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Magnetoencephalography (MEG), a direct measure of neuronal activity, is an underexplored tool in the search for biomarkers of Alzheimer's disease (AD). In this study, we used MEG source estimates of auditory gating generators, nonlinear correlations with neuropsychological results, and multivariate analyses to examine the sensitivity and specificity of gating topology modulation to detect AD. Our results demonstrated the use of MEG localization of a medial prefrontal (mPFC) gating generator as a discrete (binary) detector of AD at the individual level and resulted in recategorizing the participant categories in: (1) controls with mPFC generator localized in response to both the standard and deviant tones; (2) a possible preclinical stage of AD participants (a lower functioning group of controls) in which mPFC activation was localized to the deviant tone only; and (3) symptomatic AD in which mPFC activation was not localized to either the deviant or standard tones. This approach showed a large effect size (0.9) and high accuracy, sensitivity, and specificity (100%) in identifying symptomatic AD patients within a limited research sample. The present results demonstrate high potential of mPFC activation as a noninvasive biomarker of AD pathology during putative preclinical and clinical stages. Hum Brain Mapp 38:5180-5194, 2017. © 2017 Wiley Periodicals, Inc., (© 2017 Wiley Periodicals, Inc.)

Communication sounds are typically asymmetric in time and human listeners are highly sensitive to this short-term temporal asymmetry. Nevertheless, causal neurophysiological correlates of auditory perceptual asymmetry remain largely elusive to our current analyses and models. Auditory modelling and animal electrophysiological recordings suggest that perceptual asymmetry results from the presence of multiple time scales of temporal integration, central to the auditory periphery. To test this hypothesis we recorded auditory evoked fields (AEF) elicited by asymmetric sounds in humans. We found a strong correlation between perceived tonal salience of ramped and damped sinusoids and the AEFs, as quantified by the amplitude of the N100m dynamics. The N100m amplitude increased with stimulus half-life time, showing a maximum difference between the ramped and damped stimulus for a modulation half-life time of 4 ms which is greatly reduced at 0.5 ms and 32 ms. This behaviour of the N100m closely parallels psychophysical data in a manner that: i) longer half-life times are associated with a stronger tonal percept, and ii) perceptual differences between damped and ramped are maximal at 4 ms half-life time. Interestingly, differences in evoked fields were significantly stronger in the right hemisphere, indicating some degree of hemispheric specialisation. Furthermore, the N100m magnitude was successfully explained by a pitch perception model using multiple scales of temporal integration of auditory nerve activity patterns. This striking correlation between AEFs, perception, and model predictions suggests that the physiological mechanisms involved in the processing of pitch evoked by temporal asymmetric sounds are reflected in the N100m.

The present work aims to investigate the electroencephalographic (EEG) activity elicited by the observation of emotional pictures selected from the International Affective Picture System (IAPS) database. We analyzed the evoked activity within time intervals of increasing duration taking into account the related ratings of Valence and Arousal. The scalp statistical maps of Power Spectral Density (PSD), related to pictures with high valence, revealed an enhanced activity across frontal areas in the theta band and the involvement of fronto-parietal circuits in the alpha band. Difference in the processing of low and high arousing pictures, however, seems to be highly dependent on the valence dimension: for low valenced pictures, the difference in arousal was processed immediately after the observation of the picture, while for the high-valenced ones the processing took part in the second part of the observation. These results appear to be congruent with the literature, while the novelty of the current study is represented by the comparison of the activity elicited in different time windows by both the Arousal and Valence dimensions. It is possible, in this way, to observe how the processing of one variable influences the other, creating a dynamic description of the Valence-Arousal space.

Previous studies have reported a visual analogue of the auditory mismatch negativity (MMN) response that is based on sensory memory. The neural generators and attention dependence of the visual MMN (vMMN) still remain unclear. We used magnetoencephalography (MEG) and spatio-temporal source localization to determine the generators of the sensory-memory-based vMMN response to non-attended deviants. Ten participants were asked to discriminate between odd and even digits presented at the center of the visual field while grating patterns with different spatial frequencies were presented outside the focus of attention. vMMN was calculated as the difference between MEG responses to infrequent gratings in oddball blocks and the same gratings in equiprobable blocks. The peak latency of the vMMN response was between 100 and 160 ms. The neuromagnetic sources of the vMMN localized in the occipital cortex differed from the sources evoked by the equiprobable gratings and were stimulus-dependent. Our results suggest the existence of separate neural systems for pre-attentive memory-based detection of visual change and provide new evidence that the vMMN is feature-specific.

The amplitude variability of the M50 component of neuromagnetic responses is commonly used to explore the brain's ability to modulate its response to incoming repetitive or novel auditory stimuli, a process conceptualized as a gating mechanism. The goal of this study was to identify the spatial and temporal characteristics of the cortical sources underlying the M50 network evoked by tones in a passive oddball paradigm. Twenty elderly subjects [10 patients diagnosed with mild cognitive impairment (MCI) or probable Alzheimer disease (AD) and 10 age-matched controls] were examined using magnetoencephalographic (MEG) recordings and the multi-dipole Calibrated Start Spatio-Temporal (CSST) source localization method. We identified three cortical regions underlying the M50 network: prefrontal cortex (PF) in addition to bilateral activation of the superior temporal gyrus (STG). The cortical dynamics of the PF source within the 30-100 ms post-stimulus interval was characterized and was found to be comprised of two subcomponents, Mb1c and Mb2c. The PF source was localized for 10/10 healthy subjects, whereas 9/10 MCI/AD patients were lacking the PF source for both tone conditions. The selective activation of the PF source in healthy controls along with the inactivation of the PF region for MCI/AD patients, enabled us to examine the dynamics of this network of activity when it was functional and dysfunctional, respectively. We found significantly enhanced activity of the STG sources in response to both tone conditions for all subjects who lacked a PF source. The reported results provide novel insights into the topology and neurodynamics of the M50 auditory network, which suggest an inhibitory role of the PF source that normally suppresses activity of the STG sources., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Proportional reasoning is very important logical skill required in mathematics and science problem solving as well as in everyday life decisions. However, there is a lack of studies on neurophysiological correlates of proportional reasoning. To explore the brain activity of healthy adults while performing a balance scale task, we used high-resolution EEG techniques and graph-theory based connectivity analysis. After unskilled subjects learned how to properly solve the task, their cortical power spectral density (PSD) maps revealed an increased parietal activity in the beta band. This indicated that subjects started to perform calculations. In addition, the number of inter-hemispheric connections decreased after learning, implying a rearrangement of the brain activity. Repeated performance of the task led to the PSD decrease in the beta and gamma bands among parietal and frontal regions along with a synchronization of lower frequencies. These findings suggest that repetition led to a more automatic task performance. Subjects were also divided in two groups according to their scores on the test of logical thinking (TOLT). Although no group differences in the accuracy and reaction times were found, EEG data showed higher activity in the beta and gamma bands for the group that scored better on TOLT. Learning and repetition induced changes in the pattern of functional connectivity were evident for all frequency bands. Overall, the results indicated that higher frequency oscillations in frontal and parietal regions are particularly important for proportional reasoning.

While the relationship between sensory stimulation and tasks and the size of the cortical activations is generally unknown, the visual modality offers a unique possibility of an experimental manipulation of stimulus size-related increases of the spatial extent of cortical activation even during the earliest activity in the retinotopically organized primary visual cortex. We used magnetoecephalography (MEG), visual stimuli of increasing size, and numerical simulations on realistic cortical surfaces to explore the effects of increasing spatial extent of the activated cortical sources on the neuromagnetic fields, location estimation biases, and source resolution. Source localization was performed assuming multiple dipoles in a sphere model using an efficient, automatically restarted multi-start simplex minimizer within the Calibrated Start Spatio-Temporal (CSST) algorithm. We found size-related effects on amplitude and latencies and differences in relative locations of the earliest occipital sources evoked by stimuli of increasing size presented at the same eccentricity. This finding was confirmed by single patch simulations. Additionally, simulations of multiple extended sources demonstrated size-related increase in limits in source resolution for bilaterally simulated sources, biases in location estimates for a given separation of sources, and limits in source resolution due to source multiplicity within a hemisphere.

Previous neuroimaging studies have shown that complex visual stimuli, such as faces, activate multiple brain regions, yet little is known on the dynamics and complexity of the activated cortical networks during the entire measurable evoked response. In this study, we used simulated and face-evoked empirical MEG data from an oddball study to investigate the feasibility of accurate, efficient, and reliable spatio-temporal tracking of cortical pathways over prolonged time intervals. We applied a data-driven, semiautomated approach to spatio-temporal source localization with no prior assumptions on active cortical regions to explore non-invasively face-processing dynamics and their modulation by task. Simulations demonstrated that the use of multi-start downhill simplex and data-driven selections of time intervals submitted to the Calibrated Start Spatio-Temporal (CSST) algorithm resulted in improved accuracy of the source localization and the estimation of the onset of their activity. Locations and dynamics of the identified sources indicated a distributed cortical network involved in face processing whose complexity was task dependent. This MEG study provided the first non-invasive demonstration, agreeing with intracranial recordings, of an early onset of the activity in the fusiform face gyrus (FFG), and that frontal activation preceded parietal for responses elicited by target faces.

Face-related processing has been demonstrated already in the early evoked response around 100 ms after stimulus. The aims of this study were to explore these early responses both at sensor and cortical source level and to explore to what extent they might be modulated by a change in face stimulus. Magnetoencephalographic (MEG) recordings, a visual oddball paradigm, and a semiautomated spatiotemporal source localization method were used to investigate cortical responses to changes in face stimuli. Upright and inverted faces were presented in an oddball paradigm with four conditions; standards and deviants differing in emotion or identity. The task in all conditions was silent counting of the target face with glasses. Deviant face stimuli elicited larger MEG responses at about 100 ms than standard ones did but only for upright faces. Spatiotemporal source localization up to 140 ms after stimulus revealed activation of parietal and temporal sources in addition to occipital ones, all of which demonstrated differences in locations and dynamics for standards, deviants, and targets. Peak latencies of the identified cortical sources were shorter for deviants than standards, again only for upright faces. Our results showed differences in cortical responses to standards and deviants that were more pronounced for upright than for inverted faces, suggesting early detection of face-related changes in visual stimulation. The observed effect provides new evidence for the face sensitivity of the early neuromagnetic response around 100 ms., (Copyright 2010 Elsevier B.V. All rights reserved.)

The early dissociation in cortical responses to faces and objects was explored with magnetoencephalographic (MEG) recordings and source localization. To control for differences in the low-level stimulus features, which are known to modulate early brain responses, we created a novel set of stimuli so that their combinations did not have any differences in the visual-field location, spatial frequency, or luminance contrast. Differing responses to face and object (flower) stimuli were found at about 100 ms after stimulus onset in the occipital cortex. Our data also confirm that the brain response to a complex visual stimulus is not merely a sum of the responses to its constituent parts; the nonlinearity in the response was largest for meaningful stimuli.

We present the four key areas of research-preprocessing, the volume conductor, the forward problem, and the inverse problem-that affect the performance of EEG and MEG source imaging. In each key area we identify prominent approaches and methodologies that have open issues warranting further investigation within the community, challenges associated with certain techniques, and algorithms necessitating clarification of their implications. More than providing definitive answers we aim to identify important open issues in the quest of source localization.

The detection of a change in a face stimulus was studied in an oddball paradigm. Event-related potentials (ERPs) and MEG responses to face stimuli were recorded in four conditions: 1) happy standard, neutral deviant; 2) neutral standard, neutral deviant; 3) inverted happy standard, inverted neutral deviant; 4) inverted neutral standard, inverted neutral deviant. In all conditions, the target was a face with glasses. Neutral deviants elicited a negative deflection (with a maximum around 280 ms) in ERP and MEG responses, an effect similar to auditory mismatch negativity. Face inversion diminished deviance-related negativity, implying an important role of face recognition in the observed effect. Emotional content and larger physical differences between stimuli in conditions 1 and 3 compared to conditions 2 and 4 did not show statistically significant effect on the neutral-deviant-related negativity.

A MUItiple SIgnal Classification-based (MUSIC) approach for neuromagnetic multi-source localization (Mosher et al. [1992] (IEEE Trans Med Eng BME-39:541-557) was evaluated through numerical simulations and by applying it to visually evoked neuromagnetic responses. A series of two-dipole and three-dipole spatio-temporal data were generated to examine effects of 1) source configurations, 2) temporal correlations, 3) noise, and 4) subspace dimensionality assumptions on the number of MUSIC metric maxima, their amplitudes, and how the resulting metric maxima locations relate to the actual source locations. In its present form, i.e., using simple one-dipole scanning over an assumed source subspace, MUSIC resulted either in 1) peaks sufficiently close to 1, but fewer than the actual number of sources which affected location estimation accuracy, or 2) the peaks were too low to qualify as source locations. Our simulations indicate difficulties in defining threshold values as to which peak values are close enough to 1 while avoiding significant type II errors (i.e., accepting peaks which should not be interpreted as source locations). Modifications to the MUSIC approach are necessary in order for the method to be considered of practical value for reliably localizing multiple neuromagnetic sources in empirical cases in which a high degree of temporal correlation between sources is likely (e.g., visual data)., (Copyright (c) 1997 Wiley-Liss, Inc.)

Numerical simulations were conducted to examine multi-source spatio-temporal resolution for neuromagnetic field distributions "measured" by a large sensor array (i.e., 135). spatio-temporal field distributions were generated by a series of two-dipole and three-dipole configurations in which source locations, orientations, and temporal dynamics of individual sources were systematically varied to represent classes of cases of interest for neuromagnetic studies. The specific goals of our numerical simulations were to examine multi-source resolution and parameter estimation accuracy as a function of 1) specific multi-source configurations; 2) different time courses, i.e., degree of temporal correlation; 3) measurement noise; 4) spatio-temporal modeling strategy (i.e., sequential fitting of instantaneous field distributions, two-step spatio-temporal modeling); 5) source modeling assumptions associated with model order; and 6) effects of initial modeling assumptions (i.e., starting points for the nonlinear minimization procedure derived by MUltiple SIgnal Classification (MUSIC), sequential instantaneous fitting, and arbitrary selections). The ability to determine the number of active sources by different approaches is compared, and the consequences on the accuracy of estimated solutions for simulated data are discussed. In all cases, model adequacy was assessed using reduced chi-square as a measure of goodness-of-fit. The present simulations demonstrate that location estimation was more robust and accurate compared to the estimation of temporal dynamics of individual sources. Implications for spatio-temporal modeling of neuromagnetic empirical data are suggested., (Copyright (c) 1997 Wiley-Liss, Inc.)