The Role of the Primary Sensory Cortices in Early Language Processing.

The results of this magnetoencephalography study challenge two long-standing assumptions regarding the brain mechanisms of language processing: First, that linguistic processing proper follows sensory feature processing effected by bilateral activation of the primary sensory cortices that lasts about 100 msec from stimulus onset. Second, that subsequent linguistic processing is effected by left hemisphere networks outside the primary sensory areas, including Broca's and Wernicke's association cortices. Here we present evidence that linguistic analysis begins almost synchronously with sensory, prelinguistic verbal input analysis and that the primary cortices are also engaged in these linguistic analyses and become, consequently, part of the left hemisphere language network during language tasks. These findings call for extensive revision of our conception of linguistic processing in the brain.

Is it time to replace the Wada test and put awake craniotomy to sleep?

The question we address here is whether the invasive presurgical brain mapping approaches of direct cortical stimulation and of the Wada procedure can be replaced by noninvasive functional neuroimaging methods (functional magnetic resonance imaging [fMRI], magnetoencephalography [MEG], transcranial magnetic stimulation and [TMS]). First, we outline the reasons for contemplating such a replacement. Second, we present evidence to the effect that the efficacy of the invasive and noninvasive methods, while suboptimal, is comparable. Third, we discuss additional advantages of noninvasive presurgical brain mapping and conclude that there are no longer compelling reasons for opting for invasive mapping in many if not most cases provided that the non-invasive methods are available.

Comparing the efficacy of awake and sedated MEG to TMS in mapping hand sensorimotor cortex in a clinical cohort.

Non-invasive methods such as Transcranial Magnetic Stimulation (TMS) and magnetoencephalography (MEG) aid in the pre-surgical evaluation of patients with epilepsy or brain tumor to identify sensorimotor cortices. MEG requires sedation in children or patients with developmental delay. However, TMS can be applied to awake patients of all ages with any cognitive abilities. In this study, we compared the efficacy of TMS with MEG (in awake and sedated states) in identifying the hand sensorimotor areas in patients with epilepsy or brain tumors. We identified 153 patients who underwent awake- (n = 98) or sedated-MEG (n = 55), along with awake TMS for hand sensorimotor mapping as part of their pre-surgical evaluation. TMS involved stimulating the precentral gyrus and recording electromyography responses, while MEG identified the somatosensory cortex during median nerve stimulation. Awake-MEG had a success rate of 92.35 % and TMS had 99.49 % (p-value = 0.5517). However, in the sedated-MEG cohort, TMS success rate of 95.61 % was significantly higher compared to MEG's 58.77 % (p-value = 0.0001). Factors affecting mapping success were analyzed. Logistic regression across the entire cohort identified patient sedation as the lone significant predictor, contrary to age, lesion, metal, and number of antiseizure medications (ASMs). A subsequent analysis replaced sedation with anesthetic drug dosage, revealing no significant predictors impacting somatosensory mapping success under sedation. This study yields insights into the utility of TMS and MEG in mapping hand sensorimotor cortices and underscores the importance of considering factors that influence eloquent cortex mapping limitations during sedation.

Concordance between Wada, Transcranial Magnetic Stimulation, and Magnetoencephalography for Determining Hemispheric Dominance for Language: A Retrospective Study.

Determination of language hemispheric dominance (HD) in patients undergoing evaluation for epilepsy surgery has traditionally relied on the sodium amobarbital (Wada) test. The emergence of non-invasive methods for determining language laterality has increasingly shown to be a viable alternative. In this study, we assessed the efficacy of transcranial magnetic stimulation (TMS) and magnetoencephalography (MEG), compared to the Wada test, in determining language HD in a sample of 12 patients. TMS-induced speech errors were classified as speech arrest, semantic, or performance errors, and the HD was based on the total number of errors in each hemisphere with equal weighting of all errors (classic) and with a higher weighting of speech arrests and semantic errors (weighted). Using MEG, HD for language was based on the spatial extent of long-latency activity sources localized to receptive language regions. Based on the classic and weighted language laterality index (LI) in 12 patients, TMS was concordant with the Wada in 58.33% and 66.67% of patients, respectively. In eight patients, MEG language mapping was deemed conclusive, with a concordance rate of 75% with the Wada test. Our results indicate that TMS and MEG have moderate and strong agreement, respectively, with the Wada test, suggesting they could be used as non-invasive substitutes.

Transcranial magnetic stimulation and magnetoencephalography are feasible alternatives to invasive methods in optimizing responsive neurostimulation device placement.

Responsive neurostimulation (RNS) is a treatment option for patients with refractory epilepsy when surgical resection is not possible due to overlap of the irritative zone and eloquent cortex. Presurgical evaluations for RNS placement typically rely on invasive methods. This study investigated the potential of transcranial magnetic stimulation (TMS) and magnetoencephalography (MEG) to provide key presurgical information non-invasively. We hypothesized that these non-invasive methods may assist in optimizing RNS placement by providing useful information for seizure localization by MEG and eloquent cortex mapping by TMS. A retrospective chart review identified nine patients who underwent RNS placement (mean age = 20.4 years [SD = 5.6], two-thirds were female). Characterization of the irritative zone using MEG was successful in eight of nine patients. Non-invasive mapping of relevant eloquent cortex was attempted in all patients. TMS was successful in eight of nine patients, and MEG was successful in two of six patients. Importantly, patients mapped with non-invasive modalities experienced an average seizure reduction of 77 % at their most recent clinic visit, compared to 75 % seizure reduction in those with invasive evaluations, indicating appropriate RNS placement. These data demonstrate that TMS and MEG can provide key information for RNS and may be feasible alternatives to invasive methods for assisting in decision making regarding RNS placement. Non-invasive methods for determining RNS placement have a high rate of success when data from multiple non-invasive modalities converge and can inform more accurate placement of intracranial electrodes prior to RNS placement or mitigate their need.

Single-trial magnetoencephalography signals encoded as an unfolding decision process.

The model of a stochastic decision process unfolding in motor and premotor regions of the brain was encoded in single-trial magnetoencephalographic (MEG) recordings while ten healthy subjects performed a sensorimotor Reaction Time (RT) task. The duration of single-trial MEG signals preceding the motor response, recorded over the motor cortex contralateral to the responding hand, co-varied with RT across trials according to the model's prediction. Furthermore, these signals displayed the same properties of a "rising-to-a-fixed-threshold" decision process as posited by the model and observed in the activity of single neurons in the primate cortex. The present findings demonstrate that non-averaged, single-trial MEG recordings can be used to test models of cognitive processes, like decision-making, in humans.

Ventromedial prefrontal volume predicts understanding of others and social network size.

Cognitive abilities such as Theory of Mind (ToM), and more generally mentalizing competences, are central to human sociality. Neuroimaging has associated these abilities with specific brain regions including temporo-parietal junction, superior temporal sulcus, frontal pole, and ventromedial prefrontal cortex. Previous studies have shown both that mentalizing competence, indexed as the ability to correctly understand others' belief states, is associated with social network size and that social group size is correlated with frontal lobe volume across primate species (the social brain hypothesis). Given this, we predicted that both mentalizing competences and the number of social relationships a person can maintain simultaneously will be a function of gray matter volume in these regions associated with conventional Theory of Mind. We used voxel-based morphometry of Magnetic Resonance Images (MRIs) to test this hypothesis in humans. Specifically, we regressed individuals' mentalizing competences and social network sizes against gray matter volume. This revealed that gray matter volume in bilateral posterior frontal pole and left temporoparietal junction and superior temporal sucus varies parametrically with mentalizing competence. Furthermore, gray matter volume in the medial orbitofrontal cortex and the ventral portion of medial frontal gyrus, varied parametrically with both mentalizing competence and social network size, demonstrating a shared neural basis for these very different facets of sociality. These findings provide the first fine-grained anatomical support for the social brain hypothesis. As such, they have important implications for our understanding of the constraints limiting social cognition and social network size in humans, as well as for our understanding of how such abilities evolved across primates.

Temporo-parietal brain activity as a longitudinal predictor of response to educational interventions among middle school struggling readers.

Spatiotemporal brain activation profiles were obtained from 27 middle school students experiencing difficulties in reading comprehension as well as word-level skills (RD) and 23 age- and IQ-matched non-reading impaired students during performance of an oral pseudoword reading task using Magnetoencephalography (MEG). Based on their scores on standardized reading fluency tests 1 year later, students with RD who showed significant improvement were classified as Adequate Responders (AR) whereas those not demonstrating such gains were classified as Inadequate Responders (IR). At baseline, activation profiles of the AR group featured increased activity in the left supramarginal and angular gyri, as well as in the superior and middle temporal gyri, bilaterally compared to IR. The degree of activity in these regions was a significant predictor of the amount of subsequent gains in reading fluency. These results extend previous functional brain imaging findings of beginning readers, suggesting that recruitment of brain areas that typically serve as key components of the brain circuit for reading is an important factor in determining response to intervention in older struggling readers.

The Clinical Utility of Transcranial Magnetic Stimulation in Determining Hemispheric Dominance for Language: A Magnetoencephalography Comparison Study.

PURPOSE: Transcranial magnetic stimulation (TMS) has recently emerged as a noninvasive alternative to the intracarotid sodium amytal (Wada) procedure for establishing hemispheric dominance (HD) for language. The accuracy of HD determined by TMS was examined by comparing against the HD derived by magnetoencephalography (MEG), a prominent clinical technique with excellent concordance with the Wada procedure. METHODS: Sixty-seven patients (54 patients ≤18 years) underwent language mapping with TMS and MEG as part of clinical epilepsy and tumor presurgical assessment. Language was mapped in MEG during an auditory word recognition paradigm, and a laterality index was calculated using the number of dipoles and their spatial extent in the two hemispheres. Transcranial magnetic stimulation language mapping was performed as patients performed a naming task, and TMS-induced speech disruptions were recorded during 5-Hz TMS applied to anterior and posterior language cortices. Transcranial magnetic stimulation laterality index was estimated using the number and type of speech disruption in the language regions of each hemisphere. RESULTS: Transcranial magnetic stimulation and MEG estimates of HD were concordant in 42 (63%) patients, resulting in a sensitivity of 74% and a specificity of 72%. The overall accuracy of TMS was 73%, equivalent to an odds ratio of 7.35. CONCLUSIONS: In this first large-scale comparative study in a clinical population, we demonstrate that TMS is a safe and reliable noninvasive tool in determining HD for language. Improving the accuracy of TMS by optimizing TMS parameters and improving task choice will further facilitate the use of TMS to characterize language function, especially in pediatrics.

The influence of sex chromosome aneuploidy on brain asymmetry.

The cognitive deficits present in individuals with sex chromosome aneuploidies suggest that hemispheric differentiation of function is determined by an X-Y homologous gene [Crow (1993); Lancet 342:594-598]. In particular, females with Turner's syndrome (TS) who have only one X-chromosome exhibit deficits of spatial ability whereas males with Klinefelter's syndrome (KS) who possess a supernumerary X-chromosome are delayed in acquiring words. Since spatial and verbal abilities are generally associated with right and left hemispheric function, such deficits may relate to anomalies of cerebral asymmetry. We therefore applied a novel image analysis technique to investigate the relationship between sex chromosome dosage and structural brain asymmetry. Specifically, we tested Crow's prediction that the magnitude of the brain torque (i.e., a combination of rightward frontal and leftward occipital asymmetry) would, as a function of sex chromosome dosage, be respectively decreased in TS women and increased in KS men, relative to genotypically normal controls. We found that brain torque was not significantly different in TS women and KS men, in comparison to controls. However, TS women exhibited significantly increased leftward brain asymmetry, restricted to the posterior of the brain and focused on the superior temporal and parietal-occipital association cortex, while KS men showed a trend for decreased brain asymmetry throughout the frontal lobes. The findings suggest that the number of sex chromosomes influences the development of brain asymmetry not simply to modify the torque but in a complex pattern along the antero-posterior axis.

The auditory and association cortex and language evaluation methods.

This chapter presents a summary of current notions regarding cortical specialization for language and a description of the methods employed for the assessment of that specialization. We distinguish between the "canonical" model of language specialization as it evolved from the early observations of Broca and Wernicke, implicating the inferior frontal gyrus and the posterior temporal cortex of the speech dominant hemisphere (usually the left) and its modern variants that are based on both detailed studies of lesion-symptom correlations and on the results of functional brain mapping methods. The latter fall into two categories. The first includes the invasive ones, namely the Wada procedure for assessing hemispheric dominance for speech and cortical stimulation mapping (whether intraoperative or extraoperative) for identifying cortical nodes or "hubs" of the neuronal network for language. The second category includes the noninvasive methods of functional magnetic resonance imaging, magnetoencephalography, and transcranial magnetic stimulation used for both assessment of hemispheric dominance for language and for localization of the cortical nodes of the language network. The advantages and the shortcomings of all methods are juxtaposed to facilitate selection of particular methods of assessment of the locus of the language network in particular cases.

Crossed cerebral lateralization for verbal and visuo-spatial function in a pair of handedness discordant monozygotic twins: MRI and fMRI brain imaging.

To examine the nature of hemispheric lateralization for neural processes underlying verbal fluency and visuo-spatial attention, we investigated a single pair of handedness discordant monozygotic (MzHd) twins. Imaging of the brain was undertaken using magnetic resonance imaging (MRI) and functional magnetic resonance imaging (fMRI) in combination with manual performance tasks. The twins were discordant for MRI anatomical asymmetries of the pars triangularis and planum temporale, whose asymmetry was consistent with verbal laterality on fMRI. Thus, the right-handed twin had left lateralized verbal with right lateralized visuo-spatial attention, while the left-handed twin had right lateralized verbal with left lateralized visuo-spatial activation; these data lend further support for to the conclusions of Sommer et al.

On the relative merits of invasive and non-invasive pre-surgical brain mapping: New tools in ablative epilepsy surgery.

Cortical Stimulation Mapping (CSM) and the Wada procedure have long been considered the gold standard for localizing motor and language-related cortical areas and for determining the language and memory-dominant hemisphere, respectively. In recent years, however, non-invasive methods such as magnetoencephalography (MEG), functional magnetic resonance imaging (fMRI), and transcranial magnetic stimulation (TMS) have emerged as promising alternatives to the aforementioned procedures, particularly in cases where the invasive localization of eloquent cortex has proven to be challenging. To illustrate this point, we will first introduce the evidence of the compatibility of invasive and non-invasive methods and subsequently outline the rationale and the conditions where the latter methods are applicable.

Concordance of the Resting State Networks in Typically Developing, 6-to 7-Year-Old Children and Healthy Adults.

Though fairly well-studied in adults, less is known about the manifestation of resting state networks (RSN) in children. We examined the validity of RSN derived in an ethnically diverse group of typically developing 6- to 7-year-old children. We hypothesized that the RSNs in young children would be robust and would reliably show significant concordance with previously published RSN in adults. Additionally, we hypothesized that a smaller sample size using this robust technique would be comparable in quality to pediatric RSNs found in a larger cohort study. Furthermore, we posited that compared to the adult RSNs, the primary sensorimotor and the default mode networks (DMNs) in this pediatric group would demonstrate the greatest correspondence, while the executive function networks would exhibit a lesser degree of spatial overlap. Resting state functional magnetic resonance images (rs-fMRI) were acquired in 18 children between 6 and 7 years recruited from an ethnically diverse population in the Mid-South region of the United States. Twenty RSNs were derived using group independent component analysis and their spatial correspondence with previously published adult RSNs was examined. We demonstrate that the rs-fMRI in this group can be deconstructed into the fundamental RSN as all the major RSNs previously described in adults and in a large sample that included older children can be observed in our sample of young children. Further, the primary visual, auditory, and somatosensory networks, as well as the default mode, and frontoparietal networks derived in this group exhibited a greater spatial concordance with those seen in adults. The motor, temporoparietal, executive control, dorsal attention, and cerebellar networks in children had less spatial overlap with the corresponding RSNs in adults. Our findings suggest that several salient RSNs can be mapped reliably in small and diverse pediatric cohort within a narrow age range and the evolution of these RSNs can be studied reliably in such groups during early childhood and adolescence.

Brain activation profiles during kinesthetic and visual imagery: An fMRI study.

The aim of this study was to identify brain regions involved in motor imagery and differentiate two alternative strategies in its implementation: imagining a motor act using kinesthetic or visual imagery. Fourteen adults were precisely instructed and trained on how to imagine themselves or others perform a movement sequence, with the aim of promoting kinesthetic and visual imagery, respectively, in the context of an fMRI experiment using block design. We found that neither modality of motor imagery elicits activation of the primary motor cortex and that each of the two modalities involves activation of the premotor area which is also activated during action execution and action observation conditions, as well as of the supplementary motor area. Interestingly, the visual and the posterior cingulate cortices show reduced BOLD signal during both imagery conditions. Our results indicate that the networks of regions activated in kinesthetic and visual imagery of motor sequences show a substantial, while not complete overlap, and that the two forms of motor imagery lead to a differential suppression of visual areas.

Language mapping using high gamma electrocorticography, fMRI, and TMS versus electrocortical stimulation.

OBJECTIVE: The aim of the present study was to compare localization of the language cortex using cortical stimulation mapping (CSM), high gamma electrocorticography (hgECoG), functional magnetic resonance imaging (fMRI), and transcranial magnetic stimulation (TMS). METHODS: Language mapping using CSM, hgECoG, fMRI, and TMS were compared in nine patients with epilepsy. Considering CSM as reference, we compared language mapping approaches based on hgECoG, fMRI, and TMS using their sensitivity, specificity, and the results of receiver operating characteristic (ROC) analyses. RESULTS: Our results show that areas involved in language processing can be identified by hgECoG, fMRI, and TMS. The average sensitivity/specificity of hgECoG, fMRI, and TMS across all patients was 100%/85%, 50%/80%, and 67%/66%, respectively. The average area under the ROC curve of hgECoG, fMRI, and TMS across CSM-positive patients was 0.98, 0.76, and 0.68, respectively. CONCLUSIONS: There is considerable concordance between CSM, hgECoG, fMRI, and TMS language mapping. Our results reveal that hgECoG, fMRI, and TMS are valuable tools for presurgical language mapping. SIGNIFICANCE: Language mapping on the basis of hgECoG, fMRI, and TMS can provide important additional information, therefore, these methods can be used in conjunction with CSM or as an alternative, when the latter is deemed impractical.

Altered cross-frequency coupling in resting-state MEG after mild traumatic brain injury.

Cross-frequency coupling (CFC) is thought to represent a basic mechanism of functional integration of neural networks across distant brain regions. In this study, we analyzed CFC profiles from resting state Magnetoencephalographic (MEG) recordings obtained from 30 mild traumatic brain injury (mTBI) patients and 50 controls. We used mutual information (MI) to quantify the phase-to-amplitude coupling (PAC) of activity among the recording sensors in six nonoverlapping frequency bands. After forming the CFC-based functional connectivity graphs, we employed a tensor representation and tensor subspace analysis to identify the optimal set of features for subject classification as mTBI or control. Our results showed that controls formed a dense network of stronger local and global connections indicating higher functional integration compared to mTBI patients. Furthermore, mTBI patients could be separated from controls with more than 90% classification accuracy. These findings indicate that analysis of brain networks computed from resting-state MEG with PAC and tensorial representation of connectivity profiles may provide a valuable biomarker for the diagnosis of mTBI.

Breathing as a Fundamental Rhythm of Brain Function.

Ongoing fluctuations of neuronal activity have long been considered intrinsic noise that introduces unavoidable and unwanted variability into neuronal processing, which the brain eliminates by averaging across population activity (Georgopoulos et al., 1986; Lee et al., 1988; Shadlen and Newsome, 1994; Maynard et al., 1999). It is now understood, that the seemingly random fluctuations of cortical activity form highly structured patterns, including oscillations at various frequencies, that modulate evoked neuronal responses (Arieli et al., 1996; Poulet and Petersen, 2008; He, 2013) and affect sensory perception (Linkenkaer-Hansen et al., 2004; Boly et al., 2007; Sadaghiani et al., 2009; Vinnik et al., 2012; Palva et al., 2013). Ongoing cortical activity is driven by proprioceptive and interoceptive inputs. In addition, it is partially intrinsically generated in which case it may be related to mental processes (Fox and Raichle, 2007; Deco et al., 2011). Here we argue that respiration, via multiple sensory pathways, contributes a rhythmic component to the ongoing cortical activity. We suggest that this rhythmic activity modulates the temporal organization of cortical neurodynamics, thereby linking higher cortical functions to the process of breathing.

Functional connectivity changes detected with magnetoencephalography after mild traumatic brain injury.

Mild traumatic brain injury (mTBI) may affect normal cognition and behavior by disrupting the functional connectivity networks that mediate efficient communication among brain regions. In this study, we analyzed brain connectivity profiles from resting state Magnetoencephalographic (MEG) recordings obtained from 31 mTBI patients and 55 normal controls. We used phase-locking value estimates to compute functional connectivity graphs to quantify frequency-specific couplings between sensors at various frequency bands. Overall, normal controls showed a dense network of strong local connections and a limited number of long-range connections that accounted for approximately 20% of all connections, whereas mTBI patients showed networks characterized by weak local connections and strong long-range connections that accounted for more than 60% of all connections. Comparison of the two distinct general patterns at different frequencies using a tensor representation for the connectivity graphs and tensor subspace analysis for optimal feature extraction showed that mTBI patients could be separated from normal controls with 100% classification accuracy in the alpha band. These encouraging findings support the hypothesis that MEG-based functional connectivity patterns may be used as biomarkers that can provide more accurate diagnoses, help guide treatment, and monitor effectiveness of intervention in mTBI.

Comparison of brain network models using cross-frequency coupling and attack strategies.

Several neuroimaging studies have suggested that functional brain connectivity networks exhibit "small-world" characteristics, whereas recent studies based on structural data have proposed a "rich-club" organization of brain networks, whereby hubs of high connection density tend to connect among themselves compared to nodes of lower density. In this study, we adopted an "attack strategy" to compare the rich-club and small-world organizations and identify the model that describes best the topology of brain connectivity. We hypothesized that the highest reduction in global efficiency caused by a targeted attack on each model's hubs would reveal the organization that better describes the topology of the underlying brain networks. We applied this approach to magnetoencephalographic data obtained at rest from neurologically intact controls and mild traumatic brain injury patients. Functional connectivity networks were computed using phase-to-amplitude cross-frequency coupling between the δ and ß frequency bands. Our results suggest that resting state MEG connectivity networks follow a rich-club organization.