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.

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.

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.

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.

Auditory Verb Generation Performance Patterns Dissociate Variants of Primary Progressive Aphasia.

Primary progressive aphasia (PPA) is a clinical syndrome in which patients progressively lose speech and language abilities. Three variants are recognized: logopenic (lvPPA), associated with phonology and/or short-term verbal memory deficits accompanied by left temporo-parietal atrophy; semantic (svPPA), associated with semantic deficits and anterior temporal lobe (ATL) atrophy; non-fluent (nfvPPA) associated with grammar and/or speech-motor deficits and inferior frontal gyrus (IFG) atrophy. Here, we set out to investigate whether the three variants of PPA can be dissociated based on error patterns in a single language task. We recruited 21 lvPPA, 28 svPPA, and 24 nfvPPA patients, together with 31 healthy controls, and analyzed their performance on an auditory noun-to-verb generation task, which requires auditory analysis of the input, access to and selection of relevant lexical and semantic knowledge, as well as preparation and execution of speech. Task accuracy differed across the three variants and controls, with lvPPA and nfvPPA having the lowest and highest accuracy, respectively. Critically, machine learning analysis of the different error types yielded above-chance classification of patients into their corresponding group. An analysis of the error types revealed clear variant-specific effects: lvPPA patients produced the highest percentage of "not-a-verb" responses and the highest number of semantically related nouns (production of baseball instead of throw to noun ball); in contrast, svPPA patients produced the highest percentage of "unrelated verb" responses and the highest number of light verbs (production of take instead of throw to noun ball). Taken together, our findings indicate that error patterns in an auditory verb generation task are associated with the breakdown of different neurocognitive mechanisms across PPA variants. Specifically, they corroborate the link between temporo-parietal regions with lexical processing, as well as ATL with semantic processes. These findings illustrate how the analysis of pattern of responses can help PPA phenotyping and heighten diagnostic sensitivity, while providing insights on the neural correlates of different components of language.

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.

A Neural Biomarker for Hallucinations: Medial Prefrontal Aberrations in Neural Connectivity Predict Self-Agency Deficits and Hallucination Severity in Schizophrenia.

Prior studies have shown that the medial prefrontal cortex (mPFC) represents one neural substrate that mediates judgments of self-agency (i.e., the awareness that 'I am the originator of my actions'). Patients with schizophrenia (SZ) manifest cardinal self-agency deficits that contribute to debilitating psychotic symptoms (e.g. hallucinations) and distort reality monitoring. This is the first study in which we examine across 2 SZ samples, the mPFC site that underlies self-agency deficits during an explicit reality-monitoring task (i.e., while subjects distinguish self-generated information from externally-derived information) in one SZ sample, and link intrinsic functional connectivity (iFC) during rest within this a priori task-evoked self-agency seed with hallucination symptoms in a different SZ sample. In particular, we examined the iFC between the mPFC site that underlies self-agency deficits with all other brain regions in SZ using resting-state functional magnetic resonance imaging (fMRI). Resting-state fMRI data were collected from 32 SZ and 28 age, gender, and education-matched healthy control (HC) subjects. Functional connectivity maps were computed for each subject and compared between the HC and SZ groups. Within-group and between-group analyses revealed that aberrant iFC in this a priori-defined mPFC 'self-agency seed' predicted hallucination severity. The present findings reveal that the neural aberrations in this mPFC site represents one cardinal biomarker that underlies explicit self-agency deficits during a reality-monitoring task in one SZ sample that generalized to aberrant iFC differences in a different SZ sample and predicted worsening psychotic hallucinatory experiences. This region may represent a key neurobiological target for treatment avenues to improve hallucinatory symptoms.

NUTMEG: Open Source Software for M/EEG Source Reconstruction.

Neurodynamic Utility Toolbox for Magnetoencephalo- and Electroencephalography (NUTMEG) is an open-source MATLAB-based toolbox for the analysis and reconstruction of magnetoencephalography/electroencephalography data in source space. NUTMEG includes a variety of options for the user in data import, preprocessing, source reconstruction, and functional connectivity. A group analysis toolbox allows the user to run a variety of inferential statistics on their data in an easy-to-use GUI-driven format. Importantly, NUTMEG features an interactive five-dimensional data visualization platform. A key feature of NUTMEG is the availability of a large menu of interference cancelation and source reconstruction algorithms. Each NUTMEG operation acts as a stand-alone MATLAB function, allowing the package to be easily adaptable and scripted for the more advanced user for interoperability with other software toolboxes. Therefore, NUTMEG enables a wide range of users access to a complete "sensor-to- source-statistics" analysis pipeline.

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.

Optimizing Magnetoencephalographic Imaging Estimation of Language Lateralization for Simpler Language Tasks.

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.

Intervention-specific patterns of cortical function plasticity during auditory encoding in people with schizophrenia.

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

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.

Beta-band activity in medial prefrontal cortex predicts source memory encoding and retrieval accuracy.

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.

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.

Complex-value coherence mapping reveals novel abnormal resting-state functional connectivity networks in task-specific focal hand dystonia.

Resting-state imaging designs are powerful in modeling functional networks in movement disorders because they eliminate task performance related confounds. However, the most common metric for quantifying functional connectivity, i.e., bivariate magnitude coherence (Coh), can sometimes be contaminated by spurious correlations in blood-oxygen level dependent (BOLD) signal due to smoothing and seed blur, thereby limiting the identification of true interactions between neighboring neural populations. Here, we apply a novel functional connectivity metric., i.e., imaginary coherence (ICoh), to BOLD fMRI data in healthy individuals and patients with task-specific focal hand dystonia (tspFHD), in addition to the traditional magnitude Coh metric. We reconstructed resting-state sensorimotor, basal ganglia, and default-mode networks using both Coh and ICoh. We demonstrate that indeed the ICoh metric eliminates spatial blur around seed placement and reflects slightly different networks from Coh. We then identified significant reductions in resting-state connectivity within both the sensorimotor and basal ganglia networks in patients with tspFHD, primarily in the hemisphere contralateral to the affected hand. Collectively, these findings direct our attention to the fact that multiple networks are decoupled in tspFHD that can be unraveled by different functional connectivity metrics, and that this aberrant communication contributes to clinical deficits in the disorder.

Resting-state networks and the functional connectome of the human brain in agenesis of the corpus callosum.

The corpus callosum is the largest white matter fiber bundle connecting the two cerebral hemispheres. In this work, we investigate the effect of callosal dysgenesis on functional magnetic resonance imaging (fMRI) resting-state networks and the functional connectome. Since alternate commissural routes between the cerebral hemispheres exist, we hypothesize that bilateral cortical networks can still be maintained in partial or even complete agenesis of the corpus callosum (AgCC). However, since these commissural routes are frequently indirect, requiring polysynaptic pathways, we hypothesize that quantitative measurements of interhemispheric functional connectivity in bilateral networks will be reduced in AgCC compared with matched controls, especially in the most highly interconnected cortical regions that are the hubs of the connectome. Seventeen resting-state networks were extracted from fMRI of 11 subjects with partial or complete AgCC and 11 matched controls. The results show that the qualitative organization of resting-state networks is very similar between controls and AgCC. However, interhemispheric functional connectivity of precuneus, posterior cingulate cortex, and insular-opercular regions was significantly reduced in AgCC. The preserved network organization was confirmed with a connectomic analysis of the resting-state fMRI data, showing five functional modules that are largely consistent across the control and AgCC groups. Hence, the reduction or even complete absence of callosal connectivity does not affect the qualitative organization of bilateral resting-state networks or the modular organization of the functional connectome, although quantitatively reduced functional connectivity can be demonstrated by measurements within bilateral cortical hubs, supporting the hypothesis that indirect polysynaptic pathways are utilized to preserve interhemispheric temporal synchrony.

Autism traits in individuals with agenesis of the corpus callosum.

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

Aberrant Oscillatory Activity during Simple Movement in Task-Specific Focal Hand Dystonia.

In task-specific focal hand dystonia (tspFHD), the temporal dynamics of cortical activity in the motor system and how these processes are related to impairments in sensory and motor function are poorly understood. Here, we use time-frequency reconstructions of magnetoencephalographic (MEG) data to elaborate the temporal and spatial characteristics of cortical activity during movement. A self-paced finger tapping task during MEG recording was performed by 11 patients with tspFHD and 11 matched healthy controls. In both groups robust changes in beta (12-30 Hz) and high gamma (65-90 Hz) oscillatory activity were identified over sensory and motor cortices during button press. A significant decrease [p < 0.05, 1% False Discovery Rate (FDR) corrected] in high gamma power during movements of the affected hand was identified over ipsilateral sensorimotor cortex in the period prior to (-575 ms) and following (725 ms) button press. Furthermore, an increase (p < 0.05, 1% FDR corrected) in beta power suppression following movement of the affected hand was identified over visual cortex in patients with tspFHD. For movements of the unaffected hand, a significant (p < 0.05, 1% FDR corrected) increase in beta power suppression was identified over secondary somatosensory cortex (S2) in the period following button press in patients with tspFHD. Oscillatory activity within in the tspFHD group was however not correlated with clinical measures. Understanding these aberrant oscillatory dynamics can provide the groundwork for interventions that focus on modulating the timing of this activity.

The role of corpus callosum development in functional connectivity and cognitive processing.

The corpus callosum is hypothesized to play a fundamental role in integrating information and mediating complex behaviors. Here, we demonstrate that lack of normal callosal development can lead to deficits in functional connectivity that are related to impairments in specific cognitive domains. We examined resting-state functional connectivity in individuals with agenesis of the corpus callosum (AgCC) and matched controls using magnetoencephalographic imaging (MEG-I) of coherence in the alpha (8-12 Hz), beta (12-30 Hz) and gamma (30-55 Hz) bands. Global connectivity (GC) was defined as synchronization between a region and the rest of the brain. In AgCC individuals, alpha band GC was significantly reduced in the dorsolateral pre-frontal (DLPFC), posterior parietal (PPC) and parieto-occipital cortices (PO). No significant differences in GC were seen in either the beta or gamma bands. We also explored the hypothesis that, in AgCC, this regional reduction in functional connectivity is explained primarily by a specific reduction in interhemispheric connectivity. However, our data suggest that reduced connectivity in these regions is driven by faulty coupling in both inter- and intrahemispheric connectivity. We also assessed whether the degree of connectivity correlated with behavioral performance, focusing on cognitive measures known to be impaired in AgCC individuals. Neuropsychological measures of verbal processing speed were significantly correlated with resting-state functional connectivity of the left medial and superior temporal lobe in AgCC participants. Connectivity of DLPFC correlated strongly with performance on the Tower of London in the AgCC cohort. These findings indicate that the abnormal callosal development produces salient but selective (alpha band only) resting-state functional connectivity disruptions that correlate with cognitive impairment. Understanding the relationship between impoverished functional connectivity and cognition is a key step in identifying the neural mechanisms of language and executive dysfunction in common neurodevelopmental and psychiatric disorders where disruptions of callosal development are consistently identified.

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.