain the
neurocognitive impairments seen in
depression. Motivation has been defined
as ``the ability to initiate appropriate activity either spontaneously or in response to

2 01

AU S T I N E T A L

environmental cues'' (Lezak, 1995). Since

the implied stimulusreward associations
are partly predicated upon the ability to experience pleasure, motivation must also in
some way be closely linked to hedonic drive
and, in turn, to affect. It is difficult to
imagine one without the other. Our understanding of motivation is based predominantly on the study of patients with
frontal lobe lesions, in whom both motivation and affect are significantly compromised, suggesting, at least in those
patients, ``that affect and drive (i.e. motivation) are two sides of the same coin''
(Lezak, 1995). It is not clear, therefore, that
to study reduced motivation is not in some
sense to study depression.
A number of studies have proposed that
impaired motivation in depressed patients
can be measured as lack of an appropriate
response to explicit reward (Miller &
Lewis, 1977; Layne, 1980; Henriques et
al,
al, 1994), where depressed patients may
not perceive reward as reinforcing because
of a low hedonic capacity (Meehl, 1975;
Hughes et al,
al, 1985). This lack of response
to reward may manifest as a response bias.
Conservative response bias, or the tendency
for patients with depression to require a
greater degree of certainty (or reward) before they respond, has been put forward
as a cause of impaired performance by
some (Miller & Lewis, 1977; Henriques et
al,
al, 1994), but not all (Deptula et al,
al, 1991;
Channon et al,
al, 1993) authors. Henriques
et al (1994) in a controlled study of subjects
with `dysphoria' (defined by their score on
the Beck Depression Inventory), found a
lack of improvement in task performance
in response to financial incentive, while response to neutral and punishment conditions was the same in both groups
implying that subjects with dysphoria were
selectively less responsive to reward
mechanisms than controls. This lack of
response to financial incentive was also
reported by Richards & Ruff (1989) in
their sample of out-patients with depression. These studies did not establish how
tasks varied in their sensitivity to motivation: indeed, they assumed that finding the
effect for one task meant it could be
generalised to all tasks.
Elliott et al (1997) suggested that response bias to negative feedback within
the testing paradigm was associated with
impaired cognitive performance in subjects
with depression compared with controls.
Their findings suggested that a subject's
awareness of failure on one problem

202

dramatically increased the chance of failure

on the subsequent problem. The authors
proposed two possible explanations: either
subjects with depression demonstrate a lack
of adequate response to negative feedback
(with inability to expend greater effort on
a subsequent task); or they have a stronger
negative reaction to negative feedback
manifesting cognitively as a `negative cognitive set' (Beck, 1963) and perform more
poorly as a result. Given that the authors
submitted their data-set to many post hoc
statistical tests, the findings were by nature,
exploratory. Indeed, other studies (Purcell
et al,
al, 1997; Shah et al,
al, 1999) using a similar
paradigm in subjects with equally severe
depression have not reported similar
results.
Negative cognitive set (Beck, 1963) was
not explicitly measured by Elliott et al
(1997), but its effect upon cognitive performance has also been explored using tasks
that test memory for negatively valenced
words. Many studies have demonstrated
that such words are selectively recalled over
positively or neutrally valenced words, implying that the subject with depression has
increased access to them (Matt et al,
al, 1992).
Clearly, a motivation deficit has the
potential to impair the performance of all
neurocognitive tasks. That it fails to do this
invites the proposition that some tasks are
more sensitive to such effects than others.
This section has highlighted the need to
clarify the concepts before the interaction
between motivation, depressed affect and
cognitive function can be understood.

Recovery from depression: is there

persistent neuropsychological
impairment?
A small number of studies have compared
the performance of subjects who have recovered from depression with that of
matched controls. Using this design,
Paradiso et al (1997) found significant neurocognitive impairment in subjects who had
recovered from unipolar depression which
was most marked on set-shifting tasks and
not related to medication status. Marcos
et al (1994) in a study of subjects with
DSMIIIR (American Psychiatric Association, 1987) melancholia who had recovered
for 3 months or more, reported persistent
deficits in both immediate memory and delayed recall of visual and verbal material,
and block design.
Testing before and after recovery is a
potentially powerful method of identifying

and distinguishing state- from trait-related

cognitive deficits, but the prospective studies done to date also have methodological
limitations. In particular they frequently
use inadequate definitions of recovery
(Sternberg & Jarvik, 1976; Jones et al,
al,
1988; Peselow et al,
al, 1991; Bazin et al,
al,
1994; Moreaud et al,
al, 1996), do not control
for the potential effects of medication and
electroconvulsive therapy and fail to show
that task performance is within the normative range at recovery (Tarbuck & Paykel,
1995). Abas et al (1990) tested elderly patients with endogenous depression on a
number of memory measures and reported
that half of those performing poorly at baseline were still impaired at recovery in spite of
improved Mini-Mental State Examination
(MMSE; Folstein et al,
al, 1975) scores and a
lack of clinical evidence for incipient dementia and independent of medication status. In
a similar sample of elderly patients, Beats et
al (1996) also found that many, but not all
deficits had remitted upon recovery: specifically, measures of simple and choice
reaction times, perseveration on the setshifting task and verbal fluency did not fully
recover. Peselow et al (1991) in a study of
patients with unipolar depression treated
with imipramine for 4 weeks, reported significant improvement in all mnemonic measures in treatment responders only. They
concluded that, in memory tasks at least,
recovery of mood was associated with significant cognitive improvement. This finding echoed the earlier findings of a small
study by Calev et al (1986) and that of
Bazin et al (1994) neither of which found
residual impairment in either explicit (verbal and visual) or implicit memory tasks
upon recovery. In contrast, Sternberg &
Jarvik (1976) reported that in endogenous
subjects responding to a tricyclic antidepressant after 4 weeks, improvement in immediate memory was related to degree of
depressive recovery, while performance on
learning and short-term memory tasks remained impaired. Trichard et al (1995) in
a controlled study of executive task performance in middle-aged subjects with severe depression, reported improved performance
performance
on the verbal fluency task but not the Stroop
task upon recovery. Thus, at present a residual deficit in mnemonic and executive function appears to be seen in some patients with
a history of depression. Its rela-tionship
rela-tionship to
crucial epidemiological variables such as age,
treatment, duration and chronicity
chronicity of illness
and number of episodes (Kessing, 1998),
remains to be more clearly determined.

C O G NI T I V E D E F I C I T S IIN
N D E P R E S S I ON

Relationship between age,

microvascular disease and
cognitive impairment in depression
Age is associated with a progressive decline
in cognitive function. In particular, mental
processing becomes slowed; there is poorer
performance on effortful tasks; and mental
inflexibility, susceptibility to distractors
and perseveration become more prominent.
These are the very tasks in which subjects
with depression, and especially those with
severe depression (endogenous or melancholic), are impaired, and thus age per se
is a significant confounder for cognitive
impairment in depression (Jorm, 1986).
Advancing age is also associated with
an increase in microvascular brain disease,
which appears to be particularly marked
in subjects with late-onset depression
(Brown et al,
al, 1992). Current aetiological
models of late-life depression have focused
particularly on the presence of microvascular disease in deep white matter suggested
by magnetic resonance imaging studies
(see Hickie & Scott, 1998 for a review). Severe cognitive impairment is also frequently
found in older patients with severe depression and, in a significant proportion, appears not to be fully reversible (Abas et al,
al,
1990; Alexopoulos et al,
al, 1993; Hickie et
al,
al, 1997). Many older patients have concurrent hypertension, cardiovascular and
cerebrovascular disease, and longitudinal
studies suggest that patients with depression with these medical risk factors may
be at increased risk of cognitive impairment
and/or dementia (Hickie & Scott, 1998 for
review). Thus, some older patients with
persistent cognitive deficits due to treatment-resistant depression may have a comorbid incipient vascular dementia.
A number of studies have examined the
relationship between magnetic resonance
imaging and cognitive task performance in
older subjects with depression, and all report a significant correlation between the
presence of deep white matter hyperintensities in subjects with late-onset depression
and poorer cognitive task performance, in
particular on executive and psychomotor
tasks (Hickie et al,
al, 1995; Lesser et al,
al,
1996; Kramer-Ginsberg et al,
al, 1999).
Although microvascular pathology, which
in some cases is associated with vascular
dementia, may account for the persistent
cognitive deficits seen in older subjects with
late-onset depression, such processes currently seem unlikely to contribute to the
persistent cognitive deficits reported in

many younger (i.e. under 60 years old) subjects with depression. However, we do not
yet understand the neurobiological consequences of severe depression. It remains
possible that there are vascular sequelae
that we can only see with available technology when expressed in the ageing brain.
Alternatively there may be vascular factors
that predispose to depression in severe
early-onset cases or may even mediate the
effects of precipitating life events.

DISCUSSION
Methodological limitations
of cognitive testing in depression
There are a number of significant limitations associated with the use and interpretation of standard neurocognitive testing in
psychiatric disorders such as depression.
While it is easy to equate a deficient neurocognitive function with the location of a
neuroanatomical defect,
``many putatively `localising' neuropsychological
procedures were derived from studies of patients with focal lesions . . . they reflect a view of
brain ^ behaviour relationships based upon vascular anatomy . . . whether this understanding
of cerebral localisation applies to less focal diseases remains to be determined'' (Caine,1986).

Most cognitive tasks tap a number of cognitive domains, making it difficult to tease
out the primary functional deficit associated with impairment on any one task.
The WCST, which has been the classic tool
to detect a frontal lesion, exemplifies a
number of these issues. In particular, it
relies on examiner feedback for its performance and assesses several key cognitive
domains: shifting the sorting rule when
negative feedback to a previous positive
stimulusreward association occurs; memorising previous rules to ensure efficient
rule testing; and establishing or rejecting
rules by deductive reasoning (Dehaene &
Changeux, 1991). The use of properly constructed test batteries assessing a broad
range of functions in order to allow for assessment of patterns of impairment may go
some way to circumventing this problem
but it is unlikely to solve it (Keefe, 1995).
This is particularly the case for executive
function, where the nature of the neuropsychological construct itself remains controversial. Indeed there is strong evidence
that the general factor, or Spearman's g,
which identifies covariation between performance on many tests, may be the critical

measure of frontal lobe function (Duncan et

al,
al, 1995).
Finally, while most neurocognitive
tasks are designed to eliminate or minimise
the effects of reward and reinforcement, it
is not possible to do this for executive tasks
that are dependent on feedback for their
performance. The structured nature of
testing may mask deficits in motivation,
self-monitoring and planning which often
contribute to the clinical presentation
associated with depression.

Neurocognitive `double
dissociations' and the putative
pathogenesis of depression
The gold standard in any attempt at localisation of neuropathophysiology by means
of neurocognitive testing is the identification of mutually exclusive profiles of cognitive impairment or `double dissociations',
which are in turn linked with focal anatomical lesions (Gazzaniga et al,
al, 1998). The
double dissociation method has been a
powerful tool in identifying different domains of prefrontal function in animal
lesion studies (Dias et al,
al, 1996; Rolls,
1996). In humans, this method is most applicable to the study of subjects with either
focal brain lesions or relatively focal neuropathology such as Parkinson's disease or
Huntington's chorea. In complex disorders
such as depression, the assumption that impaired neurocognitive function will reveal
the nature of the neural defect underlying
the disorder remains speculative.
While double dissociations are more
difficult to demonstrate in subjects with
functional psychiatric disorders, there is
an emerging body of work which suggests
that this may be feasible. Austin et al
(1999), using a battery with a large number
of frontal tasks, demonstrated a dissociation between two sets of key frontal
domains: set-shifting and working memory
on the one hand, and inhibitory control on
the other. Human lesion (Grattan et al,
al,
1994) and imaging (Courtney et al,
al, 1997)
work has suggested an association between
the dorsolateral prefrontal cortex and frontal cognitive deficits in depression, with a
relative sparing of lateral orbitofrontal
and anterior cingulate regions which have
been associated with inhibitory control as
reflected by performance on the Stroop
task (Pardo et al,
al, 1990; Bench et al,
al,
1993). Such hypotheses require specific
testing in activation studies with functional
imaging.

203

AU S T I N E T A L

Integrating the neurocognitive

and affective manifestations
of depression into a functional
neuroanatomical framework
There is now significant evidence, both from
animal and human studies, suggesting the
existence of distinct, parallel functional networks or loops linking prefrontal and subcortical regions (Alexander et al,
al, 1986,
1990; Cummings, 1993). Disruption in several of these functional networks has now
been implicated in the pathogenesis of a
number of psychiatric disorders including
major depression (Austin & Mitchell, 1995).
It was originally hypothesised (Cummings, 1993) that patients with depression
have impaired function in the limbic loop
with effects upon the affective, autonomic
and vegetative domains. This has been partially supported by a number of imaging
studies suggesting that some regions functionally linked to the anterior cingulate (part
of the limbic loop), and the subgenual
prefrontal cortex (PFC), are key functional
regions modulating affect in depression
(Austin et al,
al, 1992b
1992b; Drevets et al,
al, 1997;
Mayberg et al,
al, 1997). Drevets et al (1997) demonstrated significant reduction in both perfusion and, more intriguingly, brain volume
in the subgenual region in patients with unipolar and bipolar depression. Finally, Goodwin et al (1993) and Mayberg et al (1997)
both demonstrated normalisation of perfusion in the anterior cingulate upon recovery.
Findings from activation studies in normal control subjects and subjects with depression are strongly suggestive of a close
integration between the dorsolateral prefrontal cortex (DLPFC) (implicated in the
set-shifting deficits of depression described
above) and the subgenual cingulate in
depression. Thus, Teasdale et al (1999)
reported in normal subjects that certain
components of the medial prefrontal cortex
(including the anterior cingulate) appear to
be involved in the cognitive induction of a
negative affect, thereby implying close integration between the dorsolateral and limbic
circuits. Mayberg et al (1999) examined the
impact of negative mood induction, both in
normal control subjects and those subjects
who had recovered from depression, on
cerebral perfusion. Induced sadness was
associated with an increase in subgenual
cingulate cerebral blood flow and a decrease
in DLPFC, while recovery from depression
was associated with the reverse pattern.
Intriguingly, an earlier lesion study by
Bechara et al (1996) demonstrated that

204

patients with ventromedial lesions had

relatively preserved cognitive function, except for decision-making, which was impaired when this relied upon the ability to
attach emotional salience to the task situation. Their findings, like those of Teasdale
et al (1999) and Mayberg et al (1999), suggest that affect and cognitive function may
be anatomically linked at the level of the
ventromedial or orbitofrontal regions. Exactly how this maps onto the reciprocal
interaction between two key prefrontal
regions (dorsolateral and orbitofrontal)
and their frontal subcortical connections
remains a challenge. Nevertheless, in light
of these findings, the initial proposal that
the frontosubcortical networks (Alexander
et al,
al, 1986, 1990) essentially operate
independently needs to be revised.

Are these neuropsychological

deficits simply epiphenomena
of depression?
The commonly held view that neuropsychological deficits in depression are simply epiphenomena of age, poor motivation,
inattention or response bias now appears
somewhat dated. Correlational studies
evaluating the impact of age, task difficulty
and depression severity upon task performance in depression partially favour the
effortfulautomatic hypothesis. What such
a finding may mean remains uncertain.
One view is simply an extension of the epiphenomena perspective: if patients feel unwell they will not try so hard. However,
this fails to acknowledge that the subjective
basis of all experience, including action, is
neuronal. An increased sense of effort will
have a neurobiology. A possible explanation for this is that failure of executive function in depression may be closely related to
an increased sense of subjective effort that
involves the prefrontal cortex.
A small number of studies indicate persistent cognitive impairment upon recovery
in mood disorder, as noted above. These
findings are reported in all age groups,
although more frequently in older subjects.
Thus, while psychosocial explanations of
mood disorder are often uncritically accepted, the presence of neuropsychological
deficits is important evidence that enduring
brain abnormalities are implicated in the
aetiology of depressive disorder. If cognitive impairment were simply secondary to
the severity of depressed mood, then it
would be expected to fully recover upon remission of the episode, and certainly would

not be expected to appear in young subjects

with dysphoria (mild depression).

Do these cognitive deficits help

us identify the functional
neuropathology of depressive
disorders?
If cognitive deficits are intrinsic expressions
of the brain changes in depressive illness,
and we believe they are, can they help us
identify the functional neuropathology of
depressive disorders? The consistent impairments of memory function, which are
not dependent on the acute mood changes
associated with diurnal mood variation
when tested using almost purely mnemonic
tests (Moffoot et al,
al, 1994), suggest that as
we learn more about memory mechanisms
in humans we shall learn more about depression. Selective set-shifting deficits
both on cognitive and affective set-shifting
tasks are also assuming an increasing interest in depression. Restricted lesions of
the ventromedial prefrontal cortex have
profound effects upon executive function,
the recognition of emotion in others and,
probably, upon the experience of mood (Damasio, 1994; Rolls et al,
al, 1994; Hornak et al,
al,
1996). The apparent localisation to quite a
small brain area of a critical link between
affect and cognition comes as something of
a surprise, but it is supported by a number
of functional imaging studies and by some
recent neuropsychological studies in depression (Murphy et al,
al, 1999; Austin et al,
al, 1999).

ACKNOWLEDGEMENTS
We are most grateful to Professor Perminder Sachdev
forhis
forhisexcellentcommentson
excellentcommentson anearliermanuscript and
to Professor Gordon Parker forhiseditorialoverview.

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CLINICAL IMPLICATIONS

Mood lowering and cognitive impairment deserve to be considered as comparably

important manifestations of depressive disorder.
&

Formal cognitive testing could be a useful adjunct in the clinical evaluation of

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LIMITATIONS
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MARIE-PAULE AUSTIN, MD, Mood Disorders Unit and Department of Liaison Psychiatry, Prince of Wales
Hospital, Sydney, Lecturer, School of Psychiatry, University of New South Wales; PHILIP MITCHELL, MD,
Director, Mood Disorders Unit, Prince of Wales Hospital, Sydney, Professor, School of Psychiatry, University of
New South Wales; GUY M.GOODWIN, FRCPsych,W. A. Handley Professor of Psychiatry, Oxford University

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Cognitive deficits in depression: Possible implications for

functional neuropathology

MARIE-PAULE AUSTIN, PHILIP MITCHELL and GUY M. GOODWIN

BJP 2001, 178:200-206.
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