Non-invasive detection of language-related prefrontal high gamma band activity with beamforming MEG

Hashimoto H., Hasegawa Y., Araki T., et al. Non-invasive detection of language-related prefrontal high gamma band activity with beamforming MEG. Scientific Reports 7, 14262 (2017); https://doi.org/10.1038/s41598-017-14452-3.High gamma band (>50 Hz) activity is a key oscillatory phenomenon of brain activation. However, there has not been a non-invasive method established to detect language-related high gamma band activity. We used a 160-channel whole-head magnetoencephalography (MEG) system equipped with superconducting quantum interference device (SQUID) gradiometers to non-invasively investigate neuromagnetic activities during silent reading and verb generation tasks in 15 healthy participants. Individual data were divided into alpha (8-13 Hz), beta (13-25 Hz), low gamma (25-50 Hz), and high gamma (50-100 Hz) bands and analysed with the beamformer method. The time window was consecutively moved. Group analysis was performed to delineate common areas of brain activation. In the verb generation task, transient power increases in the high gamma band appeared in the left middle frontal gyrus (MFG) at the 550-750 ms post-stimulus window. We set a virtual sensor on the left MFG for time-frequency analysis, and high gamma event-related synchronization (ERS) induced by a verb generation task was demonstrated at 650 ms. In contrast, ERS in the high gamma band was not detected in the silent reading task. Thus, our study successfully non-invasively measured language-related prefrontal high gamma band activity

Improving language mapping in clinical fMRI through assessment of grammar.

IntroductionBrain surgery in the language dominant hemisphere remains challenging due to unintended post-surgical language deficits, despite using pre-surgical functional magnetic resonance (fMRI) and intraoperative cortical stimulation. Moreover, patients are often recommended not to undergo surgery if the accompanying risk to language appears to be too high. While standard fMRI language mapping protocols may have relatively good predictive value at the group level, they remain sub-optimal on an individual level. The standard tests used typically assess lexico-semantic aspects of language, and they do not accurately reflect the complexity of language either in comprehension or production at the sentence level. Among patients who had left hemisphere language dominance we assessed which tests are best at activating language areas in the brain.MethodWe compared grammar tests (items testing word order in actives and passives, wh-subject and object questions, relativized subject and object clauses and past tense marking) with standard tests (object naming, auditory and visual responsive naming), using pre-operative fMRI. Twenty-five surgical candidates (13 females) participated in this study. Sixteen patients presented with a brain tumor, and nine with epilepsy. All participants underwent two pre-operative fMRI protocols: one including CYCLE-N grammar tests (items testing word order in actives and passives, wh-subject and object questions, relativized subject and object clauses and past tense marking); and a second one with standard fMRI tests (object naming, auditory and visual responsive naming). fMRI activations during performance in both protocols were compared at the group level, as well as in individual candidates.ResultsThe grammar tests generated more volume of activation in the left hemisphere (left/right angular gyrus, right anterior/posterior superior temporal gyrus) and identified additional language regions not shown by the standard tests (e.g., left anterior/posterior supramarginal gyrus). The standard tests produced more activation in left BA 47. Ten participants had more robust activations in the left hemisphere in the grammar tests and two in the standard tests. The grammar tests also elicited substantial activations in the right hemisphere and thus turned out to be superior at identifying both right and left hemisphere contribution to language processing.ConclusionThe grammar tests may be an important addition to the standard pre-operative fMRI testing

Adaptação portuguesa do Dutch Linguistic Intraoperative Protocol: avaliação da sintaxe e nomeação em craniotomia em paciente acordado

A renewed interest in studying the neural basis of Language has emerged since a clear relationship between speaking and the brain tissue was established. This study is focused on the assessment of language functions in patients with a specific kind of brain tumour, a low-grade glioma (LGG). These patients, who are submitted to an awake brain surgery, are assessed pre-, post- and intra-surgery, while using Direct Electrical Stimulation (DES), so that the neurosurgeon can optimise the extent of the resection and avoid language deterioration. The Dutch Linguistic Intraoperative Protocol (DuLIP) was developed in the Netherlands, consisting of a test battery for evaluating Phonology, Semantics, Syntax and Articulation. Since in Portugal there is no validated instrument to serve this purpose, the DuLIP was adapted to European Portuguese (EP). The process included a cultural adaptation and the collection of normative data from the Portuguese population. The DuLIP-EP consists of a total of 18 tasks. The focus of the present Thesis is only Syntax and Naming skills. To culturally adapt DuLIP, some changes had to be introduced regarding image choice and words frequency. After applying the battery test to 144 participants, a statistical analysis was performed aiming to find differences in scores per task, regarding gender, age and education level (years of study). Related to Syntax, a relationship between active/passive voice sentences and accuracy rate was analysed, as well as the influence of education level on the capacity of processing these sentence types. Similar to the original study, significant differences were found considering age and years of study. Younger and highly educated participants performed better across all the tasks. No association was found regarding education level and performance on the task where active/passive voice sentences were presented. Future work aims to achieve an identical number of items per task, a wider sample collected in all regions of Portugal, in order to perform a larger number of comparisons than the original study. It would also be important to apply DuLIP-EP to some clinical cases.Uma vez descoberta a ligação entre o falar e o cérebro, surgiu interesse em estudar a base neuronal associada à Linguagem. Este estudo tem como foco a avaliação das funções cerebrais associadas à Linguagem em pacientes com gliomas de baixo grau, um tipo de tumor cerebral. Estes pacientes, submetidos a craniotomia acordada, são avaliados pré, pós e intra cirurgia, aquando do uso de electroestimulação intraoperatória (EEI), com o objetivo de otimização da resseção tumoral, evitando sequelas com impacto na Linguagem. O Dutch Linguistic Intraoperative Protocol (DuLIP), foi desenvolvido na Holanda e consiste numa bateria de testes para avaliação da Fonologia, Semântica, Sintaxe e Articulação neste âmbito. Em Portugal não existe nenhum instrumento validado com este propósito pelo que foi criada uma versão portuguesa, o DuLIP-EP. O processo incluiu uma adaptação cultural e a aplicação à população portuguesa para recolha de dados normativos. O DuLIP-EP resultou num protocolo de 18 tarefas. Na presente dissertação, o foco recai na área da Sintaxe e na tarefa de Nomeação. Para adaptar culturalmente o DuLIP, algumas mudanças tiveram de ser executas face à sua versão original, nomeadamente, na escolha das imagens e frequência das palavras usadas. Após a aplicação a 144 participantes, foi elaborada a análise estatística e averiguada a existência de diferenças significativas entre as pontuações obtidas por tarefa e as variáveis: idade, sexo e nível de educação (anos de estudos). Na área da Sintaxe, foi estudada a relação entre a presença de frases na voz ativa/passiva e a taxa de acerto, assim como a influência do nível de educação na capacidade de processamento deste tipo de frases. À semelhança do estudo original, diferenças significativas foram encontradas no que concerne à idade e anos de estudo. O grupo jovens/alta educação tem, globalmente, uma melhor performance. Não foi encontrada relação entre o nível de educação e a performance na prova que engloba frases na voz ativa/passiva. Como futuro trabalho, planeia-se alcançar um idêntico número de participantes e itens por tarefa, por forma a alargar o número de comparações ao estudo original, sendo também importante a aplicação do DuLIP-EP a casos clínicos.Mestrado em Terapia da Fal

MAPPING LANGUAGE FUNCTION AND PREDICTING CORTICAL STIMULATION RESULTS WITH INTRACRANIAL ELECTROENCEPHALOGRAPHY

To avoid post-operative language impairments after surgery for drug-resistant epilepsy, clinicians rely primarily on electrocortical stimulation mapping (ESM), but this can trigger afterdischarges, clinical seizures, or cause uncomfortable sensations. Moreover, ESM can be time-consuming and the results are usually all-or-none, complicating their interpretation. These practical limitations have long motivated spatial-temporal analysis of passive intracranial electroencephalographic (iEEG) recordings as an alternative or complementary technique that can map cortical function at all sites simultaneously, resulting in significant time savings without adverse side-effects. However, there has not yet been widespread clinical adoption of passive iEEG for pre-operative language mapping, largely because of a failure to realize the potential advantages of iEEG over ESM and other methods for language mapping. The overall goals of this dissertation were to improve and validate passive iEEG as a method for mapping human language function prior to surgical resection for epilepsy and other brain disorders. This was accomplished through three separate aims. First, a spatial-temporal functional mapping (STFM) system was developed and tested for online passive iEEG mapping, providing immediate mapping feedback to both clinicians and researchers. The system output was compared to ESM and to canonical regions of interest in the human language network. In the second aim, the STFM system was used to study the fine temporal dynamics by which Broca’s area is activated and interacts with other areas of language network during a sentence completion task. This study showed that Broca’s area plays a pivotal role in the coordination of language networks responsible for lexical selection. Finally, the third aim sought to reconcile inconsistencies between the results of STFM and ESM. Agreement between these methods has not been as good for language mapping as it has been for motor mapping, which may be due to propagation of ESM effects to cortical areas connected to the site of stimulation. We used cortico-cortical evoked potentials to estimate the effective connectivity of stimulation sites to other sites in the language network. We found that this method improved the accuracy of STFM in predicting ESM results and helped explain similarities and differences between STFM and ESM language maps

Electroencephalogram Based Causality Graph Analysis in Behavior Tasks of Parkinson’s Disease Patients

Electroencephalographic (EEG) signals of the human brains represent electrical activities for a number of channels recorded over a the scalp. The main purpose of this thesis is to investigate the interactions and causality of different parts of a brain using EEG signals recorded during a performance subjects of verbal fluency tasks. Subjects who have Parkinson\u27s Disease (PD) have difficulties with mental tasks, such as switching between one behavior task and another. The behavior tasks include phonemic fluency, semantic fluency, category semantic fluency and reading fluency. This method uses verbal generation skills, activating different Broca\u27s areas of the Brodmann\u27s areas (BA44 and BA45). Advanced signal processing techniques are used in order to determine the activated frequency bands in the granger causality for verbal fluency tasks. The graph learning technique for channel strength is used to characterize the complex graph of Granger causality. Also, the support vector machine (SVM) method is used for training a classifier between two subjects with PD and two healthy controls. Neural data from the study was recorded at the Colorado Neurological Institute (CNI). The study reveals significant difference between PD subjects and healthy controls in terms of brain connectivities in the Broca\u27s Area BA44 and BA45 corresponding to EEG electrodes. The results in this thesis also demonstrate the possibility to classify based on the flow of information and causality in the brain of verbal fluency tasks. These methods have the potential to be applied in the future to identify pathological information flow and causality of neurological diseases

Quantitative Multimodal Mapping Of Seizure Networks In Drug-Resistant Epilepsy

Over 15 million people worldwide suffer from localization-related drug-resistant epilepsy. These patients are candidates for targeted surgical therapies such as surgical resection, laser thermal ablation, and neurostimulation. While seizure localization is needed prior to surgical intervention, this process is challenging, invasive, and often inconclusive. In this work, I aim to exploit the power of multimodal high-resolution imaging and intracranial electroencephalography (iEEG) data to map seizure networks in drug-resistant epilepsy patients, with a focus on minimizing invasiveness. Given compelling evidence that epilepsy is a disease of distorted brain networks as opposed to well-defined focal lesions, I employ a graph-theoretical approach to map structural and functional brain networks and identify putative targets for removal. The first section focuses on mesial temporal lobe epilepsy (TLE), the most common type of localization-related epilepsy. Using high-resolution structural and functional 7T MRI, I demonstrate that noninvasive neuroimaging-based network properties within the medial temporal lobe can serve as useful biomarkers for TLE cases in which conventional imaging and volumetric analysis are insufficient. The second section expands to all forms of localization-related epilepsy. Using iEEG recordings, I provide a framework for the utility of interictal network synchrony in identifying candidate resection zones, with the goal of reducing the need for prolonged invasive implants. In the third section, I generate a pipeline for integrated analysis of iEEG and MRI networks, paving the way for future large-scale studies that can effectively harness synergy between different modalities. This multimodal approach has the potential to provide fundamental insights into the pathology of an epileptic brain, robustly identify areas of seizure onset and spread, and ultimately inform clinical decision making

Mapping Sensorimotor Function and Controlling Upper Limb Neuroprosthetics with Electrocorticography

Electrocorticography (ECoG) occupies a unique intermediate niche between microelectrode recordings of single neurons and recordings of whole brain activity via functional magnetic resonance imaging (fMRI). ECoG’s combination of high temporal resolution and wide area coverage make it an ideal modality for both functional brain mapping and brain-machine interface (BMI) for control of prosthetic devices. This thesis demonstrates the utility of ECoG, particularly in high gamma frequencies (70-120 Hz), for passive online mapping of language and motor behaviors, online control of reaching and grasping of an advanced robotic upper limb, and mapping somatosensory digit representations in the postcentral gyrus. The dissertation begins with a brief discussion of the framework for neuroprosthetic control developed by the collaboration between Johns Hopkins and JHU Applied Physics Laboratory (JHU/APL). Second, the methodology behind an online spatial-temporal functional mapping (STFM) system is described. Trial-averaged spatiotemporal maps of high gamma activity were computed during a visual naming and a word reading task. The system output is subsequently shown and compared to stimulation mapping. Third, simultaneous and independent ECoG-based control of reaching and grasping is demonstrated with the Modular Prosthetic Limb (MPL). The STFM system was used to identify channels whose high gamma power significantly and selectively increases during either reaching or grasping. Using this technique, two patients were able to rapidly achieve naturalistic control over simple movements by the MPL. Next, high-density ECoG (hdECoG) was used to map the cortical responses to mechanical vibration of the fingertips. High gamma responses exhibited a strong yet overlapping somatotopy that was not well replicated in other frequency bands. These responses are strong enough to be detected in single trials and used to classify the finger being stimulated with over 98% accuracy. Finally, the role of ECoG is discussed for functional mapping and BMI applications. ECoG occupies a unique role among neural recording modalities as a tool for functional mapping, but must prove its value relative to stimulation mapping. For BMI, ECoG lags microelectrode arrays but hdECoG may provide a more robust long-term interface with optimal spacing for sampling relevant cortical representations

Multi-Modality Assessment Of Language Function

The work presented as part of this dissertation represents a multi-modality study of language structure and function. The primary functional modality employed is task-related electrocorticography (ECoG). This is complemented by discussion and evaluation of previously published functional magnetic resonance imaging (fMRI) data. Language-related structure is explored using diffusion-weighted magnetic resonance imaging in conjunction with ECoG data. The scientific questions pursued are broad and include reevaluation of previously proposed theories. We start by taking the first steps in validating our naming-related ECoG approach by comparing our results from a small cohort of patients to the clinical gold-standard technique of electrical brain stimulation. This evaluation begins to address a clinical problem involving the insensitivity of electrical brain stimulation in language mapping of young children. Thus, our patients across all studies are a mixture of children, adolescents, and adults. Combining data presented within this thesis, data from other members of our team, and published data from teams at other institutions, evidence suggests that language-related ECoG mapping is a powerful language mapping tool when it is employed with an appropriate task. The task employed here is a now well-studied auditory descriptive naming task. Language-related ECoG is then utilized to dissect language function mechanistically employing contrast tasks alongside the descriptive naming task. Working memory and language functions of the frontal lobe are dissected and conclusions are drawn to shed light on their degree of overlap and interaction during ongoing language processing. Evidence of secondary auditory processing and language comprehension gained from other modalities is reevaluated. In particular, reverse speech and signal-correlated noise are employed and evaluated as control tasks for non-language-specific auditory function. A discrepancy between language-related ECoG and language-related fMRI is discovered in regards to the use of reverse speech as such a control task. It is found that signal correlated noise may be more reliable in identifying non-language auditory functions of the temporal lobe. Age-old questions of language-related connectivity are explored by combining diffusion-weighted magnetic resonance imaging tractography with language-related ECoG findings to evaluate terminations of the arcuate fasciculus. Results support recent evidence suggesting that the precentral gyrus is an important termination of this language-related white matter pathway. New models modifying century-old, entrenched models are evaluated in light of these findings and proposals for follow-up work that may create further clarity are provided. Finally, the thesis rounds out with a study exploring the effects of focal interictal epileptiform activity upon ongoing language processes; contributing beyond the neuroscience of language to the epilepsy literature, in honor of the patients providing the data for these studies. Our data demonstrates that such localized pathological activity can have clinically imperceptible effects upon language functions, suggesting one possible mechanism toward cognitive deficits frequently reported in such patients

Modulation of Network Oscillations by Brain Stimulation

Finding new and effective treatments for mental illness represents one of the largest challenges of our time due the large number of people affected. Despite long and careful study there have been few recent breakthroughs in pharmacological treatments of mental illness. To address this, the National Institute of Mental Health (NIMH) has recently begun to focus on the investigation of network level correlates of mental illnesses. Patients with mental illness often exhibit aberrant neural oscillatory activity, thus making the network level a promising scale for the identification of measureable neural correlates of mental illnesses. At the network level, neural activity is primarily in the form of cortical oscillations which may be recorded noninvasively with electroencephalography (EEG). Such EEG oscillations are the result of synchronized activity from many cells in the neocortex. However the exact mechanisms of how oscillations arise and spread throughout the brain remain unknown. Non-invasive brain stimulation is a promising treatment modality because it specifically targets activity of brain networks. Unlike pharmacological treatments, stimulation with electric and magnetic fields directly targets electrical activity of many cells in a network. In particular, transcranial alternating current stimulation appears to be especially suited for targeting oscillations in brain networks. Despite the promise of these brain stimulation techniques, the underlying mechanisms remain unknown. The studies presented in this dissertation address two critical gaps in the treatment of mental illnesses. (1) How does rhythmic network activity arise from cellular and synaptic components? And (2) how does brain stimulation interact with ongoing network activity? Only by understanding how network activity arises and how it interacts with brain stimulation we may begin to design brain stimulation paradigms for treatment of mental illness.Doctor of Philosoph