Systemic lupus erythematosus (SLE) is a chronic and multisystemic autoimmune disorder characterized by protean clinical manifestations. Neuropsychiatric SLE (NPSLE) is one of the most common manifestations of lupus, and it has hindered improvements in the survival of these patients over the last 5 decades (1). Of the various symptoms of NPSLE, cognitive impairment, which primarily affects attention, planning, reasoning, working memory, and executive function, has been frequently described (2). It is evident that the cognitive functioning of patients with NPSLE is inferior to that of lupus patients without neuropsychiatric symptoms and that of healthy individuals (3, 4), as they demonstrate poorer performance in a number of domains of cognitive function testing, in particular, attention, information processing, learning, memory, and executive function (3–5).
Real-time functional magnetic resonance imaging (fMRI) of the brain while subjects were performing cognitive function tasks revealed that brain activities, which were manifested by blood oxygen level–dependent (BOLD) signals, were significantly altered in patients with NPSLE as compared with healthy subjects (6, 7). However, since these fMRI studies involved lupus patients with neuropsychiatric manifestations, the findings failed to give insights as to whether the real-time brain activities in lupus patients without clinically overt neuropsychiatric symptoms were altered. Such knowledge is particularly relevant because it is currently believed that lupus patients, even those without clinically obvious neuropsychiatric symptoms, perform poorer cognitively on neuropsychiatric tests than do healthy individuals (4, 8, 9).
Until recently, we used brain fMRI to evaluate the event-related brain activities of lupus patients without neuropsychiatric symptoms (10). Using the Wisconsin Card Sorting Test (WCST) for assessing neural activities corresponding to response selection and feedback evaluation, which evaluate the performance of goal-directed tasks and strategic planning skills of executive function, respectively, lupus patients without neuropsychiatric symptoms demonstrated significantly increased brain activities in regions that enhanced event anticipation, attention, and working memory during RS to compensate for their poor strategic planning as a result of deactivated brain regions involved in motor planning, decision-making, sensory integration, error detection, and conflict processing (10). Very recently, a study performed by another group of investigators using a different functional imaging protocol demonstrated attenuated brain activities in the cerebellum, posterior cingulate, and the adjacent precuneus in the default mode network in lupus patients without neuropsychiatric manifestations (11). While both of these studies demonstrated altered brain signals in certain anatomic regions of the brain in lupus patients without neuropsychiatric symptoms, it is pathologically more relevant to map the functional abnormalities that occur in neural circuits by analyzing sequential activation of the brain while patients are going through various sequential stages of cognitive function testing.
The WCST, which is primarily regarded as a unitary system for evaluating executive function that recruits cognitive processes as a whole during task performance, has been increasingly used to identify the neural basis of different cognitive stages of executive function. Using tailored set-shifting tasks derived from the original WCST (12), the modified version of the WCST was able to demonstrate that the prefrontal cortex, hippocampus, and striatum were sequentially involved across cognitive set-shifting processes in a stage-specific manner (12–15). We therefore undertook this fMRI study using the modified WCST to explore brain activities across all stages of cognitive set-shifting processes in patients with new-onset SLE who did not have clinically overt neuropsychiatric symptoms. Our goal was to map the potential functional abnormalities in neural circuits by analyzing event-related sequential activation of the brain.
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- PATIENTS AND METHODS
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We found that the cortico–basal ganglia–thalamic–cortical circuit, which is involved in response inhibition, was dysfunctional in lupus patients, even if they did not manifest clinically overt neuropsychiatric symptoms. To compensate for the dysfunction of the circuit in the lupus patients, the contralateral cerebellar and frontal areas of the brain were activated. Additionally, lupus patients showed altered activities at the amygdala and hippocampus while they tried to maintain prepotent rules during cognitive set-shifting.
While experiencing the maximum cognitive demand for withholding the previous prepotent rule and the response inhibition throughout the cognitive set-shifting processes, healthy subjects showed increased brain activation in the right middle frontal gyrus, the right GP, and both thalami in a synchronous pattern across the cognitive set-shifting processes (Figure 3A). The dorsolateral prefrontal cortex is involved in working memory, in the switching of cognitive sets, and in the inhibitory control of the prepotent response (20, 22). Since the right middle frontal gyrus belongs to the dorsolateral prefrontal cortex, it implies that it participates in conditions that require functional working memory and switching of cognitive sets. Furthermore, it was previously proposed that response suppression required the functional integrity of the prefrontal cortex, basal ganglia, and thalami. Functionally, these 3 regions form the cortico–basal ganglia–thalamic–cortical circuit that was believed to coordinate the function of the cortical regions involved (21–25).
Figure 3. Brain signal changes across the cognitive set-shifting process. A, Cortico–basal ganglia loop activity in healthy control subjects. B, Left thalamus activity in healthy controls and patients with new-onset systemic lupus erythematosus (SLE). C, Cerebellar–contralateral frontal activity in SLE patients. The Talairach x, y, and z coordinates for the right declive of the cerebellar vermis are shown in the key to C to distinguish the two graphs. Red/yellow areas indicate activation; green/blue areas indicate deactivation. Numbered images at the bottom correspond to the numbered β score graphs at the top. Values are the mean and images are the composite of 14 healthy control subjects and 14 SLE patients. NF = negative feedback; RS = response selection; PF = positive feedback. Color figure can be viewed in the online issue, which is available at http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)1529-0131.
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Studies have identified the indirect pathway that connected these regions, showing that the cortex, striatum, external segment of the GP, subthalamic nucleus, internal segment of the GP, thalami, and cortex were involved sequentially in implementing response suppression and in changing the behavioral set (26). However, we did not observe brain activation at the right GP and right thalamus in patients with SLE when the cognitive demand for inhibitory response control was dominant, implying that information flow from the striatum to the thalamus was compromised, which resulted in the deficit of response control in SLE patients under this circumstance. Although the left thalamus was still activated in the lupus patients, the magnitude of the activation signal in the same region was lower than that in the healthy controls (Figure 3B).
Besides its role in the response inhibition circuit, a number of lesion studies have shown that the GP is one of the important neural components that mediate executive cognitive function (27, 28). For example, patients with advanced Parkinson's disease were unable to shift attention after undergoing bilateral pallidotomy (29). Similarly, disturbance of metabolism in the thalamus was demonstrated in children with Sturge-Weber syndrome (30), of which cognitive dysfunction is one of the most common symptoms. Therefore, the absence of activity in the right GP and right thalamus in our lupus patients suggests that they had impaired response inhibition and reduced capability for behavioral change secondary to dysfunction of the cortico–basal ganglia–thalamic–cortical circuit.
Notably, the absence of brain activation at the right GP and right thalamus as mentioned above was coupled with an increase in brain activity at the declive of the right cerebellar vermis in lupus patients. A few anatomic, physiologic, and neuroimaging studies demonstrated that cerebellar damage led to impairment of executive function, spatial cognition, language, and personality change (31). On the other hand, overreliance on cerebellar activities was demonstrated in patients with schizophrenia, alcoholism, and cocaine abuse during evaluation of working memory, verbal working memory, and executive control, respectively (32–35). In our study, the increased activity in the right cerebellum was coupled with activation of the left prefrontal cortex (left superior frontal gyrus and middle frontal gyrus) in lupus patients. This activation pattern is reminiscent of increased brain activation in the left frontal–right cerebellar circuit in alcoholics during verbal memory testing (34), which is consistent with the observations that cerebellar activation often occurs in conjunction with contralateral frontal lobe activation (35). In our study, analysis of brain activities at the declive of the cerebellar vermis and the left middle and superior frontal gyri revealed a rather similar activation pattern during the course of cognitive set-shifting (Figure 3C), further implying the conjugated role of the right cerebellum and left frontal regions during different stages of cognitive set-shifting.
Cerebellar activities, coupled with brain activation in the contralateral frontal areas, have been suggested to compensate for articulatory and inhibitory controls in patients with alcoholism and cocaine abuse, respectively, in order to maintain normal cognitive function (34, 35). Taken together with another recent finding of the cerebellum–basal ganglia interconnections in an anatomic study performed in primates (36), we postulated that in patients with SLE, the increased right cerebellar activities and its coupled left prefrontal activities may serve to compensate for the dysfunction of inhibitory control secondary to the compromised cortico–basal ganglia–thalamic–cortical circuit in order to maintain the performance of the set-shifting tasks. Consistent with the findings of other functional imaging studies, the compensatory activations that aided the dysfunctional cortico–basal ganglia–thalamic circuit found in our study illustrate the adaptability and plasticity of the brain to recruiting neural networks to serve those functions that have been damaged. For example, in order to maintain performance levels, generalized brain activations were demonstrated in subjects with age-related degeneration in motor performance of the hands (37). Relevant to SLE, a few recent studies demonstrated generalized brain activation in lupus patients during the performance of neuropsychological tasks (6, 7, 10, 38). Importantly, compensatory BOLD signal intensity decreased in lupus patients with disease duration of >10 years, suggesting that compensatory activations may decrease when irreversible neuron damage has set in (38).
When being challenged to adapt to a new rule during cognitive-set shifting, the right parahippocampal gyrus and left posterior cingulate were activated in SLE patients in order to reconfigure their response strategy and to adapt to a new rule, whereas among the healthy controls, no significant brain activities in these two regions were observed. The altered activities of the posterior cingulate and parahippocampus were consistent with two recently published studies in SLE patients without NPSLE and in patients with schizophrenia (11, 39), which suggested that there was attenuation of the intrinsic default mode network, episodic memory problem, and related cognitive deficits. The default mode network is regarded as a resting state of brain function and is involved in the planning of future events and ongoing information processing.
The condition contrast second NF > second PF indicated brain regions where involvement of new rule generation dominated the maintenance of an established rule. In healthy controls, both hippocampi were deactivated during this condition contrast, indicating their involvement in maintaining an identified rule. Most brain regions that contributed more to rule generation than to rule maintenance in SLE patients and healthy subjects overlapped, suggesting that brain activities underlying this cognitive process remained intact in lupus patients. Further analysis revealed that activities of both hippocampi initially decreased during the “generate” event, when the identity of the new rule was unknown. Subsequently, during the “update” and “maintain” events, while the new rule was identified and maintained in memory, both hippocampi were activated. This finding is consistent with the putative role of the hippocampus in set-shifting, in which decreased hippocampal activity at the generation event would facilitate active forgetting of the previous rule and a shift to a new cognitive set, while the subsequent increased hippocampal activity at the update and maintenance events would enhance learning of the new rule to guide ensuing trials (15). Interestingly, the left amygdala appeared to follow a synchronous activity pattern with both hippocampi across all stages of set-shifting (Figure 4A).
Figure 4. Brain signal changes in the hippocampus and amygdala across the cognitive set-shifting process. A, Hippocampal and amygdala activity in healthy control subjects. B, Right hippocampal activity in healthy controls and patients with new-onset systemic lupus erythematosus (SLE). Red/yellow areas indicate activation; green/blue areas indicate deactivation. Numbered images at the bottom correspond to the numbered β score graphs at the top. Values are the mean and images are the composite of 14 healthy control subjects and 14 SLE patients. NF = negative feedback; RS = response selection; PF = positive feedback. Color figure can be viewed in the online issue, which is available at http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)1529-0131.
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The neural activity underlying FE has been proposed as a result of the response to reward or punishment of the feedback stimulus (14). Hippocampal activities appear to be reinforced and maintained by the amygdala through the generation of rewards (40), suggesting the coupled role of the amygdala and the hippocampus in set-shifting processes observed in our study. However, involvement of the left hippocampus and left amygdala in rule maintenance was absent in our SLE patients, implying a compromise of the active forgetting–learning dynamics in set-shifting despite the fact that the right hippocampus was still required to maintain the established rule in a pattern similar to that in healthy controls (Figure 4B). As in patients with SLE, altered amygdala and hippocampal activities within the default mode network have been demonstrated in patients with depression and Alzheimer's disease (41, 42). These findings may signify a potential common pathologic basis of the disrupted forgetting–learning dynamics that involves the amygdala and hippocampi in patients with SLE, depression, and dementia.
While further mechanistic evaluation is required to explain the BOLD signal changes, especially those involved in hippocampus–amygdala coupling, and the absence of BOLD signals in the hippocampus and amygdala in our patients with SLE, the well-investigated anti–N-methyl-D-aspartate (NMDA) receptor antibodies and anti–ribosomal P antibodies may be potentially contributory. The NMDA receptors are mainly expressed in the neurons of the hippocampi and amygdala. Under physiologic conditions, the neurotransmitter glutamate activates the receptors and mediates learning and memory by manipulating synaptic plasticity (43). In animal models, antagonizing the NR2 subunit of the NMDA receptor (anti-NR2 antibody) led to impaired memory and learning (43). Because anti-NR2 is present in the serum and cerebrospinal fluid of NPSLE patients (43), a potential pathogenetic role of anti-NR2 antibody in cognitive dysfunction has been advocated (44). Indeed, anti-NR2 purified from lupus patients was able to induce cognitive impairment, memory deficits, and hippocampal neurotoxicity in BALB/c mice (45, 46). It was recently shown that anti-NR2 antibody exerted its cytotoxic effects on neurons by increasing intracellular calcium levels through inhibition of the binding capacity of zinc at the zinc-binding site of the NMDA receptor, resulting in reduced cell viability (47).
As for the anti–ribosomal P antibodies, a clinical study in the 1980s demonstrated that the serum titer of anti–ribosomal P antibodies was selectively raised in lupus patients with active psychosis, although not all subsequent studies were able to replicate the associations between the antibodies and psychosis as well as depression in patients with SLE (48). Nevertheless, induction of autoimmune depression in C3H/HeJ mice by intracerebroventricular injection of affinity-purified anti–ribosomal P antibodies revealed that the antibodies bound specifically to the pyramidal cell layer and dentate gyrus of the hippocampus and other areas of the limbic system that could be significantly counteracted by antiidiotypic antibodies to anti–ribosomal P antibodies (49).
This study has a few limitations. First, the sample size is relatively small. However, sample sizes of this magnitude have consistently demonstrated sufficient sensitivity of BOLD signals to achieve statistical significance (14, 15). Second, patients with SLE were given prednisolone treatment at the time of the fMRI scan, and the possible effects of medication on BOLD signals may confound the interpretation of our results. Since the majority of patients underwent fMRI scanning within 2 months of the diagnosis of SLE, with a mean ± SD exposure to initial immunosuppressive therapy of 36.86 ± 35.5 days (range 8–143 days) prior to the scan, the effect of treatment on BOLD signals should be minimal.
In summary, our findings demonstrate that patients with SLE, even without clinically overt neuropsychiatric symptoms, had abnormal sequential brain activities involving the basal ganglia, hippocampi, and amygdala, which indicated a compromised cortico–basal ganglia–thalamic–cortical circuit and hippocampus–amygdala coupling in comparison with healthy subjects. These results translate into a potential compromise in response inhibition and the active forgetting–learning dynamics in lupus patients. Moreover, patients with SLE demonstrated overreliance on the cerebellar–contralateral frontal conjunction activities to compensate for the dysfunction of the compromised cortico–basal ganglia–thalamo–cortical circuit. While scientifically, our results highlight a potential pathologic brain network, which should prompt further investigation into the functional neuropathophysiology of cognitive dysfunction in patients with SLE, the practical clinical implication is that physicians who treat lupus patients may need to be aware of their potential reluctance to change their existing knowledge and adapt to new information, such as in situations where pharmacologic treatment and lifestyle need to be modified for the optimization of disease control and the prevention of organ damage.