R. Banerjee & B.K. Chakrabarti (Eds.)
Progress in Brain Research, Vol. 168
Copyright r 2008 Elsevier B.V. All rights reserved
Identification of neuroanatomical substrates of
set-shifting ability: evidence from patients with focal
Pritha Mukhopadhyay1,?, Aparna Dutt1, Shyamal Kumar Das2, Arindam Basu3,
Avijit Hazra4, Tapan Dhibar5and Trishit Roy2
1Department of Psychology, University College of Science and Technology, 92 APC Road, Calcutta 700009, India
2Department of Neuromedicine, Bangur Institute of Neuroscience and Psychiatry, Calcutta 700025, India
3Department of ENT, Guru Teg Bahadur Medical Centre, 11, D.L. Khan Road, Calcutta 700027, India
4Department of Pharmacology, Institute of Postgraduate Medical Education and Research, 244 B, A.J.C. Bose Road,
Calcutta 700020, India
5Department of Neuroradiology, Bangur Institute of Neuroscience and Psychiatry, Calcutta, India
Abstract: This work concerns the investigation of executive functions in patients with focal brain lesion.
In order to identify the underlying substrates for executive functions, 54 patients with focal cortical (n=30),
subcortical (n=13) and cerebellar damage (n=10) (M=9; F=1) in the age range of 24–65 years with
a minimum of Class V education have been investigated. The patients were admitted to the Department
of Neuromedicine of Bangur Institute of Neurology, Calcutta. Each patient with focal lesion was
matched with a healthy normal subject controlling for age and education. The socio-economic background
was also taken into consideration. Controls were selected from the families of other patients admitted to the
institution and also from individuals who volunteered to act as controls. Here too, rigid criteria have
been followed to select the normals. Mini Mental State Examination (MMSE) and General Health
Questionnaire (GHQ) were administered to screen out the neurological and psychiatric abnormalities
in selection of normal control and Wisconsin Card Sorting Test (WCST) was administered to find out
the executive function, in terms of set-shifting ability. Since standard anatomical groupings can obscure
more specific brain–behavior relations, group-comparison design does not always allow determination
of the effective lesion responsible for a particular deficit (Godefroy et al., 1998). The Classification
and Regression Tree (CART) analysis has been used to determine the brain–behavior relationships.
The result reveals that the frontal lobes are essential determinants of set-shifting capacity. However, for
optimal execution of set-shifting function, the frontal lobes require participation of other cortical,
subcortical and cerebellar regions. The result has been discussed in the light of the existing theories and
Keywords: executive function; set-shifting ability; perseverative error
?Corresponding author. Tel.: +91-33-25598022;
‘Executive function’ refers to ‘higher’ function of
the prefrontal cortex (Milner, 1964; Luria, 1966;
Stuss and Benson, 1986) and traditionally has been
used synonymously with the term ‘frontal skills’.
The term ‘executive skills’ implies activities that
help to adapt to one’s environment. It is one’s
ability to plan, initiate, organize, sequence, moni-
tor and shift cognitive set to achieve a goal. The
function called ‘cognitive set shifting’ means ones
ability to shift from one perceptual attribute or
thought to another on the basis of feedback from
changing environments. Cognitive set shifting is
also known as ‘attentional set shifting’.
The Wisconsin Card Sorting Test (WCST) has
been considered as a key measure in the diagnosis
of frontal lobe dysfunction (Milner, 1963, 1964;
Drewe, 1974; Arnett et al., 1994). Cognitive set
shifting is most often substantiated by the WCST.
Successful performance on WCST requires certain
capacities: cognitive flexibility, cognitive set per-
sistence, concept identification, hypothesis genera-
tion and the ability to use response feedback
information. Hence, set-shifting capacity is not a
single unitary function and it’s measure, the
WCST, is a complex problem-solving task that
requires multiple cognitive processes (Anderson
et al., 1991; Dehaene and Changeux, 1991) most
probably involving of brain regions other than the
Evidence from neuropsychological, electrophy-
siological and functional neuroimaging research
supports the role of frontal lobes as a critical node
in the neuroanatomical network underlying set-
shifting capacity. Different regions within the
frontal lobes have been reported to underlie
successful performance on the WCST (Milner,
1963; Drewe, 1974; Rogers et al., 2000; Monchi
et al., 2001; Nagahama et al., 2001; Konishi et al.,
2002). Reports are however contradictory regard-
ing the lateralization of set-shifting function within
the frontal lobes. While left dorsolateral prefrontal
dominance (DLPFC) on WCST performance
correlates with certain neuropsychological and
neuroimaging studies (Milner, 1971; Berman and
Weinberger, 1990; Grafman et al., 1990; Goldstein
et al., 2004), right hemispheric lateralization has
also been reported (Robinson et al., 1980; Owen
et al., 1993; Haut et al., 1996; Stuss et al., 2000).
Few studies however, did not indicate any laterali-
zing effects (Nelson, 1976; Bornstein, 1986).
WCST scores correlate with frontal lobe dys-
function in a substantial proportion of patients
with non-frontal cerebral damage, though clinical
assumption regarding the involvement of other
Hermann and Wyler (1988) and Drake et al.
(2000) in their studies on patients with temporal
lobe epilepsy, confirmed that damage to brain
regions outside the prefrontal cortex may result in
frontal lobe dysfunction as measured by perfor-
mance on the WCST. Though laterality effect with
poorer performance on WCST was associated with
non-dominant temporal lobe pathology (Corcoran
and Upton, 1993), no difference was observed on
WCST performance between left and right tem-
(Trenerry and Jack, 1994; Hermann and Wyler,
1998; Martin et al., 2000).
Involvement of other non-frontal regions of the
brain including inferior parietal lobule, the visual
association and the inferior temporal cortices
along with the DLPFC during WCST perfor-
mance gets support from functional neuroimaging
studies (Berman et al., 1995; Rogers et al., 2000).
The role of cortical–subcortical circuits in
‘frontal’ functions (Evarts et al., 1984; Cummings,
1993) is also significant. Subcortical structures like
the basal ganglia have been implicated in WCST
performance in both lesion and functional neuroi-
maging studies (Rogers et al., 2000; Monchi et al.,
2001; Swainson and Robbins, 2001). Deficit in
WCST performance has been observed following
right basal ganglia stroke (Swainson and Robbins,
2001), dorsal and ventral caudate nucleus lesions
(Mendez et al., 1989) and thalamic lesions (Ghika-
Shchmid and Bogousslavsky, 2000; Annoni et al.,
The role of the cerebellum in executive function
has been suggested by Schmahmann and Sherman
(1998) who identified the ‘cerebellar cognitive
affective syndrome’ characterized by impairment
of executive and other cognitive functions in
patients with cerebellar lesions. Other lesion and
neuroimaging studies too have suggested the role
of the cerebellum in executive function (Berman
et al., 1995; Nagahama et al., 1996; Le et al., 1998;
Levisohn et al., 2000).
It is apparent therefore that a unified neuro-
anatomical substrate for cognitive dysfunction is
yet to emerge and there remains the need to
explore the neural substrates underlying executive
function. The present study aims to identify the
neuroanatomical substrates underlying set-shifting
ability in patients with focal brain lesions at
The study included 54 patients of either sex with
focal cortical (n=31), subcortical (n=13) and
cerebellar damage (n=10). They were in the age
range of 16–65 years and admitted to the Depart-
ment of Neuromedicine of Bangur Institute of
Neuroscience and Psychiatry, Calcutta. Ethical
clearance for the study was obtained from the
institutional ethics committee.
For inclusion, the patients had to be right
handed, with a minimum education up to the fifth
standard and suffering from their first cerebral,
subcortical or cerebellar insult due to stroke or
tumor. They had to have computerized tomogra-
phy (CT) or magnetic resonance imaging (MRI)
scans showing a single unilateral lesion involving a
maximum of two anatomically distinct cerebral
structures (in case of cerebral lesions) or restricted
either to the basal ganglia or the thalamus (in case
of subcortical lesion) or one of the cerebellar
hemispheres (in case of cerebellar lesion).
Those with a history of past stroke, head injury,
epilepsy, central nervous system infection, meta-
bolic encephalopathies, neurodegenerative disor-
ders like Alzheimer’s disease or Parkinsonism,
primary aphasia, significant motor weakness or
major psychiatric disorders were excluded. Also
excluded were subjects on sedative, neuroleptic or
anticonvulsant medication and those with a
history of alcohol or substance abuse. Significant
disease of major organ systems such as hepatic,
renal or pulmonary disease was a further exclusion
Each patient with a focal lesion was matched
with a healthy control subject for age and
education. The socioeconomic background was
also taken into consideration. Controls were
selected from families of other patients and also
from individuals who volunteered. The control
subjects had no history of neurological and
psychiatric disorders, with Mini Mental State
Examination (MMSE) score above 25 and a
General Health Questionnaire (GHQ) score com-
patible with the cut-off point for normality. It was
also ensured that they were not on any drugs
known to affect the central nervous system
function and had no history of alcohol or
The following tests/questionnaires were applied:
1. Wisconsin Card Sorting Test (Heaton et al.,
2. Mini Mental State Examination (Folstein
et al., 1975).
3. General Health Questionnaire (Goldberg and
4. Edinburgh Handedness Inventory (Oldfield,
Majority of the patients were admitted to the
Department of Neuromedicine of Bangur Institute
of Neuroscience and Psychiatry, Calcutta. Clinical
characteristics were assessed through careful his-
tory and neurological examination by the attend-
ing neurologist. Neuroimaging
interpreted by the neurologist and a neuroradio-
logist and a consensus opinion taken. Thereafter,
informed consent was obtained from the patient.
Each control subject also underwent neurological
examination by the neurologist. Both patients and
controls were screened for their handedness with
the Edinburgh Handedness Inventory and screened
for cognitive dysfunction with the MMSE.
The WCST was employed according to stan-
dardized procedures (Heaton et al., 1993) to assess
executive function in terms of set-shifting abilities.
The test measures the ability to change strategy in
response to altered feedback about performance.
In this test, the subject was asked to match a series
of response cards to one of the four stimulus cards.
The WCST response and stimulus cards vary
along three dimensions: color of the elements,
form of elements and number of the elements on
each card. The subject was not told explicitly as to
which dimension correctly represented the sorting
principle, but after each attempted match of a
response card to a stimulus card, the examiner
informed the subject whether or not his/her
preceding response was correct. By generating
hypotheses about the correct sorting principle,
and testing these hypotheses through trial and
error, the subject was able to determine whether
he/she is to sort the cards according to color,
form or number. Following 10 consecutive correct
responses (‘completion of a category’), the exami-
ner covertly changed the sorting principle. The test
was continued until the subject completed 6
categories or until all the 128 cards were used,
whichever came first.
In the present study, performance on the WCST
was evaluated by (a) the number of categories
completed and by two measures of perseverative
tendencies, (b) percent perseverative responses and
(c) percent perseverative errors.
When the subject persisted in responding to a
stimulus characteristic (color, form or number) that
was previously in operation but which had been
changed subsequently, the response was considered
to match the ‘perseverated-to’ principle and was
scored as perseverative. Once a perseverated-to-
principle has been established and is operative,
responses that match the perseverated-to-principle
are scored as perseverative regardless of whether
they are correct or incorrect. There are three rules
for detecting perseveration, the details of which
have been outlined in the WCST manual (Heaton
et al., 1993). Perseverative responses include both
errors and correct responses satisfying the persever-
ated-to-principle according to one of the three rules
of perseveration. The total number of perseverative
responses is divided by the total number of trials
administered and multiplied by hundred to get the
‘percent perseverative response’ score. Perseverative
errors are those responses which are incorrect and
also satisfy the perseverated-to-principle according
to one of the three rules of perseveration. The total
number of perseverative errors is divided by the
total number of trials administered and multiplied
by 100 to get the ‘percent perseverative error’ score.
The raw percent perseverative response and percent
perseverative error scores are transformed to
normalized standard scores. Standard scores on
WCST range from r54 to Z107.
This was carried out using SPSS version 11.0
software. A p value less than 0.05 was used to
determine significance. Since age and education
had a normal distribution in the study population,
comparison between groups with respect to these
two variables was assessed by parametric tests.
Non-parametric tests were chosen for neuropsy-
chological variables as no assumption regarding
their distribution was made and the sample size
was relatively small.
Standard anatomical groupings can obscure
more specific brain–behavior relations. Group
comparison design does not allow determination
of the effective lesion responsible for a particular
deficit (Godefroy et al., 1998). The classification
and regression tree (CART) statistical procedure
(Breiman et al., 1984) used in several brain–
behavior relationship studies (Stuss et al., 2000;
Alexander et al., 2003) has been found to be more
successful in the determination of the nature of
We employed the R software for statistical
analysis (2007) for CART analysis. The CART
procedure, as a supervised learning algorithm, runs
a recursive regression tree-like structure searching
for the best classifier of a specific outcome variable
based on a set of predictor variables. In this study,
CART was employed defining lesion sites as the
outcomes variables and WCST test scores as the
predictor variables. We used the test scores to find
a set of classifiers to differentiate between lesions.
The purpose of CART was thus to enable
prediction of lesion sites based on test scores.
Comparison between cortical lesion patient group
The impairment in the cortical lesion group
compared to control is evident from Table 1.
Performance was significantly impaired in all the
variables of WCST — the patients achieved
significantly less number of categories, showed
more perseverative responses and made more
Comparison between subcortical lesion patient
group and control
This is depicted in Table 2. Patients with sub-
cortical lesions also performed poorly compared to
controls, achieving significantly fewer categories,
showing more percent perseverative responses and
making more percent perseverative errors.
Comparison between cerebellar lesion patient group
Comparison of WCST performance of patients
with cerebellar lesions and control subjects is
presented in Table 3. However, here there was no
significant difference in percent perseverative
responses, although these patients made signifi-
cantly more percent perseverative errors and
achieved significantly lesser number of categories
CART analysis on percent perseverative responses
On the basis of percent perseverative responses
(Fig. 1), the CART procedure initially provided
the firstspliton the
responses score at 80. Those who had scores equal
to or greater than 80 were then classified on the
basis of whether the score was W86.5. CART
identified left cerebellar lesions (LCB) as scores
with more than 86.5, and left temporoparietal
lesions (LTP) as having scores between 80 and
86.5. Those who had scores less than 80 were
classified into left frontal (LF) and right thalamic
(RTH) lesion groups on the basis of scores at less
than 72.5 for LF lesions.
Table 1. Comparison of cortical lesion patients and matched normal controls on the Wisconsin Card Sorting Test
Test parameterNormal controls (n=31) Cortical lesion patients (n=31)
Number of categories completed
Note: Values represent mean7standard deviation.
Table 2. Comparison of subcortical lesion patients and matched normal controls on the Wisconsin Card Sorting Test
Test parameterNormal controls (n=13)Subcortical lesion patients (n=13)
Number of categories completed
Note: Values represent mean7standard deviation.
Table 3. Comparison of cerebellar lesion patients and matched normal controls on the Wisconsin Card Sorting Test
Test parameter Normal controls (n=10) Cerebellar lesion patients (n=10)
Number of categories completed
Note: Values represent mean7standard deviation; NS, not significant.
CART analysis on percent perseverative errors
On the basis of percent perseverative error scores
(Fig. 2), the CART procedure classified right
frontal (RF) from the rest of the lesions on the
basis of a score less than 63.5. LTP lesions scored
between 75.5 to less than 87.5. Scores equal to or
greater than 87.5 distinguished LCB lesions.
In this study, patients with focal brain lesions,
irrespective of the lesion site, performed poorly on
the WCST parameters of category completion,
percent perseverative responses and percent perse-
verative errors, in contrast to their healthy
counterparts. Poor function on the aforesaid
variables perhaps restricted the patients from
operating on the feedback provided by the
examiner. Utilization of feedback from the exami-
ner is the basis on which the performer takes
decision to shift set from one category to other
based on color, form and number on WCST task.
Poor utilization of feedback thereby revealed the
impairment in set-shifting capacity in each of the
three lesion groups in terms of the reduced
numbers of categories achieved by them.
Fig. 1. Classification and regression tree (CART) analysis output for perseverative response scores (PR).
Fig. 2. Classification and regression tree (CART) analysis out-
put for perseverative error scores (PE).
The results of CART analysis in the present
study revealed the following pattern based on
perseverative response score: LFoRTHoLTP
oLCB. Indirectly this indicates that lesions in
these four anatomical zones are involved in
perseverative response, with frontal lesions per-
haps being the most damaging and cerebellar
lesions the least. We did not find authoritative
references on influence of LF lesions on persevera-
tive responses. Possible involvement of other
regions suggests that the frontal lobe is not the
only site to explain perseverative response. Rather,
at least these four regions may form part of the
cortico–subcortical–cerebellar network that can
explain perseverative responses.
Involvement of different regions of the brain in
perseverative response can be explained by a
concept of executive function that postulates set
shifting to be a multifaceted rather than a unitary
entity. Since set shifting involves multiple cognitive
components, it may be presumed that each of these
independent components are subserved by differ-
ent anatomical circuits in the brain and not by
the frontal lobes alone. Other recent studies
have also indicated that patients with non-
frontal lesions exhibit significant difficulty on the
WCST (Drake et al., 2000; Ghika-Shchmid and
Bogousslavsky, 2000; Levisohn
Annoni et al., 2003).
The association of LF lesions with perseverative
responses could be attributed to the requirement
of a WCST task to involve verbal mediation for
its optimal performance. The findings of Berman
et al. (1995) and Nagahama et al. (1996) suggest
that although WCST is a visual task and essential
visual processes are mediated by non-verbal
systems in the right prefrontal regions, set shifting
in WCST could require participation of the verbal
systems in the left hemisphere also. The involve-
ment of the LTP region further substantiates the
reason put forward for explaining left hemispheric
participation in perseverative response.
Our observation suggests perseverative responses
following RTH lesion. However, this is at variance
with previous studies where the most pronounced
impact on executive function has been observed in
bilateral and left unilateral thalamic infarctions
(Rousseaux, 1994). On the other hand Van der
et al., 2000;
Werf et al. (1999) have reported a case of RTH
involvement. On the WCST, a 44-year-old patient
with right lacunar thalamic infarction was unable
to sort according to color and therefore was unable
to achieve a single category. Their findings
correlated with hypoperfusion of the right frontal
cortex on brain single photon emission CT, sugge-
sting that dysexecutive symptoms resulted from
disconnection of the prefrontal cortex from the
brainstem activating nuclei due to the strategic
localization of the right thalamic infarction.
The propensity for patients with cortical or
subcortical lesions to make perseverative errors in
comparison to healthy controls corroborates pre-
vious reports (Drewe, 1974; Owen et al., 1993;
Stuss et al., 2000; Goldstein et al., 2004) on this
aspect of executive function. The cerebellar lesion
group also made perseverative errors. Levisohn
et al. (2000) made a similar observation in children
who underwent resection of cerebellar tumors. The
authors attributed the greater perseverative errors
in such children to their difficulty in shifting
attention. The role of cerebellum in shifting
attention has also been suggested by Akshoomoff
and Courchesne (1994) in a functional MRI study
that revealed cerebellar activation during non-
spatial shifting of selective attention. The authors
suggested that the cerebellar cortex participates in
the ‘‘rapid sequential changes and adjustment of
neural activity to proceed from one condition to
another’’, while the neocerebellar participation in
attention arises from the need to predict, prepare
for and adjust to imminent information acquisi-
tion, analysis or action (Allen et al., 1997).
On the basis of perseverative error score, CART
could identify RF, LTP and LCB as three
anatomical sites (with the pattern RFoLTPo
LCB) where lesions could result in variations in
perseverative error scores. Of the three, those with
RF lesions were distinguished from the other sites
by the lowest scores, suggesting that these patients
may have difficulty in employing effective mechani-
sms to inhibit previously learnt contextual rules.
Earlier studies have also indicated perseverative
errors as the main signs of frontal dysfunction
(Robinson et al., 1980; Owen et al., 1993; Haut et al.,
1996; Barcelo and Knight, 2002). Some studies
indicate the left hemispheric effect (Drewe, 1974;
Goldstein et al., 2004). Stuss et al. (2000) have
demonstrated that patients with either left or right
focal frontal lesion are impaired on the ‘persevera-
tion to preceding criterion’ score in the WCST, but
the right prefrontal group was impaired more
severely than the left prefrontal group. The
‘perseveration to preceding criterion’ score is
similar to perseverative errors as scored by Heaton
et al. (1993) and as followed in the present work.
Previous studies have suggested that the tendency
of RF lesion patients to make more perseverative
errors than the LF lesion patients may be reflective
of the greater sustained attention and monitoring
role of the right frontal lobe (Sandson and Albert,
1987; Wilkins et al., 1987). Functional neuroima-
ging studies also suggest RF predominance in the
process of attentional set shifting (Monchi et al.,
2001; Nagahama et al., 2001).
Observations from this study thus suggest that
perseveration is possibly a bilateral phenomena
resulting from the loss of integrity of the frontal
lobes along with non-frontal cortical, subcortical
and cerebellar regions. The involvement of non-
frontal cortical regions gets support from positron
emission tomography findings of Berman et al.
(1995) who reported activation of a complex
network of regions involving inferior parietal
lobule, visual association cortices and the infero-
lateral temporal cortices in addition to the
prefrontal cortex during the performance of
WCST in normal subjects. The same study also
showed activation of portions of the cerebellum
The significant difficulty of frontal patients to
inhibit previous incorrect responses which results
in perseverative behavior is possibly due to
interference in the presumed inhibitory role of the
dopaminergic pathways in the prefrontal cortex.
Roberts et al. (1994) have hypothesized that
attentional set shifting is mediated by a balanced
interaction of prefrontal and striatal dopaminergic
activity, with enhanced
depressed prefrontal dopaminergic function and
impaired shifting following elevated prefrontal
dopaminergic or depressed striatal dopaminergic
function. The prefrontal cortex mediated inhibi-
tory control of cortical and subcortical regions
gains support from the physiological viewpoint
through event-related potential (ERP) studies
(Stuss and Knight, 2002).
The discordance in frontal lobe function or
frontal-like performance following lesions in any
part of the brain can be explained from the
cognitive viewpoint by the dynamic filtering theory
(Shimamura, 2000) which suggests dynamic inter-
play of selecting, maintaining, updating and
rerouting between the prefrontal cortex and
regions in the posterior cortex through feedfor-
ward and feedback activations. The prefrontal
cortex orchestrates these signals by maintaining
certain activations and inhibiting others. As such,
the prefrontal cortex refines cortical activity by
increasing signal to noise ratio. Possibly, this
modulation could extend beyond the cortex to the
subcortical and cerebellar regions.
The frontal lobes are the essential determinants of
set-shifting capacity. The present findings are in
conformity with reports of neuropsychological
Janowsky et al., 1989; Arnett et al., 1994) which
indicate that set-shifting ability as measured by
WCST is predominantly affected by frontal lobe
lesions. The present observations are also in line
with more objective data obtained through func-
tional neuroimaging studies which have confirmed
the involvement of the prefrontal cortex in the
performance of the WCST (Nagahama et al., 1996,
2001; Rogers et al., 2000; Monchi et al., 2001;
Konishi et al., 2002). However, the frontal lobes
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