EF Review Promise and Challenges

8/11/2019 EF Review Promise and Challenges

1/29

J Neuropsychiatry Clin Neurosci 14:4, Fall 2002 377

SPECIAL ARTICLES

Executive Control

Function: A Review of ItsPromise and Challengesfor Clinical ResearchA Report From the Committee on Research ofthe American Neuropsychiatric Association

Donald R. Royall, M.D.Edward C. Lauterbach, M.D.

Jeffrey L. Cummings, M.D.

Allison Reeve, M.D.Teresa A. Rummans, M.D.Daniel I. Kaufer, M.D.W. Curt LaFrance, Jr., M.D.C. Edward Coffey, M.D.

Received August 20, 2002. From the Committee on Research of theAmerican Neuropsychiatric Association. Address correspondence toDr. Royall, The University of Texas Health Science Center, 7703 FloydCurl Drive, San Antonio, TX 78229-3900. E-mail: [email protected].

Copyright 2002 American Psychiatric Publishing, Inc.

This report reviews the state of the literature andopportunities for research related to executivecontrol function (ECF). ECF has recently beenseparated from the specific cognitive domains(memory, language, and praxis) traditionally used

to assess patients. ECF impairment has been asso-ciated with lesions to the frontal cortex and itsbasal gangliathalamic connections. No single pu-tative ECF measure can yet serve as a gold stan-dard. This and other obstacles to assessment ofECF are reviewed. ECF impairment and related

frontal system lesions and metabolic disturbanceshave been detected in many psychiatric and medi-cal disorders and are strongly associated with

functional outcomes, disability, and specific prob-lem behaviors. The prevalence and severity of ECF

deficits in many disorders remain to be deter-mined, and treatment has been attempted in onlya few disorders. Much more research in these ar-eas is necessary.

(The Journal of Neuropsychiatry and ClinicalNeurosciences 2002; 14:377405)

The Research Committee of the American Neuropsy-chiatric Association has chosen the subject of exec-utive control function (ECF) for this report because ofits impression that ECF is vital to human autonomy anda major determinant of problem behavior and disabilityin neuropsychiatric disorders. The core of this review is

based on a literature search conducted in the spring of1998. It was the Committees intention to examine factoranalyses of putative executive measures, community-

based epidemiological studies of the prevalence of ECFimpairment, and placebo-controlled clinical trials withexecutive outcome measures. All English-language ar-ticles and reviews published after 1966 that containedthe keywords frontal or executive and were listedin the MEDLINE, EMBASE, PsychLit, or PsycINFO da-tabases were considered. These articles were then sep-arately cross-indexed with the keywords controlled(including both placebo controlled and controlledclinical trial subheadings), prevalence, and factors.

Broad terms were used because of our impression thatfew data would be available at this stage in the litera-tures development. Peer-reviewed articles were re-


2/29

378 J Neuropsychiatry Clin Neurosci 14:4, Fall 2002

EXECUTIVE CONTROL FUNCTION

tained. As we expected, very few relevant articles wereidentified. However, the original search was then fur-ther supplemented by backtracking to original sourcesand scholarly reviews of related topics. In addition, theoriginal computer search strategy was repeated in Jan-uary 2001 to take advantage of the exponentially in-

creasing volume of research in this area.In this review, we hope to provide a comprehensive,

albeit still superficial, overview of the progress in ECFassessment. This concept is rapidly evolving across awide range of disciplines. We first discuss the history ofECF and review its anatomical substrates. Then we ad-dress the obstacles to defining an executive gold stan-dard. Next we examine recent functional neuroimagingstudies. These have raised important questions aboutthe localization of executive processes. We explore therelevance of ECF to various neuropsychiatric disorders.ECF may be particularly relevant to disability and prob-lem behavior. Finally, we examine the possibilities for

treatment of ECF impairment and suggest an agenda forfuture research.

HISTORICAL BACKGROUND

The executive functions broadly encompass a set ofcognitive skills that are responsible for the planning, ini-tiation, sequencing, and monitoring of complex goal-directed behavior. Although a coherent framework ofexecutive control has yet to be developed, two centralthemes are emerging.

The first theme associates ECF with specific highercognitive functions such as insight, will, abstraction, and

judgment, which are mostly dependent on the frontallobes.1,2 This view implies that, like memory or lan-guage, the executive cognitive functions are acquiredskills that can be directly measured. ECF impairmentresults in the loss of these capacities.

The second theme emphasizes the cybernetic (fromthe Greek kybernetes, meaning pilot) aspects of exec-utive function. Executive functionscontrolthe executionof complex activities. This view implies first that ECFinteracts with nonexecutive processes, and second thatECF impairment is made visible only via the disorga-

nized operations of nonexecutive domains. The cyber-netic view of frontal function is not necessarily incom-patible with the older emphasis on higher cognitiveabilities, but it does bring a new emphasis on the dy-namic interactions between frontal control systems andthe processes they interact with.

The frontal lobes have been associated with thehigher cognitive functions since at least the famouscase of Phineas Gage.3 However, the more limited sense

of executive control has only recently emerged. Thisconcept follows efforts to apply cybernetic principals tohuman behavior. For example, Miller et al. in 19604 ap-plied the systems engineering concept of TOTE (TestOperate Test Exit) procedures to human cognition. Luriain 19695 initiated the modern era of clinical executive

function assessment with his careful descriptive studyof frontal head injuries among World War II veterans.In his book The Working Brain (1973),6 he described theclinical manifestations of disruption to a functional sys-tem for the programming, regulation, and verificationof behavior. As early as 1977, Butterfield and Belmont7

described executive function as the faculty in use[when] a subject spontaneously changes a control pro-cess . . . as a reasonable response to an objective changein an information processing task (p. 244). Norman andShallice developed the concept of a supervisory atten-tional system in 1980.8 This idea has been further re-fined into the central executive,9,10 although the na-

ture and functions of the central executive are still amatter of debate.1113

Clinicians soon associated frontal lobe injuries withthe loss of behavioral regulation predicted by Shallice,Norman,14,15 and Duncan.16 Meanwhile, Marsden in1982 pointed to the notable role of the basal gangliain organizing and controlling motor actions.17 Majoradvances followed the work of Alexander and col-leagues.18,19 Working with primates, they demonstratedthat the frontal lobes were associated with distinct basalgangliathalamocortical circuits. Lesions to these cir-cuits produce frontal lobe behavior and personalitychanges. Moreover, Goldman-Rakic and colleaguesdemonstrated that the effects of frontal cortical lesionscan be reproduced all along the related circuit.2023 Thisresearch explained the appearance of frontal syn-dromes following subcortical lesions and greatly ex-panded the list of conditions that could potentially affectexecutive control.

In 1990, DeKosky and Scheff24 identified mesiofrontalsynaptic density as the strongest pathological determi-nant of dementia severity ratings that has yet been re-ported in Alzheimers disease (AD). This finding opensup the possibility that frontal pathology, and by exten-sion ECF impairment, may be the essential feature of

dementia. Later studies have shown that only pathologyin the frontal cortex (or select afferents) is both necessaryand sufficient to explain the clinically recognized de-mentia in AD25 and non-AD dementias.26

Concurrent with these developments, researchers us-ing functional imaging began to identify frontal meta-

bolic deficits and correlate them with clinical pathologyin conditions as diverse as schizophrenia, major de-pression, and attention-deficit/hyperactivity disorder


3/29


ROYALL et al.

(ADHD). These and other clinical correlations led, in1994, to the inclusion of ECF in the American Psychi-atric Associations definition of dementia.27

However, the clinical assessment of executive func-tion has lagged behind these advances. This is partly

because of the lack of suitable measures. The Stroop

Color/Word Interference Test (Stroop), the Trail MakingTest Part B (Trails B) of the Halstead-Reitan battery, theConceptualization Task of the Dementia Rating Scale,and a variety of other tests of abstraction and mentalcontrol have been offered as putative ECF measures.28

The Wisconsin Card Sorting Test (WCST) is perhaps thebest described ECF test (see box, p. 391), but these andother formal executive measures are often impracticalfor widespread use outside of academic settings.

In 1990, Kaye et al. introduced the Behavioral Dyscon-trol Scale (BDS), a brief compilation of clinical itemsadapted from the work of Luria.29,30 In 1992, Royall et al.introduced the Executive Interview (EXIT25),31 followed

in 1998 by CLOX: An Executive Clock Drawing Task.32Most recently, the Frontal Assessment Battery (FAB)33 has

been introduced. This instrument is similar to the BDSand the EXIT25 in that it is a compilation of simple clini-cal ECF assessments. However, the FAB differs from ear-lier measures in that its item set was designed to elicitseveral distinct executive tasks, each of which can be sig-nificantly correlated with frontal metabolic changes.

Another approach to ECF assessment has been toidentify the behavioral sequelae of executive dyscontroland to measure these. Behavior rating scales, such as theNeuropsychiatric Inventory (NPI),34 contain subtests for

behaviors that have been specifically associated withfrontal lesions. The Behavioural Assessment of the Dys-executive Syndrome (BADS)35 and the Frontal Lobe Per-sonality Scale (FLOPS)36 have been explicitly developedto measure dysexecutive behavior syndromes.

This new generation of ECF instruments can be ad-ministered by clinicians in almost any setting. Conse-quently, executive impairment has been demonstratedin almost every major neuropsychiatric disorder (re-viewed below). In many of these conditions, measuresof executive function are more strongly associated withfunctional status, level of care, and need for servicesthan are either syndrome-specific positive symptoms

(e.g., psychosis, mood disturbance, or memory loss) ornonexecutive cognitive domains.

ANATOMICAL SUBSTRATES OF ECF

The Prefrontal Cortex

The role of the prefrontal cortex in executive function issuggested by its unique structure and pattern of con-

nectivity.37 The prefrontal cortex (Brodmann areas [BA]811, 24, 25, 32, 4547) comprises more than 30% of the

brains weight and surface area. It is a phylogeneticallyrecent structure, representing only 10% to 20% of theprimate brain.38

The frontal cortex can be grossly divided into two cy-

toarchitectural regions. The posterior portion is agran-ular in nature. This term refers to the minimal repre-sentation of the internal granular layer IV in posteriorfrontal cortical sections. In contrast, the regions that aremost closely associated with executive function (e.g., theanterior [prefrontal] portion of the frontal lobes,which comprises the dorsolateral and orbital/medial re-gions) consist of granular cortex. This term refers to acortical architecture in which layer IV is distinct andwell developed. Layer IV is most developed in BA 46and becomes progressively less distinct as one movesventrally and posteriorly from there.

Cortical layer IV is rich in inhibitory GABAergic in-

terneurons. These interneurons receive input frombioaminergic nuclei in the brainstem and feed for-ward to provide inhibition to local pyramidal cells incortical layers III and V. GABAergic interneurons have

been implicated in the executive impairments of schizo-phrenia39 and may represent one of the principal targetsof atypical neuroleptics.

Several unique aspects of the prefrontal cortex sug-gest that it mediates ECF. First, the prefrontal cortex isconnected to more brain regions than any other corticalregion. Only the primary sensorimotor cortices and sub-cortical sensorimotor relay nuclei do not have direct orsimple indirect connections to the prefrontal cortex. Sec-ond, the frontal cortices are metamodal: they receivedirect cortical input only from other heteromodal asso-ciation areas. Thus, they are positioned to act on infor-mation that has already been processed at lower levels.The integrative nature of prefrontal regions is reflectedeven at the cellular level. Many frontal neurons increasetheir firing rate in response to the combined activity ofsensory and motor regions. Additionally, frontal firingpatterns may be altered by manipulating the motiva-tional importance of environmental stimuli. Third, theprefrontal cortex is the major neocortical target for in-formation processed in the limbic circuits. It is the only

cortical region positioned to integrate cognitive and sen-sorimotor information with emotional valences and in-ternal motivations. Fourth, although wide areas of thecortex project into the basal gangliathalamocortical cir-cuits, the prefrontal cortex is that systems major target.Thus, the frontal lobe is the only cortical region capableof integrating motivational, mnemonic, emotional, so-matosensory, and external sensory information into uni-fied, goal-directed action.


4/29



In addition, the prefrontal cortex has bilateral connec-tions to the basal gangliathalamocortical circuits tar-gets in the thalamus. Similarly, the prefrontal cortex has

bilateral connections to its afferents in the parietal, tem-poral, and occipital association cortices, the limbic cir-cuits, and the major brainstem biogenic aminergic nu-

clei, as well as to the cholinergic neurons of the nucleusbasalis of Meynert. These connections put the prefrontalcortex in a unique position to modify the information itacts on. Moreover, in the case of the major brainstem

bioaminergic nuclei, which project diffusely to the cor-tex, the prefrontal cortex is positioned to indirectly in-fluence the activity of the nonfrontal cortex as well.

Frontal Basal GangliaThalamocortical CircuitsCertain subcortical lesions can affect ECF either directlyor indirectly via frontal cortical metabolic changes (e.g.,

by diaschisis). The caudate, putamen, pallidum, nucleusaccumbens, and thalamus are related to the frontal cor-

tex through basal gangliathalamocortical behavioralcontrol circuits (Figure 1A).19,40,41 Although each ofthese circuits passes through different structures, all ofthe frontal circuits are similar in design.

The neurochemistry of these circuits connections isknown.42 Excitatory glutamatergic fibers from the cortexproject to the neostriatum (caudate, putamen); then in-hibitory GABAergic fibers project to the globus palli-dus/substantia nigra and from there to specific targetsin the thalamus. These connections form dynamically

balanced direct and indirect circuits connecting the pre-frontal cortex to the thalamus. The thalamus closes thecircuit by projecting back to prefrontal cortical regionsvia stimulatory glutamatergic fibers. Cholinergic projec-tions to the frontal cortex facilitate thalamic activation

of that structure. Dopamine (DA) projections from theventral tegmentum also innervate the cortex. DA pro-

jections from the nigra innervate the striatum.In each circuit, the corresponding frontal cortical re-

gion and striatum receives inputs from cortical regionsthat are more posterior.4346 These inputs provide in-

sights into each circuits functional role by revealing theprocesses with which it interacts. The dorsofrontal cir-cuit receives information from the parietal and temporalcortex. These regions provide access to complex spatialand temporal information. The orbitofrontal circuit re-ceives input from visual and auditory processing areasin the occipital and temporal lobes, as well as limbiccenters in the amygdala and temporal poles. The ante-rior cingulate/mesiofrontal cortex receives input fromthe hippocampus, amygdala, and paralimbic cortex.Some authors have labeled the anterior cingulate circuitparalimbic for this reason.

Several aspects of this circuitry also deserve special

mention. First, these circuits funnel information fromwidespread cortical areas into relatively small thala-mocortical targets. These targets are all in the prefrontalcortex, consistent with the role of these circuits in be-havioral/cognitive control. Second, the behaviors thatmark each circuit can be reproduced by lesions at vari-ous points along their path. For example, the ability toperform certain visuospatial working memory tasks(which involve the short-term maintenance of informa-tion during its manipulation) is dependent on the integ-rity of the dorsolateral prefrontal cortex.23 However, thesame tasks are disrupted by lesions to the caudate20 andto the mediodorsal thalamic nucleus21,22 in the dorso-frontal circuit. This association suggests that frontal cor-tical damage is a sufficient but not a necessary cause of

FIGURE 1. Functional sequelae of caudate impairment (adapted from Kelly & McCulloch87). A: A functional lesion to the left caudateputamen (CDT) results in disinhibition of the ipsilateral globus pallidus (GP), with resultant inhibition of the thalamus(Thal) and loss of cortical tone (CTX). B: These relationships are predicted by the basal gangliathalamocortical circuitanatomy of Alexander et al.19 and can explain the loss of executive control following subcortical lesions in such circuits.


5/29


ROYALL et al.

executive dyscontrol. Finally, the circuits appear to bediscrete (i.e., nonoverlapping) and spatially constrained.At the level of the cortex, they are widely separated.Cortical lesions can divorce the behaviors associatedwith one circuit from another. Subcortically, however,the circuits are in much closer proximity. This anatomy

suggests that subcortical pathology is likely to lesionmultiple circuits simultaneously, mixing the syndromestogether.

Three frontal circuits are particularly relevant to ex-ecutive control: the dorsolateral prefrontal circuit, thelateral orbitofrontal circuit, and the anterior cingulatecircuit.18,47

Dorsolateral Prefrontal Circuit: The dorsolateral convex-ities of the frontal lobes consist of BA 812, 46, and 47.The blood supply for these regions is from the middlecerebral artery. In the dorsolateral circuit, corticofugalpathways project to the dorsolateral caudate nucleus,

which also receives input from the posterior parietal cor-tex and the premotor area. The circuit then connects tothe dorsolateral portion of the globus pallidus and therostral substantia nigra reticulata and continues to theparvocellular region of the medial dorsal and ventralanterior thalamic nuclei. The circuit is closed via tha-lamic projections back to the frontal dorsolateral con-vexity. Lesions to this circuit have been implicated in avariety of higher cognitive functions, including goal se-lection, planning, sequencing, response set formation,set shifting, verbal and spatial working memory, self-monitoring, and self-awareness (metacognition).38,4852

The WCST consistently activates dorsolateral frontal re-gions.

Lateral Orbitofrontal Circuit: The orbit of the frontallobes refers to a continuous region including ventral an-terior and inferior lateral regions (BA 1015 and 47). Me-dial regions are vascularly supplied by the anterior ce-rebral artery, and lateral regions lie in the territory of themiddle cerebral artery. Cortical projections terminate onthe ventromedial caudate nucleus, which also receivesinput from other cortical association areas, including thesuperior temporal gyrus (auditory) and inferior tem-poral gyrus (visual), as well as brainstem regions (e.g.,

the reticular formation). Projections continue to the dor-somedial aspect of the internal globus pallidus and tothe rostromedial portion of the substantia nigra reticu-lata. Pathways continue to the magnocellular region ofthe medial dorsal and ventral anterior thalamic nuclei,and then return to the lateral orbitofrontal region.

The orbitofrontal circuit appears to be involved in theinitiation of social and internally driven behaviors andthe inhibition of inappropriate behavioral responses.48,52

Orbitofrontal function may be particularly relevant torisk assessment. Choosing between small but likely re-wards and large yet unlikely rewards activates inferiorand orbitofrontal regions.53 Impairment on the go/no-go task has been associated with orbitofrontal lesionsin animals54 and humans.55 Orbitofrontal lesions also

lead to clinical features such as environmental depen-dency and utilization behavior.5658

Anterior Cingulate Circuit: Frontal regions involved inthis circuit are medially located (BA medial 913, 24, and32), and receive their blood supply from the anteriorcerebral artery. The circuit connects to the ventral stria-tum (nucleus accumbens and olfactory tubercle), whichreceives additional input from paralimbic associationcortex, including anterior temporal pole, amygdala, in-ferior hippocampus, and entorhinal cortex. The circuitcontinues to the ventral pallidum and rostrodorsal sub-stantia nigra, and then to the medial dorsal thalamic

nucleus. It terminates at the anterior cingulate, com-pleting the circuit.

The anterior cingulate is important in monitoring be-havior and error correction. The Stroop activates the an-terior cingulate and its mesiofrontal extensions.59 TheEXIT2531 has also been specifically associated with leftmesiofrontal cerebral blood flow by single-photon emis-sion computed tomography (SPECT).60

OBSTACLES TO DEFINING AN EXECUTIVEGOLD STANDARD

One of the obstacles to ECF research has been the lackof a clear gold standard measure against which pu-tative ECF measures can be compared. This measurewould presumably call upon specific frontal functionsand be selectively vulnerable to frontal pathologies.However, this may not be an achievable goal for threereasons. First, since the frontal lobe represents so muchof the brains weight and surface area, it seems unlikelythat any one measure could assess its functions compre-hensively. We may be searching for a frontal-executive

battery, not an executive measure. Second, the anatomyof frontal systems suggests that specific subcortical pa-

thologies are also relevant to ECF. Thus, we may noteven be looking for a frontal battery so much as a frontalsystem battery. Finally, the cybernetic character of ECFimplies an intimate relationship between ECF and itsassociated targets. We will need to qualitatively distin-guish between the loss of executive control over a non-executive domain and a primary disruption of the do-main itself.

For example, although some tasks (e.g., the WCST, the


6/29



Stroop, the Category Test, the EXIT25, and Trails B) havebeen specifically associated with frontal structural ormetabolic changes,6166 they can also be affected by moreposterior lesions.6770 WCST performance is not specificfor frontal lobe damage unless deficits in comprehen-sion or visual search are controlled.71 Furthermore, both

the WCST and the Stroop measure multiple dimensionsof executive control in factor-analytic studies. These di-mensions may not be localizable to the frontal lobeseven if frontal systems are a major determinant of theirvariance.

Peterson et al.59 provide an example of this problemfor the Stroop. This measure activated multiple nonfron-tal cortical regions, which in turn resolved themselvesinto seven discriminable factors. These factors were in-terpreted as representing distributed neuronal networkssupporting error monitoring, working memory, selectiveattention, and motor planning (among others). Althoughseveral Stroop factors shared the anterior cingulate, cin-

gulate activation does not uniquely explain Stroop vari-ance, and many nonfrontal lesions have the potential toaffect Stroop performance. Nevertheless, activation stud-ies have been criticized for their sensitivity to subclini-cal differences in performance.72 Frontal lesions selec-tively affect the Stroop in actual patients.73 Thus, poorStroop performance may yet be indicative of frontal pa-thology, despite the complexity of activation studies.

It appears that neither the measures used to assessECF nor the biological substrates they activate are easilylocalizable. Four important dichotomies need to be ad-dressed before these apparent discrepancies can be re-solved. Each will be discussed in turn.

1. Frontal Lobe vs. Frontal System:Frontal cortical le-sions may be sufficient, but are not necessarycauses of executive impairment.

2. Structure vs. Function:Frontal cortical function maybe compromised by subcortical lesions (i.e., vas-cular disease) in the absence of demonstrable localcortical pathology.

3. Control vs. Process:Executive functions control per-formance in other neuropsychological domains.Some tasks that were previously ascribed to non-executive domains may be sensitive to frontal sys-

tem pathology because they require executive con-trol. Conversely, lesions outside the frontal systemsmay undermine ECF test performance, in the ab-sence of executive dyscontrol, by disrupting theprocesses being controlled during the task.

4. Executive Function vs. Executive Function(s): Somemeasures may be sensitive to only a subset of ex-ecutive functions.

Frontal Lobe vs. Frontal System

It has proven difficult to localize specific executiveoperations to specific prefrontal regions. Rather, ECFmay depend on the integrity of frontal systems. For ex-ample, LHermitte et al.57 have described the phenom-enon of utilization behavior (in which a patient au-

tomatically utilizes a familiar object in a habitual way,regardless of its appropriateness to the current context)following orbitofrontal lesions. The same behavior has

been described following massive bilateral frontal le-sions74 and mesiofrontal lesions,75 both of which mightinvolve orbitofrontal regions. However, utilization be-havior has also been reported following lesions to otherfrontal system structures, including the caudate76 andthalamus.77 The unity of frontal circuit activity can bededuced from factor analyses of regional brain metab-olism: 70% of regional variance in total cerebral glucoseutilization can be explained by a single factor that con-tains the frontal circuits (e.g., the frontal cortex, cingu-

late gyrus, caudate nucleus, putamen, and thalamus)and temporal cortex.78

There may be several reasons for the difficulty in mak-ing clinicopathological correlations between ECF andfrontal lesions: 1) the taxonomy of executive impairmentshas not been adequately developedmany authors maynot be comparing identical phenomena; 2) although dis-crete prefrontal pathways have been partially estab-lished, precise anatomical boundaries are not well de-fined, especially at the cortical level, and certain frontalfunctions are limited to subregions of traditional BA re-gions of interest;79 3) lesions to the frontal lobes are oftennot well defined or do not follow clear and reproducible

boundaries across subjects (e.g., most frontal strokescause additional damage to subcortical or posterior re-gions); 4) frontal lobe pathology, such as tumors, stroke,or trauma, frequently results in remote effects secondaryto vascular changes, pressure effects, and disconnectionof neural pathways. Data from psychosurgery (tumorevacuation or frontal leukotomy) can be especially diffi-cult to interpret for several reasons: a) these studies oftenuse abnormal patients to begin with, b) cognitive out-come assessment is often rudimentary, and c) follow-upis typically short term (i.e., months rather than years).

Nonetheless, it now appears that there are regional

differences in behavioral sequelae of frontal cortical le-sions.5,38,8082 Damage to the dorsolateral prefrontal cor-tex impairs planning, hypothesis generation, and be-havioral control. Episodic memory encoding andretrieval is affected by ventrolateral lesions. Workingmemory is affected by more dorsal pathology. Orbito-frontal lesions lead to impaired insight, judgment, andimpulse control. These traits were part of PhineasGages deterioration. Mesiofrontal/anterior cingulate le-


7/29


ROYALL et al.

sions lead to indifference and attentional dyscontrol. Pa-tients generate little speech or behavior spontaneously,yet may respond correctly if prompted.

Moreover, the dysexecutive neuropsychological pro-file of prefrontal cortical disorders such as frontotem-poral dementia can also be observed in subcortical frontal

system disorders such as Parkinsons disease (PD),Huntingtons disease (HD), progressive supranuclearpalsy,83 or subcortical vasculopathy.84 Even neuropsy-chiatric disorders such as major depression and schizo-phrenia are associated with a similar pattern on psycho-metric testing, suggesting that they too may involvefrontal system pathology.85,86

In summary, executive functions have been difficultto localize within the frontal cortex. This situationmight be improved with more careful attention to le-sion location and a formal approach to frontobehav-ioral nomenclature. Nonetheless, the logic of frontal

basal gangliathalamocortical networks suggests that

frontal system lesions are both sufficient and necessaryto executive impairments.

Structure vs. FunctionAnother dichotomy that deserves attention is that be-tween frontal structure and function. Executive controlcan be compromised without a frontal cortical lesion.Frontal function can be indirectly affected by lesions tofrontal lobe afferents or related frontal system circuitstructures. Conversely, lesions to corticofugal tracts candisconnect the frontal operations from the processesthey control.

Human and animal studies suggest that subcorticallesions to frontal system networks may remotely affectfrontal cortical metabolism (e.g., by diaschisis), eitherincreasing or decreasing frontal metabolism. Figure 1Apresents the results of a study by Kelly and McCulloch87

in which rats received a 500-ng injection of muscimol (aGABAergic agonist) to the left caudate nucleus. This le-sion resulted in a functional caudate lesion on that side.The effects of this lesion were studied using [14C]2-deoxyglucose autoradiography. Brain regions that weremetabolically active at the time of injection took up thisradioligand. Regions that were metabolically inactive,including the left caudate, did not take up the tracer. In

each section, the right (unaffected) side served as thelefts control.Figure 1B demonstrates that the caudate lesion re-

sulted in disinhibition of the ipsilateral globus pallidus,leading to increased inhibition of the ipsilateral medialthalamic nucleus, resulting in reduced activation of theipsilateral cortex. In short, a discrete subcortical lesionin frontal networks may lead to remote changes in fron-tal cortical metabolic function. This finding can be un-

derstood in the context of frontal circuit anatomy (Fig-ure 1A) and may help to explain the finding of frontal

behavioral syndromes and ECF impairment in subcor-tical dementias,88 as well as the specific association be-tween subcortical vasculopathy and frontal hypometab-olism in vascular dementia (VaD) and late-onset major

depression.8991

Patients with PD, major depression, and schizophre-nia often appear hypofrontal by functional neuroim-aging.9295 In PD and major depression, this may be re-lated to cortical deafferentation of medial nigral orventral tegmental DA inputs.96 The hypofrontality of

both disorders is associated with tests that are linked toDA physiology.97,98 Alternatively, these deficits might berelated to cortical deafferentation of the thalamic in-puts.19,90,99 Medial thalamic infarction results in frontalcortical hypometabolism by positron emission tomog-raphy (PET) and SPECT.100,101 Thalamic outputs to thefrontal cortex can be disrupted indirectly after globus

pallidus lesions.102However, executive impairments are not only asso-

ciated with frontal hypometabolism. In obsessive-compulsive disorder (OCD), cortical hypermetabo-lism103 is associated with poor performance on ECFmeasures.104 Similarly, in HD the degree of prefrontalactivation during the WCST is inversely proportionalto the subjects performance, yet is statistically associ-ated with the amount of caudate atrophy.105

These seemingly paradoxical findings may be under-stood from the point of view of frontal systems physi-ology. OCD has been associated with hypometabolismin the globus pallidus and thalamic disinhibition. Tha-lamic disinhibition might result in increased thalamo-cortical glutamatergic tone (Figure 1A). Thalamocorticalglutamatergic inputs co-localize with inhibitory dopa-mine D1 receptors on pyramidal cell dendrites in theprefrontal cortex.40 The balance between these opposinginfluences affects prefrontal signal-to-noise process-ing.106 Either increasing glutamatergic excitation or di-minishing dopaminergic pyramidal cell inhibitionshould lead to increased pyramidal cell activity, at theexpense of signal specificity. A precise range of DA re-ceptor activity within the prefrontal cortex must bemaintained for optimal function.107108 In the case of

OCD, DAs inhibitory effects may be overwhelmed byincreased glutamatergic tone.In summary, executive control depends on the integ-

rity of frontal systems. Executive impairment may fol-low disruption of frontal system information process-ing, regardless of the location of the lesion within thesystem or the direction of the perturbation. In somecases, remote lesions can affect processing within thefrontal circuits.


8/29



TABLE 1. Examples of executive and nonexecutive frontalcapacities (after Lezak28)

This model emphasizes that executive control may be either only asubset of frontal functions or an emergent property of frontalsystems. For example, the capacity to formulate an efficient

problem-solving strategy, or to anticipate likely outcomes, althoughperhaps related to the frontal cortex, is not necessarily anexecutive skill. In contrast, the loss of executive control followingfrontal system lesions divorces capacity from its successfulimplementation.

Nonexecutive frontal capacities:1. Can the patient form efficient problem-solving strategies?2. Can the patient use past experience to anticipate future

problems?

Similarly, we might ask:Can the patient abstract?Can the patient self-monitor his or her behavior?Can the patient anticipate future consequences of his or her actions?Can the patient give a reason for his or her actions?

Executive frontal system capacities:1. Does the patient disregard nonadaptive strategies?2. Does the patient modify ongoing behavior in response to

dynamic task requirements?

Similarly, we might ask:Does the patient remember whats important?Does the patient get where he or she needs to go?Does the patient make appropriate decisions?Does the patient finish what he or she starts?Does the patient comply with treatment?

Control vs. Process

Lezak28 has offered a simple test for defining what con-stitutes an executive measure. Questions about exec-utive functions explain how or whether a person goesabout doing something . . . questions about [traditional]cognitive functions are generally phrased in terms of

what or how much. (p. 42). This simple dichotomycleaves the vast array of frontal functions into controlfunctions and their target processes. Either may be de-pendent on frontal activities; however, only the controlfunctions are executive in a cybernetic sense. The sub-set of frontal functions that are executive depends onhow the question is asked (Table 1).28

This distinction can be addressed experimentally. Forexample, there is an extensive literature associatingschizophrenia with deficits on the WCST. However, pa-tients with schizophrenia benefit from cueing during theWCST test procedure.109 In other words, they can gen-erate the abstract concepts demanded by the task, but

they do not apply them unless prompted. Thus, althoughthe abstract concept formation demanded by the WCSTmay in fact be localizable to the frontal lobes, it is notnecessarily an executive control function in the limitedsense required by Lezak because it merely addresseswhat patientscan do and not whether they do it when

needed. In contrast, the failure of patients with schizo-phrenia to inhibit automatic but inappropriate verbalresponses on tests such as the Stroop110 would be moreconsistent with Lezaks view of executive control.

Authors who emphasize a cybernetic view of ECFpoint to the potential to observe executive dyscontrol

in performance on many seemingly nonexecutivetasks.12,111 By analogy, at least some variance in all neu-ropsychometric tests may be specifically attributable tothe executive control demanded by the testingparadigm(see g below). We will examine the executive controlof clock drawing, memory, and language.

The clock-drawing task (CDT) has traditionally beenviewed as a visuospatial task, sensitive to right hemi-sphere pathology.112 However, frontal leukotomy selec-tively affects CDT performance relative to age, disease,and education-matched control subjects.113 CDT failuresamong frontally impaired subjects challenge a chieflyvisuospatial conceptualization of the CDT and suggest

the need for a separate analysis of the executive controldemanded by the testing paradigm.

Figure 2 presents a patients performances on CLOX,an executive CDT.32 CLOX1 is an unprompted task.CLOX2 is a copied version. The visuospatial compo-nents of these tasks are similar. However, CLOX1 entailsexecutive control because it requires the subject to gen-erate a figure in the absence of relevant visual cues. Thevalidity of CLOX1 as an executive paradigm is sug-gested by the fact that, in elderly retirees, both CLOX1and the EXIT25, but neither CLOX2 nor the Mini-MentalState Examination (MMSE) makes significant indepen-dent contributions to the number of categories achievedon the WCST.114 Figure 2 presents the pattern of CLOXperformance expected in a frontal system disorder. Ex-ecutive measures (the unprompted CLOX1 and theEXIT25) are impaired. CLOX2 (copied) and the MMSEare not.

The same qualitative dissociation between controland process can be elicited in other domains, such asmemory. Memory tasks can be affected by frontal, pa-rietal, and mesiotemporal cortical lesions. However, thepattern of memory loss that follows frontal system le-sions is discriminable from traditional limbic amne-sia.115119 The ability of a memory task to activate dor-

sofrontal systems depends greatly on the structureprovided to the subject during memory testing.120,121 Forexample, the intentional, goal-directed retrieval of in-formation results in frontal activation relative to inci-dental cued recall.122 Patients with frontal lesions are un-impaired in their ability to recall cued information, buthave difficulty with tasks that require them to organize,sequence, or monitor the information themselves. Thus,they have trouble with free recall, temporal order, and


9/29


ROYALL et al.

FIGURE 2. CLOX performance in subcortical frontal system vasculopathy. Results shown are for a 77-year-old right-handed male withtype 2 frontal system vascular dementia. CLOX1 is represented at left, CLOX2 at center; at right, the patients MMSE

pentagon item is provided for comparison. Total CLOX scores appear in the box below each drawing. CLOX is scored on a 15-point metric; lower scores indicate impairment.

The CLOX has been normed to young adult control subjects. A CLOX1 score of 10/15 or a CLOX2 score of 12/15 representsthe 5th percentile for young adults. The pattern of CLOX scores obtained by this patient suggests the loss of executive controlover intact constructional skills. An isolated impairment in ECF is supported by his other test scores: EXIT25, 19/50(scores15/50 impaired; 18/50 is the mean for elderly retirees living in assisted living settings), 251 and MMSE, 29/30 (scores24/30 impaired). His ECF impairment affects memory functions as well. He freely recalls only 2 of 4 words after distractionon the Memory Impairment Scale,296 but recalls 4 of 4 with cues (total MIS score 6/8).

source memory. Similarly, confabulation among amnes-tic subjects appears to reflect mesiofrontal/anterior cin-gulate impairment, resulting in a failure to ignore active

but currently irrelevant memory traces.123

Not all memory tasks that activate frontal regions arenecessarily executive. In neuroimaging studies, tasks

that call for relatively simple episodic or semantic en-coding tend to activate the left ventrolateral prefrontalcortex.124 Those that call for retrieval activate the rightventrolateral prefrontal cortex. However, if the subjectis asked to manipulate the information while encodingor retrieving it, the focus of activation shifts towardmore dorsolateral regions.125

Language skills are also affected by ECF impairment.Arbuckle and Gold126 have associated disorganized andhyperverbose speech, but not language impairment perse, with impaired working memory and executive con-trol. Similarly, only a small amount (25%) of variance inverbal fluency scores can be explained in multivariate

regression models by tests of verbal memory, verbal at-tention, and vocabulary.127

The idea that ECF may explain some variance in mostcognitive measures, regardless of the domains they pur-port to measure, is similar to Spearmans concept ofgeneral intelligence or g.128 g represents theshared variance across domains and has been repeatedlyobserved in batteries of multiple cognitive measures.For example, in normal aging there are significant de-clines in cognitive test performance across several do-

mains. Salthouse et al.129 found moderate age-relateddeclines on a battery of tests that included the WCST,Trail Making, Wechsler Adult IntelligenceScaleRevised(WAIS-R) Block Design, and Digit Symbol Substitution(DSS).

However, correlation-based analyses revealed that the

age-related effects on different measures were not in-dependent. Instead, the effect of age was observed spe-cifically in the fraction of variance (averaging 58%)sharedacross all measures (i.e., g); g has been local-ized to dorsolateral prefrontal cortex by PET130 and as-sociated with working memory (also associated withdorsolateral prefrontal cortex; see below)131,132 and withformal executive measures.133

In summary, there is no established framework forinterpretation of the executive functions. Some authorsemphasize the frontal lobes and their importance inplanning, hypothesis generation, and abstraction. Oth-ers, however, work within a more limited subset of fron-

tal functions. These authors see ECF as a specific subsetof frontal lobe activities, revealed by the examination ofhow the frontal systems interact with other systems toproduce and control complex goal-directed activities.

Executive Function vs. Executive FunctionAnother dichotomy that has yet to be resolved iswhether there is a single executive control, as opposedto multiple controls for discrete operations. The idea ofa single executive is implied in the concept of the cen-


10/29



tral executive and the multimodal nature of the frontallobes anatomy and functional connections. Researchershave developed computer models of subject task per-formance on putative frontal measures that success-fully model patient task performance on four frontaltasks (the WCST, the Stroop task, motor sequencing, and

a context-dependent memory task).134

Frontal-type er-rors on all tasks can be observed after degrading a singledomain (working memory).

However, patients with frontal lesions often displaydisassociations in their performance on select frontaltasks. This effect might be due to regional differences inthe types of processes to which frontal mechanisms areapplied.135 Although the frontal lobes appear to be lessfunctionally committed than more posterior cortical re-gions,136 their functions can be roughly divided alongfour spatial dimensions: leftverbal/rightnonverbal,anteriorcognitive/posteriormotor, ventralperception/dorsalaction, and medialinternal focus/lateralexternal

focus. Thus, the verbal aspects of working memory tasksmay activate the left dorsolateral prefrontal cortex andnonverbal aspects may activate the right.137139 Evenwithin the domain of nonverbal working memory, recallof faces activates more ventral regions of the right dor-solateral frontal cortex than does recall of spatial loca-tion.140 This functional specificity may go all the waydown to the cellular level.141

Goldman-Rakic has suggested that different prefron-tal areas may perform the same operation on differentinputs.23 This hypothesis is consistent with the func-tional segregation of the basal gangliathalamocortical

circuits. Support for a modular organization of frontalfunction has been developed in humans.142 Cognitivetest performance is most closely related to dorsofrontalcerebral glucose metabolism, whereas social behaviorand disturbances of comportment are related to mesio-/orbitofrontal metabolism. Similarly, dorsal regions of the

anterior cingulate are activated by attention-demandingStroop-like interference tasks, whereas ventral regions ofthe anterior cingulate respond when similar tasks are ap-plied to emotionally laden content.143

Dimensions of Executive Control: There are many puta-tive ECF measures144 (Table 2). However, it is not at allclear that these all test the same dimensions of executivecontrol. Our literature review identified several studiescontaining factor analyses of putative ECF measures(Table 3). Interpreting these studies can be difficult.145

Few have been intentionally designed to address ECF.Prior to about 1998, most authors interpreted their re-

sults without regard to ECF or frontal function. Instead,factors with strong loadings by ECF measures werethought to represent vigilance or attention. The dif-ferences between ECF and simple attention have beenextensively studied.146 It is relevant to the cybernetic for-mulation of ECF that judgment, concept formation,problem solving, and decision making are seldommentioned in factor analyses of ECF measures.

Putative ECF measures do not load onto a single,overarching executive construct. Most studies find mul-tiple dimensions of executive control. The availablestudies tend to confirm a rule discoveryfactor labeled by

TABLE 2. Selected neuropsychological tests of frontal executive skills

Measures Dimensions Reference

Formal testsCalifornia Card Sorting Test CG, P, I Beatty & Monson 1990297

Category Test CG, wM(v) DeFilippis et al 1979298; Reitan & Wolfson 1995299

Concept Generation Test CG, wM(v) Levine et al 1995300

Porteus Mazes P, wM(s) Mettler 1952301; Porteus 1965302

Ravens Progressive Matrices wM(s), CG Raven et al 1977303

Stroop Color-Word Interference Test I, wM(v) Stroop 1935304

Tinker Toy Test CG, wM(s) Lezak 199528

Tower of Hanoi wM(s), P, I Welsh et al 1990305

Tower of London wM(s), P, I Norman & Shallice 19808; Shallice 198214

Wisconsin Card Sorting Test CG, P, I Grant & Berg 1948306; Milner 196361

Bedside screening instrumentsBehavioral Dyscontrol Scale I Grigsby et al 199230

CLOX: An Executive Clock Drawing Task wM(s), CG Royall et al 199832

Controlled Oral Word Association Test CG, wM(v) Benton & Hamsher 1989307

Design Fluency CG, wM(s) Jones-Gotman & Milner 1977308

Executive Interview (EXIT25) I, CG wM(v & s) Royall et al 199231; Royall et al 1998251

Go/No-Go I, wM(v) Shue & Douglas 1992309

Trail Making Test, Part B I, wM(s) U. S. Army 1944310; Reitan 1958311; Reitan & Wolfson 1995299

Note: Dimensions of executive control functions (ECF) refer to those developed in factor-analytic studies, including Concept Generation(CG), Inhibition (I), spatial (s) and verbal (v) Working Memory (wM), and Planning (P).


11/29


ROYALL et al.

tests such as the WCST categories; aworking memory fac-tor labeled by tests such as the California Verbal Learn-ing Test, the Wechsler Intelligence Scale for ChildrenRevised (WISC-R), Digit Span (verbal), and the Towerof London (nonverbal); an attentional control factor la-

beled by tests such as the Continuous Performance Task

or Digit Cancellation; and a response inhibitionfactor la-beled by tests such as the WISC-R Digit Span Back-wards, Trails B, or the Stroop. Rule discovery and work-ing memory are most closely related to dorsolateralcortical function. Attentional control and response in-hibition depend more on ventromedial regions.

These domains are fairly robust. Different authorshave found the same instruments to load together indifferent samples. For example, Trails B and the Stroopco-label a single factor (response inhibition) in Grodzinskyand Diamonds study of boys with ADHD,147 Robertsonet al.s study of normal adults,148 Mahurin et al.s studyof schizophrenic patients,149 and Arbuckle et al.s study

of elderly adults.150 In addition, there is limited evidencethat ECF factors are multimodal. For example, Taylor etal.151 found that both verbal and design fluency tasksloaded on the same factor. This finding suggests that theexecutive control identified in this paradigm may beequally applicable to both verbal and constructionalprocesses, presumably mediated by different cerebralhemispheres.

Unfortunately, most of the available ECF factor-analytic studies have methodological flaws. Large sam-ple sizes are needed before stable factor structures canemerge. Executive and nonexecutive measures need to

be included, and key reference measures should beused across samples to facilitate comparisons.

Two recent studies can serve as models for futurework.152,153 Kanne et al.152 examined the factor structureof a comprehensive battery of neuropsychological mea-sures, including several ECF measures, among 407 ADpatients and 261 elderly control subjects. Control dataexhibited a different factor structure than that found indata for AD patients. Control test scores loaded on asingle factor (i.e., they showed high g). In contrast, thedata from AD cases was best represented by a three-factor model. The authors labeled these factors MentalControl, Memory-Verbal, and Visuospatial. Digit Span,

verbal fluency, and the Mental Control subtest of theWechsler Memory Scale loaded on the Mental Controlfactor. This factor explained most of the variance in bothearly AD and moderately advanced AD subgroups. Au-topsies were later performed on 41 AD subjects. Each fac-tor was significantly correlated with the severity of ADpathology in a different cortical region. The Mental Con-trol factor correlated significantly (r0.39, P0.01) withfrontal cortical neurofibrillary tangle counts. Digit Sym-

bol Substitution, a test that is often purported to measureECF, did not load on the Mental Control factor, nor wasit correlated with frontal pathology.

Miyake et al.153 examined putative ECF measures, in-cluding the WCST, the Tower of Hanoi (TOH), randomnumber generation (RNG), operation span, and dual

tasking in a moderately large sample of college students(N137). A confirmatory factor analysis of these mea-sures indicated three moderately correlated but discri-minable factors, which they labeled Set Shifting, Inhi-

bition, and Updating. Structural equation modelsshowed that these three factors contribute differentiallyto each of the complex ECF measures. The Set Shiftingfactor contributed most to WCST performance, the In-hibition factor contributed most to TOH, and both In-hibition and Updating contributed to RNG. The Updat-ing factor also contributed to operation span scores. Thistype of analysis reveals that 1) classical ECF measuresare often multidimensional; 2) no single measure com-prehensively assesses all ECF domains; and 3) specificcombinations of ECF measures may compliment eachother, while others may be redundant.

For a discussion of the Wisconsin Card Sorting Test asa possible gold-standard ECF measure, see box (p. 391).

FUNCTIONAL IMAGING AND EXECUTIVECONTROL

Lesion studies associate response inhibition with the or-bitofrontal region,attentional controlwith the mesiofron-

tal region, and working memory (verbal and nonverbal)andrule discoverywith the dorsolateral region.162 Theseobservations are generally supported by neuroimaging.Bench et al.65 studied the associations between a modi-fied Stroop and regional cortical metabolism PET. Dur-ing the Stroops interference condition, the right orbito-frontal cortex and posterior parietal cortex were bothactivated (i.e., control and process). However, these re-gions may both be under the control of the anterior cin-gulate. The anterior cingulate is thought to be importantin error detection and sequencing of ongoing actionplans.143 It has been shown to be activated by stimulithat are incongruent with expectation and that mayneed correction. Liotti et al.163 have studied the temporalsequencing of cortical activity during the Stroops inter-ference condition, using event-related potentials (ERPs).Differences in ERP between Incongruent compared withCongruent trials first appear in the anterior cingulate(peaking at 410 ms), then in the temporoparietal cortex(500800 ms post stimulus).

Working memory tasks activate dorsolateral prefron-


12/29


13/29


14/29


15/29


ROYALL et al.

THE WISCONSIN CARD SORTING TEST AS A GOLD STANDARD ECF MEASURE

The Wisconsin Card Sorting Test (WCST) is arguably the best-characterized measure of executive control functions (ECF). It hasbeen validated in lesion and neuroimaging studies. It has beenemployed in factor analyses of putative executive measures, andits internal factor structure has been studied. Norms are available

for children and adults. It has been employed in a wide variety ofclinical conditions.

However, the WCST is a complex task, ill suited for routineclinical applications. It requires equipment (the cards),considerable training and experience, and 45 minutes toadminister. The subject is asked to match 128 response cards toone of four stimulus cards on the basis of a sorting rule that isdetermined by the examiner. Each response card contains a designrepresented by three features: color (yellow, green, red, blue),number (14), and figure (circles, stars, triangles, crosses). Sortscan be made by any of these features. The subject must deducethe current sorting rule on the basis of on feedback from theexaminer. After the subject has matched 10 consecutive cardscorrectly, the examiner covertly changes the rule. This changerequires the subject to deduce the new rule and successfully

employ it. WCST summary scores reflect the total number ofcategories achieved, the total number of errors, the number andpercentage of perseverative errors, and the percentage ofconceptual level responses.

In neuroimaging studies, the WCST appears to activate thedorsolateral prefrontal cortex, particularly on the left.64,95,154,155,163

However, activation of other brain regions has also beenobserved, including the right anterior prefrontal region64 and, to alesser extent, both mesiofrontal/anterior cingulate65 andorbitofrontal regions.167 Thus, the WCST appears to activate allthree frontal circuits, bilaterally, with a preferential selection forthe left dorsolateral prefrontal system.

The WCSTs ability to activate widespread frontal regionsmay be due to the tasks demands for multiple executive skills. Infact, lesion studies in monkeys given WCST analogs demonstrateregionally specific effects on certain WCST elements. Dorsolateralprefrontal lesions affect extradimensional (ED) set shifts,wherein the animal must shift its attention from one element ofthe stimulus to a different aspect of it. Orbitofrontal lesions spareED set shifting, but selectively impair set reversal, wherein apreviously learned element must be ignored.156

In humans, concept generation, sustained attention, verbal andnonverbal working memory, and response inhibition could all beargued to contribute to overall WCST performance. To the extentthat these features are discriminable aspects of the task, they

ought to label separate factors. Factor-analytic studies of theWCST itself suggest three major factors in children,157 normaladults,158 and patients with psychiatric illnesses.159

However, results are mixed. WCST categories and WCSTpercentage correct co-label a single factor in Mirskys factor

analysis of putative ECF measures.160 WCST conceptualresponses label a factor that is shared by verbal and designfluency tasks in Levin et al.s study of head-injured children.161

WCST perseverative errors label a factor that is shared by theCategory Test and Trail Making Part B in Shute & Huertassstudy of normal young adults.161 A distinction between WCSTcategories and WCST perseverative errors is supported by theobservation that Trails B and WCST categories load on differentfactors in Robertson et al.s study of normal adults.148 However,five WCST subtests, including Categories and PerseverativeErrors, load on a single factor in Grodzinsky & Diamonds studyof boys with attention-deficit/hyperactivity disorder,147 whileTrails B and verbal fluency tasks load on another. Most of thesestudies have too few subjects to support an analysis of very manymeasures. In fact, most probably have too few subjects to produce

a stable factor structure. This limitation may explain why mostauthors report data for only one or two WCST subscales, makingtheir interpretation difficult. In the only factor analysis thatreported all WCST subscales, they loaded on a single factor.

It should be noted that not all putative executive tasks are sodifficult to localize. Working memory tasks such as delayedmatching to sample, go/no-go, or the n-back paradigm (inwhich the subject must keep track of a stimulus n-back in acontinuous list of sequentially presented stimuli) consistentlyactivate very specific regions of interest in the prefrontal cortex.The specificity of these tasks can be demonstrated down to thelevel of single-unit pyramidal neuron recordings. The difficulty inlocalizing putative ECF measures such as the WCST arises fromtheir inherent complexities. However, although clinical taskscould be designed that might be more localizable, it is unclearthat they would share more complex measures associations withdisability, problem behavior, or diagnosis/prognosis.

In summary, the WCST may be the best validated of anyputative ECF measure. It is reasonably specifically affected byfrontal lesions, and it reasonably selectively activates the leftdorsofrontal cortex in activation studies. Multiple executivefunctions can be ascribed to the various WCST subtests, but thisassertion is difficult to prove empirically. Neither neuroimagingnor factor analyses have localized specific and robust WCST-related factors to the frontal lobes.

tal regions. The left hemisphere may mediate verbalworking memory. The right may mediate nonverbalworking memory.138 There is some overlap betweenthese regions and other executive tasks. Verbal fluencytests tend to activate the left dorsofrontal cortex,164,165

although in one study a test of category fluency acti-

vated the right dorsolateral prefrontal cortex relative toa baseline reading task.166 Tasks requiring sustained at-tention have also been found to activate the right dor-solateral prefrontal cortex.167

However, the factor-analytic studies reviewed above

suggest that most ECF measures are complicated tasksthat may draw on several executive domains simulta-neously. The Tower of London, for example, loads on twofactors in Culbertson and Zillmers study of boys withattention-deficit/hyperactivity disorder (ADHD)168 andon three separate factors in Levin et al.s study of head-

injured children,169

and it has been reported to activatethe left dorsolateral prefrontal cortex170 and mesiofron-tal/anterior cingulate.171 In a functional MRI (fMRI)study by Peterson et al.,59 seven factors were derivedfrom the brain regions activated by the Stroop. The an-


16/29



terior cingulate (mesiofrontal system) loaded signifi-cantly on each of these seven factors (see Liotti et al.163).

The nonspecificity of putative ECF clinical measuresis in sharp contrast to the relatively discrete frontal ac-tivations associated with certain tasks in neuroimagingstudies. The delayed response, A-not-B, go/no-

go, n-back, and object retrieval paradigms all re-producibly activate very specific frontal regions. How-ever, it should be kept in mind that the skills represented

by these tasks are achieved by human beings very earlyin development, long before clinically relevant executiveskills have developed. The A-not-B, delayed response,and object retrieval paradigms are essentially in place inhuman infants by the age of 12 months.172174 Thus,these easily localized tasks, while clearly dependent onfrontal functions, may be merely the heteromodal pro-cesses on which truly cybernetic executive functionsoperate.

APPLICABILITY TO NEUROPSYCHIATRICDISORDERS

Assuming that the obstacles to ECF assessment can beovercome, what is the promise of this domain? First, itis important to realize that ECF impairment, frontal sys-tem lesions, and frontal metabolic deficits have been de-tected in a wide variety of both neuropsychiatric andmedical disorders. This commonality offers the possi-

bility of unified disability and behavioral outcomes as-sessments that could be validly applied across a widevariety of conditions.175,176 Moreover, treatment and as-sessment strategies that are developed in one conditionmay be relevant to many others as well. Second, ECFmay predict disability more accurately than tests basedon other cognitive domains. And third, certain behav-ioral features may serve as indices of ECF impairment.These could have prognostic and treatment significance.

ECF Deficits Are Common

Our literature review identified only a single community-based study of the prevalence of ECF impairment. Pre-sumably, such studies have been limited by the dearth ofreliable, valid ECF measures that could be suitable for

use in epidemiological or clinical trials. Grigsby et al.

177

used a brief ECF measure, the Behavioral DyscontrolScale (BDS), that is essentially a compilation of items

based on the work of Luria. They examined the preva-lence of BDS failure in a community sample (N1,145;mean age[SD]72.97.2 years) of community-dwelling elderly persons residing in southwestern Col-orado. The mean level of education in this sample was10.53.7 years. Many subjects were Hispanic.

The authors found a high prevalence of ECF impair-ments: 25.5% of their subjects showed impairment onthe BDS. Half of these had normal Mini-Mental StateExamination scores.178 The MMSE has been criticized forpoor sensitivity to early cognitive decline in older per-sons and for poor specificity for dementia in minority

and undereducated samples.179

However, the BDS wasa stronger predictor of impaired functional status thanthe MMSE, suggesting that this samples ECF impair-ment was already functionally significant.

This study is notable for several reasons. First, itpoints out how little is actually known about the com-munity prevalence of ECF impairment. Second, it illus-trates how traditional measures tend to underestimatethe severity of cognitive impairment in ECF-impairedsubjects. These issues are relevant to both case definitionand disability assessment.180 The American PsychiatricAssociation in 1994 added ECF impairment to its list ofthe domains that should be considered when making a

diagnosis of dementia.27 Nonetheless, there are no largedementia studies that use ECF-sensitive measures intheir case definitions. The frequency of ECF impairmentreported by Grigsby et al.177 is almost twice the rate ofdementia reported by most studies. Royall et al.181 havereported similar results among well elderly retirees withadvanced education and excellent health (N561; meanage78.1 years). Although 86% pass the MMSE at 24/30(mean 27.7), 32% fail the EXIT25 and 42% fail CLOX1 atthe 5th percentile for young adults. The EXIT25 andCLOX 1, but neither the MMSE nor CLOX2, distinguishlevel of care in fully adjusted models. The advent of bed-side ECF measures such as the BDS, CLOX, EXIT25, andFAB now makes it feasible to explore the epidemiologyof this domain.

The need for this work is suggested by the previousdocumentation of ECF deficits in a wide range of neu-ropsychiatric disorders. Some functional disorders,such as schizophrenia, major depression, alcoholism,and certain personality disorders, have been found to

be associated with regionally specific frontal atrophyand cytoarchitectural disorganization.182184 ECF is af-fected by both cortical and subcortical structural disor-ders.

Schizophrenia: A well-developed literature links thefunctional, behavioral, and cognitive deficits of schizo-phrenia with frontal system impairment.185,186 Schizo-phrenia is associated with diminished frontal gray andtotal white matter volumes187 without clear cell loss.188

These changes disproportionately affect frontal, particu-larly inferior ventrolateral and orbitofrontal, regions ofinterest.187 The severity of orbitofrontal atrophy is cor-related with negative symptoms.189 There are dorsolat-


17/29


ROYALL et al.

eral prefrontal metabolic and regional cerebral bloodflow reductions at rest95,190 and during activation by ex-ecutive tasks.97,191 Executive deficits are present from the

beginning of the disorder, even among drug-nave, first-episode cases.192 It may be interesting to note that onlymeasures related to rule discovery and working mem-

ory are initially affected (see Dimensions of ExecutiveControl, pp. 386387 above). Attentional control and re-sponse inhibition impairments appear later.193

Major Depression: There is also evidence of frontal sys-tem pathology in major depression.194 Major depressionis associated with reduced frontal metabolism in bothunipolar and bipolar presentations.94 There is also evi-dence of selective cortical atrophy195 and widespread al-terations in frontal cortical architecture in depressed pa-tients.183,196,197 Frontal stroke is strongly associated withpoststroke depressive syndromes.198 Frank major de-pression may also follow basal ganglia lesions.91,102,199

The executive impairments of depression improve withresolution of its symptoms.200

Structural Brain Disease: Frontal system pathology iscommon in AD,201 VaD, and traumatic brain injury.202

In addition, ECF impairments have been reported in awide variety of neurodegenerative disorders, includingamyotrophic lateral sclerosis, frontotemporal dementia,HD, Lewy body dementia, PD, and progressive supra-nuclear palsy.203207

In AD, frontal lobe pathology generally correlates bet-ter with dementia severity than hippocampal or temporalcortical AD pathology.25,208 In fact, frontal cortical syn-aptic density is the strongest reported pathological cor-relate of dementia severity (r0.79 vs. the MMSE).24,209

This pathology is associated with reduced cerebralblood flow by SPECT and is associated with an earlydecline in ECF measures.210 ECF impairment is corre-lated with functional status in AD211 and is present rela-tive to age-matched control subjects in preclinical casesof age-associated memory impairment.212

VaD disproportionately affects frontal systems.213,214

Subcortical lesions indirectly affect frontal cortical me-tabolism, particularly if they include lacunar infarctionsof the basal ganglia and thalamus, or anterior periven-

tricular hyperintensities.

90

White matter lesions are spe-cifically associated with poor performance on tests offrontal function.215,216 Aneurysm of the anterior com-municating artery is another common cause of ECF im-pairment.217

Diabetes Mellitus: Patients with diabetes mellitus showimpairment on ECF measures. These tests include theDSS,218,219 verbal fluency220 (not found by Perlmuter et

al.218), abstract reasoning,220,221 Grooved Pegboard,222

Trail Making,222,223 Stroop-Word Naming,222 Picture Ar-rangement,222 CLOX1, and the EXIT25.223 Keymeulen etal.224 have documented regionally specific frontotem-poral hypoperfusion by SPECT in chronic type 1 (insulin-dependent) diabetic patients, but not recent-onset cases

or age-matched normal control subjects. The potentialcauses of ECF impairment among diabetic patients mightinclude subcortical vascular disease, polypharmacy, iat-rogenic hypoglycemia, and/or concurrent major depres-sion.

Normal Aging: Old age may be associated with frontalsystem deficits even in the absence of AD or ischemicvascular disease.225228 Reduced executive control can bedetected in healthy adults as young as age 45 to 65 yearsrelative to education- and gender-matched 20- to 35-year-olds.229 In longitudinal studies, ECF deteriorates atan exponential rate.230 Interestingly, the pattern of age-

related cognitive decline in nonexecutive domains ismost consistent with the loss of executive control overintact processes (see Control vs. Process, pp. 384385above).115,116,231,235

Disproportionately frontal age-associated metabolicdeficits have been observed by functional neuroimagingin healthy volunteers ranging in age from 18 to 78years.236 In animals, age-related frontal task perfor-mance has been associated with diminished dopami-nergic (D2) and alpha-2-adrenergic (2) activity in theprefrontal cortex.107,237,238 In humans, the age-associateddecline in regional D2receptor density is linearly relatedto frontal cortical and anterior cingulate metabolism byPET and associated with diminished WCST and Stroopperformance.239,240

There is also structural age-associated frontal systempathology. Coffey et al., examining the MRIs of healthyelders free from vascular disease or hypertension, re-ported an age-related cortical atrophy that dispropor-tionately affected frontal relative to temporal, parietal,and hippocampal regions.241 Recent studies suggest thatage-related atrophy disproportionately affects mesio-frontal and dorsofrontal more than orbitofrontal re-gions. There are also age-related increases in caudateand putamen hyperintensities. These lesions occur in

many apparently healthy elderly persons and can pro-duce executive impairment that is comparable in sever-ity to frontal lobe degeneration.242

ECF Impairment and Disability

Because functional outcomes, medication compliance,cooking, housekeeping, and working are all examplesof goal-directed activities, they are inherently vulnera-

ble to executive dyscontrol.243 Thus, frontal system pa-


18/29



thology/metabolic impairment and psychometric ECFmeasures are emerging as robust predictors of diseaseseverity and functional disability across diagnoses.

For example, the effects of ECF impairment have beendescribed in rehabilitation settings.244 Allen245,246 has de-veloped the Allen Cognitive Levels (ACL) Assessment.

The ACL is essentially a functional status measure thatprovides information on a variety of executive tasks.Scores on this version correlate moderately to stronglywith performance on activities of daily living in subjectswith dementia (Feeding, r0.83; Toileting, r0.75;Grooming,r0.74; Dressing,r0.74; Housekeeping, r0.68; Ambulation, r0.67; Bathing, r0.65; Cooking,r0.65; Shopping,r0.64; Laundry,r0.60; Telephone,r0.58; Finances,r0.52; Transportation,r0.32; Med-ication, r0.32; all significant at P0.05). Velligan etal.247 have associated the majority of variance in ACLscores with neuropsychological measures of workingmemory and response inhibition (e.g., ECF factors de-

rived from factor analyses). In schizophrenia, frontalneuroimaging and ECF performance are better predic-tors of long-term functional outcomes than is successfultreatment of psychosis.248 Roughly 25% of community-dwelling schizophrenic adults can be expected to haveECF impairment.249 This is comparable to the prevalenceof ECF impairment in well elderly persons.177 Elderlyretirees are as executively impaired as schizophrenic pa-tients when the two groups are matched to the servicesthey receive from their respective institutions.250

The association of ECF with level of care has beenspecifically examined in the context of retirement com-munities.31,181 Retirement communities are essentiallyclosed systems in which a residents living setting maychange in proportion to the services and supervision heor she requires. Royall et al.251 examined the relativeability of the EXIT25, the MMSE, demographic vari-ables, physical health status (age, Cumulative IllnessRating Scale score, and number of medications pre-scribed), and behavior problems (Nursing Home Behav-ior Problem Scale score) to predict level of care in onesuch facility. In a stepwise linear regression model, fivevariables made significant independent contributions.Together, these variables accounted for 57% of the totalvariance in level of care (R20.57; F29.2, df7,154,

P

0.0001). The EXIT25 loaded first (R

2

0.43;F

119.52,df7,154,P0.0001).In a second retirement community, Royall et al.181

found that ECF measures distinguish levels of care evenamong noninstitutionalized retirees with normal MMSEscores. Moreover, the use of prosthetic devices declinedwith ECF impairment, even as level of care increased.This finding suggests that ECF impairment may under-mine a disabled persons capacity to adopt assistive de-

vices and that this impairment develops before cogni-tive impairment is detected in nonexecutive domains. Inelderly community residents, executive measures ex-plain independent variance in functional status, beyondthat explained by specific cognitive domains29,252 andmay be the strongest determinant of functional status.253

The effect of longitudinal change in ECF on functionalstatus is comparable to that of age and more importantthan that of comorbid medical conditions.230 These re-sults suggest that ECF is a major determinant of level ofcare in elderly populations.

Finally, we note that ECF may explain significantvariance in more specialized functional capacities, suchas financial and medical decision-making.254,255 Dymeket al.256 found that the EXIT25 explained 45% of thevariance in a rational reasons standard of decision-making and 56% of the variance in understandingtreatment, independently of a comprehensive batteryof cognitive measures, including verbal fluency. This is

remarkable because the EXIT25 has little face validityas a measure of verbal reasoning or abstraction. In-stead, like the Stroop, it appears to invoke responseinhibition or attentional control factors. These may bemore relevant to complex decision-making than iswidely appreciated (see Control vs. Process, pp. 384385 above, and Table 1).

ECF Impairment and Problem Behavior

Certain problem behaviors can be specifically associatedwith frontal system dysfunction in general, and withECF impairment in particular.257 Informant-based rat-ings of these behaviors may be useful as indicators fordamage to these networks.82 The FLOPS attempts to iso-late frontal-type behaviors into three domains: apathy,disinhibition, and executive dysfunction (i.e., im-paired abstraction), each theoretically linked to a differ-ent frontal circuit (mesiofrontal, orbitofrontal, and dor-solateral, respectively).36

The latter construct may be misleading. First, it im-plies that apathy and disinhibition are not dysexecu-tive behaviors, when in fact they fit the cybernetic def-inition of ECF. Second, it implies that impairments in

judgment and abstraction are indicative of executive im-pairment, when in fact they may not be (see Dimensions

of Executive Control, pp. 386387 above). Items address-ing working memory might have been a better behav-ioral indicator of dorsolateral executive dysfunction.

Frith has described the behavioral deficits of schizo-phrenia in terms of three similar factors based on factor-analytic models derived from clinical ratings,258,259

namely negative symptoms (apathy), positive symp-toms (hallucinations and delusions), and disorganiza-tion. Negative symptoms arise from the inability to


19/29


ROYALL et al.

generate plans, goals, or intentions. Patients cannot spon-taneously initiate complex behaviors. Martinot et al.260

have specifically correlated negative symptom indices tocentral D2receptors in schizophrenia. In contrast, disor-ganization arises from the failure to control automatic at-tentional resources. Patients do not inhibit their attention

from wandering to irrelevant cues in the environment.Negative symptoms and disorganization, but not posi-tive symptoms, are associated with poor cognitive testperformance in schizophrenia,149,261,262 particularly ontests of ECF, including the WCST, the Stroop test, andTrail Making.263,264 It is important to note that thesesymptom clusters are not unique to schizophrenia. Ap-athy and negative symptoms can be recognized acrossthe full spectrum of conditions that affect ECF.265267

Attempts have been made to fit Liddles system ofthree frontal syndromes into the neuroanatomical modelof cortical-striatal-thalamic circuits described by Cum-mings.82 Mahurin et al.149 have associated negative

symptoms and disorganization with poor performanceon specific, but not overlapping, ECF measures. Nega-tive symptoms were associated with tests of verbal flu-ency, cognitive flexibility, and working memory (all as-sociated with dorsolateral prefrontal cortex, especiallyleft). Disorganization was associated with attentionalECF measures such as Trails B and the Stroop (associ-ated with dorsolateral and orbitofrontal cortices, respec-tively, especially right). Similarly, Liddle and Morris264

associated Psychomotor Poverty with verbal fluency, theStroop, and Trails A. Disorganization was associatedwith Trails B and WCST perseverative errors. Thesesame instruments label the first extracted factor Cogni-tive Flexibility in Shute and Huertass study of normalyoung adults.174 Berman et al.268 have associated realitydistortion and positive symptoms with deficits on mea-sures of working memory.

TREATMENT OF ECF IMPAIRMENT

ECF offers a new perspective from which to study thepharmacotherapy of major neuropsychiatric disorders.Moreover, there may be regionally specific differencesin ECF treatment response. Dopamine D1receptor ago-

nists improve performance on working memoryrelatedtasks that are thought to be dependent on dorsolateralprefrontal activity. The response is nonlinear (an inverted shape). Too much or too little DA activity can ad-versely affect function.269 The response to DA can be pre-dicted by performance on working memorysensitivetasks such as Digit Span. Normal aging is associated with

both diminished dopaminergic function and impairedDigit Span performance, suggesting one possible and

potentially reversible explanation for age-associated cog-nitive decline. Norepinephrine 2agonists also improveworking memoryrelated tasks,107 whereas 1 agonistsimpair working memory.270 In contrast, serotonin defi-ciency impairs function on tasks that have been relatedto orbitofrontal activity.271

Nevertheless, our literature review did not identifyany clinical trials of ECF impairment. However, our col-lateral review identified many studies that could be in-terpreted from this perspective. Much depends on onesdefinition of an executive measure. DSS or WAIS-Rsubtests such as Category Formation are sometimes sug-gested to invoke ECF. However, they seldom co-labelfactors with other ECF measures. On the other hand, therecognition that frontal lesions lead to reproducible pat-terns of behavioral disorganization suggests that even

behavioral outcomes may be sensitive to ECF-relatedchange. We have chosen to limit our discussion to thefew studies with less ambiguous executive outcomes.

Initial results look promising. ECF psychometric andfrontal system neuroimaging deficits have been foundto respond to treatment in ADHD, major depression,and schizophrenia. Each has well-documented frontal/ECF deficits and a well-developed ECF literature.

In ADHD, studies have repeatedly demonstrated theeffect of stimulants such as methylphenidate (Ritalin,Focalin),d-amphetamine (Dexedrine) or pemoline (Cy-lert) on impulsive behavior and response inhibitiontests.154,272 Stimulants also appear to improve verbal andspatial working memory.273,274 These drugs have mixedagonist effects at postsynaptic dopaminergic D1 andnoradrenergic 2receptors.

An emerging literature suggests that selective seroto-nin reuptake inhibitors (SSRIs) may have efficacy againstthe cognitive impairments of depression275,276 However,all SSRIs may not be equally effective. The apathetic be-havior profile of depression, along with the relationshipof apathy to hypodopaminergic states, provides a ratio-nale for the specific use of sertraline against depression-associated ECF impairment277 (see ECF Impairment andProblem Behavior, pp. 394395). Ventral tegmental DAinputs are directed largely toward the mesiofrontal cortexand nucleus accumbens (in the mesiofrontal circuit).Wolfe et al.98 have associated a dysexecutive pattern of

neuropsychological test scores with low cerebrospinalfluid (CSF) homovanillic acid levels in patients with Par-kinsons disease, major depression, and an apathetic sub-set of AD cases. Similarly, negative symptoms in schizo-phrenia have been associated with low levels of CSF DAmetabolites.278 Sertraline, unlike the other availableSSRIs, is a potent DA reuptake inhibitor.279 It is roughlyhalf as potent as amphetamine,280 although this effect isnot likely to be seen at usual therapeutic doses.


20/29



Keefe et al.281 have published a meta-analysis of theeffects of atypical antipsychotics on cognitive functionamong patients with schizophrenia. Fifteen studies werereviewed (including three double-blind controlled tri-als). After correction for multiple comparisons, signifi-cant improvement was found in the DSS, verbal fluency,

and executive function. Three double-blind trials havecompared the effects of atypical antipsychotics to halo-peridol on cognition, using ECF measures. Schizo-phrenic subjects treated with risperidone have beenfound to perform better than those treated with halo-peridol on Trails B (but not Trails A)282 and tests of ver-

bal working memory.283 Schizophrenic subjects treatedwith clozapine have been found to perform better thanthose treated with haloperidol on tests of verbal flu-ency.284 And schizophrenic subjects treated with quetia-pine have been found to perform better than thosetreated with haloperidol on tests of verbal and designfluency.285 The ability of atypical agents to improve ECF

specifically would be important. Frontal metabolic func-tion and performance on ECF measures are better indi-cations of long-term functional outcomes than is the suc-cessful reduction of psychotic symptoms.248

It is important to note that antipsychotic medicationsmay have differential effects on ECF-related symptomclusters. Positive symptoms remit with traditional anti-psychotic treatment, but cognitive impairment doesnot.286,287 Both positive symptoms and cognition im-prove with the atypical antipsychotic clozapine. Thesedifferential effects may reflect frontal cortical DA recep-tor distributions.288 Prefrontal cortical GABAergic inter-neurons (in layer IV) express dopamine D2

289 and D4290

receptors that may mediate the antipsychotic effects ofneuroleptics. In contrast, pyramidal cells in layers IIIand V express high densities of D1receptors. D1recep-tors mediate WCST performance in humans.108 Thesereceptors are downregulated in schizophrenia291 and byconventional antipsychotic agents.269 D1receptor block-ade can lead to worsened performance on putative ex-ecutive measures.292294

RESEARCH AGENDA

Much more research is needed with regard to ECF. First,there needs to be a definitive taxonomy, both of the dif-ferent dimensions of executive control and of the clinicalphenomena associated with them. Both questions can beapproached through latent class analyses, which are use-ful in the absence of a gold standard.295 This taxonomyshould be independent of the features of any single dis-order. Negative symptoms, for example, are no morespecific to schizophrenia than apathy is to depression.

Second, neuroimaging and advanced statistical tech-niques are pushing us toward the limits of a localizationmodel of executive control. Neither the executive func-tions themselves nor the instruments that purport tomeasure them map reliably into specific regions of in-terest. However, once factor analyses, cluster analyses,

grade of membership, or discriminant modeling studieshave defined the major frontal syndromes and their as-sociated psychometric characteristics, it will be possibleto map them to specific (yet distributed) neural net-works. Notable advances in this regard have alreadytaken place (e.g., Liddle and Morriss264 approach to theneurobehavioral symptoms of schizophrenia, Mahurinand colleagues149 efforts to co-localize psychometricfactors with distributed networks of cortical regions de-rived from functional neuroimaging, Kanne and co-workers152 pathological correlations with frontal fac-tor scores, and Pet

Documents

EF Review Promise and Challenges