Search

Mathematical modeling of the relationship between the functional activity and the structural wiring of the brain has largely been undertaken using non-linear and biophysically detailed mathematical models with regionally varying parameters. While this approach provides us a rich repertoire of multistable dynamics that can be displayed by the brain, it is computationally demanding. Moreover, although neuronal dynamics at the microscopic level are nonlinear and chaotic, it is unclear if such detailed nonlinear models are required to capture the emergent meso-(regional population ensemble) and macro-scale (whole brain) behavior, which is largely deterministic and reproducible across individuals. Indeed, recent modeling effort based on spectral graph theory has shown that an analytical model without regionally varying parameters and without multistable dynamics can capture the empirical magnetoencephalography frequency spectra and the spatial patterns of the alpha and beta frequency bands accurately. In this work, we demonstrate an improved hierarchical, linearized, and analytic spectral graph theory-based model that can capture the frequency spectra obtained from magnetoencephalography recordings of resting healthy subjects. We reformulated the spectral graph theory model in line with classical neural mass models, therefore providing more biologically interpretable parameters, especially at the local scale. We demonstrated that this model performs better than the original model when comparing the spectral correlation of modeled frequency spectra and that obtained from the magnetoencephalography recordings. This model also performs equally well in predicting the spatial patterns of the empirical alpha and beta frequency bands.

IntroductionNeurophysiological manifestations selectively associated with amyloid beta and tau depositions in Alzheimer's disease (AD) are useful network biomarkers to identify peptide specific pathological processes. The objective of this study was to validate the associations between reduced neuronal synchrony within alpha oscillations and neurofibrillary tangle (NFT) density in autopsy examination, in patients with AD.MethodsIn a well-characterized clinicopathological cohort of AD patients (n = 13), we quantified neuronal synchrony within alpha (8-12 Hz) and delta-theta (2-8 Hz) oscillations, using magnetoencephalography during the disease course, within six selected neocortical and hippocampal regions, including angular gyrus, superior temporal gurus, middle frontal gyrus, primary motor cortex, CA1, and subiculum, and correlated these with regional NFT density quantified at histopathological examination.ResultsAbnormal synchrony in alpha, but not in delta-theta, significantly predicted the NFT density at post mortem neuropathological examination.DiscussionReduced alpha synchrony is a sensitive neurophysiological index associated with pathological tau, and a potential network biomarker for clinical trials, to gauge the extent of network dysfunction and the degree of rescue in treatments targeting tau pathways in AD.

Semantic representations are processed along a posterior-to-anterior gradient reflecting a shift from perceptual (e.g., it has eight legs) to conceptual (e.g., venomous spiders are rare) information. One critical region is the anterior temporal lobe (ATL): patients with semantic variant primary progressive aphasia (svPPA), a clinical syndrome associated with ATL neurodegeneration, manifest a deep loss of semantic knowledge. We test the hypothesis that svPPA patients perform semantic tasks by over-recruiting areas implicated in perceptual processing. We compared MEG recordings of svPPA patients and healthy controls during a categorization task. While behavioral performance did not differ, svPPA patients showed indications of greater activation over bilateral occipital cortices and superior temporal gyrus, and inconsistent engagement of frontal regions. These findings suggest a pervasive reorganization of brain networks in response to ATL neurodegeneration: the loss of this critical hub leads to a dysregulated (semantic) control system, and defective semantic representations are seemingly compensated via enhanced perceptual processing.

Combat-related mild traumatic brain injury (cmTBI) is a leading cause of sustained physical, cognitive, emotional, and behavioral disabilities in Veterans and active-duty military personnel. Accurate diagnosis of cmTBI is challenging since the symptom spectrum is broad and conventional neuroimaging techniques are insensitive to the underlying neuropathology. The present study developed a novel deep-learning neural network method, 3D-MEGNET, and applied it to resting-state magnetoencephalography (rs-MEG) source-magnitude imaging data from 59 symptomatic cmTBI individuals and 42 combat-deployed healthy controls (HCs). Analytic models of individual frequency bands and all bands together were tested. The All-frequency model, which combined delta-theta (1-7 Hz), alpha (8-12 Hz), beta (15-30 Hz), and gamma (30-80 Hz) frequency bands, outperformed models based on individual bands. The optimized 3D-MEGNET method distinguished cmTBI individuals from HCs with excellent sensitivity (99.9 ± 0.38%) and specificity (98.9 ± 1.54%). Receiver-operator-characteristic curve analysis showed that diagnostic accuracy was 0.99. The gamma and delta-theta band models outperformed alpha and beta band models. Among cmTBI individuals, but not controls, hyper delta-theta and gamma-band activity correlated with lower performance on neuropsychological tests, whereas hypo alpha and beta-band activity also correlated with lower neuropsychological test performance. This study provides an integrated framework for condensing large source-imaging variable sets into optimal combinations of regions and frequencies with high diagnostic accuracy and cognitive relevance in cmTBI. The all-frequency model offered more discriminative power than each frequency-band model alone. This approach offers an effective path for optimal characterization of behaviorally relevant neuroimaging features in neurological and psychiatric disorders.

ObjectiveGliomas are intrinsic brain tumors with the hallmark of diffuse white matter infiltration, resulting in short- and long-range network dysfunction. Preoperative magnetoencephalography (MEG) can assist in maximizing the extent of resection while minimizing morbidity. While MEG has been validated in motor mapping, its role in speech mapping remains less well studied. The authors assessed how the resection of intraoperative electrical stimulation (IES)-negative, high functional connectivity (HFC) network sites, as identified by MEG, impacts language performance.MethodsResting-state, whole-brain MEG recordings were obtained from 26 patients who underwent perioperative language evaluation and glioma resection that was guided by awake language and IES mapping. The functional connectivity of an individual voxel was determined by the imaginary coherence between the index voxel and the rest of the brain, referenced to its contralesional pair. The percentage of resected HFC voxels was correlated with postoperative language outcomes in tasks of increasing complexity: text reading, 4-syllable repetition, picture naming, syntax (SYN), and auditory stimulus naming (AN).ResultsOverall, 70% of patients (14/20) in whom any HFC tissue was resected developed an early postoperative language deficit (mean 2.3 days, range 1-8 days), compared to 33% of patients (2/6) in whom no HFC tissue was resected (p = 0.16). When bifurcated by the amount of HFC tissue that was resected, 100% of patients (3/3) with an HFC resection > 25% displayed deficits in AN, compared to 30% of patients (6/20) with an HFC resection < 25% (p = 0.04). Furthermore, there was a linear correlation between the severity of AN and SYN decline with percentage of HFC sites resected (p = 0.02 and p = 0.04, respectively). By 2.2 months postoperatively (range 1-6 months), the correlation between HFC resection and both AN and SYN decline had resolved (p = 0.94 and p = 1.00, respectively) in all patients (9/9) except two who experienced early postoperative tumor progression or stroke involving inferior frontooccipital fasciculus.ConclusionsImaginary coherence measures of functional connectivity using MEG are able to identify HFC network sites within and around low- and high-grade gliomas. Removal of IES-negative HFC sites results in early transient postoperative decline in AN and SYN, which resolved by 3 months in all patients without stroke or early tumor progression. Measures of functional connectivity may therefore be a useful means of counseling patients about postoperative risk and assist with preoperative surgical planning.

ObjectivesAuditory cortical activation of the two hemispheres to monaurally presented tonal stimuli has been shown to be asynchronous in normal hearing (NH) but synchronous in the extreme case of adult-onset asymmetric hearing loss (AHL) with single-sided deafness. We addressed the wide knowledge gap between these two anchoring states of interhemispheric temporal organization. The objectives of this study were as follows: (1) to map the trajectory of interhemispheric temporal reorganization from asynchrony to synchrony using magnitude of interaural threshold difference as the independent variable in a cross-sectional study and (2) to evaluate reversibility of interhemispheric synchrony in association with hearing in noise performance by amplifying the aidable poorer ear in a repeated measures, longitudinal study.DesignThe cross-sectional and longitudinal cohorts were comprised of 49 subjects (AHL; N = 21; 11 male, 10 female; mean age = 48 years) and NH (N = 28; 16 male, 12 female; mean age = 45 years). The maximum interaural threshold difference of the two cohorts spanned from 0 to 65 dB. Magnetoencephalography analyses focused on latency of the M100 peak response from auditory cortex in both hemispheres between 50 msec and 150 msec following monaural tonal stimulation at the frequency (0.5, 1, 2, 3, or 4 kHz) corresponding to the maximum and minimum interaural threshold difference for better and poorer ears separately. The longitudinal AHL cohort was drawn from three subjects in the cross-sectional AHL cohort (all male; ages 49 to 60 years; varied AHL etiologies; no amplification for at least 2 years). All longitudinal study subjects were treated by monaural amplification of the poorer ear and underwent repeated measures examination of the M100 response latency and quick speech in noise hearing in noise performance at baseline, and postamplification months 3, 6, and 12.ResultsThe M100 response peak latency values in the ipsilateral hemisphere lagged those in the contralateral hemisphere for all stimulation conditions. The mean (SD) interhemispheric latency difference values (ipsilateral less contralateral) to better ear stimulation for three categories of maximum interaural threshold difference were as follows: NH (≤ 10 dB)-8.6 (3.0) msec; AHL (15 to 40 dB)-3.0 (1.2) msec; AHL (≥ 45 dB)-1.4 (1.3) msec. In turn, the magnitude of difference values were used to define interhemispheric temporal organization states of asynchrony, mixed asynchrony and synchrony, and synchrony, respectively. Amplification of the poorer ear in longitudinal subjects drove interhemispheric organization change from baseline synchrony to postamplification asynchrony and hearing in noise performance improvement in those with baseline impairment over a 12-month period.ConclusionsInterhemispheric temporal organization in AHL was anchored between states of asynchrony in NH and synchrony in single-sided deafness. For asymmetry magnitudes between 15 and 40 dB, the intermediate mixed state of asynchrony and synchrony was continuous and reversible. Amplification of the poorer ear in AHL improved hearing in noise performance and restored normal temporal organization of auditory cortices in the two hemispheres. The return to normal interhemispheric asynchrony from baseline synchrony and improvement in hearing following monoaural amplification of the poorer ear evolved progressively over a 12-month period.

Semantic representations are processed along a posterior-to-anterior gradient reflecting a shift from perceptual (e.g., it has eight legs) to conceptual (e.g., venomous spiders are rare) information. One critical region is the anterior temporal lobe (ATL): patients with semantic variant primary progressive aphasia (svPPA), a clinical syndrome associated with ATL neurodegeneration, manifest a deep loss of semantic knowledge. We test the hypothesis that svPPA patients perform semantic tasks by over-recruiting areas implicated in perceptual processing. We compared MEG recordings of svPPA patients and healthy controls during a categorization task. While behavioral performance did not differ, svPPA patients showed indications of greater activation over bilateral occipital cortices and superior temporal gyrus, and inconsistent engagement of frontal regions. These findings suggest a pervasive reorganization of brain networks in response to ATL neurodegeneration: the loss of this critical hub leads to a dysregulated (semantic) control system, and defective semantic representations are seemingly compensated via enhanced perceptual processing.

Theta-band (∼6 Hz) rhythmic activity within and over the medial PFC ("midfrontal theta") has been identified as a distinctive signature of "response conflict," the competition between multiple actions when only one action is goal-relevant. Midfrontal theta is traditionally conceptualized and analyzed under the assumption that it is a unitary signature of conflict that can be uniquely identified at one electrode (typically FCz). Here we recorded simultaneous MEG and EEG (total of 328 sensors) in 9 human subjects (7 female) and applied a feature-guided multivariate source-separation decomposition to determine whether conflict-related midfrontal theta is a unitary or multidimensional feature of the data. For each subject, a generalized eigendecomposition yielded spatial filters (components) that maximized the ratio between theta and broadband activity. Components were retained based on significance thresholding and midfrontal EEG topography. All of the subjects individually exhibited multiple (mean 5.89, SD 2.47) midfrontal components that contributed to sensor-level midfrontal theta power during the task. Component signals were temporally uncorrelated and asynchronous, suggesting that each midfrontal theta component was unique. Our findings call into question the dominant notion that midfrontal theta represents a unitary process. Instead, we suggest that midfrontal theta spans a multidimensional space, indicating multiple origins, but can manifest as a single feature at the sensor level because of signal mixing.SIGNIFICANCE STATEMENT "Midfrontal theta" is a rhythmic electrophysiological signature of the competition between multiple response options. Midfrontal theta is traditionally considered to reflect a single process. However, this assumption could be erroneous because of "mixing" (multiple sources contributing to the activity recorded at a single electrode). We investigated the dimensionality of midfrontal theta by applying advanced multivariate analysis methods to a multimodal MEG/EEG dataset. We identified multiple topographically overlapping neural sources that drove response conflict-related midfrontal theta. Midfrontal theta thus reflects multiple uncorrelated signals that manifest with similar EEG scalp projections. In addition to contributing to the cognitive control literature, we demonstrate both the feasibility and the necessity of signal demixing to understand the narrowband neural dynamics underlying cognitive processes.

Reading aloud requires mapping an orthographic form to a phonological one. The mapping process relies on sublexical statistical regularities (e.g. 'oo' to |uː|) or on learned lexical associations between a specific visual form and a series of sounds (e.g. yacht to/jɑt/). Computational, neuroimaging, and neuropsychological evidence suggest that sublexical, phonological and lexico-semantic processes rely on partially distinct neural substrates: a dorsal (occipito-parietal) and a ventral (occipito-temporal) route, respectively. Here, we investigated the spatiotemporal features of orthography-to-phonology mapping, capitalizing on the time resolution of magnetoencephalography and the unique clinical model offered by patients with semantic variant of primary progressive aphasia (svPPA). Behaviourally, patients with svPPA manifest marked lexico-semantic impairments including difficulties in reading words with exceptional orthographic to phonological correspondence (irregular words). Moreover, they present with focal neurodegeneration in the anterior temporal lobe, affecting primarily the ventral, occipito-temporal, lexical route. Therefore, this clinical population allows for testing of specific hypotheses on the neural implementation of the dual-route model for reading, such as whether damage to one route can be compensated by over-reliance on the other. To this end, we reconstructed and analysed time-resolved whole-brain activity in 12 svPPA patients and 12 healthy age-matched control subjects while reading irregular words (e.g. yacht) and pseudowords (e.g. pook). Consistent with previous findings that the dorsal route is involved in sublexical, phonological processes, in control participants we observed enhanced neural activity over dorsal occipito-parietal cortices for pseudowords, when compared to irregular words. This activation was manifested in the beta-band (12-30 Hz), ramping up slowly over 500 ms after stimulus onset and peaking at ∼800 ms, around response selection and production. Consistent with our prediction, svPPA patients did not exhibit this temporal pattern of neural activity observed in controls this contrast. Furthermore, a direct comparison of neural activity between patients and controls revealed a dorsal spatiotemporal cluster during irregular word reading. These findings suggest that the sublexical/phonological route is involved in processing both irregular and pseudowords in svPPA. Together these results provide further evidence supporting a dual-route model for reading aloud mediated by the interplay between lexico-semantic and sublexical/phonological neurocognitive systems. When the ventral route is damaged, as in the case of neurodegeneration affecting the anterior temporal lobe, partial compensation appears to be possible by over-recruitment of the slower, serial attention-dependent, dorsal one.

The relationship between the brain's structural wiring and the functional patterns of neural activity is of fundamental interest in computational neuroscience. We examine a hierarchical, linear graph spectral model of brain activity at mesoscopic and macroscopic scales. The model formulation yields an elegant closed-form solution for the structure-function problem, specified by the graph spectrum of the structural connectome's Laplacian, with simple, universal rules of dynamics specified by a minimal set of global parameters. The resulting parsimonious and analytical solution stands in contrast to complex numerical simulations of high dimensional coupled nonlinear neural field models. This spectral graph model accurately predicts spatial and spectral features of neural oscillatory activity across the brain and was successful in simultaneously reproducing empirically observed spatial and spectral patterns of alpha-band (8-12 Hz) and beta-band (15-30 Hz) activity estimated from source localized magnetoencephalography (MEG). This spectral graph model demonstrates that certain brain oscillations are emergent properties of the graph structure of the structural connectome and provides important insights towards understanding the fundamental relationship between network topology and macroscopic whole-brain dynamics. .

This study examined global resting-state functional connectivity of neural oscillations in individuals with chronic tinnitus and normal and impaired hearing. We tested the hypothesis that distinct neural oscillatory networks are engaged in tinnitus with and without hearing loss. In both tinnitus groups, with and without hearing loss, we identified multiple frequency band-dependent regions of increased and decreased global functional connectivity. We also found that the auditory domain of tinnitus severity, assayed by the Tinnitus Functional Index, was associated with global functional connectivity in both auditory and nonauditory regions. These findings provide candidate biomarkers to target and monitor treatments for tinnitus with and without hearing loss.

Auditory working memory impairments feature prominently in schizophrenia. However, the existence of altered and perhaps compensatory neural dynamics, sub-serving auditory working memory, remains largely unexplored. We compared the dynamics of induced high gamma power (iHGP) across cortex in humans during speech-sound working memory in individuals with schizophrenia (SZ) and healthy comparison subjects (HC) using magnetoencephalography (MEG). SZ showed similar task performance to HC while utilizing different brain regions. During encoding of speech sounds, SZ lacked the correlation of iHGP with task performance in posterior superior temporal gyrus (STGp) that was observed in healthy subjects. Instead, SZ recruited the visual word form area (VWFA) during both stimulus encoding and response preparation. Importantly, VWFA activity during encoding correlated with the magnitude of SZ hallucinations, task performance and an independent measure of verbal working memory. These findings suggest that VWFA plasticity is harnessed to compensate for STGp dysfunction in schizophrenia patients with hallucinations.

Combat-related mild traumatic brain injury (mTBI) is a leading cause of sustained impairments in military service members and veterans. Recent animal studies show that GABA-ergic parvalbumin-positive interneurons are susceptible to brain injury, with damage causing abnormal increases in spontaneous gamma-band (30-80 Hz) activity. We investigated spontaneous gamma activity in individuals with mTBI using high-resolution resting-state magnetoencephalography source imaging. Participants included 25 symptomatic individuals with chronic combat-related blast mTBI and 35 healthy controls with similar combat experiences. Compared with controls, gamma activity was markedly elevated in mTBI participants throughout frontal, parietal, temporal, and occipital cortices, whereas gamma activity was reduced in ventromedial prefrontal cortex. Across groups, greater gamma activity correlated with poorer performances on tests of executive functioning and visuospatial processing. Many neurocognitive associations, however, were partly driven by the higher incidence of mTBI participants with both higher gamma activity and poorer cognition, suggesting that expansive upregulation of gamma has negative repercussions for cognition particularly in mTBI. This is the first human study to demonstrate abnormal resting-state gamma activity in mTBI. These novel findings suggest the possibility that abnormal gamma activities may be a proxy for GABA-ergic interneuron dysfunction and a promising neuroimaging marker of insidious mild head injuries.

Schizophrenia is a neurocognitive illness characterized by behavioral and neural impairments in both early auditory processing and higher order verbal working memory. Previously we have shown intervention-specific cognitive performance improvements with computerized, targeted training of auditory processing (AT) when compared to a computer games (CG) control intervention that emphasized visual processing. To investigate spatiotemporal changes in patterns of neural activity specific to the AT intervention, the current study used magnetoencephalography (MEG) imaging to derive induced high gamma band oscillations (HGO) during auditory encoding, before and after 50 h (∼10 weeks) of exposure to either the AT or CG intervention. During stimulus encoding, AT intervention-specific changes in high gamma activity occurred in left middle frontal and left middle-superior temporal cortices. In contrast, CG intervention-specific changes were observed in right medial frontal and supramarginal gyri during stimulus encoding, and in bilateral temporal cortices during response preparation. These data reveal that, in schizophrenia, intensive exposure to either training of auditory processing or exposure to visuospatial activities produces significant but complementary patterns of cortical function plasticity within a distributed fronto-temporal network. These results underscore the importance of delineating the specific neuroplastic effects of targeted behavioral interventions to ensure desired neurophysiological changes and avoid unintended consequences on neural system functioning.

In patients with medically refractory epilepsy, resective surgery is the mainstay of therapy to achieve seizure freedom. However, ∼20-50% of cases have intractable seizures post-surgery due to the imprecise determination of epileptogenic zone. Recent intracranial studies suggest that high frequency oscillations between 80 and 200 Hz could serve as one of the consistent epileptogenicity biomarkers for localization of the epileptogenic zone. However, these high frequency oscillations are not adopted in the clinical setting because of difficult non-invasive detection. Here, we investigated non-invasive detection and localization of high frequency oscillations and its clinical utility in accurate pre-surgical assessment and post-surgical outcome prediction. We prospectively recruited 52 patients with medically refractory epilepsy who underwent standard pre-surgical workup including magnetoencephalography (MEG) followed by resective surgery after determination of the epileptogenic zone. The post-surgical outcome was assessed after 22.14 ± 10.05 months. Interictal epileptic spikes were expertly identified, and interictal epileptic oscillations across the neural activity frequency spectrum from 8 to 200 Hz were localized using adaptive spatial filtering methods. Localization results were compared with epileptogenic zone and resected cortex for congruence assessment and validated against the clinical outcome. The concordance rate of high frequency oscillations sources (80-200 Hz) with the presumed epileptogenic zone and the resected cortex were 75.0% and 78.8%, respectively, which is superior to that of other frequency bands and standard dipole fitting methods. High frequency oscillation sources corresponding with the resected cortex, had the best sensitivity of 78.0%, positive predictive value of 100% and an accuracy of 78.84% to predict the patient's surgical outcome, among all other frequency bands. If high frequency oscillation sources were spatially congruent with resected cortex, patients had an odds ratio of 5.67 and 82.4% probability of achieving a favourable surgical outcome. If high frequency oscillations sources were discordant with the epileptogenic zone or resection area, patient has an odds ratio of 0.18 and only 14.3% probability of achieving good outcome, and mostly tended to have an unfavourable outcome (χ2 = 5.22; P = 0.02; φ = -0.317). In receiver operating characteristic curve analyses, only sources of high-frequency oscillations demonstrated the best sensitivity and specificity profile in determining the patient's surgical outcome with area under the curve of 0.76, whereas other frequency bands indicate a poor predictive performance. Our study is the first non-invasive study to detect high frequency oscillations, address the efficacy of high frequency oscillations over the different neural oscillatory frequencies, localize them and clinically validate them with the post-surgical outcome in patients with medically refractory epilepsy. The evidence presented in the current study supports the fact that HFOs might significantly improve the presurgical assessment, and post-surgical outcome prediction, where it could widely be used in a clinical setting as a non-invasive biomarker.

Motor cortical beta activity (13-30 Hz) is a hallmark signature of healthy and pathological movement, but its behavioural relevance remains unclear. Using high-precision magnetoencephalography (MEG), we show that during the classical event-related desynchronisation (ERD) and event-related synchronisation (ERS) periods, motor cortical beta activity in individual trials (n > 12,000) is dominated by high amplitude, transient, and infrequent bursts. Beta burst probability closely matched the trial-averaged beta amplitude in both the pre- and post-movement periods, but individual bursts were spatially more focal than the classical ERS peak. Furthermore, prior to movement (ERD period), beta burst timing was related to the degree of motor preparation, with later bursts resulting in delayed response times. Following movement (ERS period), the first beta burst was delayed by approximately 100 milliseconds when an incorrect response was made. Overall, beta burst timing was a stronger predictor of single trial behaviour than beta burst rate or single trial beta amplitude. This transient nature of motor cortical beta provides new constraints for theories of its role in information processing within and across cortical circuits, and its functional relevance for behaviour in both healthy and pathological movement.

Sensorimotor deficits are prevalent in many neurodevelopmental disorders like autism, including one of its common genetic etiologies, a 600 kb reciprocal deletion/duplication at 16p11.2. We have previously shown that copy number variations of 16p11.2 impact regional brain volume, white matter integrity, and early sensory responses in auditory cortex. Here, we test the hypothesis that abnormal cortical neurophysiology is present when genes in the 16p11.2 region are haploinsufficient, and in humans that this in turn may account for behavioral deficits specific to deletion carriers. We examine sensorimotor cortical network activity in males and females with 16p11.2 deletions compared with both typically developing individuals, and those with duplications of 16p11.2, using magnetoencephalographic imaging during preparation of overt speech or hand movements in tasks designed to be easy for all participants. In deletion carriers, modulation of beta oscillations (12-30 Hz) were increased during both movement types over effector-specific regions of motor cortices compared with typically developing individuals or duplication carriers, with no task-related performance differences between cohorts, even when corrected for their own cognitive and sensorimotor deficits. Reduced left hemispheric language specialization was observed in deletion carriers but not in duplication carriers. Neural activity over sensorimotor cortices in deletion carriers was linearly related to clinical measures of speech and motor impairment. These findings link insufficient copy number repeats at 16p11.2 to excessive neural activity (e.g., increased beta oscillations) in motor cortical networks for speech and hand motor control. These results have significant implications for understanding the neural basis of autism and related neurodevelopmental disorders.SIGNIFICANCE STATEMENT The recurrent ∼600 kb deletion at 16p11.2 (BP4-BP5) is one of the most common genetic etiologies of ASD and, more generally, of neurodevelopmental disorders. Here, we use high-resolution magnetoencephalographic imaging (MEG-I) to define with millisecond precision the underlying neurophysiological signature of motor impairments for individuals with 16p11.2 deletions. We identify significant increases in beta (12-30 Hz) suppression in sensorimotor cortices related to performance during speech and hand movement tasks. These findings not only provide a neurophysiological phenotype for the clinical presentation of this genetic deletion, but also guide our understanding of how genetic variation encodes for neural oscillatory dynamics.

Brain-machine interfaces (BMIs) translate brain signals into control signals for an external device, such as a computer cursor or robotic limb. These signals can be obtained either noninvasively or invasively. Invasive recordings, using electrocorticography (ECoG) or intracortical microelectrodes, provide higher bandwidth and more informative signals. Rehabilitative BMIs, which aim to drive plasticity in the brain to enhance recovery after brain injury, have almost exclusively used non-invasive recordings, such electroencephalography (EEG) or magnetoencephalography (MEG), which have limited bandwidth and information content. Invasive recordings provide more information and spatiotemporal resolution, but do incur risk, and thus are not usually investigated in people with stroke or traumatic brain injury (TBI). Here, in this paper, we describe a new BMI paradigm to investigate the use of higher frequency signals in brain-injured subjects without incurring significant risk. We recorded EEG in TBI subjects who required hemicraniectomies (removal of a part of the skull). EEG over the hemicraniectomy (hEEG) contained substantial information in the high gamma frequency range (65-115 Hz). Using this information, we decoded continuous finger flexion force with moderate to high accuracy (variance accounted for 0.06 to 0.52), which at best approaches that using epidural signals. These results indicate that people with hemicraniectomies can provide a useful resource for developing BMI therapies for the treatment of brain injury.

Combat-related mild traumatic brain injury (mTBI) is a leading cause of sustained cognitive impairment in military service members and Veterans. However, the mechanism of persistent cognitive deficits including working memory (WM) dysfunction is not fully understood in mTBI. Few studies of WM deficits in mTBI have taken advantage of the temporal and frequency resolution afforded by electromagnetic measurements. Using magnetoencephalography (MEG) and an N-back WM task, we investigated functional abnormalities in combat-related mTBI. Study participants included 25 symptomatic active-duty service members or Veterans with combat-related mTBI and 20 healthy controls with similar combat experiences. MEG source-magnitude images were obtained for alpha (8-12 Hz), beta (15-30 Hz), gamma (30-90 Hz), and low-frequency (1-7 Hz) bands. Compared with healthy combat controls, mTBI participants showed increased MEG signals across frequency bands in frontal pole (FP), ventromedial prefrontal cortex, orbitofrontal cortex (OFC), and anterior dorsolateral prefrontal cortex (dlPFC), but decreased MEG signals in anterior cingulate cortex. Hyperactivations in FP, OFC, and anterior dlPFC were associated with slower reaction times. MEG activations in lateral FP also negatively correlated with performance on tests of letter sequencing, verbal fluency, and digit symbol coding. The profound hyperactivations from FP suggest that FP is particularly vulnerable to combat-related mTBI.

BackgroundAlthough they form a unitary phenomenon, the relationship between extracranial M/EEG and transmembrane ion flows is understood only as a general principle rather than as a well-articulated and quantified causal chain.MethodWe present an integrated multiscale model, consisting of a neural simulation of thalamus and cortex during stage N2 sleep and a biophysical model projecting cortical current densities to M/EEG fields. Sleep spindles were generated through the interactions of local and distant network connections and intrinsic currents within thalamocortical circuits. 32,652 cortical neurons were mapped onto the cortical surface reconstructed from subjects' MRI, interconnected based on geodesic distances, and scaled-up to current dipole densities based on laminar recordings in humans. MRIs were used to generate a quasi-static electromagnetic model enabling simulated cortical activity to be projected to the M/EEG sensors.ResultsThe simulated M/EEG spindles were similar in amplitude and topography to empirical examples in the same subjects. Simulated spindles with more core-dominant activity were more MEG weighted.Comparison with existing methodsPrevious models lacked either spindle-generating thalamic neural dynamics or whole head biophysical modeling; the framework presented here is the first to simultaneously capture these disparate scales.ConclusionsThis multiscale model provides a platform for the principled quantitative integration of existing information relevant to the generation of sleep spindles, and allows the implications of future findings to be explored. It provides a proof of principle for a methodological framework allowing large-scale integrative brain oscillations to be understood in terms of their underlying channels and synapses.

In patients with gliomas, changes in hemispheric specialization for language determined by magnetoencephalography (MEG) were analyzed to elucidate the impact of treatment and tumor recurrence on language networks. Demonstration of reorganization of language networks in these patients has significant implications on the prevention of postoperative functional loss and recovery. Whole-brain activity during an auditory verb generation task was estimated from MEG recordings in a group of 73 patients with recurrent gliomas. Hemisphere of language dominance was estimated using the language laterality index (LI), a measure derived from the task. The initial scan was performed prior to resection; patients subsequently underwent surgery and adjuvant treatment. A second scan was performed upon recurrence prior to repeat resection. The relationship between the shift in LI between scans and demographics, anatomic location, pathology, and adjuvant treatment was analyzed. Laterality shifts were observed between scans; the median percent change was 29.1% across all patients. Laterality shift magnitude and relative direction were associated with the initial position of language dominance; patients with increased lateralization experienced greater shifts than those presenting more bilateral representation. A change in LI from left or right to bilateral (or vice versa) occurred in 23.3% of patients; complete switch occurred in 5.5% of patients. Patients with tumors within the language-dominant hemisphere experienced significantly greater shifts than those with contralateral tumors. The majority of patients with glioma experience shifts in language network organization over time which correlate with the relative position of language lateralization and tumor location.

The extent to which development of the brain language system is modulated by the temporal onset of linguistic experience relative to post-natal brain maturation is unknown. This crucial question cannot be investigated with the hearing population because spoken language is ubiquitous in the environment of newborns. Deafness blocks infants' language experience in a spoken form, and in a signed form when it is absent from the environment. Using anatomically constrained magnetoencephalography, aMEG, we neuroimaged lexico-semantic processing in a deaf adult whose linguistic experience began in young adulthood. Despite using language for 30 years after initially learning it, this individual exhibited limited neural response in the perisylvian language areas to signed words during the 300-400 ms temporal window, suggesting that the brain language system requires linguistic experience during brain growth to achieve functionality. The present case study primarily exhibited neural activations in response to signed words in dorsolateral superior parietal and occipital areas bilaterally, replicating the neural patterns exhibited by two previously case studies who matured without language until early adolescence (Ferjan Ramirez N, Leonard MK, Torres C, Hatrak M, Halgren E, Mayberry RI. 2014). The dorsal pathway appears to assume the task of processing words when the brain matures without experiencing the form-meaning network of a language.

Priming has been a powerful tool for the study of human memory and especially the memory representations relevant for language. However, although it is well established that lexical access can be primed, we do not know exactly what types of computations can be primed above the word level. This work took a neurobiological approach and assessed the ways in which the complex representation of a minimal combinatory phrase, such as red boat, can be primed, as evidenced by the spatiotemporal profiles of magnetoencephalography (MEG) signals. Specifically, we built upon recent progress on the neural signatures of phrasal composition and tested whether the brain activities implicated for the basic combination of two words could be primed. In two experiments, MEG was recorded during a picture naming task where the prime trials were designed to replicate previously reported combinatory effects and the target trials to test whether those combinatory effects could be primed. The manipulation of the primes was successful in eliciting larger activity for adjective-noun combinations than single nouns in left anterior temporal and ventromedial prefrontal cortices, replicating prior MEG studies on parallel contrasts. Priming of similarly timed activity was observed during target trials in anterior temporal cortex, but only when the prime and target shared an adjective. No priming in temporal cortex was observed for single word repetition and two control tasks showed that the priming effect was not elicited if the prime pictures were simply viewed but not named. In sum, this work provides evidence that very basic combinatory operations can be primed, with the necessity for some lexical overlap between prime and target suggesting combinatory conceptual, as opposed to syntactic processing. Both our combinatory and priming effects were early, onsetting between 100 and 150ms after picture onset and thus are likely to reflect the very earliest planning stages of a combinatory message. Thus our findings suggest that at the earliest stages of combinatory planning in production, a combinatory memory representation is formed that affects the planning of a relevantly similar combination on a subsequent trial.

BackgroundMild traumatic brain injury (mTBI) is a leading cause of sustained impairments in military service members, Veterans, and civilians. However, few treatments are available for mTBI, partially because the mechanism of persistent mTBI deficits is not fully understood.MethodsWe used magnetoencephalography (MEG) to investigate neuronal changes in individuals with mTBI following a passive neurofeedback-based treatment programme called IASIS. This programme involved applying low-intensity pulses using transcranial electrical stimulation (LIP-tES) with electroencephalography monitoring. Study participants included six individuals with mTBI and persistent post-concussive symptoms (PCS). MEG exams were performed at baseline and follow-up to evaluate the effect of IASIS on brain functioning.ResultsAt the baseline MEG exam, all participants had abnormal slow-waves. In the follow-up MEG exam, the participants showed significantly reduced abnormal slow-waves with an average reduction of 53.6 ± 24.6% in slow-wave total score. The participants also showed significant reduction of PCS scores after IASIS treatment, with an average reduction of 52.76 ± 26.4% in PCS total score.ConclusionsThe present study demonstrates, for the first time, the neuroimaging-based documentation of the effect of LIP-tES treatment on brain functioning in mTBI. The mechanisms of LIP-tES treatment are discussed, with an emphasis on LIP-tES's potentiation of the mTBI healing process.

Primary progressive aphasia is a syndrome characterized by progressive loss of language abilities with three main phenotypic clinical presentations, including logopenic, non-fluent/agrammatic, and semantic variants. Previous imaging studies have shown unique anatomic impacts within language networks in each variant. However, direct measures of spontaneous neuronal activity and functional integrity of these impacted neural networks in primary progressive aphasia are lacking. The aim of this study was to characterize the spatial and temporal patterns of resting state neuronal synchronizations in primary progressive aphasia syndromes. We hypothesized that resting state brain oscillations will show unique deficits within language network in each variant of primary progressive aphasia. We examined 39 patients with primary progressive aphasia including logopenic variant (n = 14, age = 61 ± 9 years), non-fluent/agrammatic variant (n = 12, age = 71 ± 8 years) and semantic variant (n = 13, age = 65 ± 7 years) using magnetoencephalographic imaging, compared to a control group that was matched in age and gender to each primary progressive aphasia subgroup (n = 20, age = 65 ± 5 years). Each patient underwent a complete clinical evaluation including a comprehensive battery of language tests. We examined the whole-brain resting state functional connectivity as measured by imaginary coherence in each patient group compared to the control cohort, in three frequency oscillation bands-delta-theta (2-8 Hz); alpha (8-12 Hz); beta (12-30 Hz). Each variant showed a distinct spatiotemporal pattern of altered functional connectivity compared to age-matched controls. Specifically, we found significant hyposynchrony of alpha and beta frequency within the left posterior temporal and occipital cortices in patients with the logopenic variant, within the left inferior frontal cortex in patients with the non-fluent/agrammatic variant, and within the left temporo-parietal junction in patients with the semantic variant. Patients with logopenic variant primary progressive aphasia also showed significant hypersynchrony of delta-theta frequency within bilateral medial frontal and posterior parietal cortices. Furthermore, region of interest-based analyses comparing the spatiotemporal patterns of variant-specific regions of interest identified in comparison to age-matched controls showed significant differences between primary progressive aphasia variants themselves. We also found distinct patterns of regional spectral power changes in each primary progressive aphasia variant, compared to age-matched controls. Our results demonstrate neurophysiological signatures of network-specific neuronal dysfunction in primary progressive aphasia variants. The unique spatiotemporal patterns of neuronal synchrony signify diverse neurophysiological disruptions and pathological underpinnings of the language network in each variant.

Blast mild traumatic brain injury (mTBI) is a leading cause of sustained impairment in military service members and veterans. However, the mechanism of persistent disability is not fully understood. The present study investigated disturbances in brain functioning in mTBI participants using a source-imaging-based approach to analyze functional connectivity (FC) from resting-state magnetoencephalography (rs-MEG). Study participants included 26 active-duty service members or veterans who had blast mTBI with persistent post-concussive symptoms, and 22 healthy control active-duty service members or veterans. The source time courses from regions of interest (ROIs) were used to compute ROI to whole-brain (ROI-global) FC for different frequency bands using two different measures: 1) time-lagged cross-correlation and 2) phase-lock synchrony. Compared with the controls, blast mTBI participants showed increased ROI-global FC in beta, gamma, and low-frequency bands, but not in the alpha band. Sources of abnormally increased FC included the: 1) prefrontal cortex (right ventromedial prefrontal cortex [vmPFC], right rostral anterior cingulate cortex [rACC]), and left ventrolateral and dorsolateral prefrontal cortex; 2) medial temporal lobe (bilateral parahippocampus, hippocampus, and amygdala); and 3) right putamen and cerebellum. In contrast, the blast mTBI group also showed decreased FC of the right frontal pole. Group differences were highly consistent across the two different FC measures. FC of the left ventrolateral prefrontal cortex correlated with executive functioning and processing speed in mTBI participants. Altogether, our findings of increased and decreased regionalpatterns of FC suggest that disturbances in intrinsic brain connectivity may be the result of multiple mechanisms, and are associated with cognitive sequelae of the injury.

ObjectiveSeizures are more frequent in patients with Alzheimer's disease (AD) and can hasten cognitive decline. However, the incidence of subclinical epileptiform activity in AD and its consequences are unknown. Motivated by results from animal studies, we hypothesized higher than expected rates of subclinical epileptiform activity in AD with deleterious effects on cognition.MethodsWe prospectively enrolled 33 patients (mean age, 62 years) who met criteria for AD, but had no history of seizures, and 19 age-matched, cognitively normal controls. Subclinical epileptiform activity was assessed, blinded to diagnosis, by overnight long-term video-electroencephalography (EEG) and a 1-hour resting magnetoencephalography exam with simultaneous EEG. Patients also had comprehensive clinical and cognitive evaluations, assessed longitudinally over an average period of 3.3 years.ResultsSubclinical epileptiform activity was detected in 42.4% of AD patients and 10.5% of controls (p = 0.02). At the time of monitoring, AD patients with epileptiform activity did not differ clinically from those without such activity. However, patients with subclinical epileptiform activity showed faster declines in global cognition, determined by the Mini-Mental State Examination (3.9 points/year in patients with epileptiform activity vs 1.6 points/year in patients without; p = 0.006), and in executive function (p = 0.01).InterpretationExtended monitoring detects subclinical epileptiform activity in a substantial proportion of patients with AD. Patients with this indicator of network hyperexcitability are at risk for accelerated cognitive decline and might benefit from antiepileptic therapies. These data call for more sensitive and comprehensive neurophysiological assessments in AD patient evaluations and impending clinical trials. Ann Neurol 2016;80:858-870.

Background and purposeDeletion and duplication of chromosome 16p11.2 (BP4-BP5) have been associated with developmental disorders such as autism spectrum disorders, and deletion subjects exhibit a large (20-ms) delay of the auditory evoked cortical response as measured by magnetoencephalography (M100 latency). The purpose of this study was to use a multimodal approach to test whether changes in white matter microstructure are associated with delayed M100 latency.Materials and methodsThirty pediatric deletion carriers, 9 duplication carriers, and 39 control children were studied with both magnetoencephalography and diffusion MR imaging. The M100 latency and auditory system DTI measures were compared between groups and tested for correlation.ResultsIn controls, white matter diffusivity significantly correlated with the speed of the M100 response. However, the relationship between structure and function appeared uncoupled in 16p11.2 copy number variation carriers. The alterations to auditory system white matter microstructure in the 16p11.2 deletion only partially accounted for the 20-ms M100 delay. Although both duplication and deletion groups exhibit abnormal white matter microstructure, only the deletion group has delayed M100 latency.ConclusionsThese results indicate that gene dosage impacts factors other than white matter microstructure, which modulate conduction velocity.

Individuals with the 16p11.2 BP4-BP5 copy number variant (CNV) exhibit a range of behavioral phenotypes that may include mild impairment in cognition and clinical diagnoses of autism spectrum disorder (ASD). To better understand auditory processing impairments in populations with this chromosomal variation, auditory evoked responses were examined in children with the 16p11.2 deletion, 16p11.2 duplication, and age-matched controls. Stimuli consisted of sinusoidal binaural tones presented passively while children underwent recording with magnetoencephalography (MEG). The primary indicator of auditory processing impairment was the latency of the ∼100-ms "M100" auditory response detected by MEG, with the 16p11.2 deletion population exhibiting profoundly delayed M100 latencies relative to controls. This delay remained even after controlling for potential confounds such as age and cognitive ability. No significant difference in M100 latency was observed between 16p11.2 duplication carriers and controls. Additionally, children meeting diagnostic criteria for ASD (16p11.2 deletion carriers) exhibited nonsignificant latency delays when compared with the corresponding CNV carriers not meeting criteria for ASD. Present results indicate that 16p11.2 deletion is associated with auditory processing delays analogous to (but substantially more pronounced than) those previously reported in "idiopathic" ASD.

The development of hemispheric lateralization for language is poorly understood. In one hypothesis, early asymmetric gene expression assigns language to the left hemisphere. In an alternate view, language is represented a priori in both hemispheres and lateralization emerges via cross-hemispheric communication through the corpus callosum. To address this second hypothesis, we capitalized on the high temporal and spatial resolution of magnetoencephalographic imaging to measure cortical activity during language processing, speech preparation, and speech execution in 25 participants with agenesis of the corpus callosum (AgCC) and 21 matched neurotypical individuals. In contrast to strongly lateralized left hemisphere activations for language in neurotypical controls, participants with complete or partial AgCC exhibited bilateral hemispheric activations in both auditory or visually driven language tasks, with complete AgCC participants showing significantly more right hemisphere activations than controls or than individuals with partial AgCC. In AgCC individuals, language laterality positively correlated with verbal IQ. These findings suggest that the corpus callosum helps to drive language lateralization.Significance statementThe role that corpus callosum development has on the hemispheric specialization of language is poorly understood. Here, we used magnetoencephalographic imaging during linguistic tests (verb generation, picture naming) to test for hemispheric dominance in patients with agenesis of the corpus callosum (AgCC) and found reduced laterality (i.e., greater likelihood of bilaterality or right hemisphere dominance) in this cohort compared with controls, especially in patients with complete agenesis. Laterality was positively correlated with behavioral measures of verbal intelligence. These findings provide support for the hypothesis that the callosum aids in functional specialization throughout neural development and that the loss of this mechanism correlates with impairments in verbal performance.

Modulation of vocal pitch is a key speech feature that conveys important linguistic and affective information. Auditory feedback is used to monitor and maintain pitch. We examined induced neural high gamma power (HGP) (65-150 Hz) using magnetoencephalography during pitch feedback control. Participants phonated into a microphone while hearing their auditory feedback through headphones. During each phonation, a single real-time 400 ms pitch shift was applied to the auditory feedback. Participants compensated by rapidly changing their pitch to oppose the pitch shifts. This behavioral change required coordination of the neural speech motor control network, including integration of auditory and somatosensory feedback to initiate change in motor plans. We found increases in HGP across both hemispheres within 200 ms of pitch shifts, covering left sensory and right premotor, parietal, temporal, and frontal regions, involved in sensory detection and processing of the pitch shift. Later responses to pitch shifts (200-300 ms) were right dominant, in parietal, frontal, and temporal regions. Timing of activity in these regions indicates their role in coordinating motor change and detecting and processing of the sensory consequences of this change. Subtracting out cortical responses during passive listening to recordings of the phonations isolated HGP increases specific to speech production, highlighting right parietal and premotor cortex, and left posterior temporal cortex involvement in the motor response. Correlation of HGP with behavioral compensation demonstrated right frontal region involvement in modulating participant's compensatory response. This study highlights the bihemispheric sensorimotor cortical network involvement in auditory feedback-based control of vocal pitch.

ObjectiveAsymmetric large-amplitude slow activity is sometimes observed on interictal electroencephalography (EEG) in epilepsy. However, few studies have examined slowing during magnetoencephalography (MEG) recordings, which are performed primarily to localize interictal spikes. Also, no prior investigations have compared the sensitivity of MEG to scalp EEG in detecting slow rhythms.MethodsWe performed a retrospective cohort study of focal epilepsy patients who received MEG followed by surgical resection at our institution. We examined MEG, simultaneous EEG, and long-term EEG recordings for prominent asymmetric slow activity (delta-range, 1-4 Hz), and evaluated post-operative seizure outcomes.ResultsWe studied 132 patients with ≥ 1 year post-operative follow-up (mean, 3.6 years). Mean age was 27 (range, 3-68) years, and 55% of patients were male. Asymmetric large-amplitude slow wave activity was observed on interictal MEG in 21 of 132 (16%) patients. Interictal slowing lateralized to the hemisphere of resection in all but one (95%) patient. Among the 21 patients with interictal MEG slowing, 11 (52%) individuals had similarly lateralized EEG slowing, 7 patients had no EEG slowing, and 3 had bilateral symmetric EEG slowing. Meanwhile, none of the 111 patients without lateralized MEG slowing had asymmetric EEG slowing, suggesting significantly higher sensitivity of MEG versus EEG in detecting asymmetric slowing (χ(2)=63.4, p

One key question in neurolinguistics is the extent to which the neural processing system for language requires linguistic experience during early life to develop fully. We conducted a longitudinal anatomically constrained magnetoencephalography (aMEG) analysis of lexico-semantic processing in 2 deaf adolescents who had no sustained language input until 14 years of age, when they became fully immersed in American Sign Language. After 2 to 3 years of language, the adolescents' neural responses to signed words were highly atypical, localizing mainly to right dorsal frontoparietal regions and often responding more strongly to semantically primed words (Ferjan Ramirez N, Leonard MK, Torres C, Hatrak M, Halgren E, Mayberry RI. 2014. Neural language processing in adolescent first-language learners. Cereb Cortex. 24 (10): 2772-2783). Here, we show that after an additional 15 months of language experience, the adolescents' neural responses remained atypical in terms of polarity. While their responses to less familiar signed words still showed atypical localization patterns, the localization of responses to highly familiar signed words became more concentrated in the left perisylvian language network. Our findings suggest that the timing of language experience affects the organization of neural language processing; however, even in adolescence, language representation in the human brain continues to evolve with experience.

Schizophrenia is characterized by dysfunction in basic auditory processing, as well as higher-order operations of verbal learning and executive functions. We investigated whether targeted cognitive training of auditory processing improves neural responses to speech stimuli, and how these changes relate to higher-order cognitive functions. Patients with schizophrenia performed an auditory syllable identification task during magnetoencephalography before and after 50 hours of either targeted cognitive training or a computer games control. Healthy comparison subjects were assessed at baseline and after a 10 week no-contact interval. Prior to training, patients (N = 34) showed reduced M100 response in primary auditory cortex relative to healthy participants (N = 13). At reassessment, only the targeted cognitive training patient group (N = 18) exhibited increased M100 responses. Additionally, this group showed increased induced high gamma band activity within left dorsolateral prefrontal cortex immediately after stimulus presentation, and later in bilateral temporal cortices. Training-related changes in neural activity correlated with changes in executive function scores but not verbal learning and memory. These data suggest that computerized cognitive training that targets auditory and verbal learning operations enhances both sensory responses in auditory cortex as well as engagement of prefrontal regions, as indexed during an auditory processing task with low demands on working memory. This neural circuit enhancement is in turn associated with better executive function but not verbal memory.

OBJECTIVE: The primary aim of this study was to examine whether there is an association between magnetoencephalography-based (MEG) indices of basic cortical auditory processing and vocal affect recognition (VAR) ability in individuals with autism spectrum disorder (ASD). METHOD: MEG data were collected from 25 children/adolescents with ASD and 12 control participants using a paired-tone paradigm to measure quality of auditory physiology, sensory gating, and rapid auditory processing. Group differences were examined in auditory processing and vocal affect recognition ability. The relationship between differences in auditory processing and vocal affect recognition deficits was examined in the ASD group. RESULTS: Replicating prior studies, participants with ASD showed longer M1n latencies and impaired rapid processing compared with control participants. These variables were significantly related to VAR, with the linear combination of auditory processing variables accounting for approximately 30% of the variability after controlling for age and language skills in participants with ASD. CONCLUSIONS: VAR deficits in ASD are typically interpreted as part of a core, higher order dysfunction of the social brain; however, these results suggest they also may reflect basic deficits in auditory processing that compromise the extraction of socially relevant cues from the auditory environment. As such, they also suggest that therapeutic targeting of sensory dysfunction in ASD may have additional positive implications for other functional deficits.

Intractable focal epilepsy is a devastating disorder with profound effects on cognition and quality of life. Epilepsy surgery can lead to seizure freedom in patients with focal epilepsy; however, sometimes it fails due to an incomplete delineation of the epileptogenic zone. Brain networks in epilepsy can be studied with resting-state functional connectivity analysis, yet previous investigations using functional magnetic resonance imaging or electrocorticography have produced inconsistent results. Magnetoencephalography allows non-invasive whole-brain recordings, and can be used to study both long-range network disturbances in focal epilepsy and regional connectivity at the epileptogenic zone. In magnetoencephalography recordings from presurgical epilepsy patients, we examined: (i) global functional connectivity maps in patients versus controls; and (ii) regional functional connectivity maps at the region of resection, compared to the homotopic non-epileptogenic region in the contralateral hemisphere. Sixty-one patients were studied, including 30 with mesial temporal lobe epilepsy and 31 with focal neocortical epilepsy. Compared with a group of 31 controls, patients with epilepsy had decreased resting-state functional connectivity in widespread regions, including perisylvian, posterior temporo-parietal, and orbitofrontal cortices (P < 0.01, t-test). Decreased mean global connectivity was related to longer duration of epilepsy and higher frequency of consciousness-impairing seizures (P < 0.01, linear regression). Furthermore, patients with increased regional connectivity within the resection site (n = 24) were more likely to achieve seizure postoperative seizure freedom (87.5% with Engel I outcome) than those with neutral (n = 15, 64.3% seizure free) or decreased (n = 23, 47.8% seizure free) regional connectivity (P < 0.02, chi-square). Widespread global decreases in functional connectivity are observed in patients with focal epilepsy, and may reflect deleterious long-term effects of recurrent seizures. Furthermore, enhanced regional functional connectivity at the area of resection may help predict seizure outcome and aid surgical planning.

ObjectiveThe efficacy of epilepsy surgery depends critically upon successful localization of the epileptogenic zone. Magnetoencephalography (MEG) enables noninvasive detection of interictal spike activity in epilepsy, which can then be localized in three dimensions using magnetic source imaging (MSI) techniques. However, the clinical value of MEG in the presurgical epilepsy evaluation is not fully understood, as studies to date are limited by either a lack of long-term seizure outcomes or small sample size.MethodsWe performed a retrospective cohort study of patients with focal epilepsy who received MEG for interictal spike mapping followed by surgical resection at our institution.ResultsWe studied 132 surgical patients, with mean postoperative follow-up of 3.6 years (minimum 1 year). Dipole source modeling was successful in 103 patients (78%), whereas no interictal spikes were seen in others. Among patients with successful dipole modeling, MEG findings were concordant with and specific to the following: (1) the region of resection in 66% of patients, (2) invasive electrocorticography (ECoG) findings in 67% of individuals, and (3) the magnetic resonance imaging (MRI) abnormality in 74% of cases. MEG showed discordant lateralization in ~5% of cases. After surgery, 70% of all patients achieved seizure freedom (Engel class I outcome). Whereas 85% of patients with concordant and specific MEG findings became seizure-free, this outcome was achieved by only 37% of individuals with MEG findings that were nonspecific to or discordant with the region of resection (χ(2) = 26.4, p < 0.001). MEG reliability was comparable in patients with or without localized scalp electroencephalography (EEG), and overall, localizing MEG findings predicted seizure freedom with an odds ratio of 5.11 (95% confidence interval [CI] 2.23-11.8).SignificanceMEG is a valuable tool for noninvasive interictal spike mapping in epilepsy surgery, including patients with nonlocalized findings receiving long-term EEG monitoring, and localization of the epileptogenic zone using MEG is associated with improved seizure outcomes.

A barrier in the diagnosis of mild traumatic brain injury (mTBI) stems from the lack of measures that are adequately sensitive in detecting mild head injuries. MRI and CT are typically negative in mTBI patients with persistent symptoms of post-concussive syndrome (PCS), and characteristic difficulties in sustaining attention often go undetected on neuropsychological testing, which can be insensitive to momentary lapses in concentration. Conversely, visual tracking strongly depends on sustained attention over time and is impaired in chronic mTBI patients, especially when tracking an occluded target. This finding suggests deficient internal anticipatory control in mTBI, the neural underpinnings of which are poorly understood. The present study investigated the neuronal bases for deficient anticipatory control during visual tracking in 25 chronic mTBI patients with persistent PCS symptoms and 25 healthy control subjects. The task was performed while undergoing magnetoencephalography (MEG), which allowed us to examine whether neural dysfunction associated with anticipatory control deficits was due to altered alpha, beta, and/or gamma activity. Neuropsychological examinations characterized cognition in both groups. During MEG recordings, subjects tracked a predictably moving target that was either continuously visible or randomly occluded (gap condition). MEG source-imaging analyses tested for group differences in alpha, beta, and gamma frequency bands. The results showed executive functioning, information processing speed, and verbal memory deficits in the mTBI group. Visual tracking was impaired in the mTBI group only in the gap condition. Patients showed greater error than controls before and during target occlusion, and were slower to resynchronize with the target when it reappeared. Impaired tracking concurred with abnormal beta activity, which was suppressed in the parietal cortex, especially the right hemisphere, and enhanced in left caudate and frontal-temporal areas. Regional beta-amplitude demonstrated high classification accuracy (92%) compared to eye-tracking (65%) and neuropsychological variables (80%). These findings show that deficient internal anticipatory control in mTBI is associated with altered beta activity, which is remarkably sensitive given the heterogeneity of injuries.

Auditory feedback is used to monitor and correct for errors in speech production, and one of the clearest demonstrations of this is the pitch perturbation reflex. During ongoing phonation, speakers respond rapidly to shifts of the pitch of their auditory feedback, altering their pitch production to oppose the direction of the applied pitch shift. In this study, we examine the timing of activity within a network of brain regions thought to be involved in mediating this behavior. To isolate auditory feedback processing relevant for motor control of speech, we used magnetoencephalography (MEG) to compare neural responses to speech onset and to transient (400ms) pitch feedback perturbations during speaking with responses to identical acoustic stimuli during passive listening. We found overlapping, but distinct bilateral cortical networks involved in monitoring speech onset and feedback alterations in ongoing speech. Responses to speech onset during speaking were suppressed in bilateral auditory and left ventral supramarginal gyrus/posterior superior temporal sulcus (vSMG/pSTS). In contrast, during pitch perturbations, activity was enhanced in bilateral vSMG/pSTS, bilateral premotor cortex, right primary auditory cortex, and left higher order auditory cortex. We also found speaking-induced delays in responses to both unaltered and altered speech in bilateral primary and secondary auditory regions, left vSMG/pSTS and right premotor cortex. The network dynamics reveal the cortical processing involved in both detecting the speech error and updating the motor plan to create the new pitch output. These results implicate vSMG/pSTS as critical in both monitoring auditory feedback and initiating rapid compensation to feedback errors.

The present study developed a fast MEG source imaging technique based on Fast Vector-based Spatio-Temporal Analysis using a L1-minimum-norm (Fast-VESTAL) and then used the method to obtain the source amplitude images of resting-state magnetoencephalography (MEG) signals for different frequency bands. The Fast-VESTAL technique consists of two steps. First, L1-minimum-norm MEG source images were obtained for the dominant spatial modes of sensor-waveform covariance matrix. Next, accurate source time-courses with millisecond temporal resolution were obtained using an inverse operator constructed from the spatial source images of Step 1. Using simulations, Fast-VESTALs performance was assessed for its 1) ability to localize multiple correlated sources; 2) ability to faithfully recover source time-courses; 3) robustness to different SNR conditions including SNR with negative dB levels; 4) capability to handle correlated brain noise; and 5) statistical maps of MEG source images. An objective pre-whitening method was also developed and integrated with Fast-VESTAL to remove correlated brain noise. Fast-VESTALs performance was then examined in the analysis of human median-nerve MEG responses. The results demonstrated that this method easily distinguished sources in the entire somatosensory network. Next, Fast-VESTAL was applied to obtain the first whole-head MEG source-amplitude images from resting-state signals in 41 healthy control subjects, for all standard frequency bands. Comparisons between resting-state MEG sources images and known neurophysiology were provided. Additionally, in simulations and cases with MEG human responses, the results obtained from using conventional beamformer technique were compared with those from Fast-VESTAL, which highlighted the beamformers problems of signal leaking and distorted source time-courses.

Post-traumatic stress disorder (PTSD) is a leading cause of sustained impairment, distress, and poor quality of life in military personnel, veterans, and civilians. Indirect functional neuroimaging studies using PET or fMRI with fear-related stimuli support a PTSD neurocircuitry model that includes amygdala, hippocampus, and ventromedial prefrontal cortex (vmPFC). However, it is not clear if this model can fully account for PTSD abnormalities detected directly by electromagnetic-based source imaging techniques in resting-state. The present study examined resting-state magnetoencephalography (MEG) signals in 25 active-duty service members and veterans with PTSD and 30 healthy volunteers. In contrast to the healthy volunteers, individuals with PTSD showed: (1) hyperactivity from amygdala, hippocampus, posterolateral orbitofrontal cortex (OFC), dorsomedial prefrontal cortex (dmPFC), and insular cortex in high-frequency (i.e., beta, gamma, and high-gamma) bands; (2) hypoactivity from vmPFC, Frontal Pole (FP), and dorsolateral prefrontal cortex (dlPFC) in high-frequency bands; (3) extensive hypoactivity from dlPFC, FP, anterior temporal lobes, precuneous cortex, and sensorimotor cortex in alpha and low-frequency bands; and (4) in individuals with PTSD, MEG activity in the left amygdala and posterolateral OFC correlated positively with PTSD symptom scores, whereas MEG activity in vmPFC and precuneous correlated negatively with symptom score. The present study showed that MEG source imaging technique revealed new abnormalities in the resting-state electromagnetic signals from the PTSD neurocircuitry. Particularly, posterolateral OFC and precuneous may play important roles in the PTSD neurocircuitry model.

Traumatic brain injury (TBI) is a leading cause of sustained impairment in military and civilian populations. However, mild TBI (mTBI) can be difficult to detect using conventional MRI or CT. Injured brain tissues in mTBI patients generate abnormal slow-waves (1-4 Hz) that can be measured and localized by resting-state magnetoencephalography (MEG). In this study, we develop a voxel-based whole-brain MEG slow-wave imaging approach for detecting abnormality in patients with mTBI on a single-subject basis. A normative database of resting-state MEG source magnitude images (1-4 Hz) from 79 healthy control subjects was established for all brain voxels. The high-resolution MEG source magnitude images were obtained by our recent Fast-VESTAL method. In 84 mTBI patients with persistent post-concussive symptoms (36 from blasts, and 48 from non-blast causes), our method detected abnormalities at the positive detection rates of 84.5%, 86.1%, and 83.3% for the combined (blast-induced plus with non-blast causes), blast, and non-blast mTBI groups, respectively. We found that prefrontal, posterior parietal, inferior temporal, hippocampus, and cerebella areas were particularly vulnerable to head trauma. The result also showed that MEG slow-wave generation in prefrontal areas positively correlated with personality change, trouble concentrating, affective lability, and depression symptoms. Discussion is provided regarding the neuronal mechanisms of MEG slow-wave generation due to deafferentation caused by axonal injury and/or blockages/limitations of cholinergic transmission in TBI. This study provides an effective way for using MEG slow-wave source imaging to localize affected areas and supports MEG as a tool for assisting the diagnosis of mTBI.

ObjectiveLesion-based mapping of speech pathways has been possible only during invasive neurosurgical procedures using direct cortical stimulation (DCS). However, navigated transcranial magnetic stimulation (nTMS) may allow for lesion-based interrogation of language pathways noninvasively. Although not lesion-based, magnetoencephalographic imaging (MEGI) is another noninvasive modality for language mapping. In this study, we compare the accuracy of nTMS and MEGI with DCS.MethodsSubjects with lesions around cortical language areas underwent preoperative nTMS and MEGI for language mapping. nTMS maps were generated using a repetitive TMS protocol to deliver trains of stimulations during a picture naming task. MEGI activation maps were derived from adaptive spatial filtering of beta-band power decreases prior to overt speech during picture naming and verb generation tasks. The subjects subsequently underwent awake language mapping via intraoperative DCS. The language maps obtained from each of the 3 modalities were recorded and compared.ResultsnTMS and MEGI were performed on 12 subjects. nTMS yielded 21 positive language disruption sites (11 speech arrest, 5 anomia, and 5 other) while DCS yielded 10 positive sites (2 speech arrest, 5 anomia, and 3 other). MEGI isolated 32 sites of peak activation with language tasks. Positive language sites were most commonly found in the pars opercularis for all three modalities. In 9 instances the positive DCS site corresponded to a positive nTMS site, while in 1 instance it did not. In 4 instances, a positive nTMS site corresponded to a negative DCS site, while 169 instances of negative nTMS and DCS were recorded. The sensitivity of nTMS was therefore 90%, specificity was 98%, the positive predictive value was 69% and the negative predictive value was 99% as compared with intraoperative DCS. MEGI language sites for verb generation and object naming correlated with nTMS sites in 5 subjects, and with DCS sites in 2 subjects.ConclusionMaps of language function generated with nTMS correlate well with those generated by DCS. Negative nTMS mapping also correlates with negative DCS mapping. In our study, MEGI lacks the same level of correlation with intraoperative mapping; nevertheless it provides useful adjunct information in some cases. nTMS may offer a lesion-based method for noninvasively interrogating language pathways and be valuable in managing patients with peri-eloquent lesions.

How precisely does the brain predict the sensory consequences of our actions? Efference copy is thought to reflect the predicted sensation of self-produced motor acts, such as the auditory feedback heard while speaking. Here, we use magnetoencephalographic imaging (MEG-I) in human speakers to demonstrate that efference copy prediction does not track movement variability across repetitions of the same motor task. Specifically, spoken vowels were less accurately predicted when they were less similar to a speaker's median production, even though the prediction is thought to be based on the very motor commands that generate each vowel. Auditory cortical responses to less prototypical speech productions were less suppressed, resembling responses to speech errors, and were correlated with later corrective movement, suggesting that the suppression may be functionally significant for error correction. The failure of the motor system to accurately predict less prototypical speech productions suggests that the efferent-driven suppression does not reflect a sensory prediction, but a sensory goal.

Psychedelic drugs produce profound changes in consciousness, but the underlying neurobiological mechanisms for this remain unclear. Spontaneous and induced oscillatory activity was recorded in healthy human participants with magnetoencephalography after intravenous infusion of psilocybin--prodrug of the nonselective serotonin 2A receptor agonist and classic psychedelic psilocin. Psilocybin reduced spontaneous cortical oscillatory power from 1 to 50 Hz in posterior association cortices, and from 8 to 100 Hz in frontal association cortices. Large decreases in oscillatory power were seen in areas of the default-mode network. Independent component analysis was used to identify a number of resting-state networks, and activity in these was similarly decreased after psilocybin. Psilocybin had no effect on low-level visually induced and motor-induced gamma-band oscillations, suggesting that some basic elements of oscillatory brain activity are relatively preserved during the psychedelic experience. Dynamic causal modeling revealed that posterior cingulate cortex desynchronization can be explained by increased excitability of deep-layer pyramidal neurons, which are known to be rich in 5-HT2A receptors. These findings suggest that the subjective effects of psychedelics result from a desynchronization of ongoing oscillatory rhythms in the cortex, likely triggered by 5-HT2A receptor-mediated excitation of deep pyramidal cells.

ObjectTraumatic brain injury (TBI) is one of the leading causes of morbidity worldwide. One mechanism by which blunt head trauma may disrupt normal cognition and behavior is through alteration of functional connectivity between brain regions. In this pilot study, the authors applied a rapid automated resting state magnetoencephalography (MEG) imaging technique suitable for routine clinical use to test the hypothesis that there is decreased functional connectivity in patients with TBI compared with matched controls, even in cases of mild TBI. Furthermore, they posit that these abnormal reductions in MEG functional connectivity can be detected even in TBI patients without specific evidence of traumatic lesions on 3-T MR images. Finally, they hypothesize that the reductions of functional connectivity can improve over time across serial MEG scans during recovery from TBI.MethodsMagnetoencephalography maps of functional connectivity in the alpha (8- to 12-Hz) band from 21 patients who sustained a TBI were compared with those from 18 age- and sex-matched controls. Regions of altered functional connectivity in each patient were detected in automated fashion through atlas-based registration to the control database. The extent of reduced functional connectivity in the patient group was tested for correlations with clinical characteristics of the injury as well as with findings on 3-T MRI. Finally, the authors compared initial connectivity maps with 2-year follow-up functional connectivity in a subgroup of 5 patients with TBI.ResultsFourteen male and 7 female patients (17-53 years old, median 29 years) were enrolled. By Glasgow Coma Scale (GCS) criteria, 11 patients had mild, 1 had moderate, and 3 had severe TBI, and 6 had no GCS score recorded. On 3-T MRI, 16 patients had abnormal findings attributable to the trauma and 5 had findings in the normal range. As a group, the patients with TBI had significantly lower functional connectivity than controls (p < 0.01). Three of the 5 patients with normal findings on 3-T MRI showed regions of abnormally reduced MEG functional connectivity. No significant correlations were seen between extent of functional disconnection and injury severity or posttraumatic symptoms (p > 0.05). In the subgroup undergoing 2-year follow-up, the second MEG scan demonstrated a significantly lower percentage of voxels with decreased connectivity (p < 0.05) than the initial MEG scan.ConclusionsA rapid automated resting-state MEG imaging technique demonstrates abnormally decreased functional connectivity that may persist for years after TBI, including cases classified as "mild" by GCS criteria. Disrupted MEG connectivity can be detected even in some patients with normal findings on 3-T MRI. Analysis of follow-up MEG scans in a subgroup of patients shows that, over time, the abnormally reduced connectivity can improve, suggesting neuroplasticity during the recovery from TBI. Resting state MEG deserves further investigation as a prognostic and predictive biomarker for TBI.

Autism spectrum disorders (ASD) have numerous etiologies, including structural brain malformations such as agenesis of the corpus callosum (AgCC). We sought to directly measure the occurrence of autism traits in a cohort of individuals with AgCC and to investigate the neural underpinnings of this association. We screened a large AgCC cohort (n = 106) with the Autism Spectrum Quotient (AQ) and found that 45 % of children, 35 % of adolescents, and 18 % of adults exceeded the predetermined autism-screening cut-off. Interestingly, performance on the AQ's imagination domain was inversely correlated with magnetoencephalography measures of resting-state functional connectivity in the right superior temporal gyrus. Individuals with AgCC should be screened for ASD and disorders of the corpus callosum should be considered in autism diagnostic evaluations as well.

Despite significant research and important clinical correlates, direct neural evidence for a phonological loop linking speech perception, short-term memory and production remains elusive. To investigate these processes, we acquired whole-head magnetoencephalographic (MEG) recordings from human subjects performing a variable-length syllable sequence reproduction task. The MEG sensor data were source localized using a time-frequency optimized spatially adaptive filter, and we examined the time courses of cortical oscillatory power and the correlations of oscillatory power with behavior between onset of the audio stimulus and the overt speech response. We found dissociations between time courses of behaviorally relevant activations in a network of regions falling primarily within the dorsal speech stream. In particular, verbal working memory load modulated high gamma power in both Sylvian-parietal-temporal and Broca's areas. The time courses of the correlations between high gamma power and subject performance clearly alternated between these two regions throughout the task. Our results provide the first evidence of a reverberating input-output buffer system in the dorsal stream underlying speech sensorimotor integration, consistent with recent phonological loop, competitive queuing, and speech-motor control models. These findings also shed new light on potential sources of speech dysfunction in aphasia and neuropsychiatric disorders, identifying anatomically and behaviorally dissociable activation time windows critical for successful speech reproduction.

PurposeWorking memory (WM) represents the brain's ability to maintain information in a readily available state for short periods of time. This study examines the resting-state cortical activity patterns that are most associated with performance on a difficult working-memory task.MethodsMagnetoencephalographic (MEG) band-passed (delta/theta (1-7 Hz), alpha (8-13 Hz), beta (14-30 Hz)) and sensor based regional power was collected in a population of adult men (18-28 yrs, n = 24) in both an eyes-closed and eyes-open resting state. The normalized power within each resting state condition as well as the normalized change in power between eyes closed and open (zECO) were correlated with performance on a WM task. The regional and band-limited measures that were most associated with performance were then combined using singular value decomposition (SVD) to determine the degree to which zECO power was associated with performance on the three-back verbal WM task.ResultsChanges in power from eyes closed to open revealed a significant decrease in power in all band-widths that was most pronounced in the posterior brain regions (delta/theta band). zECO right posterior frontal and parietal cortex delta/theta power were found to be inversely correlated with three-back working memory performance. The SVD evaluation of the most correlated zECO metrics then provided a singular measure that was highly correlated with three-back performance (r = -0.73, p