This study demonstrates significant differences in brain activation patterns elicited by specific probes for cognitive and emotional response using fMRI imaging in SLE patients stratified by disease duration. Analysis of activation patterns stratified by performance accuracy, the absence of prior CNS events or structural changes on MRI in any subject and absence of significant differences in comorbid disease, current steroid doses or active systemic disease between the two groups suggest that the differences in brain activation patterns are attributable to SLE effects on the CNS, exclusive of vascular disease or other confounding influences, and these effects are a function of time, as predicted by our hypothesis.
Two fMRI studies previously reported increased regional activation patterns in patients with NPSLE in response to memory and simple motor tasks compared with healthy controls (25
). Another fMRI study of 10 pediatric SLE patients, not selected for NPSLE, also reported increased cortical activation patterns compared with healthy controls in response to memory, attention and language processing tasks (24
). Similarly, ST patients in this study demonstrated significantly increased neural activation in cortical areas associated with working memory (cingulate gyrus, prefrontal cortex, somatomotor cortex and BA40) compared with the LT group. Our findings of increased cortical activation patterns in ST patients suggest that ST patients do not display normal cognitive processes assessed by fMRI and that LT patients have evidence of greater neuronal damage reflected in decreased BOLD signal intensity. The abnormal findings in our ST population are consistent with previously reported findings of abnormal MRI, manifested as atrophy and/or focal lesions, in 25% of newly diagnosed patients (36
It is possible that the increased cortical activation pattern observed in the ST group reflects increased recruitment of neural networks to solve relatively simple tasks, implying that these patients have already sustained neurologic injury to areas related to working memory. This result is analogous to the increased cortical activation patterns reported with diffuse and focal brain damage in other neurodegenerative diseases and prior SLE studies. Functional neuroimaging studies of diffuse neurodegenerative disease such as human immunodeficiency virus (HIV), multiple sclerosis and Alzheimer’s disease demonstrate consistently increased neural activation in pathways related to cognitive processes, suggesting compensatory recruitment of neural circuitry for damaged brain (37
). Additionally, cross-sectional and longitudinal imaging of focal CNS damage (such as stroke) demonstrates similar evidence of increased neural recruitment after localized brain injury, which contributes to the reorganization of neural networks and functional recovery (40
). In this study, the LT group no longer displays the increased activation pattern demonstrated by the ST group, suggesting that this group has sustained more extensive damage. These data are supported by the performance scores. Although there was an expected performance decrement with increasing working memory load (set size) in both groups, the LT group displayed significantly greater impairment for one and two shapes. The precipitous drop in accuracy in the ST group with three shapes to a level lower than the LT group (62.33% versus 67.71%) suggests an abnormal threshold effect in the working memory response of this group. One important caveat is the potentially confounding influence of volitional parameters such as attention, concentration and motivation on performance in functional task-related studies, but there is no obvious reason to believe these should vary between groups.
The amygdala is critical to the formation of emotional memory, and we report significant group differences in amygdala activation during conscious perception of fearful faces. The amygdala response in the ST group is similar to that reported for healthy subjects (30
), whereas the decreased amygdala activation in the LT group is again indicative of regional neuronal damage. Selective damage to the amygdala associated with anti-NMDAR antibodies has been previously reported in humans (42
) and is supported by a murine model (10
). BA7 overlaps with the precuneus in the parietal lobe and is considered to be involved in somatosensory association as well as episodic memory retrieval (43
). Decreased activation of BA7 in the LT group may reflect damage to a neural network involving the amygdala and BA7, as seen in the cortical response to the memory task in this group.
The interdependency of the two paradigms was explored by using amygdala activation as a covariate in the working memory paradigm, and positive correlations were seen in areas involved in cognitive functions including working memory, sustained attention, executive function, visuospatial attention and emotional responses (the DLPFC, BA9, BA42 and BA40). The results of this analysis confirm the known connectivity of the brain regions activated by our paradigms and reinforce the hypothesis that disease-related brain damage increases with disease duration.
Because age-dependent changes in regional neural activity related to cognitive functions in healthy individuals were previously demonstrated (44
), our findings are potentially confounded by the mean age difference between groups. The study was not designed to investigate differences between SLE patients and healthy controls, but to discern differences between SLE patients with LT or ST disease duration. Not surprisingly, these groups differed in age. However, an equiperformance analysis (34
), using the data from the modified Stern-berg test, failed to demonstrate differences in BOLD signal intensity between groups when matched for performance, despite significant age differences. We therefore conclude, with the caveat that our numbers are small, that the observed decrease in brain activation patterns in the LT group in response to the two paradigms is independent of age and may be reflective of progressive disease- related neuronal dysfunction.
The SLICC DI is a validated measure of irreversible organ damage, from any etiology that has accrued since disease diagnosis, and higher scores are associated with poor outcome (21
). We predicted that, because of the protection afforded by the BBB and therefore a different proposed mechanism of injury, the DI may not be a sensitive indicator of CNS damage. None of the subjects enrolled scored damage in the neurologic domains. As expected, the DI in the LT group was greater than the ST group; however, the absence of associations found between DI and age, DI and BOLD signal intensity or BOLD signal stratified by DI suggests that the DI is not a useful predictor of brain dysfunction and that susceptibility of the brain to damage is different from that of other organs. This result reinforces our hypothesis that antibody-mediated neuronal damage in SLE requires interruption of the BBB; as a validated measure of organ damage in SLE, most of which is mediated by circulating inflammatory cytokines or autoantibodies, the DI would not be expected to reflect damage in an organ protected by the BBB. This result is supported by previous studies that have reported correlations between NPSLE and antibrain antibodies or cytokines in cerebrospinal fluid, as opposed to peripheral blood (6
) and studies showing that the progression of cognitive impairment is independent of disease activity. Most importantly, the current study suggests that DI is not a surrogate marker for neurological damage in SLE, and other measures such as fMRI must be explored.
The potential significance of medication effects is difficult to ascertain. More ST subjects were undergoing treatment with immunosuppressive medications at the time of evaluation, but exposure was equivalent between groups. Deleterious effects of cyclophosphamide on cognition have been reported in oncology; however, oncologic doses exceed those commonly used in SLE patients. Variable effects of corticosteroids on cognition have been reported and depend on the duration, total dose and timing of treatment; acute, high doses have reversible negative effects on memory performance (46
), whereas chronic use results in impaired memory performance as well as hippocampus atrophy and gray matter reduction (48
). Conversely, short-term, low-dose corticosteroid may enhance memory and learning and augment fear and anxiety responses through effects on the hippocampus and amygdala (46
). Importantly, several studies have not found significant correlations between corticosteroids and cognitive dysfunction or abnormalities in brain volume in SLE (56
). Our cross-sectional analysis of these two groups is not adequate to address this issue.
In conclusion, our results in this study indicate that use of fMRI with selected working memory and fear conditioning paradigms may provide a reliable measure of neuronal damage in SLE patients. The study design allowed us to evaluate the effect of disease duration on task-stimulated brain activation patterns that is independent of age and performance accuracy. We hypothesized that CNS damage, that is unrelated to vascular injury, is a function of circulating autoantibodies, BBB permeability and time. Patients with longer disease duration would therefore be expected to exhibit evidence of increased CNS damage. The group differences observed in behavioral performance as well as on the imaging studies support this hypothesis. We could not control for the effects of exposure to long-term medications, and this remains a potential confounder, as does age, since our numbers for the equiperformance analysis were small. Additionally, the DI was not predictive of neuronal damage in our cohort, reinforcing the hypothesis that mechanisms of tissue damage in the CNS differs from tissue damage in the periphery. Thus, studies of lupus therapeutics must begin to address CNS damage as well as disease activity and current measures of damage accrual. Further longitudinal investigations are warranted to determine the potential use of fMRI as an outcome measure in clinical trials of therapeutic agents. Identification of a noninvasive imaging technique that has the sensitivity to detect incremental change and can be used for determination of efficacy of agents designed to block antibody access to the CNS is critical to the success of a clinical trial.