Electrophysiological network alterations in adults with copy number variants associated with high neurodevelopmental risk.

Rare copy number variants associated with increased risk for neurodevelopmental and psychiatric disorders (referred to as ND-CNVs) are characterized by heterogeneous phenotypes thought to share a considerable degree of overlap. Altered neural integration has often been linked to psychopathology and is a candidate marker for potential convergent mechanisms through which ND-CNVs modify risk; however, the rarity of ND-CNVs means that few studies have assessed their neural correlates. Here, we used magnetoencephalography (MEG) to investigate resting-state oscillatory connectivity in a cohort of 42 adults with ND-CNVs, including deletions or duplications at 22q11.2, 15q11.2, 15q13.3, 16p11.2, 17q12, 1q21.1, 3q29, and 2p16.3, and 42 controls. We observed decreased connectivity between occipital, temporal, and parietal areas in participants with ND-CNVs. This pattern was common across genotypes and not exclusively characteristic of 22q11.2 deletions, which were present in a third of our cohort. Furthermore, a data-driven graph theory framework enabled us to successfully distinguish participants with ND-CNVs from unaffected controls using differences in node centrality and network segregation. Together, our results point to alterations in electrophysiological connectivity as a putative common mechanism through which genetic factors confer increased risk for neurodevelopmental and psychiatric disorders.

Oscillatory hyperactivity and hyperconnectivity in young APOE-ɛ4 carriers and hypoconnectivity in Alzheimer's disease.

We studied resting-state oscillatory connectivity using magnetoencephalography in healthy young humans (N = 183) genotyped for APOE-ɛ4, the greatest genetic risk for Alzheimer's disease (AD). Connectivity across frequencies, but most prevalent in alpha/beta, was increased in APOE-ɛ4 in a set of mostly right-hemisphere connections, including lateral parietal and precuneus regions of the Default Mode Network. Similar regions also demonstrated hyperactivity, but only in gamma (40-160 Hz). In a separate study of AD patients, hypoconnectivity was seen in an extended bilateral network that partially overlapped with the hyperconnected regions seen in young APOE-ɛ4 carriers. Using machine-learning, AD patients could be distinguished from elderly controls with reasonable sensitivity and specificity, while young APOE-e4 carriers could also be distinguished from their controls with above chance performance. These results support theories of initial hyperconnectivity driving eventual profound disconnection in AD and suggest that this is present decades before the onset of AD symptomology.

Attenuated Post-Movement Beta Rebound Associated With Schizotypal Features in Healthy People.

INTRODUCTION: Schizophrenia and schizotypal personality disorder (SPD) lie on a single spectrum of mental illness and converging evidence suggests similarities in the etiology of the 2 conditions. However, schizotypy is a heterogeneous facet of personality in the healthy population and so may be seen as a bridge between health and mental illness. Neural evidence for such a continuity would have implications for the characterization and treatment of schizophrenia. Based on our previous work identifying a relationship between symptomology in schizophrenia and abnormal movement-induced electrophysiological response (the post-movement beta rebound [PMBR]), we predicted that if subclinical schizotypy arises from similar neural mechanisms to schizophrenia, schizotypy in healthy individuals would be associated with reduced PMBR. METHODS: One-hundred sixteen participants completed a visuomotor task while their neural activity was recorded by magnetoencephalography. Partial correlations were computed between a measure of PMBR extracted from left primary motor cortex and scores on the Schizotypal Personality Questionnaire (SPQ), a self-report measure of schizotypal personality. Correlations between PMBR and SPQ factor scores measuring cognitive-perceptual, interpersonal and disorganization dimensions of schizotypy were also computed. Effects of site, age, and sex were controlled for. RESULTS: We found a significant negative correlation between total SPQ score and PMBR. This was most strongly mediated by variance shared between interpersonal and disorganization factor scores. CONCLUSION: These findings indicate a continuum of neural deficit between schizotypy and schizophrenia, with diminution of PMBR, previously reported in schizophrenia, also measurable in individuals with schizotypal features, particularly disorganization and impaired interpersonal relations.

The effects of AMPA receptor blockade on resting magnetoencephalography recordings.

The ionotropic N-methyl-D-aspartate and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors of the glutamatergic neurotransmitter system are of fundamental importance to healthy brain function. Neuroimaging studies in humans have previously been conducted using various drugs that interact with N-methyl-D-aspartate glutamate receptors, but no such studies have investigated AMPA receptor signalling. The recent approval of perampanel (Fycompa) for use in humans provides a means to specifically study the role of AMPA receptors in the pharmacological basis of neuroimaging signals. Twenty male subjects participated in this placebo-controlled crossover study that consisted of two study days separated by a minimum two-week washout period. On one occasion participants ingested a 6 mg dose of perampanel, and on the other a placebo. Ten minutes of wakeful rest was recorded before and after each dose using magnetoencephalography. Subjective ratings of intoxication were significantly higher following drug than placebo. Cluster-based randomisation testing of sensor-level magnetoencephalography data showed significant drug-induced increases in low frequency power (1-4 Hz, 4-8 Hz, 8-13 Hz, 13-30 Hz), along with a significant decrease in the high gamma range (50-90 Hz). We also observed selective increases in functional connectivity in the alpha and beta bands. The findings are consistent with preclinical work and are similar to the spectral profile of other anti-epileptic drugs.

Non-invasive brain mapping in epilepsy: Applications from magnetoencephalography.

BACKGROUND: Non-invasive in vivo neurophysiological recordings with EEG/MEG are key to the diagnosis, classification, and further understanding of epilepsy. Historically the emphasis of these recordings has been the localisation of the putative sources of epileptic discharges. More recent developments see new techniques studying oscillatory dynamics, connectivity and network properties. NEW METHOD: New analysis strategies for whole head MEG include the development of spatial filters or beamformers for source localisation, time-frequency analysis for cortical dynamics and graph theory applications for connectivity. RESULTS: The idea of epilepsy as a network disorder is not new, and new applications of structural and functional brain imaging show differences in cortical and subcortical networks in patients with epilepsy compared to controls. Concepts of 'focal' and 'generalised' are challenged by evidence of focal onsets in generalised epileptic discharges, and widespread network changes in focal epilepsy. Spectral analyses can show differences in induced cortical response profiles, particularly in photosensitive epilepsy. COMPARISON WITH EXISTING METHOD: This review focuses on the application of MEG in the study of epilepsy, starting with a brief historical perspective, followed by novel applications of source localisation, time-frequency and connectivity analyses. CONCLUSION: Novel MEG analyses approaches show altered cortical dynamics and widespread network alterations in focal and generalised epilepsies, and identification of regional network abnormalities may have a role in epilepsy surgery evaluation.

Resting-state oscillatory dynamics in sensorimotor cortex in benign epilepsy with centro-temporal spikes and typical brain development.

Benign Epilepsy with Centro-Temporal Spikes (BECTS) is a common childhood epilepsy associated with deficits in several neurocognitive domains. Neurophysiological studies in BECTS often focus on centro-temporal spikes, but these correlate poorly with morphology and cognitive impairments. To better understand the neural profile of BECTS, we studied background brain oscillations, thought to be integrally involved in neural network communication, in sensorimotor areas. We used independent component analysis of temporally correlated sources on magnetoencephalography recordings to assess sensorimotor resting-state network activity in BECTS patients and typically developing controls. We also investigated the variability of oscillatory characteristics within focal primary motor cortex (M1), localized with a separate finger abduction task. We hypothesized that background oscillations would differ between patients and controls in the sensorimotor network but not elsewhere, especially in the beta band (13-30 Hz) because of its role in network communication and motor processing. The results support our hypothesis: in the sensorimotor network, patients had a greater variability in oscillatory amplitude compared to controls, whereas there was no difference in the visual network. Network measures did not correlate with age. The coefficient of variation of resting M1 peak frequency correlated negatively with age in the beta band only, and was greater than average for a number of patients. Our results point toward a "disorganized" functional sensorimotor network in BECTS, supporting a neurodevelopmental delay in sensorimotor cortex. Our findings further suggest that investigating the variability of oscillatory peak frequency may be a useful tool to investigate deficits of disorganization in neurodevelopmental disorders.

Linear tuning of gamma amplitude and frequency to luminance contrast: evidence from a continuous mapping paradigm.

Individual differences in the visual gamma (30-100 Hz) response and their potential as trait markers of underlying physiology (particularly related to GABAergic inhibition) have become a matter of increasing interest in recent years. There is growing evidence, however, that properties of the gamma response (e.g., its amplitude and frequency) are highly stimulus dependent, and that individual differences in the gamma response may reflect individual differences in the stimulus tuning functions of gamma oscillations. Here, we measured the tuning functions of gamma amplitude and frequency to luminance contrast in eighteen participants using MEG. We used a grating stimulus in which stimulus contrast was modulated continuously over time. We found that both gamma amplitude and frequency were linearly modulated by stimulus contrast, but that the gain of this modulation (as reflected in the linear gradient) varied across individuals. We additionally observed a stimulus-induced response in the beta frequency range (10-25 Hz), but neither the amplitude nor the frequency of this response was consistently modulated by the stimulus over time. Importantly, we did not find a correlation between the gain of the gamma-band amplitude and frequency tuning functions across individuals, suggesting that these may be independent traits driven by distinct neurophysiological processes.