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measures obtained during the WCST—as this can significantly affect interpretation

of data (Takeda et al. 2010). In the light of this, Terada et al. (2011) have

demonstrated reduced rCBF in ventromedial PFC is associated with perseverative

responding in AD patients.

ID/ED testing in AD patients has produced mixed results: a subgroup (*50 %)

of mild/moderate AD patients failed to complete the ID stage of the task, and

therefore, no measure of attentional set-shifting could be obtained—although the

remainder of the patients were unimpaired on any stage of the task (Sahakian et al.

1990); a subgroup (*50 %) of mild/moderate AD patients were impaired at the ED

shift stage of the task (Dorion et al. 2002). Despite these differences in performance,

a consistent pattern has emerged from subgroups of high-functioning versus

low-functioning AD patients—that also matches findings from WCST studies (e.g.

Perry et al. 2000). This suggests distinctly different patterns of neurodegeneration in

AD patients, with those suffering from more frontal pathology exhibiting worse

performance in attentional set-shifting tasks (e.g. Terada et al. 2011).

Animal models of AD are limited by several factors, and even transgenic mouse

models (Webster et al. 2014) fail to reflect the sporadic, rather than familial, aspect

of most AD cases (LaFerla and Green 2012). There are no primate data on attentional set-shifting in AD models, and the few rat studies that could be comparable

have only investigated normal ageing performance on the ID/ED task. Aged rats are

impaired at reversal learning (Tait et al. 2013), with an ED shifting impairment

(Barense et al. 2002) that may be manifest later in life than the reversal deficit (Tait

et al. 2013). Unlike rats, aged mice have been reported unimpaired on any stage of

the ID/ED task (Young et al. 2010). Transgenic mice (producing amyloid plaques

in cortex and hippocampus in a similar pattern to AD patients) have been reported

to show a general discrimination learning deficit by 14 months of age (Zhuo et al.

2007), with an earlier onset (between three to six months) reversal learning

impairment (Zhuo et al. 2008). Discrepancies between results from AD mouse

models and human AD patients—in the form of a failure to report an attentional

set-shifting deficit in the mice—may result from differences in pathology between

the sporadic AD and the transgenic model; or they may derive from the use of a

mouse task design that is not as reliable in producing an attentional set as more

current designs (e.g. Bissonette and Powell 2012).



6 Affective Disorders and Attentional Set-Shifting

There are numerous disorders of mental health, and it is not always a simple task to

isolate them from each other. For example, depression can arise for a number of

reasons, either as a symptom of a disorder, or as a by-product of another. Equally,

affective disorders are associated with a wide range of symptoms, not all of which

are necessarily present in each case. It is, therefore, not always easy to diagnose a

disorder—or to fully dissociate one from another.



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The lack of a full understanding of the pathology of affective disorders presents

its own difficulties when investigating animal models—there is a clear cause and

progression (although not always fully consistent between cases) in neurodegenerative diseases that is yet to be completely understood in affective disorders.

Animal models often involve pharmacological manipulations, intended to simulate

the changes reported in human patients, or environmental manipulations, and

intended to induce a cognitive state in the animal similar to that in human patients.

Both have their limitations, but the cross-species translational strength of tests of

attentional set-shifting is as beneficial to research into affective disorders as it is

neurodegenerative diseases.

Affective disorders represent a range of conditions with a variety of causes—

single or recurrent major depressive disorders (MDD), bipolar disorder and

substance-induced disorder (Davidson et al. 2002)—and can be comorbid with

other disorders and diseases (Brown and Barlow 1992).

Patients with bipolar disorder are more impaired at the WCST than unipolar MDD

patients, with errors arising from perseveration (Borkowska and Rybakowski 2001).

Unipolar MDD patients are inconsistently impaired on the WCST however (Fossati

et al. 2001; Moritz et al. 2002), and observation of an impairment may depend on the

version of the WCST being used (Fossati et al. 2001), or the melancholic state of the

patients (Austin et al. 1999). Deficits in unipolar MDD arise with reduced grey

matter volume in hippocampus (Frodl et al. 2006) and reduced grey matter concentration in right medial and inferior frontal gyrus (Vasic et al. 2008).

Modelling depression in animals is limited, in that to determine a depressive

state, a response to either a known antidepressant or to a stressor must be established (Yan et al. 2010). Some rat strains have been bred specifically to reflect some

depression-like symptomology (Overstreet 2012), although models derived from

stress, such as chronic unpredictable stress (CUS) and chronic intermittent cold

stress (CIC), are also widely used. In the rodent ID/ED task, both CUS and CIC

impair reversal learning (Bondi et al. 2008; Lapiz-Bluhm et al. 2009), but only CUS

and restraint stress impair ED shifting (Bondi et al. 2008; Liston et al. 2006). All

these stress-induced deficits are, however, ameliorated by antidepressants

(Nikiforuk and Popik 2011; Danet et al. 2010; Bondi et al. 2008) in the form of

selective serotonin reuptake inhibitors (SSRIs).



7 Schizophrenia and Attentional Set-Shifting

Schizophrenia is a disorder primarily associated with reduction in volume of PFC,

hippocampus and temporal lobes, and a corresponding increase in ventricle size—

as well as abnormal function in several neurotransmitter systems. Evidence of

dopaminergic dysfunction initially led to the ‘dopamine hypothesis’ in the underlying aetiology of schizophrenia (Howes and Kapur 2009), although glutamate (e.g.

Butler et al. 2005) and serotonin (e.g. Roth et al. 2004) are also implicated in

mediating many of the symptoms.



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There are numerous studies describing attentional set-shifting impairments in

patients with schizophrenia—both in the WCST (e.g. Sullivan et al. 1993;

Nieuwenstein et al. 2001; Haut et al. 1996) and in the CANTAB ID/ED task (e.g.

Ceaser et al. 2008; Elliott et al. 1995; Pantelis et al. 1999). Schizophrenic patients

exhibit perseverative errors in the WCST (Haut et al. 1996; Sullivan et al. 1993),

and functional magnetic resonance imaging (fMRI) studies have shown reduced

activity in right frontal areas in both medicated (Volz et al. 1997) and unmedicated

(Riehemann et al. 2001) subjects. More recently, the DLPFC, in the context of

working memory during WCST performance, was observed to exhibit reduced

activity in the left hemisphere in schizophrenic patients, whilst the anterior cingulate cortex was active during set-shifting (Wilmsmeier et al. 2010). Right inferior

frontal gyrus and bilateral caudate activation also increased in schizophrenic

patients—which may appear to contradict data from Volz et al. and Riehemann

et al.—however, it is worth noting that in Wilmsmeier et al.’s study, schizophrenia

patients showed no difference in task performance to the controls, and the authors

admit that patients were selected on their capability to perform the task in the fMRI.

Early data from schizophrenic patients undertaking the CANTAB ID/ED task

show deficits in both ED shifting and reversal learning—both derived from perseveration (Elliott et al. 1995). Whilst a small number of patients failed the task at

the ID stage and did not continue on, a significantly larger number of similarly

chronically affected patients showed a failure to form set as well as to shift set

(Pantelis et al. 1999). This general impairment in task performance seems tied to

current IQ level (Ceaser et al. 2008), although ED shift performance is most

strongly determined by current IQ (Jazbec et al. 2007). The impact of current IQ on

ED shift performance exists independently of the schizophrenia itself, although the

reversal learning deficit in schizophrenic patients is not dependent on IQ (Leeson

et al. 2009). In contrast, first-episode schizophrenia patients do not suffer from a

failure to complete the ID stage, and there is only a small (Hutton et al. 1998),

sometimes insignificant (Hilti et al. 2010; Braw et al. 2008), difference between

patients and controls in failure to complete the ED shift stage of the task. This

implies a distinct progression in the way executive dysfunction changes from onset

to chronic schizophrenia (Hutton et al. 1998).

In experimental animals, various methods have been used to model aspects of

schizophrenia, or some of the deficits associated with the disorder. Administration

of phencyclidine (PCP) has been considered one of the best models for schizophrenic frontal cortex dysfunction (Jentsch and Roth 1999): subchronic administration of PCP in both rats and monkeys reduces prefrontal DA transmission

(Jentsch et al. 1997b, c), whereas acute PCP administration increases DA transmission in both rat and monkey PFC (Jentsch et al. 1997a, 1998).

In rats (see Tait et al. 2014 for review), both single dose (Egerton et al. 2005)

and subchronic PCP regimes have been shown to impair attentional set-shifting in

the ID/ED task (Rodefer et al. 2005, 2008; Egerton et al. 2008). Both the single

dose, and one subchronic, PCP regimes produce a general discrimination learning

impairment (Egerton et al. 2005), whilst another subchronic regime does not



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(Rodefer et al. 2005). There is greater variability in the effects of other adult PCP

regimes, with some reporting no effect (Deschenes et al. 2006), or only a general

learning impairment (Fletcher et al. 2005).

Like subchronic PCP administration, amphetamine sensitisation also reduces

prefrontal DA neurotransmission in rats (Hedou et al. 2001). An amphetamine

sensitisation regime induces a general discrimination learning impairment, with the

ED stage and some (Featherstone et al. 2008; Fletcher et al. 2005) or all (Fletcher

et al. 2005) reversal stages being impaired relative to controls.

Neurodevelopment models for schizophrenia involve early life intervention or

genetic manipulations. Methylazoxymethanol acetate (MAM) administration via

injection into pregnant females on day 17 of gestation provides a different model for

dopamine dysfunction in schizophrenia. MAM-treated rats are sensitive to

amphetamine (Flagstad et al. 2004), indicating consistency with amphetamine

sensitisation regimes as models of schizophrenia. Impaired reversal learning and

ED shifting has been reported in MAM-treated rats (Featherstone et al. 2007).

Neonatal PCP administration (days 7, 9 and 11) impairs ED shifting with no effect

on general discrimination, or reversal, learning (Broberg et al. 2008) in rats tested as

adults, whereas transient inaction of ventral hippocampus via infusion of tetrodotoxin in neonatal rats (day 7) induces both reversal learning and ED shifting deficits

(Brooks et al. 2012a).

Genetic mouse models for schizophrenia exist (e.g. Stachowiak et al. 2013; Chen

et al. 2006; Hikida et al. 2007), although data on attentional set-shifting are limited to

a few studies investigating more targeted mutations that simulate some of the

functional changes of schizophrenia. For example, a mutation increasing catechol-Omethyltransferase, leading to reduced PFC DA availability, induces an ED shift

deficit (Papaleo et al. 2008), and reduced PFC GABAergic interneurons results in a

failure to demonstrate set-formation (Bissonette et al. 2014). Earlier mouse studies

investigating the effects of mutation on attentional set-shifting have suffered from no

observable set-formation in control animals (e.g. Glickstein et al. 2005).

The ID/ED task, the rodent version of which having good test–retest reliability

(Tait et al. 2009, 2013; Wallace et al. 2014), has been proposed as one of the core

tests of executive function for the Cognitive Neuroscience Treatment Research to

Improve Cognition in Schizophrenia (CNTRICS) test battery (Gilmour et al. 2013;

Barch et al. 2009). The WCST has poor test–retest reliability and as such, is not

included in the National Institute of Health’s Measurement and Treatment Research

to Improve Cognition in Schizophrenia (MATRICS) test battery (Nuechterlein et al.

2008; Barnett et al. 2010). In light of the desire to establish a standardised set of

cognitive tests for schizophrenia research, and the availability of mouse genetic

models, it seems necessary to achieve a consensus on the most effective means to

measure attentional set-shifting in the mouse. To date, the most consistently successful method stems from Bissonette and colleagues (Bissonette et al. 2008, 2012,

2014; Bissonette and Powell 2012)—with mice requiring more than one ID stage to

demonstrate set-formation reliably.



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8 Attention Deficit/Hyperactivity Disorder

and Attentional Set-Shifting

Attention deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder,

with an unclear aetiology, characterised by ‘excessive motor activity, inattentiveness and impulsivity’ (Lange et al. 2010). Children with ADHD are impaired on the

WCST (Pineda et al. 1998), although, as in control subjects, performance improves

with age (Seidman et al. 1997) and is not always apparent in adult ADHD patients

(Rapport et al. 2001; Hervey et al. 2004)—although high-IQ controls exhibit fewer

non-perseverative errors than high-IQ ADHD patients (Antshel et al. 2010). Recent

data suggest that WCST impairments in adults with ADHD could arise from

comorbid bipolar disorder rather than explicitly from the ADHD itself (Silva et al.

2014).

Data from the CANTAB ID/ED task on ADHD patients are varied—and effects

may depend on sampling mechanisms (see Chamberlain et al. 2011 for review).

Some studies on children indicate no effects of ADHD on reported measures

(Goldberg et al. 2005; Corbett et al. 2009), whilst other suggest a general discrimination learning impairment with increased failure to complete stages at later

reversal stages and the ED stage (Kempton et al. 1999; Mehta et al. 2004).

A rat model of ADHD, the spontaneously hypertensive rat (SHR), shows a

general discrimination learning impairment and a failure to form set in one study

(Cao et al. 2012). A second study also reports a failure to form set, with a transient

reversal, but no general, learning impairment (Cheng and Li 2013). The data from

the second study are limited, however, by the lack of a robust ID/ED difference in

the control rats—so, it is difficult to conclude that the lack of set-formation in the

SHRs is reliable. Given the availability of ADHD animal models (Sontag et al.

2010; Wickens et al. 2011), it seems there is opportunity for further investigating

ADHD-related executive dysfunction in rats and mice using ID/ED tasks.



9 Summary and Future Directions

Attentional set-shifting using the WCST and ID/ED tasks is a valuable tool for

exploring frontally mediated dysfunction in humans and other animals. The three

major neurodegenerative diseases, AD, HD and PD, result in distinct patterns of

PFC degradation and distinct patterns of executive dysfunction that can be assessed

using attentional set-shifting. Equally, other neuropsychiatric disorders affect

structure, neurotransmitter activity and PFC-dependent executive functions.

To date, animal models of human diseases and disorders have provided support

for existing research, and opened up new avenues for progress in disease/disorder

therapies. It remains necessary, however, in light of the non-standard methodologies of rodent ID/ED tasks, to draw towards a consensus on the best technique to

measure rodent attentional set-shifting. In a globalised scientific community,



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the WCST and the CANTAB ID/ED tasks can be purchased and run according to

an established set of instructions; but this is not the case for the rodent ID/ED tasks.

Thus, whilst differences in performance in human studies can often be determined

to arise from subject pool sampling—and indeed, we should take great care to

consider such during interpretation of data—in rodents, we must consider not only

strain, gender and age, but also the specific techniques used during testing (Tait

et al. 2014). Data are remarkably consistent in pattern between the numerous

research groups running the task—but odours, digging media, and textures differ—

and indeed it is often impossible to fully replicate one group’s apparatus because of

simple lack of availability. Where possible, however, we should attempt to be

consistent with previous published research, and provide clearer explanations for

changes—and what those changes could mean to the data.

The answer to the problem of methodological inconsistency in rodent data is to

standardise the task in a fashion that is accessible globally. And that must be the

ultimate goal—as the WCST and the CANTAB ID/ED tasks can be fully automated, so a true ID/ED automated task for rodents should be our goal. There have

been attempts to automate attentional set-shifting in rodents in the past, although

each has its own flaws: no difference between ID and ED performance in a visual

task (Brigman et al. 2005); a failure to use truly compounded stimuli in a multimodal task (Scheggia et al. 2014). It remains, then, a difficult, but not insurmountable task.

Whilst concern for interpreting rodent data typically derives from methodological differences, human data are often confounded by a verbal component to task

solving. The CANTAB ID/ED task uses stimuli that are difficult to verbalise, but

the WCST, unless specifically modified, does not: colour, number and shape are all

easily translated to verbal descriptions. Some studies have made changes to the

WCST protocol seeking to address this, although the vast majority do not. Parsing

verbal from non-verbal (or minimally verbal) processing is important not only when

considering data between humans and other animals, but also when considering

data from human studies that have taken verbal components into account versus

those that have not. Imaging studies investigating the involvement of precise PFC

subregions in attentional set-shifting must be considered carefully in the context of

the type of task used.



10



Conclusion



Attentional set-shifting is an important measure of executive function—and an

important tool for exploring executive dysfunction—in both human diseases and

animal models of human diseases. Although MATRICS does not include the WCST

or ID/ED as a measure of executive function in its test battery for schizophrenia,

CNTRICS does recommend ID/ED testing—and continued use of attentional

set-shifting tasks in rodents in the search to develop new therapeutic tools for

tackling human diseases and disorders, along with similar tests in humans to explore



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cognitive function/dysfunction, means that regardless of test–retest reliability, the

current measures of attentional set-shifting in humans are vital components in the

research process. We must continue our efforts to probe executive function using the

best attentional set-shifting methodologies available to us—exposing parallels in

function between species, and where necessary, elucidating the causes of differences.



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