Distinct neurophysiology during nonword repetition in logopenic and non-fluent variants of primary progressive aphasia.

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.

Striatal networks for tinnitus treatment targeting.

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.

Multiple Midfrontal Thetas Revealed by Source Separation of Simultaneous MEG and EEG.

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.

Taking the sublexical route: brain dynamics of reading in the semantic variant of primary progressive aphasia.

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.

Sensorimotor Cortical Oscillations during Movement Preparation in 16p11.2 Deletion Carriers.

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.

Language Neuroplasticity in Brain Tumor Patients Revealed by Magnetoencephalography.

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.

Cross-modal plasticity in adult single-sided deafness revealed by alpha band resting-state functional connectivity.

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 â€‹= â€‹29) and matched controls (n â€‹= â€‹29) we estimated voxel level resting-state power and functional connectivity in the alpha band (8-12 â€‹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.

Global resting-state functional connectivity of neural oscillations in tinnitus with and without hearing loss.

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.

MEG imaging of recurrent gliomas reveals functional plasticity of hemispheric language specialization.

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.

Distinct spatiotemporal patterns of neuronal functional connectivity in primary progressive aphasia variants.

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 Contribution of the Corpus Callosum to Language Lateralization.

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 STATEMENT: The 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.

Global and regional functional connectivity maps of neural oscillations in focal epilepsy.

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.

Global MEG Resting State Functional Connectivity in Children with Autism and Sensory Processing Dysfunction.

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.

Dynamics of hemispheric dominance for language assessed by magnetoencephalographic imaging.

OBJECTIVE: The goal of the current study was to examine the dynamics of language lateralization using magnetoencephalographic (MEG) imaging, to determine the sensitivity and specificity of MEG imaging, and to determine whether MEG imaging can become a viable alternative to the intracarotid amobarbital procedure (IAP), the current gold standard for preoperative language lateralization in neurosurgical candidates. METHODS: MEG was recorded during an auditory verb generation task and imaging analysis of oscillatory activity was initially performed in 21 subjects with epilepsy, brain tumor, or arteriovenous malformation who had undergone IAP and MEG. Time windows and brain regions of interest that best discriminated between IAP-determined left or right dominance for language were identified. Parameters derived in the retrospective analysis were applied to a prospective cohort of 14 patients and healthy controls. RESULTS: Power decreases in the beta frequency band were consistently observed following auditory stimulation in inferior frontal, superior temporal, and parietal cortices; similar power decreases were also seen in inferior frontal cortex prior to and during overt verb generation. Language lateralization was clearly observed to be a dynamic process that is bilateral for several hundred milliseconds during periods of auditory perception and overt speech production. Correlation with the IAP was seen in 13 of 14 (93%) prospective patients, with the test demonstrating a sensitivity of 100% and specificity of 92%. INTERPRETATION: Our results demonstrate excellent correlation between MEG imaging findings and the IAP for language lateralization, and provide new insights into the spatiotemporal dynamics of cortical speech processing.

Abnormal resting-state functional connectivity underlies cognitive and clinical symptoms in patients with schizophrenia.

Introduction: The cognitive and psychotic symptoms in patients with schizophrenia (SZ) are thought to result from disrupted brain network connectivity. Methods: We capitalize on the high spatiotemporal resolution of magnetoencephalography imaging (MEG) to record spontaneous neuronal activity in resting state networks in 21 SZ compared with 21 healthy controls (HC). Results: We found that SZ showed significant global disrupted functional connectivity in delta-theta (2-8 Hz), alpha (8-12 Hz), and beta (12-30 Hz) frequencies, compared to HC. Disrupted global connectivity in alpha frequencies with bilateral frontal cortices was associated with more severe clinical psychopathology (i.e., positive psychotic symptoms). Specifically, aberrant connectivity in beta frequencies between the left primary auditory cortex and cerebellum, was linked to greater hallucination severity in SZ. Disrupted connectivity in delta-theta frequencies between the medial frontal and left inferior frontal cortex was associated with impaired cognition. Discussion: The multivariate techniques employed in the present study highlight the importance of applying our source reconstruction techniques which leverage the high spatial localization abilities of MEG for estimating neural source activity using beamforming methods such as SAM (synthetic aperture morphometry) to reconstruct the source of brain activity, together with functional connectivity assessments, assayed with imaginary coherence metrics, to delineate how neurophysiological dysconnectivity in specific oscillatory frequencies between distinct regions underlie the cognitive and psychotic symptoms in SZ. The present findings employ powerful techniques in spatial and time-frequency domains to provide potential neural biomarkers underlying neuronal network dysconnectivity in SZ that will inform the development of innovations in future neuromodulation treatment development.

Neurophysiological evidence of sensory prediction errors driving speech sensorimotor adaptation.

The human sensorimotor system has a remarkable ability to quickly and efficiently learn movements from sensory experience. A prominent example is sensorimotor adaptation, learning that characterizes the sensorimotor system's response to persistent sensory errors by adjusting future movements to compensate for those errors. Despite being essential for maintaining and fine-tuning motor control, mechanisms underlying sensorimotor adaptation remain unclear. A component of sensorimotor adaptation is implicit (i.e., the learner is unaware of the learning process) which has been suggested to result from sensory prediction errors-the discrepancies between predicted sensory consequences of motor commands and actual sensory feedback. However, to date no direct neurophysiological evidence that sensory prediction errors drive adaptation has been demonstrated. Here, we examined prediction errors via magnetoencephalography (MEG) imaging of the auditory cortex during sensorimotor adaptation of speech to altered auditory feedback, an entirely implicit adaptation task. Specifically, we measured how speaking-induced suppression (SIS)--a neural representation of auditory prediction errors--changed over the trials of the adaptation experiment. SIS refers to the suppression of auditory cortical response to speech onset (in particular, the M100 response) to self-produced speech when compared to the response to passive listening to identical playback of that speech. SIS was reduced (reflecting larger prediction errors) during the early learning phase compared to the initial unaltered feedback phase. Furthermore, reduction in SIS positively correlated with behavioral adaptation extents, suggesting that larger prediction errors were associated with more learning. In contrast, such a reduction in SIS was not found in a control experiment in which participants heard unaltered feedback and thus did not adapt. In addition, in some participants who reached a plateau in the late learning phase, SIS increased (reflecting smaller prediction errors), demonstrating that prediction errors were minimal when there was no further adaptation. Together, these findings provide the first neurophysiological evidence for the hypothesis that prediction errors drive human sensorimotor adaptation.

Reduced neural connectivity in the caudate anterior head predicts hallucination severity in schizophrenia.

BACKGROUND: Caudate functional abnormalities have been identified as one critical neural substrate underlying sensory gating impairments that lead to auditory phantom hallucinations in both patients with schizophrenia (SZ) and tinnitus, characterized by the perception of internally generated sounds in the absence of external environmental auditory stimuli. In this study, we tested the hypothesis as to whether functional connectivity abnormalities in distinct caudate subdivisions implicated in sensory gating and auditory phantom percepts in tinnitus, which are currently being localized for neuromodulation targeting using deep brain stimulation techniques, would be associated with auditory phantom hallucination severity in SZ. METHODS: Twenty five SZ and twenty eight demographically-matched healthy control (HC) participants, completed this fMRI resting-state study and clinical assessments. RESULTS: Between-group seed-to-voxel analyses revealed only one region, the caudate anterior head, which showed reduced functional connectivity with the thalamus that survived whole-brain multiple comparison corrections. Importantly, connectivity between the caudate anterior head with thalamus negatively correlated with hallucination severity. CONCLUSIONS: In the present study, we deliver the first evidence of caudate subdivision specificity for the neural pathophysiology underlying hallucinations in schizophrenia within a sensory gating framework that has been developed for auditory phantoms in patients with tinnitus. Our findings provide transdiagnostic convergent evidence for the role of the caudate in the gating of auditory phantom hallucinations, observed across patients with SZ and tinnitus by specifying the anterior caudate division is key to mediation of hallucinations, and creating a path towards personalized treatment approaches to arrest auditory phantom hallucinations from reaching perceptual awareness.

Multi-tasking deep network for tinnitus classification and severity prediction from multimodal structural MR images.

Objective:Subjective tinnitus is an auditory phantom perceptual disorder without an objective biomarker. Fast and efficient diagnostic tools will advance clinical practice by detecting or confirming the condition, tracking change in severity, and monitoring treatment response. Motivated by evidence of subtle anatomical, morphological, or functional information in magnetic resonance images of the brain, we examine data-driven machine learning methods for joint tinnitus classification (tinnitus or no tinnitus) and tinnitus severity prediction.Approach:We propose a deep multi-task multimodal framework for tinnitus classification and severity prediction using structural MRI (sMRI) data. To leverage complementary information multimodal neuroimaging data, we integrate two modalities of three-dimensional sMRI-T1 weighted (T1w) and T2 weighted (T2w) images. To explore the key components in the MR images that drove task performance, we segment both T1w and T2w images into three different components-cerebrospinal fluid, grey matter and white matter, and evaluate performance of each segmented image.Main results:Results demonstrate that our multimodal framework capitalizes on the information across both modalities (T1w and T2w) for the joint task of tinnitus classification and severity prediction.Significance:Our model outperforms existing learning-based and conventional methods in terms of accuracy, sensitivity, specificity, and negative predictive value.

Cortical temporal dynamics of visually guided behavior.

Little is known about the temporal dynamics of cortical activation during visually guided behavior. We measured changes in brain activity in human posterior parietal cortex (PPC) and premotor cortex (PMC) during saccades and visually guided reaching using magnetoencephalography (MEG) and novel time-frequency reconstructions of MEG (tfMEG) data. Results indicate that early high-gamma activity over the frontal eye fields (FEFs) was present during saccade preparation, and high-gamma activity progressed from the supplementary and FEFs to visual cortex during saccade execution. In contrast, early high-gamma activity over dorsal PMC and late beta activity in primary motor cortex and PPC were unique to reach preparation. During reaching, high-gamma activity progressed from sensorimotor cortex and PMC to parietooccipital cortex. These unique spatial-temporal processing patterns reflect the known connectivity of 2 different sensorimotor networks in macaques. The onset and duration of activity in these areas provides direct evidence for concurrent serial and parallel processing in the human brain during the integration of the sensorimotor inputs necessary for visually guided performance.

Abnormal Information Flow in Schizophrenia Is Linked to Psychosis.

BACKGROUND AND HYPOTHESIS: Prior research has shown that patients with schizophrenia (SZ) show disruption in brain network connectivity that is thought to underlie their cognitive and psychotic symptoms. However, most studies examining functional network disruption in schizophrenia have focused on the temporally correlated coupling of the strength of network connections. Here, we move beyond correlative metrics to assay causal computations of connectivity changes in directed neural information flow, assayed from a neural source to a target in SZ. STUDY DESIGN: This study describes a whole-brain magnetoencephalography-imaging approach to examine causal computations of connectivity changes in directed neural information flow between brain regions during resting states, quantified by phase-transfer entropy (PTE) metrics, assayed from a neural source to an endpoint, in 21 SZ compared with 21 healthy controls (HC), and associations with cognitive and clinical psychotic symptoms in SZ. STUDY RESULTS: We found that SZ showed significant disruption in information flow in alpha (8-12 Hz) and beta (12-30 Hz) frequencies, compared to HC. Reduced information flow in alpha frequencies from the precuneus to the medio-ventral occipital cortex was associated with more severe clinical psychopathology (ie, positive psychotic symptoms), while reduced information flow between insula and middle temporal gyrus was associated with worsening cognitive symptoms. CONCLUSIONS: The present findings highlight the importance of delineating dysfunction in neural information flow in specific oscillatory frequencies between distinct regions that underlie the cognitive and psychotic symptoms in SZ, and provide potential neural biomarkers that could lead to innovations in future neuromodulation treatment development.