Childhood-onset systemic lupus erythematosus (SLE) is among the most severe pediatric rheumatic diseases (“pediatric” defined as onset prior to age 16). Often diagnosed in US females of minority populations, SLE is associated with significant morbidity and at least 10 times higher mortality than that of the age-matched general population (1). The reported prevalence of neuropsychiatric involvement in SLE (NPSLE) varies between 15% and 95% (2, 3), and children with SLE tend to exhibit a more severe phenotype than adults (4).
Neuropsychiatric involvement is arguably the least understood manifestation of SLE and is associated with a complicated range of clinical presentations (5). NPSLE syndromes range from diffuse central nervous system (CNS) disorders (e.g., acute confusional state, psychosis, anxiety, and depressive disorders) including cognitive dysfunction to focal CNS syndromes (e.g., seizures, cerebrovascular disease, chorea, myelopathy, transverse myelitis, demyelinating syndrome, aseptic meningitis, headaches) and peripheral nervous system disorders (e.g., neuropathies, acute inflammatory demyelination) (6).
Cognitive dysfunction is likely second only to headache as the most commonly encountered symptom of NPSLE. Cognition impairment in NPSLE can affect any or all of the following functions: simple or complex attention, reasoning, executive skills (e.g., planning, organizing, sequencing), memory (e.g., learning, recall), visual-spatial processing, language (e.g., verbal fluency), and psychomotor speed (7–9). The severity of cognitive dysfunction in NPSLE ranges from mild impairment to severe dementia. Currently, formal neurocognitive testing is considered the criterion standard for diagnosing cognitive dysfunction in SLE (6), but the etiology of this complication remains elusive and continues to be an active research question.
Neuroimaging is a potential means to noninvasively assess brain pathology in NPSLE. Anatomic magnetic resonance imaging (MRI) has commonly revealed lesions in the brain tissue of individuals with NPSLE, but these findings have not been effective markers of active NPSLE, nor have they explained the specific cognitive changes encountered (3). While evidence of cortical and subcortical neuropathology has been demonstrated in MRI studies using magnetization transfer imaging and fluid-attenuated inversion recovery (10, 11), no clear association of these findings with clinical symptoms that could be considered when making or evaluating treatment decisions has emerged. Likewise, limited insight into patterns of cognitive deficit in NPSLE has been provided with other imaging methods, such as magnetic resonance spectrometry (10, 12, 13), positron emission tomography (PET) (14, 15), and single-photon–emission computed tomography (SPECT) (16, 17).
Functional MRI (FMRI) is a promising method for recording brain activation patterns associated with specific cognitive tasks, including patterns that could be related to the neuropathologic basis of NPSLE. Standard FMRI studies involve acquisition of serial images while the subject alternates between performing active and control tasks (FMRI paradigms). The image intensity is weighted by the relative oxygenation level of blood hemoglobin (blood oxygenation level–dependent [BOLD]). Contrast between images obtained during active and control task periods of a paradigm reflect changes in regional brain activity. Although FMRI has been helpful in delineating changes in brain activity in various chronic diseases involving cognition (18–20), its usefulness for studying brain pathology in SLE, particularly of childhood onset, has not been well explored.
In this pilot study, activation patterns on FMRI were investigated in patients with childhood-onset SLE. In addition, the relationship between FMRI activation patterns and results of formal neuropsychological testing was explored.
- Top of page
- PATIENTS AND METHODS
- AUTHOR CONTRIBUTIONS
This preliminary study introduces the application of FMRI techniques for exploring a range of neurocognitive domains in patients with childhood-onset SLE in comparison with healthy control groups. Functional imaging paradigms were chosen to exercise those domains of cognitive function that have been implicated, by formal testing, to be subject to early decline in NPSLE. Activation patterns for each of the FMRI paradigms comprised areas previously found to be activated in normal control populations in both groups included in this study. More importantly, significant and diffusely distributed differences in activation between patients with childhood-onset SLE and healthy controls were found, particularly for tasks probing working memory and attention. It is notable that significant differences in the childhood-onset SLE patients were detectable despite the small sample size and lack of clinically overt cognitive deficits.
Deficits in language ability are among the earliest markers of the presence of a developmental or acquired neurologic disorder. It has been suggested that even individuals with SLE without overt NPSLE, such as the patients in this study, have difficulties with verbal memory (55, 56). Difficulty with verbal memory (based on the results of formal neuropsychological testing) was present in some of the subjects with childhood-onset SLE in this study. Thus, tests of language processing appear to be particularly suited for studying neural substrates that are involved in NPSLE. Of particular note is that areas in which there were differences in activation patterns between childhood-onset SLE patients and controls during the verb generation task included the Wernicke area (Brodmann area 22), which is involved in language association. Whereas controls showed typical left hemisphere dominance of activation in both the Broca area (Brodmann area 44) and the Wernicke areas (32, 33), the childhood-onset SLE group did not exhibit significant activation in the Wernicke area (corrected P < 0.05). Conversely, the Broca area was covered more broadly in the group of childhood-onset SLE patients, with activation extending more inferiorly. Based on these FMRI findings, it appears that a deficit in the neural circuitry for word fluency emerges with childhood-onset SLE, suggesting that FMRI may be sensitive in detecting early influences of childhood-onset SLE on the neural substrates of semantic association and other language functions.
A variety of tests have been developed to measure attention (57, 58). The CPT-IP task used in this study was designed to measure attention by requiring focus on a continuous stream of data while responding to specific stimuli, in accordance with a set of a priori instructions (59–61). The group of childhood-onset SLE patients exhibited more extensive activation than control subjects in large tracts of the fusiform gyrus and visual associative cortex, regions associated, in previous research, with abnormal attention (62, 63). These results suggest that functional changes in these brain areas underlie attentional changes experienced in childhood-onset SLE.
Preclinical studies and biopsy findings suggest that the frontal cortex and the hippocampus mediate working memory (40, 64–66). Similarly, functional neuroimaging (SPECT, PET, FMRI) has consistently identified prefrontal and temporal brain activation during working memory performance (41, 42, 67–72). This study probed working memory via the N-Back paradigm adapted for FMRI and demonstrated that the same cortical structures were involved. Earlier investigations have revealed evidence of impairment of working memory in SLE (73). The childhood-onset SLE group in the present study exhibited stronger and more extensive activation in regions associated with working memory, suggesting that SLE has an effect in this domain. A possible explanation for this observation of increased activation in visual and attention areas during performance of this task by childhood-onset SLE patients is that they must exert greater effort to perform the task. There is evidence to suggest that increased effort will result in increased activation with the same task (42, 74, 75).
Differential activation mapping, irrespective of the FMRI task performed, tended to show more pronounced activation of the targeted cortical regions in childhood-onset SLE patients compared with controls. The cingulate gyrus, an inhibitory brain region (76), was consistently activated during control task periods in all 3 paradigms in this investigation. A possible interpretation of the decreased negative activation in the childhood-onset SLE patients would be that there is less suppression of brain activity during the control tasks of the paradigms. Extending this hypothesis, these observations could suggest that patients with childhood-onset SLE manifest an imbalance of cognitive effort, with more effort required to do the task at hand, while less is applied to inhibiting task action during control periods. Association of greater task activation with cognitive deficiency is further supported by the preponderance of significant negative correlations between task activation across paradigms and neuropsychological test scores.
The present FMRI findings reveal widespread differences and imbalances of brain activation in childhood-onset SLE patients compared with healthy controls. While the systemic nature of the disease may play a role in explaining these diffuse changes, it is also reasonable to consider damage or malfunction of connectivity of the underlying neural networks. Diffuse changes in brain network distribution are a plausible outcome of damage to critical connections between network elements, and their occurrence has been suggested previously (13). This hypothesis can be supported by previous observations of deep-seated white matter involvement in SLE (77).
This pilot study was subject to a number of limitations that should be considered in interpreting these initial results. First, minor discrepancies in the age and sex distribution and possibly socioeconomic status between the childhood-onset SLE and control groups included for each paradigm arose from the opportunistic selection of controls for this pilot study from other projects ongoing or completed in our laboratory. Although suboptimal in terms of matching controls to childhood-onset SLE subjects, without this efficiency it would not have been possible to complete the pilot study within the limited budget available. Furthermore, investigators at our institution have previously shown that sex differences in activation patterns associated with the verb generation task are very small and are not evident in studies with small sample sizes (78). We would expect this observation to hold true for the attention and working memory tasks included in this pilot study as well, and previously reported studies of these tasks and control subjects have not accounted for sex differences. Age distribution may have been a confounder in the findings on the attention task, since differences between younger and older adults performing this task have been reported previously (45).
Another possible limitation of the present study is the fact that the medications used for the treatment of SLE can affect cognition (79). Since nearly all of the patients with childhood-onset SLE in this study were treated with similar corticosteroid regimens (Table 1), the impact of medications on the results cannot be assessed conclusively. Followup work with untreated patients will be needed in order to explicitly address the role of corticosteroids in these FMRI findings. Although none of the patients with childhood-onset SLE in this study exhibited CNS or vascular involvement as assessed with standard activity and damage indices, a role of specific pathologies in explaining the observed activation differences in this limited work cannot be ruled out.
A final point worth noting is that SLE may act on the brain indirectly, through a pathologic influence on neurovascular physiology. Given that the BOLD effect used to create FMRI activation maps is based on subtle changes in blood flow to locally activated cortical areas, the etiopathogenesis of SLE, as well as possible effects of medications on vascular reactivity, could influence this effect. We attempted to control for this possible confounding factor by assessing the presence of vasculitis as defined in the SLEDAI (21, 22). None of the childhood-onset SLE patients were found to have evidence of vascular disease by this measure; however, it is still possible that there could have been an unspecified difference in neurovascular physiology between the childhood-onset SLE patients and the control subjects. Given that the differences found for each of the FMRI tasks were discrete, it seems unlikely that there is a global difference in vascular physiology between the 2 groups. However, this point may remain obscure until research reveals more about the underlying mechanisms of NPSLE.
Despite promising results in animal models, to date there are no laboratory markers or conventional imaging methods that allow for the reliable early diagnosis of cognitive dysfunction in SLE (80–82). At present, the degree of sensitivity of FMRI does not permit its use as a diagnostic tool for cognitive function in individual SLE patients. Nevertheless, based on the present findings, FMRI may be a promising approach to elucidate the areas and mechanisms involved in the development of cognitive dysfunction in SLE. Benefits from such understanding could include improved treatment strategies. Our detection of changes in brain function in childhood-onset SLE prior to overt manifestation of cognitive dysfunction encourages the establishment of longitudinal studies to measure changes in FMRI activation patterns during the early stages of disease. Use of this approach may identify categories of patients at risk for subsequent development of overt cognitive dysfunction. In future studies with larger sample sizes, connectivity analysis should be performed to further analyze the impact of childhood-onset SLE on brain network integrity.
- Top of page
- PATIENTS AND METHODS
- AUTHOR CONTRIBUTIONS
Dr. Brunner had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study design. DiFrancesco, Brunner.
Acquisition of data. DiFrancesco, Holland, Ris, Adler, Nelson, DelBello, Brunner.
Analysis and interpretation of data. DiFrancesco, Holland, Ris, Adler, Brunner.
Manuscript preparation. DiFrancesco, Holland, Ris, Adler, Nelson, DelBello, Altaye, Brunner.
Statistical analysis. DiFrancesco, Adler, Altaye, Brunner.