Neural plasticity is modified over the human menstrual cycle: Combined insight from sensory evoked potential LTP and repetition suppression.

In healthy women, fluctuations in hormones including progesterone and oestradiol lead to functional changes in the brain over the course of each menstrual cycle. Though considerable attention has been directed towards understanding changes in human cognition over the menstrual cycle, changes in underlying processes such as neural plasticity have largely only been studied in animals. In this study we explored predictive coding and repetition suppression via the roving mismatch negativity paradigm as a model of short-term plasticity (Garrido, Kilner, Kiebel, et al., 2009), and Hebbian learning via visual sensory long-term potentiation (LTP) as a model of long-term plasticity (Teyler et al., 2005). Electroencephalography (EEG) was recorded in 20 females during their early follicular and mid-luteal phases. Event-related potential (ERP) analyses were complemented with dynamic causal modelling (DCM) to characterise changes in the underlying neural architecture. More sustained variability in the ERP response to a change in tone during the luteal phase are interpreted as a delayed habituation of the P3a component in the luteal relative to the follicular phase. The additional increased forward connection strength over tone repetitions compared to the follicular phase suggests that, in this phase, females may be less efficient when processing deviations from predicted sensory input (error). In contrast, there appears to be no reliable change in sensory LTP. This suggests that predictive coding, but not Hebbian plasticity is modified in the mid-luteal compared to the follicular phase, at least at the days of the menstrual cycle tested. This finding implicates the human menstrual cycle in complex changes in neural plasticity and provides further evidence for the importance of considering the menstrual cycle when including females in electrophysiological research.

Indexing sensory plasticity: Evidence for distinct Predictive Coding and Hebbian learning mechanisms in the cerebral cortex.

The Roving Mismatch Negativity (MMN), and Visual LTP paradigms are widely used as independent measures of sensory plasticity. However, the paradigms are built upon fundamentally different (and seemingly opposing) models of perceptual learning; namely, Predictive Coding (MMN) and Hebbian plasticity (LTP). The aim of the current study was to compare the generative mechanisms of the MMN and visual LTP, therefore assessing whether Predictive Coding and Hebbian mechanisms co-occur in the brain. Forty participants were presented with both paradigms during EEG recording. Consistent with Predictive Coding and Hebbian predictions, Dynamic Causal Modelling revealed that the generation of the MMN modulates forward and backward connections in the underlying network, while visual LTP only modulates forward connections. These results suggest that both Predictive Coding and Hebbian mechanisms are utilized by the brain under different task demands. This therefore indicates that both tasks provide unique insight into plasticity mechanisms, which has important implications for future studies of aberrant plasticity in clinical populations.

Neurophysiologically-informed markers of individual variability and pharmacological manipulation of human cortical gamma.

The ability to quantify synaptic function at the level of cortical microcircuits from non-invasive data would be enormously useful in the study of neuronal processing in humans and the pathophysiology that attends many neuropsychiatric disorders. Here, we provide proof of principle that one can estimate inter-and intra-laminar interactions among specific neuronal populations using induced gamma responses in the visual cortex of human subjects - using dynamic causal modelling based upon the canonical microcircuit (CMC; a simplistic model of a cortical column). Using variability in induced (spectral) responses over a large cohort of normal subjects, we find that the predominant determinants of gamma responses rest on recurrent and intrinsic connections between superficial pyramidal cells and inhibitory interneurons. Furthermore, variations in beta responses were mediated by inter-subject differences in the intrinsic connections between deep pyramidal cells and inhibitory interneurons. Interestingly, we also show that increasing the self-inhibition of superficial pyramidal cells suppresses the amplitude of gamma activity, while increasing its peak frequency. This systematic and nonlinear relationship was only disclosed by modelling the causes of induced responses. Crucially, we were able to validate this form of neurophysiological phenotyping by showing a selective effect of the GABA re-uptake inhibitor tiagabine on the rate constants of inhibitory interneurons. Remarkably, we were able to recover the pharmacodynamics of this effect over the course of several hours on a per subject basis. These findings speak to the possibility of measuring population specific synaptic function - and its response to pharmacological intervention - to provide subject-specific biomarkers of mesoscopic neuronal processes using non-invasive data. Finally, our results demonstrate that, using the CMC as a proxy, the synaptic mechanisms that underlie the gain control of neuronal message passing within and between different levels of cortical hierarchies may now be amenable to quantitative study using non-invasive (MEG) procedures.

Hyperconnectivity in juvenile myoclonic epilepsy: a network analysis.

OBJECTIVE: Juvenile myoclonic epilepsy (JME) is a common idiopathic (genetic) generalized epilepsy (IGE) syndrome characterized by impairments in executive and cognitive control, affecting independent living and psychosocial functioning. There is a growing consensus that JME is associated with abnormal function of diffuse brain networks, typically affecting frontal and fronto-thalamic areas. METHODS: Using diffusion MRI and a graph theoretical analysis, we examined bivariate (network-based statistic) and multivariate (global and local) properties of structural brain networks in patients with JME (N = 34) and matched controls. Neuropsychological assessment was performed in a subgroup of 14 patients. RESULTS: Neuropsychometry revealed impaired visual memory and naming in JME patients despite a normal full scale IQ (mean = 98.6). Both JME patients and controls exhibited a small world topology in their white matter networks, with no significant differences in the global multivariate network properties between the groups. The network-based statistic approach identified one subnetwork of hyperconnectivity in the JME group, involving primary motor, parietal and subcortical regions. Finally, there was a significant positive correlation in structural connectivity with cognitive task performance. CONCLUSIONS: Our findings suggest that structural changes in JME patients are distributed at a network level, beyond the frontal lobes. The identified subnetwork includes key structures in spike wave generation, along with primary motor areas, which may contribute to myoclonic jerks. We conclude that analyzing the affected subnetworks may provide new insights into understanding seizure generation, as well as the cognitive deficits observed in JME patients.

Increased visual gamma power in schizoaffective bipolar disorder.

BACKGROUND: Electroencephalography and magnetoencephalography (MEG) studies have identified alterations in gamma-band (30-80 Hz) cortical activity in schizophrenia and mood disorders, consistent with neural models of disturbed glutamate (and GABA) neuron influence over cortical pyramidal cells. Genetic evidence suggests specific deficits in GABA-A receptor function in schizoaffective bipolar disorder (SABP), a clinical syndrome with features of both bipolar disorder and schizophrenia. This study investigated gamma oscillations in this under-researched disorder. METHOD: MEG was used to measure induced gamma and evoked responses to a visual grating stimulus, known to be a potent inducer of primary visual gamma oscillations, in 15 individuals with remitted SABP, defined using Research Diagnostic Criteria, and 22 age- and sex-matched healthy controls. RESULTS: Individuals with SABP demonstrated increased sustained visual cortical power in the gamma band (t 35 = -2.56, p = 0.015) compared to controls. There were no group differences in baseline gamma power, transient or sustained gamma frequency, alpha band responses or pattern onset visual-evoked responses. CONCLUSIONS: Gamma power is increased in remitted SABP, which reflects an abnormality in the cortical inhibitory-excitatory balance. Although an interaction between gamma power and medication can not be ruled out, there were no group differences in evoked responses or baseline measures. Further work is needed in other clinical populations and at-risk relatives. Pharmaco-magnetoencephalography studies will help to elucidate the specific GABA and glutamate pathways affected.

BOLD Responses in Human Primary Visual Cortex are Insensitive to Substantial Changes in Neural Activity.

The relationship between blood oxygenation level dependent-functional magnetic resonance imaging (BOLD-fMRI) and magnetoencephalography (MEG) metrics were explored using low-level visual stimuli known to elicit a rich variety of neural responses. Stimuli were either perceptually isoluminant red/green or luminance-modulated black/yellow square-wave gratings with spatial frequencies of 0.5, 3, and 6 cycles per degree. Neural responses were measured with BOLD-fMRI (3-tesla) and whole head MEG. For all stimuli, the BOLD response showed bilateral activation of early visual cortex that was greater in the contralateral hemisphere. There was variation between individuals but weak, or no evidence, of amplitude dependence on either spatial frequency or the presence of luminance contrast. In contrast, beamformer analysis of MEG data showed activation in contralateral early visual cortex and revealed: (i) evoked responses with stimulus-dependent amplitude and latency; (ii) gamma and high-beta oscillations, with spatial frequency dependent peaks at approximately 30 and 50 Hz, but only for luminance-modulated gratings; (iii) The gamma and beta oscillations appeared to show different spatial frequency tuning profiles; (iv) much weaker gamma and beta responses, and at higher oscillation frequencies, for isoluminant compared to luminance-modulated gratings. The results provide further evidence that the relationship between the fMRI-BOLD response and cortical neural activity is complex, with BOLD-fMRI being insensitive to substantial changes in neural activity. All stimuli were clearly visible to participants and so the paucity of gamma oscillations to isoluminant stimuli is inconsistent with theories of their role in conscious visual perception.

Visual gamma oscillations: the effects of stimulus type, visual field coverage and stimulus motion on MEG and EEG recordings.

Increases in the power of neural oscillations in the gamma (>40 Hz) band are a key signature of information processing in cortical neuronal networks. However, non-invasive detection of these very small oscillations is difficult due to the presence of potential artefacts (both muscular and ocular) in the same frequency band and requires highly optimised paradigms. Numerous studies have shown that the properties of visual gamma-band responses to simple pattern stimuli are highly tuned to the stimuli parameters used. The aim of this work was to compare gamma oscillation response properties across some of the more commonly used stimulus configurations. To do this, MEG and EEG recordings were made during the presentation of eight different stimulus types in a 2 × 2 × 2 design. For the first stimulus factor, "Type", the stimulus pattern was either an annulus grating or a square wave grating. For the second stimulus factor, "Field", stimuli were presented in either four visual field quadrants simultaneously or only in the lower left quadrant. Finally, for the "Move" factor, stimuli either drifted at 1.33°s(-1) or were stationary. For MEG gamma band responses, the following main effects were observed, a) gamma-band power was increased for annular stimuli compared to square wave stimuli, b) gamma-band power was increased for full field stimuli compared to single quadrant stimuli and c) gamma-band power was larger for drifting compared to stationary stimuli and were of significantly higher frequency. For the detectors used, the signal to noise ratio was substantially higher for MEG than EEG. The advantages and disadvantages of the different types of stimulus types are discussed.

The effects of elevated endogenous GABA levels on movement-related network oscillations.

The EEG/MEG signal is generated primarily by the summation of the post-synaptic potentials of cortical principal cells. At a microcircuit level, these glutamatergic principal cells are reciprocally connected to GABAergic interneurons and cortical oscillations are thought to be dependent on the balance of excitation and inhibition between these cell types. To investigate the dependence of movement-related cortical oscillations on excitation-inhibition balance, we pharmacologically manipulated the GABA system using tiagabine, which blocks GABA Transporter 1(GAT-1), the GABA uptake transporter and increases endogenous GABA activity. In a blinded, placebo-controlled, crossover design, in 15 healthy participants we administered either 15mg of tiagabine or a placebo. We recorded whole-head magnetoencephalograms, while the participants performed a movement task, prior to, one hour post, three hour post and five hour post tiagabine ingestion. Using time-frequency analysis of beamformer source reconstructions, we quantified the baseline level of beta activity (15-30Hz), the post-movement beta rebound (PMBR), beta event-related desynchronisation (beta-ERD) and movement-related gamma synchronisation (MRGS) (60-90Hz). Our results demonstrated that tiagabine, and hence elevated endogenous GABA levels causes, an elevation of baseline beta power, enhanced beta-ERD and reduced PMBR, but no modulation of MRGS. Comparing our results to recent literature (Hall et al., 2011) we suggest that beta-ERD may be a GABAA receptor mediated process while PMBR may be GABAB receptor mediated.

Spectral properties of induced and evoked gamma oscillations in human early visual cortex to moving and stationary stimuli.

In two experiments, magnetoencephalography (MEG) was used to investigate the effects of motion on gamma oscillations in human early visual cortex. When presented centrally, but not peripherally, stationary and moving gratings elicited several evoked and induced response components in early visual cortex. Time-frequency analysis revealed two nonphase locked gamma power increases-an initial, rapidly adapting response and one sustained throughout stimulus presentation and varying in frequency across observers from 28 to 64 Hz. Stimulus motion raised the sustained gamma oscillation frequency by a mean of approximately 10 Hz. The largest motion-induced frequency increases were in those observers with the lowest gamma response frequencies for stationary stimuli, suggesting a possible saturation mechanism. Moderate gamma amplitude increases to moving versus stationary stimuli were also observed but were not correlated with the magnitude of the frequency increase. At the same site in visual cortex, sustained alpha/beta power reductions and an onset evoked response were observed, but these effects did not change significantly with the presence of motion and did not correlate with the magnitude of gamma power changes. These findings suggest that early visual areas encode moving and stationary percepts via activity at higher and lower gamma frequencies, respectively.

Magnetoencephalographic correlates of processes supporting long-term memory judgments.

The sensitivity of event-related fields (ERFs) to memory retrieval processes is not well determined. This stands in sharp contrast to event-related potential (ERP) studies, as ERPs have been employed widely to address questions about the functional architecture supporting memory retrieval. Despite their success in this endeavour, however, the sensitivity of ERPs to one retrieval process-familiarity-is somewhat limited. This experiment was designed to determine the sensitivity of ERFs to familiarity, and thus to examine the functional leverage that is available to investigate item familiarity via magnetic means of indexing retrieval processing in real-time. The analyses of the ERF data focused on old/new effects, which are differences between the neural activities associated with old (previously studied) and new test items that attract correct memory judgments. The ERFs showed a level of sensitivity to changes in item familiarity superior to that reported previously in very similar studies where ERPs were acquired. Moreover, analyses of the ERF data revealed four functionally distinct old/new effects. These findings provide strong incentives for employing ERFs in subsequent studies of human memory retrieval processing operations.

Changes in rolandic mu rhythm during observation of a precision grip.

We recorded 128-channel EEG from 16 participants while they observed, imitated, and self-initiated the precision grip of a manipulandum. Mu rhythm amplitudes were significantly lower during observation of a precision grip than during observation of a simple hand extension without object interaction. Scalp topographies for subtractions of observation, imitation, and execution conditions from the control condition showed a high degree of congruence, supporting the notion of a human observation-execution matching system. Surface Laplacian transformations suggest that the decrease in mu amplitude during precision grip observation reflects desynchronization of mu rhythm generators in the sensorimotor cortex. These results support the hypothesis that sensorimotor cortex is a neural substrate involved in the representation of both self- and other-generated actions and show the mu rhythm is sensitive to subtle changes in observed motor behavior.

Neuromagnetic responses associated with perceptual segregation of pitch.

In recent EEG investigations [Johnson, 2003] [Hautus, 2005], we described a novel late negative ERP component associated with binaural processing of auditory pitch based solely on interaural timing differences ("dichotic pitch"), an acoustic phenomenon that is closely analogous to visual perception of stereoscopic depth based on retinal disparities. The present study extends this research with neuromagnetic recordings of auditory evoked fields (AEFs) elicited by dichotically-embedded pitches. Eight healthy adult subjects listened to control stimuli consisting of 500 ms segments of broadband acoustic noise presented identically to both ears via earphones, and dichotic pitch stimuli created by introducing a dichotic delay to a narrow frequency region of the same noise segments and resulting in a perception of a pitch lateralized to the left or right of auditory space. Auditory-evoked fields (AEFs) were recorded using a 151 channel whole-head MEG system. Comparison of control and dichotic-pitch AEFs showed reliable amplitude differences during a time window of 150-350 ms. AEFs over the left hemisphere showed larger effects for contralateral than ipsilateral pitches, while the right hemisphere showed no differences for differently lateralized sources. The results indicate a relatively late stage of neural processing of binaurally-derived cues for the perceptual segregation of concurrent sound sources and support a right-hemisphere dominance for the processing of sound-source localization.

Modulation of neuromagnetic oscillatory activity during the observation of oro-facial movements.

A number of MEG/EEG studies have shown modulation of endogenous sensorimotor (mu and beta) rhythms during the observation of hand movements. These modulations are similar to patterns that occur during execution of movement and it has been hypothesised that the neural substrates of these rhythms may play a role in action representation and understanding the actions of others. In this experiment we wished to determine whether similar responses would be obtained during the observation of oro-facial movements. Neuromagnetic recordings (151 channels, CTF Systems) were obtained from six healthy subjects while they (1) observed a video of an experimenter making oro-facial movements (2) imitated the same movements and (3) observed hand movements. Source scanning using synthetic aperture magnetometry (SAM) was used to find changes in source power between these active conditions compared to pre-stimulus control conditions where no movement occurred. SAM images were created with 5 mm resolution in the beta (15-35 Hz) and mu (8-15 Hz) bands and showed source power decreases over parietal, occipital and sensorimotor areas. Time-frequency analysis of virtual SAM sensors from sensorimotor areas showed event-related desynchronisation of mu and beta bands following the onset of movement in all three conditions. These data demonstrate comparable activations of visuomotor mechanisms during observation or imitation of mouth movements and during observation of hand movements. These results support the notion that sensorimotor mechanisms play a role in achieving a representation of the oro-facial gestures of others.