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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.

Objective The 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. Methods We performed a retrospective cohort study of patients with focal epilepsy who received MEG for interictal spike mapping followed by surgical resection at our institution. Results We 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 (χ2 = 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). Significance MEG 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.

Understanding neural network dysfunction in neurodegenerative disease is imperative to effectively develop network-modulating therapies. In Alzheimer's disease (AD), cognitive decline associates with deficits in resting-state functional connectivity of dif

While animal models of Alzheimer's disease (AD) have shown altered gamma oscillations (∼40 Hz) in local neural circuits, the low signal-to-noise ratio of gamma in the resting human brain precludes its quantification via conventional spectral estimates. Phase-amplitude coupling (PAC) indicating the dynamic integration between the gamma amplitude and the phase of low-frequency (4-12 Hz) oscillations is a useful alternative to capture local gamma activity. In addition, PAC is also an index of neuronal excitability as the phase of low-frequency oscillations that modulate gamma amplitude, effectively regulates the excitability of local neuronal firing. In this study, we sought to examine the local neuronal activity and excitability using gamma PAC, within brain regions vulnerable to early AD pathophysiology-entorhinal cortex and parahippocampus, in a clinical population of patients with AD and age-matched controls. Our clinical cohorts consisted of a well-characterized cohort of AD patients ( n = 50; age, 60 ± 8 years) with positive AD biomarkers, and age-matched, cognitively unimpaired controls ( n = 35; age, 63 ± 5.8 years). We identified the presence or the absence of epileptiform activity in AD patients (AD patients with epileptiform activity, AD-EPI+, n = 20; AD patients without epileptiform activity, AD-EPI-, n = 30) using long-term electroencephalography (LTM-EEG) and 1-hour long magnetoencephalography (MEG) with simultaneous EEG. Using the source reconstructed MEG data, we computed gamma PAC as the coupling between amplitude of the gamma frequency (30-40 Hz) with phase of the theta (4-8 Hz) and alpha (8-12 Hz) frequency oscillations, within entorhinal and parahippocampal cortices. We found that patients with AD have reduced gamma PAC in the left parahippocampal cortex, compared to age-matched controls. Furthermore, AD-EPI+ patients showed greater reductions in gamma PAC than AD-EPI- in bilateral parahippocampal cortices. In contrast, entorhinal cortices did not show gamma PAC abnormalities in patients with AD. Our findings demonstrate the spatial patterns of altered gamma oscillations indicating possible region-specific manifestations of network hyperexcitability within medial temporal lobe regions vulnerable to AD pathophysiology. Greater deficits in AD-EPI+ suggests that reduced gamma PAC is a sensitive index of network hyperexcitability in AD patients. Collectively, the current results emphasize the importance of investigating the role of neural circuit hyperexcitability in early AD pathophysiology and explore its potential as a modifiable contributor to AD pathobiology., Competing Interests: The authors of this manuscript do not have any conflicts of interest relevant to the content of this work., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: Alzheimer's disease (AD) is the most common form of dementia, progressively impairing cognitive abilities. While neuroimaging studies have revealed functional abnormalities in AD, how these relate to aberrant neuronal circuit mechanisms remains unclear. Using magnetoencephalography imaging we documented abnormal local neural synchrony patterns in patients with AD. To identify global abnormal biophysical mechanisms underlying the spatial and spectral electrophysiological patterns in AD, we estimated the parameters of a biophysical spectral graph model (SGM)., Methods: SGM is an analytic neural mass model that describes how long-range fiber projections in the brain mediate the excitatory and inhibitory activity of local neuronal subpopulations. Unlike other coupled neuronal mass models, the SGM is linear, available in closed-form, and parameterized by a small set of biophysical interpretable global parameters. This facilitates their rapid and unambiguous inference which we performed here on a well-characterized clinical population of patients with AD (N = 88, age = 62.73 +/- 8.64 years) and a cohort of age-matched controls (N = 88, age = 65.07 +/- 9.92 years)., Results: Patients with AD showed significantly elevated long-range excitatory neuronal time scales, local excitatory neuronal time scales and local inhibitory neural synaptic strength. The long-range excitatory time scale had a larger effect size, compared to local excitatory time scale and inhibitory synaptic strength and contributed highest for the accurate classification of patients with AD from controls. Furthermore, increased long-range time scale was associated with greater deficits in global cognition., Conclusions: These results demonstrate that long-range excitatory time scale of neuronal activity, despite being a global measure, is a key determinant in the local spectral signatures and cognition in the human brain, and how it might be a parsimonious factor underlying altered neuronal activity in AD. Our findings provide new insights into mechanistic links between abnormal local spectral signatures and global connectivity measures in AD., (© 2024. The Author(s).)

Sensory processing dysfunction not only affects most individuals with autism spectrum disorder (ASD), but at least 5% of children without ASD also experience dysfunctional sensory processing. Our understanding of the relationship between sensory dysfunction and resting state brain activity is still emerging. This study compared long-range resting state functional connectivity of neural oscillatory behavior in children aged 8-12 years with autism spectrum disorder (ASD; N=18), those with sensory processing dysfunction (SPD; N=18) who do not meet ASD criteria, and typically developing control participants (TDC; N=24) using magnetoencephalography (MEG). Functional connectivity analyses were performed in the alpha and beta frequency bands, which are known to be implicated in sensory information processing. Group differences in functional connectivity and associations between sensory abilities and functional connectivity were examined. Distinct patterns of functional connectivity differences between ASD and SPD groups were found only in the beta band, but not in the alpha band. In both alpha and beta bands, ASD and SPD cohorts differed from the TDC cohort. Somatosensory cortical beta-band functional connectivity was associated with tactile processing abilities, while higher-order auditory cortical alpha-band functional connectivity was associated with auditory processing abilities. These findings demonstrate distinct long-range neural synchrony alterations in SPD and ASD that are associated with sensory processing abilities. Neural synchrony measures could serve as potential sensitive biomarkers for ASD and SPD., Competing Interests: The authors have no competing interests to declare.

Overlapping clinical presentations in primary progressive aphasia (PPA) variants present challenges for diagnosis and understanding pathophysiology, particularly in the early stages of the disease when behavioral (speech) symptoms are not clearly evident. Divergent atrophy patterns (temporoparietal degeneration in logopenic variant lvPPA, frontal degeneration in nonfluent variant nfvPPA) can partially account for differential speech production errors in the two groups in the later stages of the disease. While the existing dogma states that neurodegeneration is the root cause of compromised behavior and cortical activity in PPA, the extent to which neurophysiological signatures of speech dysfunction manifest independent of their divergent atrophy patterns remain unknown. We test the hypothesis that nonword deficits in lvPPA and nfvPPA arise from distinct patterns of neural oscillations that are unrelated to atrophy. We use a novel structure-function imaging approach integrating magnetoencephalographic imaging of neural oscillations during a non-word repetition task with voxel-based morphometry-derived measures of gray matter volume to isolate neural oscillation abnormalities independent of atrophy. We find reduced beta band neural activity in left temporal regions associated with the late stages of auditory encoding unique to patients with lvPPA and reduced high-gamma neural activity over left frontal regions associated with the early stages of motor preparation in patients with nfvPPA. Neither of these patterns of reduced cortical oscillations was explained by cortical atrophy in our statistical model. These findings highlight the importance of structure-function imaging in revealing neurophysiological sequelae in early stages of dementia when neither structural atrophy nor behavioral deficits are clinically distinct., (© 2023 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Alzheimer's disease (AD) is a neurodegenerative disease involving cognitive impairment and abnormalities in speech and language. Here, we examine how AD affects the fidelity of auditory feedback predictions during speaking. We focus on the phenomenon of speaking-induced suppression (SIS), the auditory cortical responses' suppression during auditory feedback processing. SIS is determined by subtracting the magnitude of auditory cortical responses during speaking from listening to playback of the same speech. Our state feedback control (SFC) model of speech motor control explains SIS as arising from the onset of auditory feedback matching a prediction of that feedback onset during speaking, a prediction that is absent during passive listening to playback of the auditory feedback. Our model hypothesizes that the auditory cortical response to auditory feedback reflects the mismatch with the prediction: small during speaking, large during listening, with the difference being SIS. Normally, during speaking, auditory feedback matches its predictions, then SIS will be large. Any reductions in SIS will indicate inaccuracy in auditory feedback prediction not matching the actual feedback. We investigated SIS in AD patients [ n  =   20; mean (SD) age, 60.77 (10.04); female (%), 55.00] and healthy controls [ n  =   12; mean (SD) age, 63.68 (6.07); female (%), 83.33] through magnetoencephalography (MEG)-based functional imaging. We found a significant reduction in SIS at ∼100 ms in AD patients compared with healthy controls (linear mixed effects model, F (1,57.5)  = 6.849, p  =   0.011). The results suggest that AD patients generate inaccurate auditory feedback predictions, contributing to abnormalities in AD speech., Competing Interests: The authors declare no competing financial interests., (Copyright © 2023 Kim et al.)

Background: Neuronal- and circuit-level abnormalities of excitation and inhibition are shown to be associated with tau and amyloid-beta (Aβ) in preclinical models of Alzheimer's disease (AD). These relationships remain poorly understood in patients with AD., Methods: Using empirical spectra from magnetoencephalography and computational modeling (neural mass model), we examined excitatory and inhibitory parameters of neuronal subpopulations and investigated their specific associations to regional tau and Aβ, measured by positron emission tomography, in patients with AD., Results: Patients with AD showed abnormal excitatory and inhibitory time-constants and neural gains compared to age-matched controls. Increased excitatory time-constants distinctly correlated with higher tau depositions while increased inhibitory time-constants distinctly correlated with higher Aβ depositions., Conclusions: Our results provide critical insights about potential mechanistic links between abnormal neural oscillations and cellular correlates of impaired excitatory and inhibitory synaptic functions associated with tau and Aβ in patients with AD., Funding: This study was supported by the National Institutes of Health grants: K08AG058749 (KGR), F32AG050434-01A1 (KGR), K23 AG038357 (KAV), P50 AG023501, P01 AG19724 (BLM), P50-AG023501 (BLM and GDR), R01 AG045611 (GDR); AG034570, AG062542 (WJ); NS100440 (SSN), DC176960 (SSN), DC017091 (SSN), AG062196 (SSN); a grant from John Douglas French Alzheimer's Foundation (KAV); grants from Larry L. Hillblom Foundation: 2015-A-034-FEL (KGR), 2019-A-013-SUP (KGR); grants from the Alzheimer's Association: AARG-21-849773 (KGR); PCTRB-13-288476 (KAV), and made possible by Part the CloudTM (ETAC-09-133596); a grant from Tau Consortium (GDR and WJJ), and a gift from the S. D. Bechtel Jr. Foundation., Competing Interests: KR, PV, CC, XX, XG, HL, DM, AS, LI, RL, MG, KR, WJ, KV, GR, AR, SN No competing interests declared, KK is an employee of Ricoh Company, Ltd. The author declares that no other competing interests exist, BM serves as Medical Director for the John Douglas French Foundation; Scientific Director for the Tau Consortium; Director/Medical Advisory Board of the Larry L. Hillblom Foundation; and Scientific Advisory Board Member for the National Institute for Health Research Cambridge Biomedical Research Centre and its subunit, the Biomedical Research Unit in Dementia, UK, (© 2022, Ranasinghe et al.)

Since the first demonstrations of network hyperexcitability in scientific models of Alzheimer's disease, a growing body of clinical studies have identified subclinical epileptiform activity and associated cognitive decline in patients with Alzheimer's disease. An obvious problem presented in these studies is lack of sensitive measures to detect and quantify network hyperexcitability in human subjects. In this study we examined whether altered neuronal synchrony can be a surrogate marker to quantify network hyperexcitability in patients with Alzheimer's disease. Using magnetoencephalography (MEG) at rest, we studied 30 Alzheimer's disease patients without subclinical epileptiform activity, 20 Alzheimer's disease patients with subclinical epileptiform activity and 35 age-matched controls. Presence of subclinical epileptiform activity was assessed in patients with Alzheimer's disease by long-term video-EEG and a 1-h resting MEG with simultaneous EEG. Using the resting-state source-space reconstructed MEG signal, in patients and controls we computed the global imaginary coherence in alpha (8-12 Hz) and delta-theta (2-8 Hz) oscillatory frequencies. We found that Alzheimer's disease patients with subclinical epileptiform activity have greater reductions in alpha imaginary coherence and greater enhancements in delta-theta imaginary coherence than Alzheimer's disease patients without subclinical epileptiform activity, and that these changes can distinguish between Alzheimer's disease patients with subclinical epileptiform activity and Alzheimer's disease patients without subclinical epileptiform activity with high accuracy. Finally, a principal component regression analysis showed that the variance of frequency-specific neuronal synchrony predicts longitudinal changes in Mini-Mental State Examination in patients and controls. Our results demonstrate that quantitative neurophysiological measures are sensitive biomarkers of network hyperexcitability and can be used to improve diagnosis and to select appropriate patients for the right therapy in the next-generation clinical trials. The current results provide an integrative framework for investigating network hyperexcitability and network dysfunction together with cognitive and clinical correlates in patients with Alzheimer's disease., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Laryngeal dystonia is a debilitating disorder of voicing in which the laryngeal muscles are intermittently in spasm resulting in involuntary interruptions during speech. The central pathophysiology of laryngeal dystonia, underlying computational impairments in vocal motor control, remains poorly understood. Although prior imaging studies have found aberrant activity in the CNS during phonation in patients with laryngeal dystonia, it is not known at what timepoints during phonation these abnormalities emerge and what function may be impaired. To investigate this question, we recruited 22 adductor laryngeal dystonia patients (15 female, age range = 28.83-72.46 years) and 18 controls (eight female, age range = 27.40-71.34 years). We leveraged the fine temporal resolution of magnetoencephalography to monitor neural activity around glottal movement onset, subsequent voice onset and after the onset of pitch feedback perturbations. We examined event-related beta-band (12-30 Hz) and high-gamma-band (65-150 Hz) neural oscillations. Prior to glottal movement onset, we observed abnormal frontoparietal motor preparatory activity. After glottal movement onset, we observed abnormal activity in the somatosensory cortex persisting through voice onset. Prior to voice onset and continuing after, we also observed abnormal activity in the auditory cortex and the cerebellum. After pitch feedback perturbation onset, we observed no differences between controls and patients in their behavioural responses to the perturbation. But in patients, we did find abnormal activity in brain regions thought to be involved in the auditory feedback control of vocal pitch (premotor, motor, somatosensory and auditory cortices). Our study results confirm the abnormal processing of somatosensory feedback that has been seen in other studies. However, there were several remarkable findings in our study. First, patients have impaired vocal motor activity even before glottal movement onset, suggesting abnormal movement preparation. These results are significant because (i) they occur before movement onset, abnormalities in patients cannot be ascribed to deficits in vocal performance and (ii) they show that neural abnormalities in laryngeal dystonia are more than just abnormal responses to sensory feedback during phonation as has been hypothesized in some previous studies. Second, abnormal auditory cortical activity in patients begins even before voice onset, suggesting abnormalities in setting up auditory predictions before the arrival of auditory feedback at voice onset. Generally, activation abnormalities identified in key brain regions within the speech motor network around various phonation events not only provide temporal specificity to neuroimaging phenotypes in laryngeal dystonia but also may serve as potential therapeutic targets for neuromodulation., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Neuromodulation treatment effect size for bothersome tinnitus may be larger and more predictable by adopting a target selection approach guided by personalized striatal networks or functional connectivity maps. Several corticostriatal mechanisms are likely to play a role in tinnitus, including the dorsal/ventral striatum and the putamen. We examined whether significant tinnitus treatment response by deep brain stimulation (DBS) of the caudate nucleus may be related to striatal network increased functional connectivity with tinnitus networks that involve the auditory cortex or ventral cerebellum. The first study was a cross-sectional 2-by-2 factorial design (tinnitus, no tinnitus; hearing loss, normal hearing, n = 68) to define cohort level abnormal functional connectivity maps using high-field 7.0 T resting-state fMRI. The second study was a pilot case-control series (n = 2) to examine whether tinnitus modulation response to caudate tail subdivision stimulation would be contingent on individual level striatal connectivity map relationships with tinnitus networks. Resting-state fMRI identified five caudate subdivisions with abnormal cohort level functional connectivity maps. Of those, two connectivity maps exhibited increased connectivity with tinnitus networks-dorsal caudate head with Heschl's gyrus and caudate tail with the ventral cerebellum. DBS of the caudate tail in the case-series responder resulted in dramatic reductions in tinnitus severity and loudness, in contrast to the nonresponder who showed no tinnitus modulation. The individual level connectivity map of the responder was in alignment with the cohort expectation connectivity map, where the caudate tail exhibited increased connectivity with tinnitus networks, whereas the nonresponder individual level connectivity map did not., (© 2021 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Magnetoencephalography (MEG) is increasingly used for presurgical planning in people with medically refractory focal epilepsy. Localization of interictal epileptiform activity, a surrogate for the seizure onset zone whose removal may prevent seizures, is challenging and depends on the use of multiple complementary techniques. Accurate and reliable localization of epileptiform activity from spontaneous MEG data has been an elusive goal. One approach toward this goal is to use a novel Bayesian inference algorithm-the Champagne algorithm with noise learning-which has shown tremendous success in source reconstruction, especially for focal brain sources. In this study, we localized sources of manually identified MEG spikes using the Champagne algorithm in a cohort of 16 patients with medically refractory epilepsy collected in two consecutive series. To evaluate the reliability of this approach, we compared the performance to equivalent current dipole (ECD) modeling, a conventional source localization technique that is commonly used in clinical practice. Results suggest that Champagne may be a robust, automated, alternative to manual parametric dipole fitting methods for localization of interictal MEG spikes, in addition to its previously described clinical and research applications., Competing Interests: KS was employed by company Signal Analysis Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Cai, Chen, Findlay, Mizuiri, Sekihara, Kirsch and Nagarajan.)

Little is known about language impairment in brain tumor patients, especially in the presurgical phase. Impairment in this population may be missed because standardized tests fail to capture mild deficits. Additionally, neuroplasticity may also contribute to minimizing language impairments. We examined 14 presurgical patients with brain tumors in the language-dominant hemisphere using magnetoencephalography (MEG) while they performed a demanding picture-word interference task, that is, participants name pictures while ignoring distractor words. Brain tumor patients had behavioral picture-naming effects typically observed in healthy controls. The MEG responses also showed the expected pattern in its timing and amplitude modulation typical of controls, but with an altered spatial distribution of right hemisphere sources, in contrast to the classic left hemisphere source found in healthy individuals. This finding supports tumor-induced neural reorganization of language before surgery. Crucially, the use of electrophysiology allowed us to show the "same" neuronal response in terms of its timing and amplitude modulation in the right hemisphere, supporting the hypothesis that the processes performed by the right hemisphere following reorganization are similar in nature to those (previously) performed by the left hemisphere. We also identified one participant with a fast-growing tumor affecting large parts of critical language areas and underlying ventral and dorsal white matter tracts who showed a deviant pattern in behavior and in the MEG event-related responses. In conclusion, our results attest to the validity of using a demanding picture-naming task in presurgical patients and provide evidence for neuroplasticity, with the right hemisphere performing similar computations as the left hemisphere typically performs.

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 Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

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., (© 2020 The Authors. Human Brain Mapping published by Wiley Periodicals, Inc.)

Magnetoencephalographic imaging (MEGI) offers a non-invasive alternative for defining preoperative language lateralization in neurosurgery patients. MEGI indeed can be used for accurate estimation of language lateralization with a complex language task - auditory verb generation. However, since language function may vary considerably in patients with focal lesions, it is important to optimize MEGI for estimation of language function with other simpler language tasks. The goal of this study was to optimize MEGI laterality analyses for two such simpler language tasks that can have compliance from those with impaired language function: a non-word repetition (NWR) task and a picture naming (PN) task. Language lateralization results for these two tasks were compared to the verb-generation (VG) task. MEGI reconstruction parameters (regions and time windows) for NWR and PN were first defined in a presurgical training cohort by benchmarking these against laterality indices for VG. Optimized time windows and regions of interest (ROIs) for NWR and PN were determined by examining oscillations in the beta band (12-30 Hz) a marker of neural activity known to be concordant with the VG laterality index (LI). For NWR, additional ROIs include areas MTG/ITG and for both NWR and PN, the postcentral gyrus was included in analyses. Optimal time windows for NWR were defined as 650-850 ms (stimulus-locked) and -350 to -150 ms (response-locked) and for PN -450 to -250 ms (response-locked). To verify the optimal parameters defined in our training cohort for NWR and PN, we examined an independent validation cohort ( n = 30 for NWR, n = 28 for PN) and found high concordance between VG laterality and PN laterality (82%) and between VG laterality and NWR laterality (87%). Finally, in a test cohort ( n = 8) that underwent both the intracarotid amobarbital procedure (IAP) test and MEG for VG, NWR, and PN, we identified excellent concordance (100%) with IAP for VG + NWR + PN composite LI, high concordance for PN alone (87.5%), and moderate concordance for NWR alone (66.7%). These findings provide task options for non-invasive language mapping with MEGI that can be calibrated for language abilities of individual patients. Results also demonstrate that more accurate estimates can be obtained by combining laterality estimates obtained from multiple tasks. MEGI., (Copyright © 2020 Hinkley, De Witte, Cahill-Thompson, Mizuiri, Garrett, Honma, Findlay, Gorno-Tempini, Tarapore, Kirsch, Mariën, Houde, Berger and Nagarajan.)

Objective : The adult brain's potential for plastic reorganization is an important mechanism for the preservation and restoration of function in patients with primary glial neoplasm. Patients with recurrent brain tumors requiring multiple interventions over time present an opportunity to examine brain reorganization. Magnetoencephalography (MEG) is a noninvasive imaging modality that can be used for motor cortical network mapping which, when performed at regular intervals, offers insight into this process of reorganization. Utilizing MEG-based motor mapping, we sought to characterize the reorganization of motor cortical networks over time in a cohort of 78 patients with recurrent glioma. Methods : MEG-based motor cortical maps were obtained by measuring event-related desynchronization (ERD) in ß-band frequency during unilateral index finger flexion. Each patient presented at our Department at least on two occasions for tumor resection due to tumor recurrence, and MEG-based motor mapping was performed as part of preoperative assessment before each surgical resection. Whole-brain activation patterns from first to second MEG scan (obtained before first and second surgery) were compared. Additionally, we calculated distances of activation peaks, which represent the location of the primary motor cortex (MC), to determine the magnitude of movement in motor eloquent areas between the first and second MEG scan. We also explored which demographic, anatomic, and pathological factors influence these shifts. Results : The whole-brain activation motor maps showed a subtle movement of the primary MC from first to second timepoint, as was confirmed by the determination of motor activation peaks. The shift of ipsilesional MC was directly correlated with a frontal-parietal tumor location ( p < 0.001), presence of motor deficits ( p = 0.021), and with a longer period between MEG scans ( p = 0.048). Also, a disengagement of wide areas in the contralesional (ipsilateral to finger movement) hemisphere at the second time point was observed. Conclusions : MEG imaging is a sensitive method for depicting the plasticity of the motor cortical network. Although the location of the primary MC undergoes only subtle changes, appreciable shifts can occur in the setting of a stronger and longer impairment of the tumor on the MC. The ipsilateral hemisphere may serve as a reservoir for functional recovery., (Copyright © 2020 Bulubas, Sardesh, Traut, Findlay, Mizuiri, Honma, Krieg, Berger, Nagarajan and Tarapore.)

Single-sided deafness (SSD) or profound unilateral hearing loss is the condition where the transfer of acoustic information to the brain is restricted to one ear. SSD impairment is most evident under adverse acoustic environments with overlapping interference, which burdens cognitive resources. It is known that bilateral deafness induces cross-modal brain plasticity within visual cortical areas. Here we investigate whether similar cross-modal plasticity is observed in adult-onset SSD. In SSD patients (n ​= ​29) and matched controls (n ​= ​29) we estimated voxel level resting-state power and functional connectivity in the alpha band (8-12 ​Hz) from magnetoencephalography (MEG) data. We examined both global functional connectivity (mean functional connectivity of each voxel with the rest of the brain), and seeded functional connectivity of primary auditory cortices (A1), primary visual cortices (V1) and posterior cingulate cortex (PCC) of the default mode network (DMN). Power reduction was observed in left auditory cortex. Global functional connectivity showed reduction in frontal cortices and enhancement in visual cortex. Seeded functional connectivity of auditory cortices showed reduction in temporal, frontal and occipital regions, and enhancement in parietal cortex. Interestingly, seeded functional connectivity of visual cortices showed enhancement in visual cortices, inferior parietal lobe, post-central gyrus, and the precuneus, and reduction in auditory cortex. Seeded functional connectivity of PCC showed reduction in frontal cortical regions that are part of the DMN, attention, and working memory networks. Adult-onset SSD exhibited widespread cross-modal brain plasticity involving alterations in auditory, visual, attention, working memory and default mode networks., Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Subjective tinnitus is an auditory phantom perceptual disorder without an objective biomarker. Bothersome tinnitus in single-sided deafness (SSD) is particularly challenging to treat because the deaf ear can no longer be stimulated by acoustic means. We contrasted an SSD cohort with bothersome tinnitus (TIN; N = 15) against an SSD cohort with no or non-bothersome tinnitus (NO TIN; N = 15) using resting-state functional magnetic resonance imaging (fMRI). All study participants had normal hearing in one ear and severe or profound hearing loss in the other. We evaluated corticostriatal functional connectivity differences by placing seeds in the caudate nucleus and Heschl's Gyrus (HG) of both hemispheres. The TIN cohort showed increased functional connectivity between the left caudate and left HG, and left and right HG and the left caudate. Within the TIN cohort, functional connectivity between the right caudate and cuneus was correlated with the Tinnitus Functional Index (TFI) relaxation subscale. And, functional connectivity between the right caudate and superior lateral occipital cortex, and the right caudate and anterior supramarginal gyrus were correlated with the TFI control subscale. These findings support a striatal gating model of tinnitus and suggest tinnitus biomarkers to monitor treatment response and to target specific brain areas for innovative neuromodulation therapies.

Reality monitoring is defined as the ability to distinguish internally self-generated information from externally-derived information. The medial prefrontal cortex (mPFC) is a key brain region subserving reality monitoring and has been shown to be activated specifically during the retrieval of self-generated information. However, it is unclear if mPFC is activated during the encoding of self-generated information into memory. If so, it is important to understand whether successful retrieval of self-generated information critically depends on enhanced neural activity within mPFC during initial encoding of this self-generated information. We used magnetoencephalographic imaging (MEGI) to determine the timing and location of cortical activity during a reality-monitoring task involving self generated contextual source memory encoding and retrieval. We found both during encoding and retrieval of self-generated information, when compared to externally-derived information, mPFC showed significant task induced oscillatory power modulation in the beta-band. During initial encoding of self-generated information, greater mPFC beta-band power reductions occurred within a time window of -700 ms to -500 ms prior to vocalization. This increased activity in mPFC was not observed during encoding of externally-derived information. Additionally, increased mPFC activity during encoding of self-generated information predicted subsequent retrieval accuracy of this self-generated information. Beta-band activity in mPFC was also observed during the initial retrieval of self-generated information within a time window of 300 to 500 ms following stimulus onset and correlated with accurate retrieval performance of self-generated information. Together, these results further highlight the importance of mPFC in mediating the initial generation and awareness of participants' internal thoughts.

Accurate integration of sensory inputs and motor commands is essential to achieve successful behavioral goals. A robust model of sensorimotor integration is the pitch perturbation response, in which speakers respond rapidly to shifts of the pitch in their auditory feedback. In a previous study, we demonstrated abnormal sensorimotor integration in patients with Alzheimer's disease (AD) with an abnormally enhanced behavioral response to pitch perturbation. Here we examine the neural correlates of the abnormal pitch perturbation response in AD patients, using magnetoencephalographic imaging. The participants phonated the vowel /α/ while a real-time signal processor briefly perturbed the pitch (100 cents, 400 ms) of their auditory feedback. We examined the high-gamma band (65-150 Hz) responses during this task. AD patients showed significantly reduced left prefrontal activity during the early phase of perturbation and increased right middle temporal activity during the later phase of perturbation, compared to controls. Activity in these brain regions significantly correlated with the behavioral response. These results demonstrate that impaired prefrontal modulation of speech-motor-control network and additional recruitment of right temporal regions are significant mediators of aberrant sensorimotor integration in patients with AD. The abnormal neural integration mechanisms signify the contribution of cortical network dysfunction to cognitive and behavioral deficits in AD.

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., (© 2018 Wiley Periodicals, Inc.)

Single-sided deafness (SSD) or profound unilateral hearing loss obligates the only serviceable ear to capture all acoustic information. This loss of binaural function taxes cognitive resources for accurate listening performance, especially under adverse environments or challenging tasks. We hypothesized that adults with SSD would manifest both functional and structural brain plasticity compared to controls with normal binaural hearing. We evaluated functional alterations using magnetoencephalographic imaging (MEGI) of brain activation during performance of a moderately difficult auditory syllable sequence reproduction task and assessed structural integrity using diffusion tensor imaging (DTI). MEGI showed the SSD cohort to have increased induced oscillations in the theta band over the left superior temporal cortex and decreased induced gamma band oscillations over the frontal and parietal cortices between 175 and 475 ms following stimulus onset. DTI showed the SSD cohort to have extensive fractional anisotropy (FA) reduction in both auditory and non-auditory tracts and regions. Overlaying functional and structural changes revealed by the two imaging techniques demonstrated close registration of cortical areas and white matter tracts that expressed brain plasticity. Hence, complete loss of input from one ear in adulthood triggers both functional and structural alterations to dorsal temporal and frontal-parietal areas.

Self-agency is the experience of being the agent of one's own thoughts and motor actions. The intact experience of self-agency is necessary for successful interactions with the outside world (i.e., reality monitoring) and for responding to sensory feedback of our motor actions (e.g., speech feedback control). Reality monitoring is the ability to distinguish internally self-generated information from outside reality (externally-derived information). In the present study, we examined the relationship of self-agency between lower-level speech feedback monitoring (i.e., monitoring what we hear ourselves say) and a higher-level cognitive reality monitoring task. In particular, we examined whether speech feedback monitoring and reality monitoring were driven by the capacity to experience self-agency-the ability to make reliable predictions about the outcomes of self-generated actions. During the reality monitoring task, subjects made judgments as to whether information was previously self-generated (self-agency judgments) or externally derived (external-agency judgments). During speech feedback monitoring, we assessed self-agency by altering environmental auditory feedback so that subjects listened to a perturbed version of their own speech. When subjects heard minimal perturbations in their auditory feedback while speaking, they made corrective responses, indicating that they judged the perturbations as errors in their speech output. We found that self-agency judgments in the reality-monitoring task were higher in people who had smaller corrective responses ( p = 0.05) and smaller inter-trial variability ( p = 0.03) during minimal pitch perturbations of their auditory feedback. These results provide support for a unitary process for the experience of self-agency governing low-level speech control and higher level reality monitoring.

Speech and motor deficits are highly prevalent (>70%) in individuals with the 600 kb BP4-BP5 16p11.2 deletion; however, the mechanisms that drive these deficits are unclear, limiting our ability to target interventions and advance treatment. This study examined fundamental aspects of speech motor control in participants with the 16p11.2 deletion. To assess capacity for control of voice, we examined how accurately and quickly subjects changed the pitch of their voice within a trial to correct for a transient perturbation of the pitch of their auditory feedback. When compared to controls, 16p11.2 deletion carriers show an over-exaggerated pitch compensation response to unpredictable mid-vocalization pitch perturbations. We also examined sensorimotor adaptation of speech by assessing how subjects learned to adapt their sustained productions of formants (speech spectral peak frequencies important for vowel identity), in response to consistent changes in their auditory feedback during vowel production. Deletion carriers show reduced sensorimotor adaptation to sustained vowel identity changes in auditory feedback. These results together suggest that 16p11.2 deletion carriers have fundamental impairments in the basic mechanisms of speech motor control and these impairments may partially explain the deficits in speech and language in these individuals.

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., (© The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

This study compared magnetoencephalographic (MEG) imaging-derived indices of auditory and somatosensory cortical processing in children aged 8-12 years with autism spectrum disorder (ASD; N = 18), those with sensory processing dysfunction (SPD; N = 13) who do not meet ASD criteria, and typically developing control (TDC; N = 19) participants. The magnitude of responses to both auditory and tactile stimulation was comparable across all three groups; however, the M200 latency response from the left auditory cortex was significantly delayed in the ASD group relative to both the TDC and SPD groups, whereas the somatosensory response of the ASD group was only delayed relative to TDC participants. The SPD group did not significantly differ from either group in terms of somatosensory latency, suggesting that participants with SPD may have an intermediate phenotype between ASD and TDC with regard to somatosensory processing. For the ASD group, correlation analyses indicated that the left M200 latency delay was significantly associated with performance on the WISC-IV Verbal Comprehension Index as well as the DSTP Acoustic-Linguistic index. Further, these cortical auditory response delays were not associated with somatosensory cortical response delays or cognitive processing speed in the ASD group, suggesting that auditory delays in ASD are domain specific rather than associated with generalized processing delays. The specificity of these auditory delays to the ASD group, in addition to their correlation with verbal abilities, suggests that auditory sensory dysfunction may be implicated in communication symptoms in ASD, motivating further research aimed at understanding the impact of sensory dysfunction on the developing brain.

Tinnitus is a common auditory perceptual disorder whose neural substrates are under intense debate. One physiologically based model posits the dorsal striatum to play a key role in gating auditory phantoms to perceptual awareness. Here, we directly test this model along with the roles of auditory and auditory-limbic networks in tinnitus non-invasively by comparing resting-state fMRI functional connectivity patterns in chronic tinnitus patients against matched control subjects without hearing loss. We assess resting-state functional connectivity of the caudate dorsal striatum (area LC), caudate head (CH), nucleus accumbens (NA), and primary auditory cortex (A1) to determine patterns of abnormal connectivity. In chronic tinnitus, increases in ipsilateral striatal-auditory cortical connectivity are found consistently only in area LC. Other patterns of increased connectivity are as follows: (1) right striatal area LC, A1, CH, and NA with parietal cortex, (2) left and right CHs with dorsal pre-frontal cortex, (3) NA and A1 with cerebellum, hippocampus, visual and ventral pre-frontal cortex. Those findings provide further support for a striatal gating model of tinnitus, where dysfunctionally permissive area LC enables auditory phantoms to reach perceptual awareness.

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., (© The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Understanding neural network dysfunction in neurodegenerative disease is imperative to effectively develop network-modulating therapies. In Alzheimer's disease (AD), cognitive decline associates with deficits in resting-state functional connectivity of diffuse brain networks. The goal of the current study was to test whether specific cognitive impairments in AD spectrum correlate with reduced functional connectivity of distinct brain regions. We recorded resting-state functional connectivity of alpha-band activity in 27 patients with AD spectrum--22 patients with probable AD (5 logopenic variant primary progressive aphasia, 7 posterior cortical atrophy, and 10 early-onset amnestic/dysexecutive AD) and 5 patients with mild cognitive impairment due to AD. We used magnetoencephalographic imaging (MEGI) to perform an unbiased search for regions where patterns of functional connectivity correlated with disease severity and cognitive performance. Functional connectivity measured the strength of coherence between a given region and the rest of the brain. Decreased neural connectivity of multiple brain regions including the right posterior perisylvian region and left middle frontal cortex correlated with a higher degree of disease severity. Deficits in executive control and episodic memory correlated with reduced functional connectivity of the left frontal cortex, whereas visuospatial impairments correlated with reduced functional connectivity of the left inferior parietal cortex. Our findings indicate that reductions in region-specific alpha-band resting-state functional connectivity are strongly correlated with, and might contribute to, specific cognitive deficits in AD spectrum. In the future, MEGI functional connectivity could be an important biomarker to map and follow defective networks in the early stages of AD.