Resting state functional connectivity in SLE patients and association with cognitive impairment and blood-brain barrier permeability.

OBJECTIVE: Extensive blood-brain barrier (BBB) leakage has been linked to cognitive impairment in SLE. This study aimed to examine the associations of brain functional connectivity (FC) with cognitive impairment and BBB dysfunction among patients with SLE. METHODS: Cognitive function was assessed by neuropsychological testing (n = 77). Resting-state FC (rsFC) between brain regions, measured by functional MRI (n = 78), assessed coordinated neural activation in 131 regions across five canonical brain networks. BBB permeability was measured by dynamic contrast-enhanced MRI (n = 61). Differences in rsFC were compared between SLE patients with cognitive impairment (SLE-CI) and those with normal cognition (SLE-NC), between SLE patients with and without extensive BBB leakage, and with healthy controls. RESULTS: A whole-brain rsFC comparison found significant differences in intra-network and inter-network FC in SLE-CI vs SLE-NC patients. The affected connections showed a reduced negative rsFC in SLE-CI compared with SLE-NC and healthy controls. Similarly, a reduced number of brain-wide connections was found in SLE-CI patients compared with SLE-NC (P = 0.030) and healthy controls (P = 0.006). Specific brain regions had a lower total number of brain-wide connections in association with extensive BBB leakage (P = 0.011). Causal mediation analysis revealed that 64% of the association between BBB leakage and cognitive impairment in SLE patients was mediated by alterations in FC. CONCLUSION: SLE patients with cognitive impairment had abnormalities in brain rsFC which accounted for most of the association between extensive BBB leakage and cognitive impairment.

Role of autoantibodies and blood-brain barrier leakage in cognitive impairment in systemic lupus erythematosus.

OBJECTIVE: Cognitive impairment is common in patients with SLE but the cause is unknown. The current cross-sectional study examined the association between select SLE-related autoantibodies, other serological biomarkers and extensive blood-brain barrier (BBB) leakage in patients with SLE with and without cognitive impairment. In addition, we determined whether the relationship between SLE autoantibodies, other biomarkers and cognitive impairment differed depending on the presence or absence of concurrent extensive BBB leakage. METHODS: Consecutive patients with SLE, recruited from a single academic medical centre, underwent formal neuropsychological testing for assessment of cognitive function. On the same day, BBB permeability was determined using dynamic contrast-enhanced MRI scanning. SLE autoantibodies and other serological biomarkers were measured. Regression modelling was used to determine the association between cognitive impairment, extensive BBB leakage and autoantibodies/biomarkers. RESULTS: There were 102 patients with SLE; 90% were female and 88% were Caucasian, with a mean±SD age of 48.9±13.8 years. The mean±SD SLE disease duration was 14.8±11.0 years. Impairment in one or more cognitive tests was present in 47 of 101 (47%) patients and included deficits in information processing speed (9%), attention span (21%), new learning (8%), delayed recall (15%) and executive abilities (21%). Extensive BBB leakage was present in 20 of 79 (25%) patients and was associated with cognitive impairment (15 of 20 (75%) vs 24 of 59 (41%); p=0.01) and shorter disease duration (median (IQR): 7 (8-24 years) vs 15 (2-16 years); p=0.02). No serological parameters were associated with extensive BBB leakage and there was no statistically significant association between cognitive impairment and circulating autoantibodies even after adjusting for BBB leakage. CONCLUSIONS: Extensive BBB leakage alone was associated with cognitive impairment. These findings suggest that BBB leakage is an important contributor to cognitive impairment, regardless of circulating SLE-related autoantibodies.

The influence of skin-to-skin contact on Cortical Activity during Painful procedures in preterm infants in the neonatal intensive care unit (iCAP mini): study protocol for a randomized control trial.

BACKGROUND: Strong evidence suggests that maternal-infant skin-to-skin contact (SSC) is effective in reducing behavioural responses to pain. Given the multi-sensory benefits of SSC, it is highly likely that SSC provided during pain in early life may reduce pain-induced brain activity. The aim of this study is to examine the effect of SSC compared to 24% sucrose on pain-induced activity in the preterm infant brain during a medically required heel lance. Secondary objectives include determining (a) differences between behavioural pain response and noxious-related brain activity during heel lance and (b) rate of adverse events across groups. METHODS: We will randomly assign 126 babies (32 to 36 completed weeks gestational age) admitted to the neonatal intensive care unit, and their mothers within the first seven days of age to receive (i) SSC plus sterile water and (ii) 24% oral sucrose. Each baby will receive a medically indicated heel lance, following a no treatment baseline period. The primary outcome is noxious-related brain activity measured using an electroencephalogram (EEG) pain-specific event-related potential. Secondary outcomes include pain intensity measured using a bio-behavioural infant pain assessment tool (Premature Infant Pain Profile-Revised) and rate of adverse events. DISCUSSION: This will be the first clinical trial to compare the effect of SSC and 24% sucrose on pain-induced brain activity in the preterm infant brain during a clinical noxious stimulus, measured using EEG. Given the negative neurodevelopmental outcomes associated with unmanaged pain, it is imperative that preterm babies receive the most effective pain-reducing treatments to improve their health outcomes. Our findings will have important implications in informing optimal pain assessment and management in preterm infants. TRIAL REGISTRATION: ClinicalTrials.gov NCT03745963 . Registered on November 19, 2018.

Periodic/Aperiodic parameterization of transient oscillations (PAPTO)-Implications for healthy ageing.

Two techniques for analyzing human extracranial neurophysiological signals, namely the periodic/aperiodic parameterization of neural power spectra and the transient events framework of oscillatory activity, have recently emerged in the scientific literature. In this work, we integrate these two analysis perspectives to analyze extracranial neurophysiological signals as a series of transient rhythmic events disambiguated from the background aperiodic activity. We call this novel technique the periodic/aperiodic parametrization of transient oscillations (PAPTO). We demonstrate PAPTO by investigating resting-state sensorimotor magnetoencephalography recordings from the Cambridge Center for Ageing and Neuroscience cross-sectional study on healthy ageing (n = 600, ages 18-88). We show that PAPTO is more sensitive to neocortical transient beta rhythms compared to more conventional transient event detection algorithms and captures more variance in the resting-state occurrence rate of beta events across participants. The improved sensitivity of PAPTO reveals that the beta occurrence rate almost doubles over the adult lifespan which we discuss in terms of thalamocortical beta generation in the somatosensory cortex and the age-related decline of sensory perception.

Blood-brain barrier leakage in systemic lupus erythematosus is associated with gray matter loss and cognitive impairment.

OBJECTIVES: To examine the association between blood-brain barrier (BBB) integrity, brain volume and cognitive dysfunction in adult patients with systemic lupus erythematosus (SLE). METHODS: A total of 65 ambulatory patients with SLE and 9 healthy controls underwent dynamic contrast-enhanced MRI scanning, for quantitative assessment of BBB permeability. Volumetric data were extracted using the VolBrain pipeline. Global cognitive function was evaluated using a screening battery consisting of tasks falling into five broad cognitive domains, and was compared between patients with normal versus extensive BBB leakage. RESULTS: Patients with SLE had significantly higher levels of BBB leakage compared with controls (p=0.04). Extensive BBB leakage (affecting over >9% of brain volume) was identified only in patients with SLE (16/65; 24.6%), who also had smaller right and left cerebral grey matter volumes compared with controls (p=0.04). Extensive BBB leakage was associated with lower global cognitive scores (p=0.02), and with the presence of impairment on one or more cognitive tasks (p=0.01). CONCLUSION: Our findings provide evidence for a link between extensive BBB leakage and changes in both brain structure and cognitive function in patients with SLE. Future studies should investigate the mechanisms underlying BBB-mediated cognitive impairment, validate the diagnostic utility of BBB imaging, and determine the potential of targeting the BBB as a therapeutic strategy in patients with SLE.

Attentional dysfunction and recovery in concussion: effects on the P300m and contingent magnetic variation.

PRIMARY OBJECTIVE: To examine the effect of concussion on indices of attention using magnetoencephalography. METHODS AND PROCEDURES: Thirteen patients were recruited from the emergency department and scanned within 3-6 days of injury. Five returned for follow-up scans one and three months post-injury. Thirteen healthy controls also completed testing. During MEG acquisition, participants performed the Attention Network Test (ANT). Cognitive evoked responses to this task include a cue-evoked P300m, a contingent magnetic variation (CMV) and a target-evoked P300m. The Rivermead Postconcussion Symptom Questionnaire and Sport Concussion Assessment Tool (SCAT3) were administered in all sessions. RESULTS: Patients suffering from concussion had slower response times and benefitted more from spatial cues than did controls. Global activation for all three evoked responses was lower for patients than controls. In a small sample of patients who returned for follow-up, the CMV and target P300m improved with recovery. CONCLUSIONS: MEG-evoked responses to the ANT reveal neurophysiological evidence of attentional dysfunction within days of injury. A pattern of improvement was also observed over the course of three months for the P300m, while behavioural performance did not change significantly. Further development of this method may yield a useful adjunct to neurological examination for concussion diagnosis and monitoring.

Cost-utility analysis of magnetoencephalography used to inform intracranial electrode placement in patients with drug resistant epilepsy: a model based analysis.

OBJECTIVES: We estimated the cost-effectiveness of adding magnetoencephalography to a standard assessment for epilepsy surgery consisting of neuropsychology, magnetic resonance imagining, scalp electroencephalography, video electroencephalography and intracranial electroencephalography, in the capacity of informing intracranial electroencephalography electrode placement. METHODS: We used Microsoft Excel (2007) to construct a decision model. Discounted costs and quality adjusted life years are aggregated to calculate incremental cost-effectiveness ratios. Sensitivity analyses are conducted to assess robustness of findings. RESULTS: Our base case analysis yielded a result of $14 300 per quality adjusted life year gained. A total of 82.7% of probabilistic sensitivity analysis iterations resulted in incremental cost-effectiveness ratios below $100 000 in 2014 Canadian dollars. CONCLUSIONS: Our findings demonstrate that the inclusion of Magnetoencephalography in the assessment for epilepsy surgery in the capacity of informing intracranial electroencephalography electrode placement is likely not cost saving but does represent a reasonable allocation of resources from a value for money perspective.

Fully automated quality assurance and localization of volumetric MEG for single-subject mapping.

BACKGROUND: Robust and reproducible source mapping with magnetoencephalography is particularly challenging at the individual level. We evaluated a receiver-operating characteristic reliability (ROC-r) method for automated production of volumetric MEG maps in single-subjects. ROC-r provides quality assurance comparable to that offered by goodness-of-fit (GoF) and confidence volume (CV) for equivalent current dipole (ECD) modeling. NEW METHOD: ROC-r utilizes within-session reproducibility for quality assurance, latency identification, and thresholding of volumetric source maps. We tested ROC-r on simulated and real MEG with a strongly focal source, using somatosensory evoked fields (SEFs) elicited by bilateral median nerve stimulation (MNS). For quality assurance, the ROC-r reliable fraction (FR) was compared to the ECD GoF and CV. Peak beamformer locations and latencies identified by ROC-r were compared to the ECD for co-localization accuracy. RESULTS: The predominant component of the SEF response occurred around 35ms, contralateral to the MNS. COMPARISON WITH EXISTING METHODS: FR and 1/CV were more strongly correlated (mean Pearson's correlation: 0.76; 95% CI 0.60-0.87) than FR and GoF (0.65; 95% CI 0.32-0.85). There was no difference in the latency of the peak GoF (35.0+/-0.6ms), CV (34.8+/-0.7ms) and FR (35.5+/-0.8ms). The ECD fits and ROC-r peaks co-localized to within a mean (median) distance of 8.3+/-5.9mm (6.2mm). CONCLUSION: ROC-r volumetric mapping co-localized closely with the standard ECD approach. This analysis can be added to any whole-brain MEG source imaging protocol, and is especially useful for single-subject mapping. Additionally, the development of FR as an analogue to GoF or CV for volumetric mapping is a critical improvement for clinical applications.

Neural generators underlying concurrent sound segregation.

Although an object-based account of auditory attention has become an increasingly popular model for understanding how temporally overlapping sounds are segregated, relatively little is known about the cortical circuit that supports such ability. In the present study, we applied a beamformer spatial filter to magnetoencephalography (MEG) data recorded during an auditory paradigm that used inharmonicity to promote the formation of multiple auditory objects. Using this unconstrained, data-driven approach, the evoked field component linked with the perception of multiple auditory objects (i.e., the object-related negativity; ORNm), was found to be associated with bilateral auditory cortex sources that were distinct from those coinciding with the P1m, N1m, and P2m responses elicited by sound onset. The right hemispheric ORNm source in particular was consistently positioned anterior to the other sources across two experiments. These findings are consistent with earlier proposals of multiple auditory object detection being associated with generators in the auditory cortex and further suggest that these neural populations are distinct from the long latency evoked responses reflecting the detection of sound onset.

Human auditory cortex activity shows additive effects of spectral and spatial cues during speech segregation.

In noisy social gatherings, listeners perceptually integrate sounds originating from one person's voice (e.g., fundamental frequency (f(0)) and harmonics) at a particular location and segregate these from concurrent sounds of other talkers. Though increasing the spectral or the spatial distance between talkers promotes speech segregation, synergetic effects of spatial and spectral distances are less well understood. We studied how spectral and/or spatial distances between 2 simultaneously presented steady-state vowels contribute to perception and activation in auditory cortex using magnetoencephalography. Participants were more accurate in identifying both vowels when they differed in f(0) and location than when they differed in a single cue only or when they shared the same f(0) and location. The combined effect of f(0) and location differences closely matched the sum of single effects. The improvement in concurrent vowel identification coincided with an object-related negativity that peaked at about 140 ms after vowel onset. The combined effect of f(0) and location closely matched the sum of the single effects even though vowels with different f(0), location, or both generated different time courses of neuromagnetic activity. We propose that during auditory scene analysis, acoustic differences among the various sources are combined linearly to increase the perceptual distance between the co-occurring sound objects.

Learning related activation of somatosensory cortex by an auditory stimulus recorded with magnetoencephalography.

Advances in non-invasive neuroimaging technology now provide a means of directly observing learning within the brain. Classical conditioning serves as an ideal starting point for examining the dynamic expression of learning within the human brain, since this paradigm is well characterized using multiple levels of analysis in a broad range of species. We used MEG to expand the characterization of conditioned responses (CR) recorded from the human brain with a simultaneous examination of their spatial, temporal and spectral properties. We paired an auditory conditioned stimulus (CS+) with a somatosensory unconditioned stimulus (US). We found that when the US was randomly omitted, presentations of CS+ alone, elicited greater desynchronization of beta-band activity in contralateral somatosensory cortex compared to presentations of an auditory stimulus that was never paired with the US (CS-), and compared the CS+ following a non-reinforced extinction session. This differentiation was largest between 150 and 350ms following US omission. We show that cross-modal CRs in the primary sensorimotor system are predominantly characterized by modulation of ongoing cortical oscillations.

Semantic information alters neural activation during transverse patterning performance.

Memory tasks can be performed using multiple cognitive strategies, which are mediated by different brain systems. The transverse patterning (TP) task is dependent upon the integrity of the hippocampal system, however, we previously demonstrated successful TP following hippocampal damage using meaningful stimuli and relations (Moses, S.N., Ostreicher, M.L., Rosenbaum, R.S., Ryan, J.D., 2008. Successful transverse patterning in amnesia using semantic knowledge. Hippocampus 18, 121-124). Here, we used magnetoencephalgraphy (MEG) to directly observe the neural underpinnings of TP, and the changes that occur as stimuli and relations become more meaningful. In order to optimize our ability to detect signal from deep, non-dominant, brain sources we implemented the event-related synthetic aperture magnetometry minimum-variance beamformer algorithm (ER-SAM; Cheyne, D., Bakhtazad, L., Gaetz, W., 2006. Spatiotemporal mapping of cortical activity accompanying voluntary movements using an event-related beamforming approach. Human Brain Mapping 27, 213-229) coupled with the partial least squares (PLS) multivariate statistical approach (McIntosh, A.R., Bookstein, F.L., Haxby, J.V., Grady, C.L., 1996. Spatial pattern analysis of function brain images using partial least squares. NeuroImage 3, 143-157; McIntosh, A.R., Lobaugh, N.J., 2004. Partial least squares analysis of neuroimaging data: Applications and advances. NeuroImage 23, S250-S263). We found that increased meaningfulness elicited reduced bilateral hippocampal activation, along with increased activation of left prefrontal and temporal cortical structures, including inferior frontal (IFG), as well as anterior temporal and perirhinal cortices. These activation patterns may represent a shift towards reliance upon existing semantic knowledge. This shift likely permits successful TP performance with meaningful stimuli and relations following hippocampal damage.

A complementary analytic approach to examining medial temporal lobe sources using magnetoencephalography.

Neuropsychological and neuroimaging findings reveal that the hippocampus is important for recognition memory. However, it is unclear when and whether the hippocampus contributes differentially to recognition of previously studied items (old) versus novel items (new), or contributes to a general processing requirement that is necessary for recognition of both types of information. To address this issue, we examined the temporal dynamics and spectral frequency underlying hippocampal activity during recognition of old/new complex scenes using magnetoencephalography (MEG). In order to provide converging evidence to existing literature in support of the potential of MEG to localize the hippocampus, we reconstructed brain source activity using the beamformer method and analyzed three types of processing-related signal changes by applying three different analysis methods: (1) Synthetic aperture magnetometry (SAM) revealed event related and non-event-related spectral power changes; (2) Inter-trial coherence (ITC) revealed time-locked changes in neural synchrony; and (3) Event-related SAM (ER-SAM) revealed averaged event-related responses over time. Hippocampal activity was evident for both old and new information within the theta frequency band and during the first 250 ms following stimulus onset. The early onset of hippocampal responses suggests that general comparison processes related to recognition of new/old information may occur obligatorily.