多动症的特征化认知

i y ga 15 mp ild distinctions between ‘hot’ and ‘cool’ executive function measures. We propose an integrative model that types to current candidate genes, all of which have minor Review TRENDS in Cognitive Sciences Vol.10 No.3 March 2006 throughout the lifespan. However, the ADHD literature is yet to be identified, several genes related to monoaminer- gic neuromodulation are confirmed as minor contributors to the overall phenotypic variance [4]. Moreover, there is robust evidence of structural, functional and neurochemi- cal brain differences in ADHD, in regions that support vital cognitive functions [5]. Thus, a coherent and comprehensive model of the cognitive substrates of ADHD would be a highly desirable means of linking genetic, neurobiological and phenotypic levels of analysis, with the objective of improving diagnostic approaches and therapeutic options. Such a model should eventually encompass ADHD sustained), investigators failed to observe specific diag- nostic deficits [12]. Based on parallels between ADHD symptoms and presumed cognitive deficits and those of patients with frontal lobe disorders, researchers expanded the scope of inquiry to higher-order cognitive processes thought to be sub-served by the frontal lobes such as inhibitory control, attentional regulation and working memory – constructs grouped under the rubric of executive function (EF) [13] (see Box 1). In 1997, Barkley proposed a comprehensive theory of ADHD with deficient inhibitory control as the core deficit that secondarily disrupts other EF processes [14]. The explicit testable prediction that inhibitory deficits and broad EF dysfunc- The heritability of ADHD is, however, both substantial and solidly established. Although major risk genes have ‘behavioral condition’ that is diagnosed subjectively [3]. continuous performance task [11]. However, when specific attentional processes were targeted (i.e. divided, selective, incorporates new neuroanatomical findings and empha- sizes the interactions between parallel processing path- ways as potential loci for dysfunction. Such a reconceptualization provides a means to transcend the limits of current models of executive dysfunction in ADHD and suggests a plan for future research on cognition grounded in neurophysiological and develop- mental considerations. Introduction Attention-deficit/hyperactivity disorder (ADHD) is characterized by pervasive behavioral symptoms of hyperactivity, impulsivity and inattention, beginning in childhood [1]. Despite its high prevalence and associated lifelong impairment [2], ADHD remains controversial because of the use of psychostimulants for treatment of a Characterizing cogn beyond executive d F. Xavier Castellanos1, Edmund J.S. Sonu and Rosemary Tannock3 1Institute for Pediatric Neuroscience, NYU Child Study Center, 2 2Department of Psychology, University of Southampton, Southa 3Brain and Behavior Research Program, The Hospital for Sick Ch The hypothesis that Attention-Deficit/Hyperactivity Dis- order (ADHD) reflects a primary inhibitory executive function deficit has spurred a substantial literature. However, empirical findings and methodological issues challenge the etiologic primacy of inhibitory and executive deficits in ADHD. Based on accumulating evidence of increased intra-individual variability in ADHD, we reconsider executive dysfunction in light of effects at best [4]. Similarly, active areas of potentially related research, such as psychopharmacology [7] or neuroimaging [8,9], which have been recently reviewed elsewhere, are not covered, but will certainly contribute to fully integrated models. Our purposes here are to reassess currently dominant cognitive models of ADHD in light of empirical and conceptual challenges and to highlight an integrative model that incorporates emerging neuroana- tomical perspectives. We believe that this approach will provide a more robust framework for the translational multidisciplinary efforts that are already underway in laboratories throughout the world. Evolving cognitive models of ADHD The explicit criteria for ADHD that were first codified in 1980 (see historical review in [10]) emphasized inattention as much as hyperactivity, based on robust objective evidence of behavioral inattention and performance deficits on a laboratory measure of attention, the tion in ADHD: sfunction -Barke1,2, Michael P. Milham1 Lexington Avenue, New York, NY 10016, USA ton SO17 1BJ, UK ren, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada preponderantly based on children of elementary school age. As neuropsychological differences are most detectible at this age [6], this brief review will generally exclude studies on preschool-age-children or adults, despite remarkable consistency between cognitive deficits across these wide age ranges. We defer attempts to synthesize initial efforts at linking cognitive and neuronal pheno- taking into account measurement error, established the EF deficit model as the dominant paradigm over the past Corresponding author: Castellanos, F.X. (castef01@med.nyu.edu). Available online 7 February 2006 www.sciencedirect.com 1364-6613/$ - see front matter Q 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.tics.2006.01.011 tion should be observable in all children with ADHD, useful intermediate phenotype (endophenotype) for deli- Box 1. Executive function: is there a central executive? There is no consensus definition of ‘executive function’ (EF). The term is generally used to describe a broad range of ‘top-down’ cognitive processes and abilities that enable flexible, goal-directed behavior. Examples of such processes include planning and implementing strategies for performance, initiation and discontinu- ation of actions, inhibiting habitual or prepotent responses or task- irrelevant information, performance monitoring, vigilant attention and set switching. Researchers have struggled to understand whether the broad range of ‘executive’ functions are supported by a single unitary process or a diverse array of cognitive processes. Although some have argued for the existence of a unitary process based in the frontal lobes, neuroimaging and focal lesion studies fail to support this notion. The frontal lobes have proven to be heterogeneous, with numerous anatomically and functionally distinct subregions, each associated with a different subset of executive functions [20]. As such, current models favor a conception of EF as a collection of higher-order cognitive control processes [21]. (See http://www. aboutkidshealth.ca/ofhc/news/SREF/4144.asp for further develop- mental perspectives on EF.) Review TRENDS in Cognitive Sciences Vol.10 No.3 March 2006118 neating risk genes corresponding to a neuropsychologi- cally distinct subtype of ADHD. The usefulness of the Stop task is also apparently supported by a meta-analysis of 17 studies (nearly 1200 decade and catalyzed a burgeoning literature [15–19], much of it focused on inhibition as the core deficit in ADHD. Testing inhibition as the primary executive deficit in ADHD Of several types of inhibitory processes, only executive motor inhibition has clear replicated evidence in ADHD [24]. The bulk of this support derives from Go/No-Go tasks [25] and particularly, the Stop task [26] (see Box 2). Converging lesion and imaging studies pinpoint the right inferior prefrontal cortex as a crucial region for effective Stop task performance [27,28]. Additionally, evidence of familiality [29–31] suggests that the Stop task could be a Box 2. Measuring executive inhibition: the Stop Task The Stop Signal Task examines an individual’s ability to stop a prepotent motor response and is unique among tasks used to measure inhibitory control in that it permits an estimation of the latency of the inhibitory process. It involves two tasks that differ with respect to frequency, predictability, and stimulus parameters (modality, intensity). The Go-Task, presented on every trial, is a speeded forced-choice reaction time task that requires participants to respond to a stimulus referred to as the Go-Signal. The Stop-Task, occurring randomly and infrequently (e.g. 25% of Go trials), involves presentation of a Stop Signal (SS; often an auditory tone) that countermands the Go response requirements (i.e. participants are to immediately inhibit the response to the Go-Signal). The task assumes that ability to inhibit the Go response depends on the outcome of a race between two independent processes (response generation/execution, response inhibition) [22]. If the inhibitory process wins, the planned action is stopped; otherwise, the Go response continues to completion. Thus, inhibitory control depends on the Go response time, the within-subject variability of the Go response time, and the reaction time to the SS (SSRT). SSRT is the primary performance variable, indicating the speed of the inhibitory process; faster SSRT’s reflect efficient inhibitory control [23]. www.sciencedirect.com children) reporting significant longer Stop Signal reaction times (SSRT) in ADHD (Cohen’s effect size, dZ0.58) [18]. However, several potential confounds complicate the interpretation of this difference. First, children with ADHD also exhibit significantly slower RTs to Go stimuli (dZ0.52) which may disproportionately influence the calculation of the SSRT. Second, they demonstrate even greater Go stimulus RT variability (dZ0.72) which challenges the Stop task’s assumption of SSRT invariance and undermines the feasibility of using a tracking procedure to establish appropriate interval between Stop and Go signals to produce equal proportions of successful and failed inhibitions [18]. More generally, the Stop task imposes subtle but continuous demands on stimulus anticipation, response preparation, speed of stimulus processing, and the ability to hold task instructions on- line [27] and children with ADHD may be impaired in each of these processes [19,32,33]. The alternative of examining motor inhibition with the simpler Go/No-Go task may also be problematic. Electrophysiological studies of Go/No-Go tasks in ADHD, which allow a more precise dissection of effects, find nonspecific deficits that are not limited to No- Go trials [34–37]. Also casting doubt on the centrality of inhibitory deficits is the largest study of stimulant naı¨ve boys (nZ75) with severe pervasive ADHD (Hyperkinetic Disorder) and matched controls (nZ70) which found strikingly similar rates of No-Go errors and mean Go RT on a computerized Go/No-Go task [38]. Thus, these counterfactuals fail to support the strong hypothesis of deficient inhibition as the primary cognitive deficit in ADHD. Is executive dysfunction intrinsic to ADHD? When meta-analyses are extended to the broader domain of executive function, a similar pattern of significant albeit moderate associations emerges. A meta-analysis compris- ing 83 studies and over 6700 subjects found associations between ADHD and executive dysfunction across all domains tested (i.e. planning, vigilance, set shifting, and verbal and spatial working memory) ranging in effect from dZ0.4–0.7 [19]. A meta-analysis focused on working memory examined a somewhat different subset of studies and detected stronger effects (dZ0.85–1.14) when spatial working memory manipulation was distinguished from simple storage [33]. Thus, manipulation of spatial working memory appears to offer the strongest evidence in ADHD, but direct comparison studies have not yet been con- ducted. As in the case of response inhibition, EF effects are difficult to interpret because most executive function tasks fail to control for potential confounds ascribable to more ‘primitive’ cognitive or physiologic processes [39]. Two recent studies highlight the seriousness of this issue by demonstrating that when non-executive abilities are accounted for by using appropriate control tasks, little evidence of executive dysfunction remains [38,40]. The modest pattern of associations between a range of EF deficits and ADHD is frequently interpreted as providing evidence for a broader/weaker variant of the Barkley EF hypothesis. This is the result of a failure to understand the prediction of pervasive deficits, which has not been adequately tested until recently. An Review TRENDS in Cognitive Sciences Vol.10 No.3 March 2006 119 approximation of such a test was performed by pooling data from three different sites [41]. EF impairment was defined in terms of performance exceeding the 90th percentile cutoff (based on the control samples) on five EF measures. On any individual measure, between 16% and 51% of children with ADHD were classified as impaired. When multiple deficits were compared, only 31% of children with ADHD, versus 9% of controls, displayed pervasive impairment (deficits on 3 or more measures) [41]. Only 10% of ADHD children showed deficits across all five domains. By contrast, 21% of children with ADHD (and 53% of controls) were unim- paired on all five measures. This combined analysis recapitulates the conclusion that ‘EF weaknesses are neither necessary nor sufficient to cause all cases of ADHD’ ([19], p. 1336). Although not yet examined in meta- analyses, growing evidence links EF deficits to the inattention dimension of ADHD, rather than to hyper- activity/impulsivity [42,43]. Clearly the strong predictions of the EF deficit hypothesis of ADHD are not supported. Cognitive heterogeneity of ADHD: multiple pathway models The cognitive literature is thus incompatible with the assumption of pathophysiological homogeneity – of a single core deficit. Researchers have responded by building models that accept heterogeneity [41,44,45] – in which ADHD is regarded as an umbrella construct with clinical value that subsumes multiple potentially dissoci- able but overlapping cognitive profiles. So far, too few studies include measures from different functional domains (EF, reinforcement/motivational, sensory/percep- tual and motoric), so heterogeneity is largely inferred from independent studies each working within a particular functional domain. One notable exception, designed by proponents of both camps, contrasted EF and motivational models using a Stop task and a Choice Delay task in which children chose between small immediate and large delayed rewards [46]. This collaborative study produced two crucial findings: first, choices of the small immediate reward (Delay Aversion) were uncorrelated with SSRT – suggesting that inhibitory deficits and Delay Aversion in ADHD were dissociable processes. Second, performance on either task was only moderately associated with ADHD but together correctly classified nearly 90% of children with ADHD. Similar results were found in preschool children with ADHD [47] and in a study of the mediating pathways between hydrocephalus and hyperactivity [48], highlight- ing that neither EF nor Delay Aversion models are individually sufficient to account for neuropsychological findings in ADHD. Towards an integration of multiple pathway models ‘Hot’ and ‘cool’ executive functions In considering potential synthetic linkages between EF and processes related to motivation such as underlie Delay Aversion, a line of work on the development of EF is particularly pertinent. Noting the functional differen- tiations within frontal cortices, Zelazo and Muller distinguish between more purely cognitive aspects of EF www.sciencedirect.com associated with dorsolateral prefrontal cortex (DLPFC) which are characterized as ‘cool’ as contrasted with relatively ‘hot’ affective aspects of EF associated with orbital and medial prefrontal cortex (OMPFC) [49,50]. In this schema, ‘cool’ EF is elicited by relatively abstract, decontextualized problems, such as most of the EF tasks tested so far in ADHD (e.g. [15,16,19,24,33]), including Stroop, flanker, Go/No-Go, Stop, continuous performance and working memory tasks, which focus on the ability to suppress automatic processes or prepotent responses and/ or maintain task instructions or representations in working memory. ‘Hot’ EF ‘is required for problems that are characterized by high affective involvement or demand flexible appraisals of the affective significance of stimuli’ ([49], p. 455). Based on the inarguable association of moderately impaired performance on ‘cool’ EF tasks and ADHD [19], Zelazo and Muller proposed that ADHD should be considered a disorder of ‘cool’ EF [49]. We believe this may be premature, reflecting the preponderance of studies which have used just such a conclusion as a starting point. Rather, we propose that inattention symptoms may be associated with deficits in ‘cool’ EF, whereas hyperactivity/impulsivity symptoms will be found to reflect ‘hot’ EF deficits. This gives rise to the possibility that some individuals with ADHD will mani- fest primarily ‘hot’ EF dysfunction, whereas others will show mainly ‘cool’ EF deficits and others will have both types. For example, risky decision making in the Iowa gambling task – an index of ‘hot’ EF – was associated with hyperactivity/impulsivity symptoms but not symptoms of inattention, or ‘cool’ EF measures such as working memory or IQ [51]. The increasing literature on the impact of reinforce- ment contingencies on ADHD comprising 22 studies with nearly 1200 children was recently reviewed [52]. Although the range of approaches used in these studies is too disparate to allow quantitative meta-analyses, the authors highlight clear evidence of delay aversion, and some support for greater behavioral and lower psycho- physiological sensitivity to reinforcements in ADHD [52]. Abnormalities or inconsistencies in maintaining instruc- tional set (‘cool’) or motivational state (‘hot’) may also account for the substantial variability in responding that emerges in many cognitive tasks and in behavioral descriptions of ADHD [39] (see Box 3). In summary, whereas the literature surrounding executive dysfunction in ADHD has mostly focused on ‘cool’ EF with modest success, the presence of impairments in incentive, motivational and reward-related processing suggests that both ‘hot’ and ‘cool’ EF deficits should be assessed, with particular attention to developmental aspects and symptom subtypes [53–55]. Spiraling cortico-striato-thalamo-cortical circuits A recent synthesis highlights the neuroanatomical sub- strates for interactions between motivational and cognitive processes as potential loci of dysfunction in various forms of psychopathology, including ADHD [56] (see Figure 1). Dysfunction of distributed cortico-striato-thalamo-cortical loops is implicated in all neurophysiological models of psychopathology. However, models of parallel reciprocal Review TRENDS in Cognitive Sciences Vol.10 No.3 March 2006120 Box 3. Intra-individual variability and ADHD Ironically, one of the most consistent manifestations of ADHD is the high prevalence of ‘moment-to-moment variability and inconsistency loops have failed to address ‘how information can be transformed across functional regions to help implement the learning and adaptability that is necessary in the development of goal-directed behaviors’ ([50], p. 322). The delineation of complex non-reciprocal pathways consisting in performance. Such response variability is the one ubiquitous finding in ADHD research across a variety of speeded-reaction-time (RT) tasks, laboratories and cultures’ ([45], p. 624). Such variability can be quantified by decomposing RT responses into the sum of a normally distributed random variable, m (Figure Ia), and an indepen- dent exponentially distributed variable, t (Figure Ib), which accounts for the positive skew of ‘ex-Gaussian’ RT distributions (Figure Ic). Children with ADHD who had almost identical m values to those of controls differed markedly from controls in the skew of the RT distributions and in the derived values of t (Figure Id), yielding a remarkable diagnostic efficiency of 96% [60]. The implication that c