Tasks Insensitive To Orbitofrontal Cortex Abnormality

Spatial Working Memory

Figure 5:4 shows the results from the spatial working memory task. The number of within- search errors increased significantly with search set size (F(1.3, 37) = 22, p < 0.001 (with Greenhouse-Geisser correction)). There was no significant difference between the means of the groups on the number of within-search errors (ANOVA: F(2, 40) = 0.5, p = 0.6).

The number o f between-search errors increased significantly with search set size (F(1.3, 37) = 150, p < 0.001 (with Greenhouse-Geisser correction)). There was a significant difference between the means of the groups on the number o f between-search errors (ANOVA: F(2, 40) = 3, p = 0.04: Planned comparisons: CvH: p = 0.6; HvL: p = 0.06). This is a reflection of the Low group scoring significantly more between-search errors than the control group. This difference was not correlated with age, sex or VIQ.

Figure 5:4 Spatial Working Memory search errors (Mean ± SEM)

a) 1.00n 0.7 5- Î2 2 c .i 0.50- o o z 0.2 5- 0.00 2 3 4 5 6 7 8 Number of boxes Control - ^ H lg h b)

a) Within-search errors; b) Between-

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E 2 «■ S o I S 6- n o o z 2 3 4 5 6 7 8 Low Number of boxes Control —^ H ig h Low

The Stroop Colour and Word Test

There were no significant differences between the means o f the groups on the Stroop (ANOVA: F(2, 40) = 1, p = 0.4).

5.4

Discussion

The Autistic groups were found to achieve significantly fewer categories on WCST than controls. Although such a result is consistent with orbitofrontal cortex abnormality, similar performances have been noted following damage to other regions of the frontal lobe and other areas of the brain [Corcoran and Upton 1993; Upton and Corcoran 1995; Stuss et al.

2000]. Error pattern analysis in the two Autistic groups demonstrated no significant increase in perservative errors, but a significant increase in correct responses. This pattern reflects a loss of set (the child was able to match the cards according to the current criterion, but could not sustain this consistently for 10 consecutive cards for the category to be achieved).

Several studies have reported poor performance o f individuals with Autism on the WCST (e.g. Prior and Hoffmann 1990; Rumsey and Hamburger 1990; Bennetto et al. 1996). The nature o f the errors has not been reported in some of these studies (e.g. Rumsey and Hamburger 1990), making interpretation of the results difficult. Bennetto et al. reported

no significant difference in set maintenance between individuals with Autism and their matched controls [Bennetto et al. 1996]. This discrepancy may be due to the lower intellectual ability of the subjects in Bennetto's study (mean VIQ = 85). Individuals with learning disability may show increased set loss compared to average ability controls. This issue could be addressed by comparing the Low group (in this study) with ability matched controls. Further research is therefore needed.

Findings in the literature relating to the perseverative errors on the WCST in Autism are conflicting. One study reported increased levels of perseverative errors [Bennetto et al.

1996]. However, Hughes et al. report that perseverative error rates in a computerised task similar to WCST were not different in subjects with Autism from the rates of controls matched for learning disability [Hughes et al. 1994].

Failure to maintain set has been associated with orbitofrontal cortex abnormality. Stuss et al. reported increased set loss in patients with orbitofrontal cortex lesions [Stuss et al.

2000] and in frontal leucotomy patients [Stuss et al. 1983]. Nagahama et al. found in a PET study that controlling for maintenance of set reduced orbitofrontal cortex activation [Nagahama et al. 1996].

Several possible cognitive reasons for set loss have been proposed [Stuss et al. 2000]. Firstly, failure to suppress responses to irrelevant (but salient) stimuli may be responsible. However, the results from the Stroop test suggest that, at least to some extent, this skill is intact in individuals with Autism. Poor sustained attention would also result in set loss. However, there was no significant correlation between sustained attention scores and the number of correct responses on WCST. A third alternative is that the children had difficulty remembering which category they were currently sorting to. Consistent with this, there was a significant correlation between the Rivermead scores and the number of correct responses.

The performance of the three groups did not differ significantly on the two other measures aimed at assessing orbitofrontal cortex function (rule reversal and extinction). This test has

[Rolls et al. 1994] and children (unpublished data from Vargha-Khadem’s laboratory). The intact performance of the children with Autism on the rule reversal and extinction may arguably suggest that poor orbitofrontal function can not explain the WCST results. However the complexity o f WCST, and hence its sensitivity, is far greater than that of the computer tasks. Consistent with this, Hughes et al. found that Autistic children were able to complete the early stages of a computerised rule shifting paradigm (comparable to the rule reversal task administered in this task) [Hughes et al. 1994]. However, as the task became more complex (requiring both intra and extra dimensional shifts), the children with Autism were impaired.

The spatial working memory results suggested that the High group were similar to the control group on these measures. This lack of difference is unlikely to be due to a floor effect: neither group performed near chance levels [Owen et al. 1996b]. Further, the scores o f both groups are comparable to other reports on children’s performance on this task [Luciana and Nelson 1998]. Imaging studies suggest that the dorsolateral preffontal cortex is important for successful performance on this task [Owen et al. 1996a]. Animal studies have demonstrated that whilst dorsolateral prefrontal lesions affect spatial working memory, orbitofrontal lesions do not [Bachevalier and Mishkin 1986]. As such, the results are consistent with relatively preserved dorsolateral prefrontal cortex function in the High group.

The Low group showed a selective impairment in the spatial working memory task. They returned to a box where they had already found a token significantly more often than the control group (between-search errors). However, the Low group did not return to a box already found to be empty within a trial more often than controls (within-search errors). It is important that these results are interpreted with caution: the lack of verbal ability matched controls prevents demonstration that the deficit is associated with Autism and not learning disability. Additionally, it should be noted that the distribution o f the between- search errors on this task was bimodal (for similar pattern see Chapter 3). Two o f the children completed the task with a mean of less than 4 errors, whilst the remainder o f the children made at least 8 errors.

Spatial working memory has not been reported before in Autism. Bennetto et al.

investigated verbal working memory (e.g. Bennetto et a l 1996) and found deficits. However the tasks used in this study required the children to remember a list of sentences, and to remember the number of yellow dots on a series o f presented cards. Both o f these tasks can be argued to be assessing contextual memory rather than working memory. The children did not have to manipulate the stimuli on-line in any manner.

All three groups performed similarly on the Stroop task (consistent with previous reports, e.g. Blair et al. 2001). Although the Stroop is widely recognised as a test of frontal lobe function, understanding of the more specific areas involved is lacking. Regression analysis in a lesion study suggested that the lateral frontal cortex plays an important role [Vendrell

et al. 1995]. hnportantly for this study, patients with orbitofrontal cortex damage have been reported to perform similarly to controls on the Stroop task [Stuss 1991].

In summary, therefore, the results from this study are consistent with the hypothesis of selective abnormality of the orbitofrontal cortex in children with Autism. The possibility that this abnormality is associated with abnormality in the medial temporal lobes is conceivable in the light of the pattern of medial temporal and frontal connections (see introduction). However, a number of issues should be highlighted.

Firstly, deficits in executive functions have been found in patients with pathology outside the frontal lobes (e.g. Corcoran and Upton 1993; Upton and Corcoran 1995). Secondly, much of the evidence for localisation o f function within the frontal lobes comes from adult lesion studies. It is possible that developmental abnormality o f the frontal lobes may result in reorganisation o f function, leading to different localisation of function. However, although developmental frontal lobe damage appears to result in a more aberrant social profile than similar damage in adulthood [Dolan 1999; Anderson et a l 2000], there have been no reports of functional localisation in these children. Functional imaging is likely to be an invaluable tool in addressing this question.

than on the equivalent pen and paper tasks [Ozonoff 1995]. Although the pattern of deficit found in this chapter is not directly related to the mode of presentation, it remains possible that, for example, a manual spatial working memory task may reveal a deficit not detected by the computer version, or that a computerised version o f WCST might show different results. Further research is needed to investigate this possibility and to attempt to determine what factors create any differences (such as requirement to interact with examiner). This issue will be returned to in the final chapter o f this thesis.

Finally it should be repeated that whilst the inter-connectivity of the orbitofrontal cortex and medial temporal lobes suggests that any abnormality in either region would be compounded by aberrant projections, this does not preclude the possibility of areas outside the orbitofrontal cortex in the frontal lobes also being abnormal. Firstly, the initial pattern of pathology may include these regions. Secondly, the orbitofrontal cortex is extensively connected to the remainder of the frontal lobes (for reviews see Pandya et al. 1988; Barbas 1992), so abnormal orbitofrontal connections could affect the rest of the frontal lobes. Additionally, the medial temporal lobe is involved in functional circuits that include other regions of the frontal lobes (e.g. hippocampal formation and dorsolateral frontal cortex in spatial working memory (e.g. Aggleton et al. 1986; Owen et al. 1996a; Olton and Papas 2001)). Abnormality in these (indirect) connections may induce abnormality (albeit to a lesser extent) in these frontal lobe regions.

It is pertinent to address in this chapter the claim that an executive function disorder associated with frontal lobe abnormality underlies the syndrome of Autism (e.g. Hughes et al. 1994). There are a number of reasons to believe that this explanation of Autism is inadequate. Deficits in executive function have been noted in other neurodevelopmental psychiatric disorders including ADHD [Chelune et al. 1986], conduct disorder [Lueger and Gill 1990] and Tourette’s syndrome [Incagnoli and Kane 1981]. Deficits in executive function therefore do not necessarily result in social impairment. Further, although early frontal lobe abnormality does results in aberrant social behaviour, affected children are not necessarily Autistic [Anderson et al. 2000]. This issue will be re-examined in Chapter 10.

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