Cognitive and White Matter Tract Differences in MS and Diffuse Neuropsychiatric Systemic Lupus Erythematosus.

BACKGROUND AND PURPOSE: Multiple sclerosis and neuropsychiatric systemic lupus erythematosus are autoimmune diseases with similar CNS inflammatory and neurodegenerative characteristics. Our aim was to investigate white matter tract changes and their association with cognitive function in patients with MS and those with neuropsychiatric systemic lupus erythematosus compared with healthy controls by using diffusion tensor imaging. MATERIALS AND METHODS: Thirty patients with relapsing-remitting MS and 23 patients with neuropsychiatric systemic lupus erythematosus matched for disease severity and duration and 43 healthy controls were scanned with 3T MR imaging. The DTI was postprocessed, corrected for lesions, and analyzed with tract-based spatial statistics. Cognitive assessment included examination of processing speed; visual, auditory/verbal, and visual-spatial memory; and sustained attention and executive function. Differences were considered significant at P < .05. RESULTS: Tract-based spatial statistics analysis revealed significantly decreased fractional anisotropy and increased mean diffusivity in patients with MS compared with healthy controls, decreased fractional anisotropy in patients with MS compared with those with neuropsychiatric systemic lupus erythematosus, and an increased mean diffusivity in patients with neuropsychiatric systemic lupus erythematosus compared with healthy controls. Patients with MS showed decreased fractional anisotropy throughout central WM pathways, including the corpus callosum and the inferior longitudinal and fronto-occipital fasciculi compared with those with neuropsychiatric systemic lupus erythematosus. Altered cognitive scores in patients with MS were significantly associated with decreased fractional anisotropy and increased mean diffusivity in all examined domains, while in patients with diffuse neuropsychiatric systemic lupus erythematosus, only decreased fractional anisotropy in the superior WM pathways showed significant association with executive function. CONCLUSIONS: Patients with MS and neuropsychiatric systemic lupus erythematosus showed widespread WM tract alterations outside overt lesions, though more severe changes were identified in patients with MS. The WM tract changes were associated with cognitive dysfunction in all explored domains only in patients with MS.

Multimodal imaging in systemic lupus erythematosus patients with diffuse neuropsychiatric involvement.

OBJECTIVES: The objective of this paper is to investigate conventional and nonconventional brain magnetic resonance imaging (MRI) findings in systemic lupus erythematosus (SLE) patients with diffuse neuropsychiatric involvement (dNPSLE) compared to healthy controls (HCs). METHODS: Twenty-six (26) SLE patients with one or more diffuse NP syndromes related to the central nervous system (CNS) (dNPSLE) and 36 age- and sex-matched HCs were scanned on a 3T MRI using a multimodal imaging approach. Univariate and multivariate analyses were used to determine MRI-specific measure differences between dNPSLE and HCs for lesion burden, tissue-specific atrophy, magnetization transfer ratio (MTR) and diffusion-tensor imaging (DTI) outcomes. RESULTS: In univariate analyses, dNPSLE patients showed significantly increased T1 lesion number (p = .001) and T1-lesion volume (LV, p = .008) compared to HCs. dNPSLE patients showed decreased whole brain volume (p < .0001), gray matter volume (p < .0001), cortical volume (p < .0001) and increased lateral ventricle volume (p = .004) compared to HCs. dNPSLE patients had increased axial diffusivity (AD) of NAWM (p = .008) and NA brain tissue (p = .017) compared to HCs. In the multivariate regression analysis, decreased cortical volume was associated with SLE (R (2) = 0.59, p < .0001). CONCLUSIONS: This study shows that cortical and central atrophy are associated with SLE patients with diffuse CNS syndromes. Microscopic tissue injury in the NAWM on AD DTI measures in SLE patients indicates a predominant reduction of axonal density.

Neuropsychological impairment in systemic lupus erythematosus: a comparison with multiple sclerosis.

In this manuscript, we review literature describing the neuropsychological and brain imaging characteristics of systemic lupus erythematosus (SLE) patients. The findings are compared and contrasted with multiple sclerosis (MS) studies, revealing similarities and differences of interest to clinicians and researchers. While cognitive impairment is somewhat less common in SLE than MS, the diseases share a similar cognitive profile with deficits most prominent on tests emphasizing the speed of information processing, working memory, and visual/spatial learning, and memory. In early or more mildly affected patients, diffuse white matter damage, which may not be apparent on conventional brain imaging, plays a major role in clinical presentation and cognitive testing. The causes of white matter damage are very different, however, and in later stages of the disease MS and SLE appear to give rise to different forms of cerebral pathology. MS may be characterized by increasing brain atrophy affecting especially the cortical and deep gray matter, at least after conversion to secondary progressive course. There is less evidence for neurodegenerative changes in SLE, but patients are increasingly at risk for cerebrovascular disease. We conclude by offering some suggestions for future clinical and imaging research.

Sex-related differences in event-related potentials, face recognition, and facial affect processing in prepubertal children.

Thirty-five prepubertal children, 17 boys and 18 girls, between the ages of 8 and 11 years, were studied to examine electrophysiological and cognitive sex differences during a face-recognition-memory (FRM) task and a facial-affect-identification task (FAIT). All participants were prepubertal, as determined by J. M. Tanner's (1962) staging and endocrine evaluation. Sex-dependent event-related potential (ERP) amplitude asymmetries were found during FRM. Boys displayed greater right versus left ERP amplitude to auditory tone probes during the task, whereas girls displayed the opposite pattern. In addition, positive correlations were obtained between ERP amplitude during FRM and FAIT accuracy scores for boys, but not for girls. Results suggest that girls and boys may use different neuronal systems in the processing of faces and facial affect. Findings are consistent with developmental theories regarding sex differences in visuospatial processing.

Stimulus modality and Go/NoGo effects on P3 during parallel visual and auditory continuous performance tasks.

Task and modality effects on P3 latency, amplitude, and scalp topography were studied during parallel versions of visual (VCPT) and auditory (ACPT) continuous performance tasks using a Go/NoGo paradigm (A-X CPT). Both the ACPT and VCPT incorporated five conditions including Go and NoGo stimulus sequences as well as three other nontarget conditions. The goal was to evaluate the functional significance and modality specificity of the P300 response and the NoGo P3. Analyses were performed using both raw and normalized data to make comparisons across modalities. For both modalities, the Target X (Go) and three nontarget conditions elicited maximum P3 amplitudes over the posterior scalp sites and qualified as classical P300 responses. The NoGo condition was associated with an increase in central-frontal amplitude compared to the Target X condition. The scalp topography of the P300/P3 for Go and NoGo conditions, as well as all other conditions, was the same for both modalities, supporting the modality independent nature of both P300 and the NoGo P3. Min-Max normalization of P3 amplitudes did not change the condition-topography relationships.

Neuropsychological effects of interferon beta-1a in relapsing multiple sclerosis. Multiple Sclerosis Collaborative Research Group.

Cognitive dysfunction is common in multiple sclerosis (MS), yet few studies have examined effects of treatment on neuropsychological (NP) performance. To evaluate the effects of interferon beta-1a (IFNbeta-1a, 30 microg administered intramuscularly once weekly [Avonex]) on cognitive function, a Comprehensive NP Battery was administered at baseline and week 104 to relapsing MS patients in the phase III study, 166 of whom completed both assessments. A Brief NP Battery was also administered at 6-month intervals. The primary NP outcome measure was 2-year change on the Comprehensive NP Battery, grouped into domains of information processing and learning/memory (set A), visuospatial abilities and problem solving (set B), and verbal abilities and attention span (set C). NP effects were most pronounced in cognitive domains vulnerable to MS: IFNbeta-1a had a significant beneficial effect on the set A composite, with a favorable trend evident on set B. Secondary outcome analyses revealed significant between-group differences in slopes for Brief NP Battery performance and time to sustained deterioration in a Paced Auditory Serial Addition Test processing rate, favoring the IFNbeta-1a group. These results support and extend previous observations of significant beneficial effects of IFNbeta-1a for relapsing MS.

Validity of neural network in sleep apnea.

Clinical assessment of obstructive sleep apnea (OSA) is poor. Overnight polysomnography (OPG) is the standard reference test, but it is expensive and time-consuming. We developed an artificial neural network (ANN) using anthropomorphic measurements and clinical information to predict the apnea-hypopnea index (AHI). All patients completed a questionnaire about sleep symptoms, sleep behavior, and demographic information prior to undergoing OPG. Neck circumference, height, and weight were obtained on presentation to the sleep center. Twelve variables were used as inputs. The output was an estimate of the AHI. The network was trained with a back-propagation algorithm on 189 patients and validated prospectively on 80 additional patients. Data from the derivation group was used to calculate the 95% confidence interval of the estimated AHI. Predictive accuracy at different AHI thresholds was assessed by the c-index, which is equivalent to the area under the receiver operator characteristic curve. The c-index for predicting OSA in the validation set was 0.96 +/- 0.0191 SE, 0.951 +/- 0.0203 SE, and 0.935 +/- 0.0274 SE, using thresholds of > 10, > 15, and > 20/hour respectively. The actual AHI of the 80 patients in the validation data set fell within the 95% confidence limits of the values predicted by the ANN. This study suggests that ANN may be useful as a predictive tool for OSA.

An electrophysiological study of infants' sensitivity to the sound patterns of English speech.

The study explores 10- to 11-month-old infants' sensitivity to the phonological characteristics of their native language. Event-related potentials (ERPs) were obtained for tones that were superimposed on two versions of a story: an Unmodified version containing normal English function morphemes, and a Modified version in which the prosodic and segmental properties of a subset of function morphemes were changed to make them atypical. The 11-month-olds exhibited significantly lower amplitude ERPs to the tones during the Modified story than to the Unmodified story, whereas the 10-month-olds showed no differences. These results suggest that the 11-month-olds discriminated the two versions of the story based on their representations of the phonological properties of English. Further, the tone-probe ERP method can successfully be used to study the development of speech perception in the pre-linguistic infant.

The immune system can affect learning: chronic immune complex disease in a rat model.

Evidence is presented that the immune system can affect central nervous system functioning, leading to changes in learning. Immune complex disease is induced in rats and their behavior tested using a Lashley maze. Significant differences in behavior were found between the animals with high disease activity and those with low disease activity and the non-disease controls. These changes were not due to uremia and are most likely due to the immune response. There is some evidence immune complex deposits in the choroid plexus may play some role, but not the sole or major role in the behavioral changes. This provides a model by which immunologic processes can cause neuropsychiatric manifestations in autoimmune diseases like lupus, as well as showing that immune processes can affect behavioral functioning.

Functional neuroimaging of attention in the auditory modality.

Previous functional neuroimaging studies of attention have emphasized the visual modality. We developed an auditory version of the continuous performance test (CPT) that included simple, focused and divided attention conditions. Positron emission tomographic (PET) scans were acquired during CPT performance in normal young adults and then submitted to statistical parametric mapping. Simple attention brought about a large region of activation involving the anterior cingulate gyrus and the right anterior/mesial frontal lobe. Focused and divided attention CPT conditions were compared but there were few significant differences. The findings are consistent with activation of an anterior attention network during auditory attention, without involvement of posterior attention structures which are more likely to vary in accordance with sensory modality.

Effects of low level lead exposure on cognitive function in children: a review of behavioral, neuropsychological and biological evidence.

Low level lead exposure, at levels currently found in significant numbers of children in the U.S., has been associated with decreases in IQ and other cognitive test scores in children, as well as with decreases in developmental test scores in infants. The precise nature of the cognitive deficits is not clear. This paper reviews epidemiological and developmental neurocognitive effects of lead and addresses methodological issues that may have contributed to differences in interpretation of previous research. In an attempt to provide a rationale for the lead-related deficits reported for humans, we have reviewed studies of lead-related behavioral and electrophysiological effects seen in animals as well as findings from studies that have examined the effects of lead exposure on neurochemical subcellular and cellular mechanisms. Based on these data, future strategies are suggested for determining the possible effects of low-level lead exposure on neurocognitive functioning in children.

Slowed reaction time during a continuous performance test in children with Tourette's syndrome.

The phenomonology of Tourette's syndrome (TS) not only includes tics but also apparent deficits in attention. These attentional deficits in TS likely involve anomalies in frontal-striatal circuits. In this study, performance of 22 boys with TS and 22 age-matched boys without TS was compared on a continuous performance test (CPT) of attention. TS children demonstrated a normal capacity for discriminating targets from nontargets during the task, but showed significantly slower reaction times than controls. Severity of complex vocal tics was predictive of reaction time performance. Possible explanations for these findings are discussed and include the presence of attentional difficulties in TS, interference associated with tic suppression, a conservative strategy taken by TS children, and a general impairment of motor performance.

Single-trial latency variability does not contribute to fast habituation of the long-latency averaged auditory evoked potential in the albino rat.

Fast habituation (FH) is defined as a general reduction in long-latency, vertex-recorded, averaged auditory evoked potential (AEP) amplitude that occurs in response to the second of a pair of acoustic stimuli. Our laboratory has been studying FH in a variety of human populations with different paradigms and has interpreted it to be a measure of neural attentional mechanism(s) and/or resource allocation related to the processing of cognitive information. We have also reported an analogous phenomenon in the rat. In the present investigation, we examined the relationship between FH (viz., averaged AEP component amplitude decrement) and the single-trial latency variability of the AEP peaks comprising that component. Specifically, AEPs were obtained to 60 paired-tone stimuli from unanesthetized and restrained albino rats previously implanted with chronic skull electrodes. Using a template-matching algorithm similar to that used by Michalewski et al. (Electroenceph. clin. Neurophysiol., 1986,65:59-71), the latency variability for each animal was computed for the N1 and P2 peaks of the single-trial AEPs that were used to compose the averaged wave form. Findings indicated that (a) there was no difference in single-trial latency variability for these peaks either within or across tones, and (b) there was no relationship between single-trial latency variability for either the N1 or the P2 peaks and the overall peak-to-peak amplitude (N1-P2) of the averaged wave from in response to the second tone. Thus, FH of the N1-P2(i.e. Peak 2) amplitude in the rat is not due to an increase in latency variability across tones.

Fast habituation of the long-latency auditory evoked potential in the awake albino rat.

Fast habituation of the long-latency, vertex-recorded auditory evoked potential (AEP) peaks in humans was first described by Callaway (1973) as a reduction in AEP amplitude that occurs to the second of a pair of acoustic stimuli when both stimuli are presented with an interstimulus interval (ISI) of no more than 10 sec. When acoustic stimuli are presented in pairs with an ISI of 2 sec and an interpair interval (IPI) of approximately 10 sec, reduction in amplitude to the second tone occurs by as much as 30-50%. Fast habituation may depend somewhat on a subject's anticipation of the stimulus and on other factors related to attention and orienting. Studies in our laboratory have demonstrated this amplitude decrement to the second tone of a pair in human infants, children and adults and have explored the implications of this finding with respect to attentional processes and the allocation of cerebral resources. In the present investigation we describe an animal model of fast habituation. Here, vertex-recorded AEPs were obtained to paired tone stimuli delivered to awake adult male Sprague-Dawley rats chronically implanted with skull electrodes. Findings showed: (a) an AEP wave form with 8 distinct peaks, (b) for one component there was a marked decrement in amplitude from tone 1 to tone 2 in recordings obtained from an electrode placed slightly to the right of midline, and (c) that there were no significant differences in peak latencies across tones. This methodology may further our understanding of fast habituation in humans and may prove useful for studies of attention, orienting, and resource allocation using techniques that are not possible for use with human subjects.

Sleep apnea.

The diagnosis of sleep apnea should be considered when a patient complains of snoring and excessive daytime somnolence. Middle-aged obese men are at particular risk, although apnea can occur in women and the elderly, as well as in persons who are not obese. An overnight polysomnographic sleep study can reveal the degree and type of apnea. Effective medical therapy can provide prompt clinical improvement. General treatment measures include weight loss and, in mild cases, training the patient to sleep in a side-lying position. Continuous positive airway pressure administered by masks worn at night is especially effective. Surgical treatment can help properly selected patients. Uvulopalatopharyngoplasty, which increases the volume of the oropharynx, requires follow-up polysomnographic studies. Tracheostomy is extremely effective and can be lifesaving in severe obstructive apnea. Effective therapeutic options make early recognition and treatment of this disorder vital and successful.

Sequential use of standard and ambulatory EEG in neonatal seizures.

Adequate predictors do not exist to indicate whether seizures are likely to continue beyond the neonatal period. Thirteen neonates with seizures occurring after 7 days of age were evaluated with standard short-term electroencephalography (SEEG) during the initial seizures and with ambulatory EEG (AEEG) when each infant was within 37-44 weeks corrected age (i.e., gestational age plus chronologic age). Eight of 13 SEEGs, 10 of 13 AEEGs, and 12 of 13 with the combined use of both SEEGs and AEEGs accurately predicted the occurrence of seizures at 3-4 months corrected age. Results with SEEG and AEEG did not produce significantly different outcomes. Combined analysis of SEEG and AEEG produced significantly different results from those calculated when the two EEG types were analyzed independently (Z = 3.98, p less than 0.001). The findings indicate that the use of both of these tests may improve the ability to predict continued seizure activity in infants with neonatal seizures when compared to the use of each measure separately.

Auditory event-related potential probes and behavioral measures of aphasia.

This study examined the relationship between an auditory event-related potential probe technique measure of differential hemispheric processing and traditional tests of aphasia in aphasic patients. Subjects were 10 aphasic and 10 normal adult males. The results of the electrophysiological measures indicated that the aphasic subjects responded differently from the normal group particularly when the task required processing of verbal information. During the verbal task the aphasic group showed higher amplitude right hemisphere responses as compared to left. The normal group showed little hemispheric task related asymmetries. The pattern of electrical asymmetry in the aphasic group seems to be an indicator of severity as measured by traditional aphasia examinations.

The significance of MRI abnormalities in children with neurofibromatosis.

We prospectively evaluated 47 children with neurofibromatosis to determine whether the previously reported high signals on magnetic resonance imaging (MRI) (prolonged T2) correlated with CT, brainstem auditory evoked responses (BAER), EEG, clinical examinations, cognitive abilities, or seizure disorder. Thirty percent of children had a history of seizures and 70% had either learning disabilities or mental retardation. Overall, 74% had an abnormal MRI examination. Sixty-two percent had high signals (prolonged T2) on T2-weighted images. Abnormal signals were located primarily in the basal ganglia, brainstem, and cerebellum. Twenty-five percent of patients had abnormal EEGs, 28% had abnormal CTs, and 27% had abnormal BAER examinations. The abnormal signals on MRI did not consistently relate to findings on CT, BAER, EEG, school placement, or clinical examination. The abnormal signals presumably reflect areas of abnormal brain parenchyma, either hamartomas, heterotopias, or local areas of brain dysplasia.

Cerebral resuscitation with succinate and fructose-1, 6-diphosphate.

To test the hypotheses that succinate or fructose-1, 6-diphosphate may have a beneficial effect in global cerebral ischemia, we induced complete global cerebral ischemia for 5 minutes in rabbits by occlusion of the ascending aorta and the superior and inferior vena cavae. Fifteen minutes after restoration of cerebral blood flow, animals received an intravenous bolus of either succinate or fructose-1,6-diphosphate followed by continuous infusion. Another group of animals received fructose-1, 6-diphosphate beginning prior to aortic occlusion. Control animals received intravenous glucose by bolus, followed by infusion. Cerebrospinal fluid lactate levels were measured before occlusion and at 2 1/2 hours after occlusion, when the animals were sacrificed. In all animals electrocortical silence was demonstrated for the 5 minutes of global ischemia. The percent change in cerebrospinal fluid lactate levels in all groups was statistically similar. Only two of seven of the control animals recovered electroencephalogram amplitude during the 2 1/2 hour observation period. Time for recovery of amplitude on the electroencephalogram in animals receiving fructose-1, 6-diphosphate either before or after ischemia was statistically similar to controls. In the succinate treated group, all seven animals regained preocclusion levels of electroencephalogram amplitude within 36 minutes of the restoration of cerebral blood flow. Succinate administered after complete global cerebral ischemia resulted in significantly increased recovery of cerebral electrical activity (Fischer's exact test, p less than 0.05).