A Clinical Electrophysiological Study of Emotional Lability in Patients With Systemic Lupus Erythematosus

Thirty-two consecutive attendees (29 females, ages 19–63 years, mean age 42) at a rheumatology-led systemic lupus erythematosus clinic were recruited into the study, approved by the local research ethics committee, with informed consent obtained after study procedures had been fully explained. All participants fulfilled the 1982 American College of Rheumatologists’ research criteria for systemic lupus erythematosus. Participants completed the Hospital Anxiety and Depression Scale (HAD) 31 and the Centre for Neurological Study Lability Scale (CNS-LS), a self-report measure of affective lability. 7 Participants also underwent a clinical interview to provide information about onset, severity, and treatment of their systemic lupus erythematosus and any neuropsychiatric symptoms.

Three standard auditory tasks were employed to elicit event-related potentials: mismatch negativity, novel sound P3a and oddball P3b. Mismatch negativity standard (1000 Hz) and rare (922 Hz) tones were presented in pseudorandom sequence. All had intensity of 85dB and duration of 40 msec, including 5 msec rise and fall time. Altogether, 1000 tones (880 standard and 120 rare tones) were delivered binaurally through headphones with a constant interstimulus interval (ISI) of 500 msec. Participants were instructed to read a book while the tones were presented.

The P3b paradigm consisted of a pseudorandom sequence of 210 standard (1000 Hz) and 45 target tones (1500 Hz). For the P3a, 45 unique novel sounds were added. Participants were instructed to press a button when detecting a target tone. Before the recordings, participants listened to five target and five standard tones to ensure correct differentiation between them. Tones were delivered binaurally through headphones with interstimulus interval of 1 sec, intensity of 85dB, and duration of 40 msec, including 5 msec rise and fall time.

Electroencephalograms (EEGs) were recorded from Ag/AgCl electrodes placed along the midline (Fz, Cz, Pz) and fronto-laterally (F3, F4) according to the standard 10–20 electrode placement system, using Neuroscan software v.4.2 (Neuroscan Inc., Charlotte N.C., U.S.). Linked earlobe electrodes were reference electrodes. The ground electrode was halfway between Cz and the left earlobe. Electro-oculograms (EOGs) were recorded from an electrode located above and in between both eyes and an electrode 1 cm lateral to the outer canthus. All recordings were made in a sound-attenuated dimly lit room with sources of extraneous electrical noise minimized. EEGs and EOGs were amplified with a bandpass filter (0.15 Hz–100 Hz) and digitized at a sampling rate of 500 Hz. Latencies to peak and peak amplitude were measured for each event-related potential. Stimulus tones were generated and presented using the Neuroscan Stim package.

Continuous EEG data were processed off-line, correcting for ocular artifacts using the ocular artifact reduction algorithm in the Neuroscan v. 4.2 software package. 32 Data were epoched from 100 msec before to 500 msec or 1000 msec after tone-onset for mismatch negativity and P3, respectively. Epochs containing data outside the amplitude range +/−70 μV were rejected, and the remaining epochs were baseline corrected using the 100 msec prestimulus period. Reponses to each stimulus type were averaged separately for each participant.

To quantify mismatch negativity, evoked responses to frequent tones in the mismatch negativity paradigm were subtracted from responses to the rare tones. The resulting difference waveform was filtered using a zero-phase shift low-pass filter (cutoff 30 Hz, 48dB/oct). Mismatch negativity latency was evaluated within the 100 msec–200 msec time window as the time of occurrence of the peak of the difference waveform measured from stimulus onset.

P3a was defined as the largest positive peak occurring between 250 msec and 450 msec after onset of novel auditory stimuli. The largest positive peak between 300 msec and 800 msec in the averaged waveform recorded in response to target stimuli was taken as the P3b response. Amplitude was measured relative to prestimulus baseline. Latency was measured from stimulus onset to time of peak amplitude. These measures were taken after the waveforms had been filtered (zero-phase shift, cutoff 30 Hz, 48dB/oct) at Fz, Pz, Cz, F3 and F4. Amplitude and peak latencies of N1 responses to nontarget and target tones in the P3b paradigm were also measured.

One participant was excluded from analysis of mismatch negativity and P3 because the subject did not understand the instructions. A further recording was excluded from P3 analysis because of electrical interference.

Analyses aimed to investigate possible associations between emotional lability in systemic lupus erythematosus patients and event-related potential markers of attentional processes. Accordingly, participants were divided into two groups according to whether their scores on the Centre for Neurological Study Lability Scale were below the cutoff of 17, previously identified by Smith et al. 9 as a sensitive and specific measure of pathological emotional lability.

This study arose from the clinical observation that emotional lability seemed to be relatively common in people with systemic lupus erythematosus who were referred to a neuropsychiatry clinic. We have aimed to address two questions: first, how common is significant emotional lability in people with systemic lupus erythematosus, and second, is emotional lability in this condition associated with increased sensitivity to unexpected changes in the auditory environment, measured using electrophysiological responses? Considering clinical emotional state, we observed that 47% of unselected consecutive attendees at a rheumatology-led systemic lupus erythematosus clinic obtained scores on an emotional lability rating scale that indicated clinically significant levels of emotional lability. There were no differences between those with high and low lability scores with respect to systemic lupus erythematosus-related variables, including duration of disease, presence of active disease or drug treatment, or to psychiatric variables, including past psychiatric history, psychotropic medication, or depressive symptomatology. In line with previous observations that depression and anxiety are common in people with systemic lupus erythematosus, 2 – 4 the Hospital Anxiety and Depression Scale scores of the majority of our participants indicated borderline or probably significant depression or anxiety. Our results suggest that emotional lability is found in a relatively high proportion of patients with systemic lupus erythematosus and is not associated with general indicators of overall disease severity.

Considering the event-related potential findings, we predicted that increased emotional lability would be associated with event-related potential correlates of increased responsiveness to external stimuli. This hypothesis was proved by the latency results of the earlier event-related potentials studied but not by the amplitude data or the later P3 event-related potentials. Latencies in the event-related potentials associated with preattentive auditory processing (the N1 and the mismatch negativity) distinguished between the high and the low lability groups, with shorter latencies in the high lability group. In neither the P3a paradigm, a measure of involuntary orienting of attention to an unexpected stimulus, nor the P3b paradigm, a measure of voluntary orienting of attention to a target stimulus, and in which the peak latency occurs around 50 msec later than the P3a, 33 were significant latency differences observed. While anxiety levels differed between high and low lability groups, inclusion of Hospital Anxiety and Depression Scale anxiety subscale as a covariate in the repeated measures ANOVAs demonstrated that these anxiety differences did not underlie group differences observed in N1 and mismatch negativity responses. The results suggest that higher levels of emotional lability may be associated with faster preattentive processing of changes in the auditory environment. The absence of a relationship between the observed N1 and mismatch negativity event-related potentials and anxiety scores suggests that while anxiety may be greater in those with higher levels of emotional lability, the mechanisms relating to mood change that may be modulating these preattentive event-related potentials are not the same processes that have resulted in increased anxiety scores in the higher lability group.

While there are few event-related potential studies in systemic lupus erythematosus with which to compare our findings, it is noted that the N1 latencies observed in both our high and low lability groups were a little shorter and the P3b latencies a little longer than the values observed by Khedr et al. 16 For both these event-related potentials, however, the values observed in the current study more resembled the values observed in the systemic lupus erythematosus group than in those authors’ control group. Two further studies looking at event-related potential data in systemic lupus erythematosus 34, 35 found no change in N1 latency compared to controls. However, they did not measure emotional lability or mismatch negativity.

Though previous studies have not reported associations between event-related potentials and neuropsychiatric manifestations of systemic lupus erythematosus, generally the definition of neuropsychiatric involvement has been wide-ranging. 36 In our study the specific neuropsychiatric manifestation of lability and our electrophysiological tests were precisely defined and conceptually linked based on the observation that increased emotional lability is associated with large emotional responses to relatively small triggers, which we hypothesized to be linked to changes in attentional processes.

Pathophysiological links between systemic lupus erythematosus and emotion and attention, and psychophysiological markers of these, have not been determined. While 20 different antibodies have been identified as being associated with the presence of neuropsychiatric symptoms of systemic lupus erythematosus, 37 no specific links have been determined between particular antibodies and individual neuropsychiatric symptoms. It is possible, however, that the production of neuropsychiatric symptoms may not be associated to a specific antibody but, rather, that a range of potentially brain-reactive systemic lupus erythematosus-related antibodies may lead to neuropsychiatric symptoms and that the precise nature of these symptoms will be determined by where the blood-brain barrier has been sufficiently damaged by systemic lupus erythematosus-related pathological processes to lead to it becoming permeable to these antibodies. 38

Several aspects of this study mean the results should only be considered a preliminary exploration of this area. Although we looked for, and found within our participants, differences between those with higher and lower levels of lability, we did not study a comparison group without systemic lupus erythematosus so cannot contrast lability or event-related potential findings with the general population. Nevertheless, our results suggest increased emotional lability in people with systemic lupus erythematosus may be a significant clinical problem and should at least be inquired about as part of neuropsychiatric assessment. We cannot explore relationships between specific systemic lupus erythematosus symptoms and event-related potential or affective measures, as while participants met diagnostic criteria for systemic lupus erythematosus, no detailed characterization of lupus severity at the time of the study was available. The Centre for Neurological Study Lability Scale was developed to measure affective lability in amyotrophic lateral sclerosis 7 and subsequently demonstrated to be valid in patients with multiple sclerosis. 9 In their account of its use in multiple sclerosis, Smith et al. 9 noted a cutoff of 17 provided a sensitivity of 0.94 and a specificity of 0.83 with respect to clincial diagnosis of pathological emotional lability. In the current study we chose at the outset to use the cutoff established in that study.

In conclusion, within the limitations outlined above, this study demonstates that emotional lability is relatively common in people with systemic lupus erythematosus, suggesting that this psychiatric symptom should be considered in their neuropsychiatric assessment. Reliable clinical markers of CNS pathophysiology in people with systemic lupus erythematosus have been difficult to identify. Our observation that greater emotional lability was associated with shorter latency of preattentive electrophysiological responses to auditory stimuli indicates that future studies might usefully explore the relationship between this group of event-related potentials and clinical symptoms of neuropsychiatric systemic lupus erythematosus both cross-sectionally and prospectively.

The work was carried out at the Royal London Hospital, London E1 1BB, and the Section of Developmental Psychiatry at the University of Cambridge, Cambridge CB2 2AH, UK.