We found differential neuronal activation in several brain regions during fMRI tasks exercising VCA, working memory, and attention in children with cSLE who have NCD, compared to those with normal cognition based on formal neuropsychological testing. Furthermore, we newly report details about the relationship between the level of cognitive performance and task-driven regional brain activation in cSLE.
Previous investigations have reported various cognitive deficits in both adult SLE and cSLE, most commonly including impairment of attention, working memory, and VCA [23–25]. Earlier work applying fMRI in adults and children explored changes in neuronal networks associated with SLE in comparison to healthy controls [11, 26–30]. These studies suggest that individuals with SLE activate brain regions associated with specific cognitive tasks more strongly than their healthy counterparts. The recruitment of the additional brain regions was hypothesized to help maintain normal levels of performance by patients with cSLE or adults with SLE during a given fMRI task.
The results of our study support the use of a similar compensatory mechanism for NCD for the attention task CPT-IP. We demonstrated greater activation in an insular/superior temporal ROI in the presence of clinically overt NCD compared to no NCD while CPT-IP performance remained unaffected. Notably, a negative relationship between CPT-IP brain activation in several ROI and patients' working memory abilities, as measured by formal neuropsychological testing, was observed. A possible explanation for this finding is that CPT-IP is, in effect, a 1-back working memory task. It represents a simpler version of the N-back (2-back) task. Lack of negative association of CPT-IP activation with attention domain scores suggests that attention deficits may not be the principal drivers of compensatory activation for this task. The current study in young patients with cSLE directly supports the notion that there is a relationship between the presence of NCD and alterations in brain activation.
Mackay et al. reported that longer SLE disease durations are associated with diminished neuronal activation during an fMRI task of working memory among adults with SLE . The patients included in that study  with longer disease durations also had more disease damage and poorer working memory, making it difficult to dissect causal relationships. Conversely, in our study the NCD and noNCD groups had similar disease duration, suggesting that the duration of SLE may not be as important for brain activation differences in SLE as previously thought. Alternatively, the differences in findings between our study and Mackay's might be due to differences in how developing brains of children with cSLE and mature brains of adults with SLE respond to the underlying inflammatory processes.
Nonetheless, the observations by Mackay et al. suggest that compensatory augmentation of task activation can break down with sufficient levels of disease damage. It is plausible that the threshold for breakdown also depends on task difficulty. Unlike the CPT-IP task, we observed diminished activation in select brain regions pertaining to the N-back and VCA tasks in cSLE patients with NCD compared to those with no NCD. Thus, some neuronal activity changes we observed in children with cSLE-related NCD parallel those in adults with SLE of extended duration. Intriguingly, this decrease of activation associated with NCD occurred in the precuneus and inferior parietal areas, which are regions where cSLE patients have previously showed more brain activation than healthy controls under a working memory fMRI task .
In aggregate, our results are consistent with a model in which intact cognitive performance can be maintained in children and adults with SLE via compensatory increased neuronal activation. However, under sufficient disease burden or cognitive challenge, that compensatory pattern breaks down, resulting in diminished activation and clinically apparent cognitive dysfunction.
As a group, the children with NCD in this study had a significantly lower correct response rate than the noNCD-group during fMRI tasks probing working memory and VCA, while performance on the CPT-IP attention fMRI task showed no significant group differences. Correspondingly, while activation decreased for working memory and VCA in those with NCD, the attention task (CPT-IP) elicited stronger activations for the NCD-group on both voxel-based and ROI-based analyses. It is possible that the CPT-IP task did not challenge the study participants as much as the other fMRI tasks, allowing the NCD-group to maintain performance by means of the compensatory strategy of greater activation described above. Alternatively, the lack of CPT-IP performance differences between the NCD-group and the noNCD-group may be due to relatively well-matched attention domain z-scores in formal neuropsychological testing, or to a more robust mechanism for maintaining attentional ability compared to working memory function or VCA.
For all three fMRI tasks, there is a common thread of positive correlation between activation and attention domain formal neuropsychological testing z-scores. Thus attention deficits in the NCD-group may play a role in diminishing performance during fMRI tasks that probe working memory and VCA, and the corresponding decrease in brain activation in patients with NCD.
This study offers a framework for viewing NPSLE as a burden on brain function that elicits compensatory mechanisms, relying on neuronal plasticity to maintain cognitive performance. Plasticity has limits which, when exceeded result in clinical manifestations of cognitive deficit. In the context of brain plasticity, the course of NPSLE may have a more profound impact on children with cSLE, given their dramatic, ongoing, brain development. While children possess a greater capacity for brain plasticity in response to an assault such as NPSLE , there remains the potential for the disease not only to disrupt existing neuronal networks, as demonstrated in this study, but also to alter the development of emerging brain networks. Our cross-sectional study does not allow us to delineate whether brain development is impaired by cSLE, or whether ongoing brain maturation serves as a means to help compensate for earlier brain insults by active NPSLE. Such a critical unknown will require longitudinal studies, which will also help determine whether the observed alterations in brain activation are permanent or reversible with treatment.
A distinct strength of our study is that its participants were well-phenotyped with respect to their clinical cSLE status, and their cognitive abilities were accurately assessed using the cSLE Cognitive Battery of Standardized Tests . However, this study also suffered from some limitations. While twenty-one subjects were imaged for this study, only seven tested as having NCD by our criteria. This low number limited the statistical power for finding differences attributable to the development of NCD. Nonetheless, significant differences between groups of children with different levels of cognitive ability were detected, and one might speculate that at least some of the trends in associations would have reached statistical significance had the sample size been larger. Performance on both 2-back and VCA square completion fMRI tasks was particularly poor for the NCD group raising concern about motivation. This is dispelled to some degree by good performance by the NCD group on the CPT-IP task and the control tasks for N-back and VCA. Recruitment for this study included children in the age range of 9 to 18 years, a period of ongoing brain development. Including this span of development may have introduced age-related variability in the fMRI findings. Note, however, that the NCD and noNCD groups are well matched in age, reducing the impact of developmental stage on group difference assessments. The subject groups were not matched, however, in socioeconomic status (SES) and IQ, with the NCD group lower in both measures. The influence of these differences on our results cannot be ruled out.