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Whither Causal Models in the Neuroscience of ADHD?

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Title: Whither Causal Models in the Neuroscience of ADHD?
Language: English
Authors: Coghill, Dave, Nigg, Joel, Rothenberger, Aribert
Source: Developmental Science. Mar 2005 8(2):105-114.
Availability: Wiley-Blackwell. 350 Main Street, Malden, MA 02148. Tel: 800-835-6770; Tel: 781-388-8598; Fax: 781-388-8232; e-mail: cs-journals@wiley.com; Web site: http://www.wiley.com/WileyCDA/
Peer Reviewed: Y
Physical Description: PDF
Page Count: 10
Publication Date: 2005
Document Type: Journal Articles
Reports - Evaluative
Descriptors: Causal Models, Attention Deficit Hyperactivity Disorder, Barriers, Environmental Influences, Social Influences, Genetics, Biology, Developmental Stages, Child Development, Etiology
DOI: 10.1111/j.1467-7687.2005.00397.x
ISSN: 1363-755X
Abstract: In this paper we examine the current status of the science of ADHD from a theoretical point of view. While the field has reached the point at which a number of causal models have been proposed, it remains some distance away from demonstrating the viability of such models empirically. We identify a number of existing barriers and make proposals as to the best way for these to be overcome in future studies. These include the need to work across multiple levels of analysis in multidisciplinary teams; the need to recognize the existence of, and then model, causal heterogeneity; the need to integrate environmental and social processes into models of genetic and neurobiological influence; and the need to model developmental processes in a dynamic fashion. Such a model of science, although difficult to achieve, has the potential to provide the sort of framework for programmatic model-based research required if the power and sophistication of new neuroscience technologies are to be effectively exploited.
Abstractor: As Provided
Number of References: 64
Entry Date: 2009
Accession Number: EJ850299
Database: ERIC
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  Value: <anid>AN0016168924;5g501mar.05;2019May28.12:43;v2.2.500</anid> <title id="AN0016168924-1">Whither causal models in the neuroscience of ADHD? </title> <p>In this paper we examine the current status of the science of ADHD from a theoretical point of view. While the field has reached the point at which a number of causal models have been proposed, it remains some distance away from demonstrating the viability of such models empirically. We identify a number of existing barriers and make proposals as to the best way for these to be overcome in future studies. These include the need to work across multiple levels of analysis in multidisciplinary teams; the need to recognize the existence of, and then model, causal heterogeneity; the need to integrate environmental and social processes into models of genetic and neurobiological influence; and the need to model developmental processes in a dynamic fashion. Such a model of science, although difficult to achieve, has the potential to provide the sort of framework for programmatic model‐based research required if the power and sophistication of new neuroscience technologies are to be effectively exploited.</p> <p>The clinical construct of Attention Deficit Hyperactivity Disorder (ADHD) remains controversial. Those who doubt its validity frequently cite statements such as that made by the National Institute for Mental Health ([<reflink idref="bib25" id="ref1">25</reflink>]) that 'after years of clinical research and experience with ADHD, our knowledge about the cause or causes of ADHD remains largely speculative' (p. 3). In countering this position, clinical specialists and researchers in ADHD point out that these comments are being used out of context and cite the many genetic, neuroimaging, neurophysiological and neuropsychological studies that not only support the validity of the disorder, but also provide evidence for it having a biological basis ([<reflink idref="bib5" id="ref2">5</reflink>]). Thus while the field has reached a point at which relatively sophisticated causal theories are proposed ([<reflink idref="bib4" id="ref3">4</reflink>]; [<reflink idref="bib54" id="ref4">54</reflink>]), we still remain some distance from demonstrating a full causal model of ADHD, or its component symptom dimensions, in a way that incorporates multiple levels of analysis. That this is the case should come as no surprise. The brain is the most complex of biochemical 'machines' and this, linked with the complex polygenic genetic underpinnings of ADHD ([<reflink idref="bib58" id="ref5">58</reflink>]), would mean that a full causal model would need to 'predict a ballet choreographed interactively over time among genotype, environment, and epigenetic factors, which gives rise to a particular phenotype' ([<reflink idref="bib17" id="ref6">17</reflink>]).</p> <p>This paper explores some of the important barriers that we believe must be overcome if we are to shift from positing causal theories to demonstrating formal causal effects. To aid clarity we will utilize the developmental causal modelling framework proposed by [<reflink idref="bib32" id="ref7">32</reflink>]). This framework provides a useful notation with which to describe the interplay between the various levels of analysis required to fully describe conditions like ADHD or its component dimensions. Three within‐person levels of analysis are defined – biological, cognitive and behavioural – with a separate domain for environmental influences, which can interact at any of the three levels. Causal models are built by linking elements within the same or different levels into causal chains (Figure 1). Morton and Frith have proposed several important ground rules for guiding the construction and use of causal models (see Figure 2; [<reflink idref="bib32" id="ref8">32</reflink>]). Such models embrace the concept of change over time and encourage integration across multiple levels of analysis, providing the structure for an explanation of the disorder that is as complete as possible.</p> <p>Graph: 1 A hypothetical simplified causal model. A1refers to genetic originating causes, E1refers to environmental originating causes, Br1to the abnormal brain conditions, the struck out C1to a cognitive process which is altered by virtue of the brain condition and S1to the signs and symptoms.</p> <p>Graph: 2 Ground rules for causal modelling ([<reflink idref="bib32" id="ref9">32</reflink>]).</p> <p>The theoretical neutrality of this framework also allows for the comparison, and integration, of very different theoretical approaches. A similar causal modelling approach has been used successfully with several developmental disorders including autism ([<reflink idref="bib15" id="ref10">15</reflink>]), dyslexia ([<reflink idref="bib31" id="ref11">31</reflink>]) and conduct disorder ([<reflink idref="bib24" id="ref12">24</reflink>]). Several authors have utilized a causal modelling framework to structure discussions on the pathophysiology of ADHD ([<reflink idref="bib56" id="ref13">56</reflink>]) and to propose possible endophenotypes for ADHD ([<reflink idref="bib10" id="ref14">10</reflink>]). However, for our purposes, the framework suggests a number of considerations that can guide theoretical work on ADHD and help move towards the demonstration or evaluation of causal claims. We enumerate the most salient of these here.</p> <hd id="AN0016168924-2">The need to work across multiple levels of analysis</hd> <p>A complete causal model for ADHD or its symptom dimensions will require integration of genetic, neural, cognitive and behavioural mechanisms to describe complete causal chains occurring in development. The complexity inherent within each of these levels requires specialist knowledge and skills, and requires input from researchers with a wide range of scientific backgrounds. As a result, most researchers have, to date, worked at only one level. Thus, disparate evidence suggests the following causal pathway: genetic variations → functional abnormalities in both dopaminergic and noradrenergic neurotransmission within fronto‐striatal pathways → deficits in executive and reward‐related functioning → the behavioural manifestations of ADHD ([<reflink idref="bib10" id="ref15">10</reflink>]). Yet few studies have accepted the challenge of working across these levels of analysis in order to define their interrelationships empirically in the same sample. Exceptions are beginning to emerge. For example, functional neuroimaging (e.g. [<reflink idref="bib46" id="ref16">46</reflink>]; [<reflink idref="bib14" id="ref17">14</reflink>]) and electrophysiological studies (e.g. [<reflink idref="bib44" id="ref18">44</reflink>]; [<reflink idref="bib8" id="ref19">8</reflink>]; [<reflink idref="bib20" id="ref20">20</reflink>]) have started to describe the links between brain and cognitive function. Also a handful of pharmacogenomic ([<reflink idref="bib50" id="ref21">50</reflink>]; [<reflink idref="bib43" id="ref22">43</reflink>]) and family and genetic studies of neuropsychological functioning (e.g. [<reflink idref="bib59" id="ref23">59</reflink>]; [<reflink idref="bib13" id="ref24">13</reflink>]; [<reflink idref="bib33" id="ref25">33</reflink>]) strive to make links between the genetic and neural and cognitive levels of analysis. However, much more emphasis will need to be placed on these bridging studies in order that the causal chains linking the genetic and environmental causes of ADHD or its component symptom dimensions, through the subsequent biological and cognitive levels to the behavioural phenotype, can be understood.</p> <p>It would, for example, be informative to integrate neuroimaging/electrophysiological, psychopharmacological and/or neuropsychological protocols within the large scale molecular and behavioural genetic studies into ADHD (e.g. [<reflink idref="bib1" id="ref26">1</reflink>]). The incorporation, for example, of a neuropsychological arm into such a study would assist in the building of causal chains by exploring the associations between candidate genes and neuropsychological endophenotypes and the mediating/moderating effects of these endophenotypes on genetic effects in ADHD. Another useful strategy might be to incorporate cognitive, neuroimaging and molecular genetic methods into existing prospective epidemiological studies of the impact of perinatal factors on developmental outcomes. For example, maternal smoking during pregnancy independently impacts on the expression of attention problems, other externalizing problems and academic problems ([<reflink idref="bib6" id="ref27">6</reflink>]). The inclusion of neuroimaging and genetics strategies would permit an assessment of causal chains between maternal psychopathology, genetic susceptibility to smoking, the prenatal and perinatal environment, and ADHD or attention problems in the offspring. Similar arguments could be made for a wide range of other important domains.</p> <hd id="AN0016168924-3">The need to recognize the existence of and then effectively model heterogeneity within ADHD s...</hd> <p>This need to embrace and address vertical integration across the different levels of analysis is mirrored by the need to recognize that the heterogeneity inherent within ADHD samples will also require there to be multiple pathways within a causal model and a need for horizontal integration between these pathways at each level, and probably diagonally across levels. Until recently, simple single‐cause models dominated the ADHD literature. Such models carry an implicit suggestion that the behavioural symptoms of ADHD are a consequence of a single underlying factor such as deficient inhibitory control ([<reflink idref="bib4" id="ref28">4</reflink>]), state regulation deficits ([<reflink idref="bib51" id="ref29">51</reflink>]), or reinforcement–response abnormalities and motivational deficits ([<reflink idref="bib47" id="ref30">47</reflink>]). Whereas such theories have stimulated important findings (and indeed, note multiple processes that may be involved in ADHD), they have also tended to lead to a continuation of empirical designs that implicitly assume all children diagnosed with a given type of ADHD have the same causal aetiology. Such an assumption is unlikely to bear out, yet failure to model multiple pathways may ensure that between‐group designs (ADHD versus control) will continue to find relatively small, mixed effects. In short, single‐cause models have difficulty accounting for the heterogeneity which is being increasingly recognized as a key factor in the understanding of the causes of ADHD ([<reflink idref="bib54" id="ref31">54</reflink>]; [<reflink idref="bib35" id="ref32">35</reflink>]). Data from several datasets provide convincing evidence to suggest considerable heterogeneity within samples of ADHD subjects ([<reflink idref="bib53" id="ref33">53</reflink>]; [<reflink idref="bib35" id="ref34">35</reflink>]). While this within‐sample heterogeneity is found across all levels of analysis, the complexities are well illustrated by focusing on the cognitive level. Heterogeneity may be manifest in several ways. First, cognitive dysfunctions may be differentially associated with the inattention and hyperactivity/impulsivity dimensions. A growing corpus of research suggests that inattention but not hyperactivity/impulsivity is associated with deficits in executive functioning and working memory, and poor academic achievement, even in non‐clinical community samples ([<reflink idref="bib38" id="ref35">38</reflink>]; [<reflink idref="bib11" id="ref36">11</reflink>]; Martinussen & Tannock, in press; [<reflink idref="bib27" id="ref37">27</reflink>]). By contrast, hyperactivity/impulsivity appears to be more closely related to dysfunctions of reward mechanisms ([<reflink idref="bib53" id="ref38">53</reflink>]; [<reflink idref="bib57" id="ref39">57</reflink>]; Toplak, Jain & Tannock, under review). Second, there is growing evidence that not all individuals with ADHD manifest cognitive deficits, suggesting heterogeneity in underlying neural mechanisms and/or marked heterogeneity in risk and protective factors (e.g. [<reflink idref="bib35" id="ref40">35</reflink>]; Coghill, Rhodes & Matthews, unpublished data). Third, various cognitive deficits within individuals with ADHD may not be correlated, suggesting that ADHD may be the developmental outcome of a variety of anomalies in separable neural networks ([<reflink idref="bib53" id="ref41">53</reflink>]; [<reflink idref="bib40" id="ref42">40</reflink>]; Toplak, Jain & Tannock, under review).</p> <p>Thus causal models of ADHD will need to account not only for those both with and without cognitive deficits but also for the heterogeneity found within the cognitively affected group. Such data require us to consider the single‐cause models not as separate entities, but as potentially complementary approaches which, when viewed together, can provide a fuller appreciation of a complex multidimensional scenario. More studies are needed in which researchers investigate these contrasting theoretical models within the same samples to further the development of multi‐pathway models ([<reflink idref="bib55" id="ref43">55</reflink>]) and to identify specific causal claims more formally in ADHD. It is crucial to recognize that multiple pathways may not simply represent alternative routes into ADHD. Rather, it may be the norm for most children to have contributions from several, but not necessarily all, pathways, in varying degrees. At least three general patterns of multi‐pathway models could be generated. First, we could posit that ADHD is the common final behavioural consequence of any of several relatively independent pathways, such as 'cognitive deficit pathways' (e.g. a working memory pathway; [<reflink idref="bib21" id="ref44">21</reflink>]) and/or a non‐working memory pathway ([<reflink idref="bib39" id="ref45">39</reflink>])) and one or more non‐cognitive pathways (for example, a motivational pathway, [<reflink idref="bib55" id="ref46">55</reflink>]) and/or an adaptation to stress pathway ([<reflink idref="bib19" id="ref47">19</reflink>]). Each of these pathways on its own can result in the ADHD behavioural phenotype. Second, we could posit that ADHD is caused by a similar array of dysfunctions in each of these domains, with at least some dysfunction in all domains required before the phenotype is expressed. The extensive overlap in function demonstrated between ADHD and non‐ADHD samples would require that ADHD arises due to the small but additive and interactive effects of each pathophysiological process with the phenotype only being expressed once a threshold has been reached. Third, it may be that the correct model is a combination of the two described above. Thus, while ADHD could arise as a consequence of one of several independent pathways, an interaction between several pathways might be more common, with the detail of the interactions dictating the precise presentation severity, and possibly response to treatment. The situation for ADHD with comorbidity will, of course, be even more complex.</p> <p>This analysis points to the fact that it will be important to look beyond the frequently emphasized fronto‐striatal/executive networks in the brain to account fully for ADHD, even at the cognitive level of analysis. Thus, structural and functional neuroimaging studies and electrophysiology, including transcranial magnetic stimulation, have shown various brain abnormalities in ADHD patients (e.g. [<reflink idref="bib46" id="ref48">46</reflink>]; [<reflink idref="bib30" id="ref49">30</reflink>]; [<reflink idref="bib64" id="ref50">64</reflink>]; [<reflink idref="bib9" id="ref51">9</reflink>]; [<reflink idref="bib8" id="ref52">8</reflink>]). These studies have mostly demonstrated the now well‐recognized abnormalities in frontal cortical regions and basal ganglia. Yet, less often addressed are the morphological and functional differences that are revealed in the motor cortex, temporal and parietal lobes, cerebellum and corpus callosum ([<reflink idref="bib9" id="ref53">9</reflink>]; [<reflink idref="bib42" id="ref54">42</reflink>]). Further, the alteration of the REM‐sleep in ADHD ([<reflink idref="bib22" id="ref55">22</reflink>]) cannot be explained by the neuropsychological models described above.</p> <p>Along the same lines, recent neuropsychological studies have utilized batteries of neuropsychological tasks measuring a range of abilities dependant on a broader range of neuronal substrates. [<reflink idref="bib61" id="ref56">61</reflink>], under review) reported deficits in ADHD children on several short duration timing tasks dependant on the cerebellum for accurate performance ([<reflink idref="bib26" id="ref57">26</reflink>]). [<reflink idref="bib39" id="ref58">39</reflink>], [<reflink idref="bib40" id="ref59">40</reflink>]) described performance deficits across a wide range of tasks from the CANTAB battery including a pattern of performance on two tasks, Delayed Matching to Sample and Pattern Recognition, which mirrored those seen in patients with temporal lobe, parietal lobe or amygdalo‐hippocampal damage and Alzheimer's dementia more than patients with frontal lobe injury. Importantly, performance on both tasks was independent of behavioural inhibitory control and was improved following the administration of methylphenidate. These studies suggest that a conceptualization of ADHD largely restricted to fronto‐striatal circuits may require broadening within a multi‐pathway framework. However, further study is required to confirm the interrelationships between these and other cognitive deficits, to evaluate relative effect sizes, and to examine their relationships with genetic and environmental causal factors and associated neural mediating mechanisms.</p> <hd id="AN0016168924-4">The need to integrate environmental/social influences within genetic and neurobiological mech...</hd> <p>The causal modelling framework is neutral about the relative contribution of genetic and environmental factors as originating causes. The scientific belief that ADHD is best regarded as a biogenetic neuropsychiatric disorder receives support from the large and growing literature on the genetics and neurobiology of ADHD as cited earlier. Indeed, twin, family and adoption studies suggest a large genetic, but relatively small (mainly non‐shared) environmental component ([<reflink idref="bib41" id="ref60">41</reflink>]), which seems to remain relatively constant across levels of symptom severity ([<reflink idref="bib63" id="ref61">63</reflink>]). Molecular genetic studies implicate a number of potentially (neurobiologically) functional susceptibility genes in the pathophysiology of the condition (especially those coding for the structure of dopamine receptors (e.g. DRD4) and transporters (e.g. DAT1; [<reflink idref="bib12" id="ref62">12</reflink>])). While these different lines of evidence clearly support a role for genetic factors in ADHD, they do not suggest that this is to the exclusion of environmental factors. To point out one issue, genetic effects in the case of ADHD are necessarily expressed within, enabled by, and in some cases doubtless mediated and/or moderated by, particular biological and social environments that are at present not well mapped. Current designs are sensitive to these effects. For example geno‐environment correlations, in which the child's temperament elicits particular behavioural sequences in the social environment that in turn shape child development are expressed as genetic effects in twin study variance partitioning (see [<reflink idref="bib16" id="ref63">16</reflink>]). In short, viewing ADHD as essentially a genetically determined condition is an oversimplification at best.</p> <p>The work of Kreppner and colleagues on the impact of the early severe deprivation experienced by children adopted out of the Romanian orphanages shows a raised incidence of ADHD (among other problems), increasing as a function of length of deprivation experienced ([<reflink idref="bib23" id="ref64">23</reflink>]). This is highly suggestive of an environmental route into ADHD. The link between deprivation and ADHD is likely to be mediated by chronic changes in the neurobiology of the child, exemplifying the distinction between extrinsic causal mechanisms and intrinsic mediating factors in causal models. Similarly, neurobiological changes have been documented in animal models of environmentally induced stress ([<reflink idref="bib29" id="ref65">29</reflink>]). These studies highlight the importance of thinking clearly about the relationships between genetic and environmental influences and neurobiology: while genetic effects may well be mediated in part by neurobiological changes, they may also be mediated by psychosocial events due to genotype‐environment correlations. Further, not all neurobiologically mediated effects will have a genetic origin.</p> <hd id="AN0016168924-5">The need to properly characterize endophenotypes</hd> <p>Endophenotypes are those mediating factors, the unseen components, which sit between the observed manifestations of a disease or disorder and its originating causes. With respect to neuropsychiatric conditions, they may be neuroanatomical, biochemical, neurophysiological or neuropsychological in nature (e.g. [<reflink idref="bib17" id="ref66">17</reflink>]). They are particularly useful in helping us to develop our understanding of conditions in which complex genetic and environmental factors must be linked to a behavioural phenotype, which is difficult to define precisely and consistently. The endophenotype concept fits comfortably within the causal modelling framework, with endophenotypes representing aspects of abnormal functioning at either the biological or cognitive levels. Accurate characterization of candidate endophenotypes for ADHD may suggest simpler clues to the originating causes of this disorder than the behavioural phenotype itself. Properly characterized endophenotypes could further aid genetic research by acting as measurable markers of genetic risk. Inherent to this argument is the suggestion that by deconstructing a disorder like ADHD into its underlying component processes we will not only simplify genetic analysis but also provide alternative ways of describing and classifying those with the disorder and hopefully reduce the heterogeneity associated with the current behavioural phenotypes.</p> <p>Various criteria, which should be met by a valid endophenotype, have been described (Figure 3). [<reflink idref="bib10" id="ref67">10</reflink>]) suggest that an endophenotype should not be excluded solely on the basis that existing data suggests that they are not heritable/familial (i.e. 'genetic'); a criteria proposed by a number of authors. However, it is clearly of considerable importance to know whether or not an endophenotype relates to genetic causes of a disorder. In such cases, three further criteria apply: (<reflink idref="bib1" id="ref68">1</reflink>) the endophenotype should itself be heritable; (<reflink idref="bib2" id="ref69">2</reflink>) the endophenotype should co‐segregate with illness within families; and (<reflink idref="bib3" id="ref70">3</reflink>) the endophenotypes found in affected family members should also be found in non‐affected family members at a higher rate than in the general population ([<reflink idref="bib17" id="ref71">17</reflink>]).</p> <p>Graph: 3 Criteria for an endophenotype.</p> <p>Several potential neuropsychological endophenotypes for ADHD have been described, including a specific abnormality in reward‐related circuitry that leads to shortened delay gradients and delay aversion ([<reflink idref="bib54" id="ref72">54</reflink>]), deficits in temporal processing that result in high intra‐subject inter‐trial variability ([<reflink idref="bib52" id="ref73">52</reflink>]; [<reflink idref="bib61" id="ref74">61</reflink>]), deficits in working memory ([<reflink idref="bib39" id="ref75">39</reflink>]; [<reflink idref="bib7" id="ref76">7</reflink>]) and non‐working visual memory ([<reflink idref="bib39" id="ref77">39</reflink>]), impaired stop‐signal inhibition ([<reflink idref="bib48" id="ref78">48</reflink>]) and attentional set‐shifting ([<reflink idref="bib35" id="ref79">35</reflink>]). While each of these proposed neuropsychological endophenotypes meets several of the expected criteria, none meet them all. The heritability and co‐segregation within families remains unexplored for most endophenotypes. Only attentional set shifting and stop signal inhibition have been demonstrated to be familial and more frequent in non‐affected family members ([<reflink idref="bib35" id="ref80">35</reflink>]).</p> <p>While several of these endophenotypes have been demonstrated to be relatively sensitive markers for ADHD their specificity to ADHD is less clear ([<reflink idref="bib3" id="ref81">3</reflink>]). As previously suggested, it is unlikely that all endophenotypes will be present in all cases. It is, therefore, not surprising that cohort level analyses on such heterogeneous samples suggest high sensitivity but low specificity. This is one of the reasons for neuropsychological tests being relatively ineffective tools in the diagnosis of DSM or ICD defined ADHD. Additionally, several of the proposed endophenotypes appear to be common to several neurodevelopmental disorders. For example, working memory has also been proposed as an endophenotype for schizophrenia ([<reflink idref="bib17" id="ref82">17</reflink>]), and stop signal inhibition has been implicated in schizophrenia, language disorders, conduct disorder and autism. Indeed, the neuropsychological and neurophysiological similarities and dissimilarities between ADHD and other commonly comorbid conditions, such as conduct disorder ([<reflink idref="bib49" id="ref83">49</reflink>]; [<reflink idref="bib37" id="ref84">37</reflink>]; [<reflink idref="bib2" id="ref85">2</reflink>]) and specific learning difficulties ([<reflink idref="bib60" id="ref86">60</reflink>]), remain contentious and unresolved.</p> <p>However, this does not imply that we should abandon our search for and description of endophenotypes. Rather, it may suggest that we should be investigating potential neuropsychological rather than behaviourally defined subtypes of ADHD (see [<reflink idref="bib34" id="ref87">34</reflink>]). The neuropsychological assessment of those with ADHD could then assist in more fully describing an individual's condition and aid clinicians to decide on the most appropriate pharmacological, psychological and educational treatment strategies. A more adventurous but potentially far more profitable strategy would be to concentrate on mapping out the causal pathways both to and from cognitive deficits in delay sensitivity, behavioural inhibition, working and non‐working memory, and timing, rather than for ADHD <emph>per se</emph>.</p> <hd id="AN0016168924-6">The need to take developmental aspects seriously</hd> <p>Despite widespread recognition of ADHD as a developmental neuropsychiatric condition, very few causal explanations have seriously considered the two‐way, interactions between pre‐existing abnormal functioning and biological, cognitive, emotional, motor and social developmental processes, and their contribution to the expression of the behavioural phenotype ([<reflink idref="bib36" id="ref88">36</reflink>]; [<reflink idref="bib34" id="ref89">34</reflink>]). [<reflink idref="bib33" id="ref90">33</reflink>]) provide an outline of various temperament‐based early precursors to ADHD that warrant consideration. [<reflink idref="bib56" id="ref91">56</reflink>]) has discussed this issue with respect to the development of delay aversion and associated deficits in self‐organizational skills, suggesting that at least three related developmental phenomenon are implicated. The first is characterized by <emph>child</emph>×<emph>environment correlation</emph>, whereby the developmentally antecedent impulsive response of the child shapes their social and family environment by eliciting a punitive or negative response from parents and siblings to a failure to engage effectively with the delay‐rich environment. The second is <emph>person</emph>×<emph>environment interactions</emph>, whereby the punitive social environment, partially created by the behaviour of the child, moderates the links between underlying and early appearing impulsiveness and the emergence of a more generalized delay aversion. The final developmental process is characterized by <emph>individual accommodation</emph> to the child's underlying predisposition toward impulsiveness and the constraints this imposes on experience. It is likely that similar processes play a role in other causal pathways to ADHD.</p> <p>Causal models must also take into account the ways in which a failure of development in one cognitive ability impacts on the development of successive cognitive abilities. The potential importance of this concept to causal modelling for ADHD can be illustrated by considering the role played by working memory deficits in the development of ADHD. Working memory deficits, although relatively understudied, have been considered by many to be core cognitive risk factors for ADHD requiring accommodation within a causal model of ADHD ([<reflink idref="bib10" id="ref92">10</reflink>]). Deficits in timing ([<reflink idref="bib61" id="ref93">61</reflink>]) and non‐working visual memory ([<reflink idref="bib39" id="ref94">39</reflink>]), which, while not dependent on working memory performance, may themselves impact on the development of working memory, have been recently identified. Thus, if the usual development of accurate working memory performance is contingent upon the development of cerebellar timing functioning and spatial recognition memory, then impaired development of either of these abilities may impact on the development of spatial working memory functioning. While such hypotheses are still speculative, they warrant further investigation and illustrate the potential importance of such considerations. Further, the possibility that very basic sensory and perceptual processes may be impaired in ADHD, which, over the course of development, may manifest subsequently as impaired performance on various tasks and interpreted as 'impairments in executive function', remains relatively unexplored (e.g. [<reflink idref="bib20" id="ref95">20</reflink>]).</p> <p>Lastly, with regard to development, a causal model of ADHD must also account for changes in phenotypic expression over time. Future studies will need to differentiate between 'true' and 'apparent' changes in symptoms across the lifespan. For example, is the reduction in hyperactivity symptoms frequently noted in adolescence ([<reflink idref="bib18" id="ref96">18</reflink>]) a true shift towards normality or simply an apparent change resulting as a consequence of normative development? That is, does that shift represent a change over time, mirroring normative development, from a more visible motoric hyperactivity to an inner restlessness and fidgetiness which, while less noticeable and impacting on others, is still both impairing to the individual and remains as far removed from the normal distribution of experience as the symptoms in earlier life ([<reflink idref="bib4" id="ref97">4</reflink>])? In each case, a causal modelling paradigm would make different, testable, predictions. If the shift is towards normalization, then this should be reflected by a similar shift in the underlying pathophysiology (e.g. [<reflink idref="bib45" id="ref98">45</reflink>]), which would not be the case in the converse scenario. The accurate developmental description of each of these levels within causal chains would both aid the clarity of the resultant causal models and provide a more objective basis from which descriptions of ADHD across the lifespan, particularly in adolescence and adulthood, can be developed.</p> <hd id="AN0016168924-7">Concluding comments</hd> <p>The neuroscience of ADHD stands at a watershed. New brain study and genetic technologies provide us with the tools to examine the neurobiology of ADHD in an increasingly sophisticated and powerful way. If this is to be harnessed effectively, then research must be guided by equally sophisticated and powerful models of causes and causal processes. In this paper we have made a number of recommendations to overcome existing barriers to the development of empirically based causal models, and so facilitate model‐guided research programmes in the neuroscience of ADHD. Such programmes should routinely use both the causal and developmental contingency modelling paradigms to promote research, which seeks to clarify the associations between both the different levels of analysis within a model and the interrelationships between various models and causal pathways. Such approaches will be particularly valuable because of their ability to model heterogeneity in ADHD at a number of different levels. For instance, a reduction of phenotypic heterogeneity is crucial for further progress in the identification of susceptibility genes for ADHD or its symptoms dimensions. On a more practical level, this sort of analysis may provide the basis for identifying different psychopathophysiological subtypes of ADHD associated with different causal pathways, which has the potential to provide the basis for a new classification system. Such studies will require a concerted effort to collaborate across a range of levels; between theorists with differing perspectives, between researchers with a wide range of experimental backgrounds, and between centres to enable the recruitment of the large samples that will be required to explore the types hypotheses generated from such an approach. Such a model of science, departing as it does from the discipline‐specific and individual laboratory‐based nature of current practice, will not be easy to achieve, but without it, it will not be possible to resolve the core issues in the neuroscience of ADHD.</p> <ref id="AN0016168924-8"> <title> References </title> <blist> <bibl id="bib1" idref="ref26" type="bt">1</bibl> <bibtext> Asherson, P., & The IMAGE Consortium (2004). ADHD in the postgenomic era. 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  Data: English
– Name: Author
  Label: Authors
  Group: Au
  Data: <searchLink fieldCode="AR" term="%22Coghill%2C+Dave%22">Coghill, Dave</searchLink><br /><searchLink fieldCode="AR" term="%22Nigg%2C+Joel%22">Nigg, Joel</searchLink><br /><searchLink fieldCode="AR" term="%22Rothenberger%2C+Aribert%22">Rothenberger, Aribert</searchLink>
– Name: TitleSource
  Label: Source
  Group: Src
  Data: <searchLink fieldCode="SO" term="%22Developmental+Science%22"><i>Developmental Science</i></searchLink>. Mar 2005 8(2):105-114.
– Name: Avail
  Label: Availability
  Group: Avail
  Data: Wiley-Blackwell. 350 Main Street, Malden, MA 02148. Tel: 800-835-6770; Tel: 781-388-8598; Fax: 781-388-8232; e-mail: cs-journals@wiley.com; Web site: http://www.wiley.com/WileyCDA/
– Name: PeerReviewed
  Label: Peer Reviewed
  Group: SrcInfo
  Data: Y
– Name: PhysDesc
  Label: Physical Description
  Group: PhysDesc
  Data: PDF
– Name: Pages
  Label: Page Count
  Group: Src
  Data: 10
– Name: DatePubCY
  Label: Publication Date
  Group: Date
  Data: 2005
– Name: TypeDocument
  Label: Document Type
  Group: TypDoc
  Data: Journal Articles<br />Reports - Evaluative
– Name: Subject
  Label: Descriptors
  Group: Su
  Data: <searchLink fieldCode="DE" term="%22Causal+Models%22">Causal Models</searchLink><br /><searchLink fieldCode="DE" term="%22Attention+Deficit+Hyperactivity+Disorder%22">Attention Deficit Hyperactivity Disorder</searchLink><br /><searchLink fieldCode="DE" term="%22Barriers%22">Barriers</searchLink><br /><searchLink fieldCode="DE" term="%22Environmental+Influences%22">Environmental Influences</searchLink><br /><searchLink fieldCode="DE" term="%22Social+Influences%22">Social Influences</searchLink><br /><searchLink fieldCode="DE" term="%22Genetics%22">Genetics</searchLink><br /><searchLink fieldCode="DE" term="%22Biology%22">Biology</searchLink><br /><searchLink fieldCode="DE" term="%22Developmental+Stages%22">Developmental Stages</searchLink><br /><searchLink fieldCode="DE" term="%22Child+Development%22">Child Development</searchLink><br /><searchLink fieldCode="DE" term="%22Etiology%22">Etiology</searchLink>
– Name: DOI
  Label: DOI
  Group: ID
  Data: 10.1111/j.1467-7687.2005.00397.x
– Name: ISSN
  Label: ISSN
  Group: ISSN
  Data: 1363-755X
– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: In this paper we examine the current status of the science of ADHD from a theoretical point of view. While the field has reached the point at which a number of causal models have been proposed, it remains some distance away from demonstrating the viability of such models empirically. We identify a number of existing barriers and make proposals as to the best way for these to be overcome in future studies. These include the need to work across multiple levels of analysis in multidisciplinary teams; the need to recognize the existence of, and then model, causal heterogeneity; the need to integrate environmental and social processes into models of genetic and neurobiological influence; and the need to model developmental processes in a dynamic fashion. Such a model of science, although difficult to achieve, has the potential to provide the sort of framework for programmatic model-based research required if the power and sophistication of new neuroscience technologies are to be effectively exploited.
– Name: AbstractInfo
  Label: Abstractor
  Group: Ab
  Data: As Provided
– Name: Ref
  Label: Number of References
  Group: RefInfo
  Data: 64
– Name: DateEntry
  Label: Entry Date
  Group: Date
  Data: 2009
– Name: AN
  Label: Accession Number
  Group: ID
  Data: EJ850299
PLink https://search.ebscohost.com/login.aspx?direct=true&site=eds-live&db=eric&AN=EJ850299
RecordInfo BibRecord:
  BibEntity:
    Identifiers:
      – Type: doi
        Value: 10.1111/j.1467-7687.2005.00397.x
    Languages:
      – Text: English
    PhysicalDescription:
      Pagination:
        PageCount: 10
        StartPage: 105
    Subjects:
      – SubjectFull: Causal Models
        Type: general
      – SubjectFull: Attention Deficit Hyperactivity Disorder
        Type: general
      – SubjectFull: Barriers
        Type: general
      – SubjectFull: Environmental Influences
        Type: general
      – SubjectFull: Social Influences
        Type: general
      – SubjectFull: Genetics
        Type: general
      – SubjectFull: Biology
        Type: general
      – SubjectFull: Developmental Stages
        Type: general
      – SubjectFull: Child Development
        Type: general
      – SubjectFull: Etiology
        Type: general
    Titles:
      – TitleFull: Whither Causal Models in the Neuroscience of ADHD?
        Type: main
  BibRelationships:
    HasContributorRelationships:
      – PersonEntity:
          Name:
            NameFull: Coghill, Dave
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          Name:
            NameFull: Nigg, Joel
      – PersonEntity:
          Name:
            NameFull: Rothenberger, Aribert
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            – D: 01
              M: 03
              Type: published
              Y: 2005
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              Value: 1363-755X
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              Value: 8
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              Value: 2
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            – TitleFull: Developmental Science
              Type: main
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