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.

A Novel, Fast, Reliable, and Data-Driven Method for Simultaneous Single-Trial Mining and Amplitude-Latency Estimation Based on Proximity Graphs and Network Analysis.

Both amplitude and latency of single-trial EEG/MEG recordings provide valuable information regarding functionality of the human brain. In this article, we provided a data-driven graph and network-based framework for mining information from multi-trial event-related brain recordings. In the first part, we provide the general outline of the proposed methodological approach. In the second part, we provide a more detailed illustration, and present the obtained results on every step of the algorithmic procedure. To justify the proposed framework instead of presenting the analytic data mining and graph-based steps, we address the problem of response variability, a prerequisite to reliable estimates for both the amplitude and latency on specific N/P components linked to the nature of the stimuli. The major question addressed in this study is the selection of representative single-trials with the aim of uncovering a less noisey averaged waveform elicited from the stimuli. This graph and network-based algorithmic procedure increases the signal-to-noise (SNR) of the brain response, a key pre-processing step to reveal significant and reliable amplitude and latency at a specific time after the onset of the stimulus and with the right polarity (N or P). We demonstrated the whole approach using electroencephalography (EEG) auditory mismatch negativity (MMN) recordings from 42 young healthy controls. The method is novel, fast and data-driven succeeding first to reveal the true waveform elicited by MMN on different conditions (frequency, intensity, duration, etc.). The proposed graph-oriented algorithmic pipeline increased the SNR of the characteristic waveforms and the reliability of amplitude and latency within the adopted cohort. We also demonstrated how different EEG reference schemes (REST vs. average) can influence amplitude-latency estimation. Simulation results revealed robust amplitude-latency estimations under different SNR and amplitude-latency variations with the proposed algorithm.

Benign childhood epilepsy with centrotemporal spikes (BECTS) and developmental co-ordination disorder.

BACKGROUND: Benign epilepsy with centro-temporal spikes (BECTS) is a common childhood epilepsy syndrome also known as Rolandic Epilepsy (RE). Neurocognitive phenotypes have been described with greater focus on attention, reading and language domains but there have been far fewer studies focusing on motor functioning. This study included measures of motor, language and cognition in order to investigate the range, degree and pattern of difficulties associated with BECTS in a case series of children, but with a particular emphasis on motor skills. METHOD: Twenty-one children aged between 8 and 16years with a diagnosis of BECTS were asked to complete standardized assessments for language, cognition, motor functioning and handwriting. RESULTS: When measuring across language, cognitive and motor domains, 19 (90.48%) of the twenty-one children with a diagnosis of BECTS showed some difficulties on at least one area of functioning using standardized assessment tests. Of particular note nearly half (47.62%) of the children had some difficulties in one or more areas of motor functioning. DISCUSSION: Children with BECTS have a heterogeneous pattern of neurocognitive impairments. The presence of motor difficulties (DCD) should be considered in all children routinely seen in clinical settings with BECTS and included in any screening processes.

Ipsilateral cortical motor desynchronisation is reduced in Benign Epilepsy with Centro-Temporal Spikes.

OBJECTIVE: Magnetoencephalography (MEG) and a simple motor paradigm were used to study induced sensorimotor responses and their relationship to motor skills in children diagnosed with Benign Epilepsy with Centro-Temporal Spikes (BECTS). METHODS: Twenty-one children with BECTS and 15 age-matched controls completed a finger abduction task in MEG; movement-related oscillatory responses were derived and contrasted between groups. A subset of children also completed psycho-behavioural assessments. Regression analyses explored the relationship of MEG responses to manual dexterity performance, and dependence upon clinical characteristics. RESULTS: In children with BECTS, manual dexterity was below the population mean (p=.002) and three showed severe impairment. Our main significant finding was of reduced ipsilateral movement related beta desynchrony (MRBDi) in BECTS relative to the control group (p=.03) and predicted by epileptic seizure recency (p=.02), but not age, medication status, or duration of epilepsy. Laterality scores across the entire cohort indicated that less lateralised MRBD predicted better manual dexterity (p=.04). CONCLUSIONS: Altered movement-related oscillatory responses in ipsilateral motor cortex were associated with motor skill deficits in children with BECTS. These changes were more marked in those with more recent seizures. SIGNIFICANCE: These findings may reflect differences in inter-hemispheric interactions during motor control in BECTS.

Associations between polygenic risk for schizophrenia and brain function during probabilistic learning in healthy individuals.

A substantial proportion of schizophrenia liability can be explained by additive genetic factors. Risk profile scores (RPS) directly index risk using a summated total of common risk variants weighted by their effect. Previous studies suggest that schizophrenia RPS predict alterations to neural networks that support working memory and verbal fluency. In this study, we apply schizophrenia RPS to fMRI data to elucidate the effects of polygenic risk on functional brain networks during a probabilistic-learning neuroimaging paradigm. The neural networks recruited during this paradigm have previously been shown to be altered to unmedicated schizophrenia patients and relatives of schizophrenia patients, which may reflect genetic susceptibility. We created schizophrenia RPS using summary data from the Psychiatric Genetic Consortium (Schizophrenia Working Group) for 83 healthy individuals and explore associations between schizophrenia RPS and blood oxygen level dependency (BOLD) during periods of choice behavior (switch-stay) and reflection upon choice outcome (reward-punishment). We show that schizophrenia RPS is associated with alterations in the frontal pole (PWHOLE-BRAIN-CORRECTED  = 0.048) and the ventral striatum (PROI-CORRECTED  = 0.036), during choice behavior, but not choice outcome. We suggest that the common risk variants that increase susceptibility to schizophrenia can be associated with alterations in the neural circuitry that support the processing of changing reward contingencies. Hum Brain Mapp 37:491-500, 2016. © 2015 Wiley Periodicals, Inc.

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.

Alzheimer's disease risk variant in CLU is associated with neural inefficiency in healthy individuals.

INTRODUCTION: Genome-wide association studies identify rs11136000 in the CLU gene, which codes for Apolipoprotein J/Clusterin, as a significant risk variant for Alzheimer's disease (AD). However, the mechanisms by which this variant confers susceptibility remain relatively unknown. METHODS: Eighty-five healthy Caucasian participants underwent functional magnetic resonance imaging during a working memory (WM) task and were genotyped for CLU rs11136000/APOE loci. RESULTS: Here we show that young individuals with the CLU rs11136000 risk variant (C) have higher activation levels in memory-related prefrontal and limbic areas during a WM task. We also found subtle reductions in gray matter in the right hippocampal formation in carriers of the risk variant. DISCUSSION: We suggest that this pattern of multimodal imaging results may reflect incipient structural differences and inefficient functional activation. This study supports accumulating evidence suggesting that genetic risk for AD affects the neural networks associated with memory in healthy individuals.

Evidence for increased visual gamma responses in photosensitive epilepsy.

BACKGROUND: A sustained gamma (30-70 Hz) oscillation induced in occipital cortex by high-contrast visual stimulation has been well characterised in animal local field potential recordings and in healthy human participants using magnetoencephalography (MEG). The spatial frequency of a static grating stimulus that gives maximal gamma is also that most likely to provoke seizures in photosensitive epilepsy. METHODS: We used MEG to study visual responses induced by grating stimuli of varying contrast and size in twelve patients with photosensitive epilepsy and two matched control groups, one with epilepsy but no photosensitivity, the other healthy controls. We used a beamformer approach to localise cortical responses and to characterise the time-frequency dynamics of evoked and induced oscillatory responses. RESULTS: A greater number of patients with photosensitivity had particularly amplitude gamma responses compared to controls. Formal statistical testing failed to find a group difference. One photosensitive patient, tested before and after sodium valproate, had a peak gamma amplitude when drug naive over four times larger than the group mean for controls; this high amplitude was substantially decreased after treatment with sodium valproate. We found no difference in the frequency of the sustained gamma response between the three groups. DISCUSSION: Altered power, but not frequency, in induced cortical responses to a static grating stimulus may be a characteristic of photosensitive epilepsy. Our failure to find a group difference on statistical testing may have been due to a wide intersubject variability and heterogeneity of the photosensitive group. A high amplitude response would be in keeping with previous evidence of altered contrast gain and increased spatial recruitment in photosensitive epilepsy.

The properties of induced gamma oscillations in human visual cortex show individual variability in their dependence on stimulus size.

The role of gamma-band (typically 30-100 Hz) oscillations in visual processing is a topic of increasing interest. One hypothesis is that gamma oscillations reflect the action of GABAergic inhibitory processes in the visual cortex responsible for surround-suppression. Evidence from primate neurophysiology [Gieselmann & Thiele, A., 2008. European Journal of Neuroscience 28, 447-459.] suggests that the amplitude of the gamma-band response increases as a visual grating stimulus expands outside of the classical receptive field into the inhibitory surround; with the amplitude of the response increasing, and the frequency of the response decreasing, monotonically with stimulus size. In this study, we tested the relationship between the gamma-band response and the size of visual grating stimuli in humans using MEG. In two initial experiments we found that, while the absolute magnitude of the gamma-band response varied considerably across participants, in all cases the amplitude of the response had a monotonically increasing relationship with size. In contrast, we did not find any relationship between the frequency of the response and the size of the stimulus. Previously, the frequency of the visual gamma-band response has been found to correlate across individuals with the surface area of cortical area V1 [Schwarzkopf et al., 2012. Journal of Neuroscience 32, 1507-12.] We, however, were unable to find any correlation between the frequency or the magnitude of the gamma-band response and the dimensions of V1 cortical gray matter as measured from participants' MR images. Consistent with a saturation of the gamma-band response found for some individuals in the first two experiments, in a third experiment we found that the magnitude of the response to our largest stimulus (8°) was less than that predicted from the response to the stimulus' parts.

They played with the trade: MEG investigation of the processing of past tense verbs and their phonological twins.

How regular and irregular verbs are processed remains a matter of debate. Some English-speaking patients with nonfluent aphasia are especially impaired on regular past-tense forms like played, whether the task requires production, comprehension or even the judgement that "play" and "played" sound different. Within a dual-mechanism account of inflectional morphology, these deficits reflect disruption to the rule-based process that adds (or strips) the suffix -ed to regular verb stems; but the fact that the patients are also impaired at detecting the difference between word pairs like "tray" and "trade" (the latter being a phonological but not a morphological twin to "played") suggests an important role for phonological characteristics of the regular past tense. The present study examined MEG brain responses in healthy participants evoked by spoken regular past-tense forms and phonological twin words (plus twin pseudowords and a non-speech control) presented in a passive oddball paradigm. Deviant forms (played, trade, kwade/kwayed) relative to their standards (play, tray, kway) elicited a pronounced neuromagnetic response at approximately 130 ms after the onset of the affix; this response was maximal at sensors over temporal areas of both hemispheres but stronger on the left, especially for played and kwayed. Relative to the same standards, a different set of deviants ending in /t/--plate, trait and kwate--produced stronger difference responses especially over the right hemisphere. Results are discussed with regard to dual- and single-mechanism theories of past tense processing and the need to consider neurobiological evidence in attempts to understand inflectional morphology.