A Multimodal Imaging- and Stimulation-based Method of Evaluating Connectivity-related Brain Excitability in Patients with Epilepsy

Resting-state functional connectivity MRI (rs-fcMRI) is a technique that identifies connectivity between different brain regions based on correlations over time in the blood-oxygenation level dependent signal. rs-fcMRI has been applied extensively to identify abnormalities in brain connectivity in different neurologic and psychiatric diseases. However, the relationship among rs-fcMRI connectivity abnormalities, brain electrophysiology and disease state is unknown, in part because the causal significance of alterations in functional connectivity in disease pathophysiology has not been established. Transcranial Magnetic Stimulation (TMS) is a technique that uses electromagnetic induction to noninvasively produce focal changes in cortical activity. When combined with electroencephalography (EEG), TMS can be used to assess the brain's response to external perturbations. Here we provide a protocol for combining rs-fcMRI, TMS and EEG to assess the physiologic significance of alterations in functional connectivity in patients with neuropsychiatric disease. We provide representative results from a previously published study in which rs-fcMRI was used to identify regions with abnormal connectivity in patients with epilepsy due to a malformation of cortical development, periventricular nodular heterotopia (PNH). Stimulation in patients with epilepsy resulted in abnormal TMS-evoked EEG activity relative to stimulation of the same sites in matched healthy control patients, with an abnormal increase in the late component of the TMS-evoked potential, consistent with cortical hyperexcitability. This abnormality was specific to regions with abnormal resting-state functional connectivity. Electrical source analysis in a subject with previously recorded seizures demonstrated that the origin of the abnormal TMS-evoked activity co-localized with the seizure-onset zone, suggesting the presence of an epileptogenic circuit. These results demonstrate how rs-fcMRI, TMS and EEG can be utilized together to identify and understand the physiological significance of abnormal brain connectivity in human diseases

Cortical excitability correlates with seizure control and epilepsy duration in chronic epilepsy

OBJECTIVE: Cortical excitability differs between treatment responders and nonresponders in new‐onset epilepsy. Moreover, during the first 3 years of epilepsy, cortical excitability becomes more abnormal in nonresponders but normalizes in responders. Here, we study chronic active epilepsy, to examine whether cortical excitability continues to evolve over time, in association with epilepsy duration and treatment response. METHODS: We studied 28 normal subjects, 28 patients with moderately controlled epilepsy (≤4 seizures per year) and 40 patients with poorly controlled epilepsy (≥20 or more seizures per year). Resting motor threshold (RMT), active motor threshold (AMT), short‐interval intracortical inhibition (SICI), intracortical facilitation (ICF) and cortical silent period (CSP) were measured, using transcranial magnetic stimulation (TMS). Disease and treatment covariates were collected (age at onset of epilepsy, epilepsy duration, number of drugs prescribed, total drug load, sodium channel drug load). RESULTS: RMT and AMT were higher in patients than in normal subjects; RMT and AMT were higher in poorly controlled than moderately controlled patients. ICF at 12 msec and 15 msec were lower in poorly controlled patients than in normal subjects. Long‐interval intracortical inhibition (LICI) at 50 msec was higher in poorly controlled compared to moderately controlled patients. These differences were not explained by antiepileptic drug (AED) treatment or duration of epilepsy. RMT and AMT increased with duration in the poorly controlled group, but did not increase with duration in the moderately controlled group. INTERPRETATION: Cortical excitability differs markedly between moderately controlled and poorly controlled patients with chronic epilepsy, not explained by disease or treatment variables. Moreover, the evolution of cortical excitability over time differs, becoming more abnormal in the poorly controlled group

Understanding Epileptiform After-Discharges as Rhythmic Oscillatory Transients

Electro-cortical activity in patients with epilepsy may show abnormal rhythmic transients in response to stimulation. Even when using the same stimulation parameters in the same patient, wide variability in the duration of transient response has been reported. These transients have long been considered important for the mapping of the excitability levels in the epileptic brain but their dynamic mechanism is still not well understood. To understand the occurrence of abnormal transients dynamically, we use a thalamo-cortical neural population model of epileptic spike-wave activity and study the interaction between slow and fast subsystems. In a reduced version of the thalamo-cortical model, slow wave oscillations arise from a fold of cycles (FoC) bifurcation. This marks the onset of a region of bistability between a high amplitude oscillatory rhythm and the background state. In vicinity of the bistability in parameter space, the model has excitable dynamics, showing prolonged rhythmic transients in response to suprathreshold pulse stimulation. We analyse the state space geometry of the bistable and excitable states, and find that the rhythmic transient arises when the impending FoC bifurcation deforms the state space and creates an area of locally reduced attraction to the fixed point. This area essentially allows trajectories to dwell there before escaping to the stable steady state, thus creating rhythmic transients. In the full thalamo-cortical model, we find a similar FoC bifurcation structure. Based on the analysis, we propose an explanation of why stimulation induced epileptiform activity may vary between trials, and predict how the variability could be related to ongoing oscillatory background activity.Comment: http://journal.frontiersin.org/article/10.3389/fncom.2017.00025/ful

Dynamics of brain states and cortical excitability in paroxysmal neurological conditions

Epilepsy and migraine are neurological conditions that are characterised by periods of disruption of normal neuronal functioning. Aside from this paroxysmal feature, both conditions share genetic mutations and altered cortical excitability. People with epilepsy appear to be diagnosed with migraine more often than people without epilepsy and, likewise, people with migraine seem to be diagnosed with epilepsy more often than people without migraine. Changes in cortical excitability may help explain the pathophysiological link between both conditions, and could be a biomarker to monitor disease activity. In this thesis, the association between migraine and epilepsy and their relation to cortical excitability is further explored. A meta-analysis of previous population based studies provides epidemiological evidence for the co-occurrence of migraine and epilepsy. The combination of computer modelling with human electroencephalographic recordings offers insight into multi-stability of brain states in epilepsy. Results described in this thesis show that Transcranial Magnetic Stimulation can be used to measure cortical excitability, but that its use as a biomarker of disease activity in epilepsy is limited due to large interindividual variability. By combining Transcranial Magnetic Stimulation with electroencephalography, two novel variables that may contribute to cortical excitability are investigated: phase clustering, which possibly reflecting functional neuronal connectivity, and the non-linear residual of a stimulus-response curve, which may reflect brain state multi-stability. The results presented in this thesis suggest that the higher propensity to global synchronisation is not shared between epilepsy and migraine. These new variables have potential value to differentiate people with epilepsy, but not people with migraine, from normal controls

Consensus Paper: Neurophysiological Assessments of Ataxias in Daily Practice

The purpose of this consensus paper is to review electrophysiological abnormalities and to provide a guideline of neurophysiological assessments in cerebellar ataxias. All authors agree that standard electrophysiological methods should be systematically applied in all cases of ataxia to reveal accompanying peripheral neuropathy, the involvement of the dorsal columns, pyramidal tracts and the brainstem. Electroencephalography should also be considered, although findings are frequently non-specific. Electrophysiology helps define the neuronal systems affected by the disease in an individual patient and to understand the phenotypes of the different types of ataxia on a more general level. As yet, there is no established electrophysiological measure which is sensitive and specific of cerebellar dysfunction in ataxias. The authors agree that cerebellar brain inhibition (CBI), which is based on a paired-pulse transcranial magnetic stimulation (TMS) paradigm assessing cerebellar-cortical connectivity, is likely a useful measure of cerebellar function. Although its role in the investigation and diagnoses of different types of ataxias is unclear, it will be of interest to study its utility in this type of conditions. The authors agree that detailed clinical examination reveals core features of ataxia (i.e., dysarthria, truncal, gait and limb ataxia, oculomotor dysfunction) and is sufficient for formulating a differential diagnosis. Clinical assessment of oculomotor function, especially saccades and the vestibulo-ocular reflex (VOR) which are most easily examined both at the bedside and with quantitative testing techniques, is of particular help for differential diagnosis in many cases. Pure clinical measures, however, are not sensitive enough to reveal minute fluctuations or early treatment response as most relevant for pre-clinical stages of disease which might be amenable to study in future intervention trials. The authors agree that quantitative measures of ataxia are desirable as biomarkers. Methods are discussed that allow quantification of ataxia in laboratory as well as in clinical and real-life settings, for instance at the patients' home. Future studies are needed to demonstrate their usefulness as biomarkers in pharmaceutical or rehabilitation trials

Augmentation of Brain Function: Facts, Fiction and Controversy. Volume III: From Clinical Applications to Ethical Issues and Futuristic Ideas

The final volume in this tripartite series on Brain Augmentation is entitled “From Clinical Applications to Ethical Issues and Futuristic Ideas”. Many of the articles within this volume deal with translational efforts taking the results of experiments on laboratory animals and applying them to humans. In many cases, these interventions are intended to help people with disabilities in such a way so as to either restore or extend brain function. Traditionally, therapies in brain augmentation have included electrical and pharmacological techniques. In contrast, some of the techniques discussed in this volume add specificity by targeting select neural populations. This approach opens the door to where and how to promote the best interventions. Along the way, results have empowered the medical profession by expanding their understanding of brain function. Articles in this volume relate novel clinical solutions for a host of neurological and psychiatric conditions such as stroke, Parkinson’s disease, Huntington’s disease, epilepsy, dementia, Alzheimer’s disease, autism spectrum disorders (ASD), traumatic brain injury, and disorders of consciousness. In disease, symptoms and signs denote a departure from normal function. Brain augmentation has now been used to target both the core symptoms that provide specificity in the diagnosis of a disease, as well as other constitutional symptoms that may greatly handicap the individual. The volume provides a report on the use of repetitive transcranial magnetic stimulation (rTMS) in ASD with reported improvements of core deficits (i.e., executive functions). TMS in this regard departs from the present-day trend towards symptomatic treatment that leaves unaltered the root cause of the condition. In diseases, such as schizophrenia, brain augmentation approaches hold promise to avoid lengthy pharmacological interventions that are usually riddled with side effects or those with limiting returns as in the case of Parkinson’s disease. Brain stimulation can also be used to treat auditory verbal hallucination, visuospatial (hemispatial) neglect, and pain in patients suffering from multiple sclerosis. The brain acts as a telecommunication transceiver wherein different bandwidth of frequencies (brainwave oscillations) transmit information. Their baseline levels correlate with certain behavioral states. The proper integration of brain oscillations provides for the phenomenon of binding and central coherence. Brain augmentation may foster the normalization of brain oscillations in nervous system disorders. These techniques hold the promise of being applied remotely (under the supervision of medical personnel), thus overcoming the obstacle of travel in order to obtain healthcare. At present, traditional thinking would argue the possibility of synergism among different modalities of brain augmentation as a way of increasing their overall effectiveness and improving therapeutic selectivity. Thinking outside of the box would also provide for the implementation of brain-to-brain interfaces where techniques, proper to artificial intelligence, could allow us to surpass the limits of natural selection or enable communications between several individual brains sharing memories, or even a global brain capable of self-organization. Not all brains are created equal. Brain stimulation studies suggest large individual variability in response that may affect overall recovery/treatment, or modify desired effects of a given intervention. The subject’s age, gender, hormonal levels may affect an individual’s cortical excitability. In addition, this volume discusses the role of social interactions in the operations of augmenting technologies. Finally, augmenting methods could be applied to modulate consciousness, even though its neural mechanisms are poorly understood. Finally, this volume should be taken as a debate on social, moral and ethical issues on neurotechnologies. Brain enhancement may transform the individual into someone or something else. These techniques bypass the usual routes of accommodation to environmental exigencies that exalted our personal fortitude: learning, exercising, and diet. This will allow humans to preselect desired characteristics and realize consequent rewards without having to overcome adversity through more laborious means. The concern is that humans may be playing God, and the possibility of an expanding gap in social equity where brain enhancements may be selectively available to the wealthier individuals. These issues are discussed by a number of articles in this volume. Also discussed are the relationship between the diminishment and enhancement following the application of brain-augmenting technologies, the problem of “mind control” with BMI technologies, free will the duty to use cognitive enhancers in high-responsibility professions, determining the population of people in need of brain enhancement, informed public policy, cognitive biases, and the hype caused by the development of brain- augmenting approaches

Variability of head tissues’ conductivities and their impact in electrical brain activity research

The presented thesis endeavoured to establish the impact that the variability in electrical conductivity of human head tissues has on electrical brain imaging research, particularly transcranial direct current stimulation (tDCS) and electroencephalography (EEG). A systematic meta-analysis was firstly conducted to determine the consistency of reported measurements, revealing significant deviations in electrical conductivity measurements predominantly for the scalp, skull, GM, and WM. Found to be of particular importance was the variability of skull conductivity, which consists of multiple layers and bone compositions, each with differing conductivity. Moreover, the conductivity of the skull was suggested to decline with participant age and hypothesised to correspondingly impact tDCS induced fields. As expected, the propositioned decline in the equivalent (homogeneous) skull conductivity as a function of age resulted in reduced tDCS fields. A further EEG analysis also revealed, neglecting the presence of adult sutures and deviation in proportion of spongiform and compact bone distribution throughout the skull, ensued significant errors in EEG forward and inverse solutions. Thus, incorporating geometrically accurate and precise volume conductors of the skull was considered as essential for EEG forward analysis and source localisation and tDCS application. This was an overarching conclusion of the presented thesis. Individualised head models, particularly of the skull, accounting for participant age, the presence of sutures and deviation in bone composition distribution are imperative for electrical brain imaging. Additionally, it was shown that in vivo, individualised measurements of skull conductivity are further required to fully understand the relationship between conductivity and participant demographics, suture closure, bone compositions, skull thickness and additional factors

Sensorimotor Modulations by Cognitive Processes During Accurate Speech Discrimination: An EEG Investigation of Dorsal Stream Processing

Internal models mediate the transmission of information between anterior and posterior regions of the dorsal stream in support of speech perception, though it remains unclear how this mechanism responds to cognitive processes in service of task demands. The purpose of the current study was to identify the influences of attention and working memory on sensorimotor activity across the dorsal stream during speech discrimination, with set size and signal clarity employed to modulate stimulus predictability and the time course of increased task demands, respectively. Independent Component Analysis of 64–channel EEG data identified bilateral sensorimotor mu and auditory alpha components from a cohort of 42 participants, indexing activity from anterior (mu) and posterior (auditory) aspects of the dorsal stream. Time frequency (ERSP) analysis evaluated task-related changes in focal activation patterns with phase coherence measures employed to track patterns of information flow across the dorsal stream. ERSP decomposition of mu clusters revealed event-related desynchronization (ERD) in beta and alpha bands, which were interpreted as evidence of forward (beta) and inverse (alpha) internal modeling across the time course of perception events. Stronger pre-stimulus mu alpha ERD in small set discrimination tasks was interpreted as more efficient attentional allocation due to the reduced sensory search space enabled by predictable stimuli. Mu-alpha and mu-beta ERD in peri- and post-stimulus periods were interpreted within the framework of Analysis by Synthesis as evidence of working memory activity for stimulus processing and maintenance, with weaker activity in degraded conditions suggesting that covert rehearsal mechanisms are sensitive to the quality of the stimulus being retained in working memory. Similar ERSP patterns across conditions despite the differences in stimulus predictability and clarity, suggest that subjects may have adapted to tasks. In light of this, future studies of sensorimotor processing should consider the ecological validity of the tasks employed, as well as the larger cognitive environment in which tasks are performed. The absence of interpretable patterns of mu-auditory coherence modulation across the time course of speech discrimination highlights the need for more sensitive analyses to probe dorsal stream connectivity