Digit symbol coding and general cognitive ability in schizophrenia: worth another look?

For decades, schizophrenia researchers have sought to map specificaspects of cognitive performance onto specific neurobiologicalsystems in hopes of dividing broad cognition and neurobiologyinto more tractable components. Recent findings from studiesusing neuropsychological test batteries, in combination withemerging neurobiological evidence, argue for a complementary focus on more generalised cognitive and biological dimensions.

INTRODUCTION

TOP

INTRODUCTION

View larger version (116K):
[in this window]
[in a new window]
[as a PowerPoint slide]

An article of faith in schizophrenia cognitive research is thatit should be possible to link relatively specific behaviouralprocesses (e.g. executive functioning performance as measuredby card sorting tasks) to relatively specific neurobiologicalsubstrates (e.g. activity in dorsolateral prefrontal cortexsystems), and that such work will carve schizophrenia cognitioninto more discrete, genetically simpler, and potentially treatablecomponents. In the face of complex neurobiology and significantillness heterogeneity, progress along this path has been slow.Advances in genetics and new electrophysiological and neuroimagingtechnologies promise better defined and ever more specifictargets on the biological side of the analysis. At the same time, there are active efforts to translate precise experimentalparadigms into user-friendly instruments for the clinical measurementof behaviour.¹ It seems likely that these advances will yieldreliable and specific brain/cognition associations, some ofwhich may be particular to subgroups within the schizophreniaspectrum. But will the associations prove as useful in decipheringschizophrenia as we hope? On the behavioural side, in particular, the price of progress seems to be a focus on increasingly rarefied behaviours.^2,3 Yet, it is not clear that cognitive functioningcan be parsed meaningfully to the same degree as underlyingbiology. It may be that, in the drive to understand the illnessat a molecular and mechanistic level, the field will lose itsfocus on the complex systems of behaviour that are ultimatelythe heart of the illness and the keys to functioning in thecommunity. Notwithstanding waves of exciting new work, it remainsthe case that schizophrenia impairs most complex cognitiveoperations to a similar degree with few exceptions, that thelargest documented effect sizes in the schizophrenia cognitiveliterature have been for traditional and often simple neuropsychologicalmeasures, and that this is the class of measures that is mostclearly associated with functional outcome among people with schizophrenia (reviewed by Heinrichs⁴). These straight-forwardand persistent findings should raise questions among the faithful.

Digit symbol coding in schizophrenia

TOP

Digit symbol coding in...

Neuropsychological measures have been central to schizophreniacognitive research for decades, and their wide use continues.⁵Familiar examples include word list learning (i.e. verbal memory),card sorting (i.e. executive functioning), and span tasks (i.e.working memory). In contrast to these measures, less attentionhas been devoted to coding tasks, such as the Wechsler DigitSymbol Substitution Test.⁶ These tasks – which havenot changed fundamentally since their introduction a centuryago⁷ – reflect the coordination and speeded performanceof a number of uncomplicated scanning, matching and motor operations.Performance does not appear to be associated with particularregional or functional brain systems. However, the measuresare extremely brief (5 min to administer and score), are more reliable than other well-known neuropsychological measures,are sensitive to a wide variety of developmental and clinicalconditions, as well as normal ageing, and are often presentin research batteries.

Surprisingly, a recent meta-analysis demonstrated that thesesimple measures discriminate people with schizophrenia fromcomparison individuals better than the more widely studiedneuropsychological instruments.⁸ Across 37 studies, 1961 peoplewith schizophrenia and 1444 healthy controls, coding tasksshowed a schizophrenia impairment that was both substantial (g=–1.57) and significantly larger than effects derivedfor other measures. Indeed, only one of 36 comparison measuresconsidered in the meta-analysis showed a nearly comparableeffect across studies (category fluency, g=–1.45). Thecoding task effect was reasonably homogeneous despite strikingdifferences in samples and designs from study to study (rangeg=–1.05 to –2.02). The magnitude of the effectwas not sensitive to medication status or symptomatology. Thecoding task effect did differ in predictable ways as a functionof schizophrenia chronicity/severity groupings (i.e. first episode<chronic<very-early onset). Still, these differenceswere modest, and in each of these patient subgroups the codingtask effect size was larger than effects obtained for othercognitive variables. In addition, an offshoot analysis revealeda substantial coding task effect size among unaffected relativesof people with schizophrenia. Other studies have reported that coding performance also predicts functional status. Overall,coding tasks produce a robust impairment signal that differentiateshealthy controls from people with schizophrenia and their closerelatives better than other measures, and indexes poor prognosisand functional disability.

The meta-analysis also highlighted the generalised nature ofcognitive impairment in schizophrenia (see also Heinrich & Zakzanis⁹). Across all measures, the mean weighted effectsize was g=–0.98, and a number of familiar measures,including IQ, word list learning, story memory, mental arithmetic,and the `AX' version of the continuous performance test, showedvalues well above this average (range g=–1.10 to –1.29).Thus, the review reaffirmed a broadly generalised cognitive deficit in schizophrenia, and provided evidence of a small,disproportionate effect on simple coding tasks and, to a lesserdegree, on some other measures.

General cognitive ability in schizophrenia

TOP

General cognitive ability in...

Other work with collaborator Jim Gold suggests a `general cognitive ability' framework for understanding these results. In schizophrenia investigations, generalised cognitive impairment has oftenbeen treated as a nuisance variable or artefact that obscuresmore cognitive domain-specific effects (e.g. in domains ofverbal memory or executive functioning; see Albus & Hubmann¹⁰). However, the general ability findings are robust and similaracross heterogeneous schizophrenia subgroups and very differentsorts of analyses, suggesting that they should not be dismissedas artefact. We have used statistical modelling to characterisethe structure of cognitive performance within the schizophrenia group,¹¹ and of the cognitive deficit in affected personsrelative to healthy controls.^12,13 The latter studies wereconsistent in suggesting that about two-thirds of the diagnosiseffect on cognitive performance was mediated through a general ability factor, with a limited number of small effects (notably,in the processing speed domain)^12,13 (Fig. 1).

View larger version (20K):
[in this window]
[in a new window]
[as a PowerPoint slide]
Fig.1 Diagnosis effect on cognitive performance. Between-groups cognitive structure can be modelled by adding diagnosis as a grouping factor, and estimating parameters from diagnosis through the general cognitive factor to individual performance domains and, at the same time, from diagnosis directly to the domain factors. (a) Illustrates diagnosis effects entirely mediated through a higher order general cognitive ability factor. (b) Illustrates a model in which diagnosis affects performance domains through the general ability factor and has direct effects.

More generally, the factor-analytic literature argues for ahierarchical model of cognitive test performance – withindividual tests loading on first-order cognitive domain factors,and these factors loading in turn on a single, higher-ordergeneral cognitive ability factor. The heart of the hierarchicalmodel is the idea that generalised cognitive ability or `g'underlies much, but not all, of performance in different cognitivedomains and on individual cognitive measures.¹⁴

Thus, our modelling work and meta-analytic results convergedon key points: first, highlighting the prominence of the generalisedcognitive impairment in schizophrenia; and second, showingthat certain measures and domains, including coding tasks,were disproportionately impaired to a small but significantdegree. It seems to follow from the findings regarding generalised cognitive structure in schizophrenia that much of what is measuredby traditional neuropsychological assessment measures –whether they are generally held to tap verbal memory or executivefunctioning or some other domain – is broad cognitiveability, not independent, domain-specific performance.

Significance of findings from neuropsychological battery studies

TOP

Significance of findings from...

These lines of research frame a critical question: do generalcognitive ability interpretations of neuropsychological findingsin schizophrenia mainly reflect limitations of existing measuresor do they reveal something fundamental about the structureof cognition in this disorder? One possibility is that codingand most other neuropsychological tasks are so inherently multifactorialthat their utility for probing specific biological or treatment effects in schizophrenia is sharply limited.¹ If so, thenmeasurement techniques adapted from cognitive neuroscience,serving as intermediate phenotypes for genetically definedtargets, may finally enable researchers to carve schizophreniacognition `at its joints'.^2,3 However, this outcome is uncertain.Even assuming further progress in isolating discrete behavioursin schizophrenia and connecting them with biological markers,it could turn out that the target behaviours have been strippeddown to a degree that leaves their relationships to important everyday outcomes obscure.

Another possibility is that the generalised cognitive deficitis a fundamental manifestation of schizophrenia. If so, thenone path to improved understanding of the pathophysiology ofcognitive impairment may emerge from a fresh look at the neurobiologicalassociations of general ability. Several lines of evidenceemerging in the field are consistent with the hypothesis thatthe neurobiology underlying generalised cognitive dysfunctionis likewise general in nature. Examples include: (a) broadlyreduced grey matter and neuronal arborisation; (b) diminishedmyelin density and fibre coherence in major white matter tracts;(c) poor signal integration at the level of the cell and thenetwork due to cortical background noise and reduced neural synchrony; and (d) abnormalities associated with the brain'smain excitatory and inhibitory neurotransmitters, glutamateand ${gamma}$ -amniobutyric acid.¹² Importantly, related findings areemerging in healthy groups and among unaffected relatives ofpeople with schizophrenia.¹² Some have hypothesised rolesfor even more general biological processes, such as oxidativestress, inflammation and energy metabolism,¹⁵ possibilitiesthat might begin to recast schizophrenia as a general, systemic disorder, rather than a focal brain disease. Findings fromoutside the schizophrenia literature supporting `generalistgenes' for cognitive development, performance and impairmentalso seem relevant.¹⁶

Neuropsychological measures show an excellent ability to discriminate affected individuals and their relatives from controls andto index disability among those affected.⁴ This may be preciselybecause they are sensitive to such generalised biological effects.Coding tasks, in particular, appear to measure impairment in integrating or coordinating distributed brain networks, moreso than failures connected to specific sub-processes. This`systems' level is a potentially critical level of analysisfor schizophrenia and, therefore, the relatively diffuse measurementfocus of coding tasks and other similar measures might be seenas a strength of the instruments rather than a weakness.¹ Insum, emerging evidence provides a basis for renewed interestin the generalised cognitive deficit in schizophrenia and suggeststhat investigation of associations at more integrated levelsof cognition and neurobiology should be pursued in balancewith more mechanistically targeted research.

REFERENCES

TOP