Improving the quality of combined EEG-TMS neural recordings: artifact removal and time analysis

The combination of TMS (transcranial magnetic stimulation) and EEG (electroencephalography) allows a functional assessment of cortical regions in a controlled, non-invasive way and without the need of having subjects under study perform a task. Thanks to this combination, a characterization of the cerebral signals of schizophrenic patients (16) and healthy controls (15), through the TMS-evoked potentials (TEPs), will be performed. Two protocols will be evaluated: SICI (short-interval intracortical inhibition) and LICI (long-interval intracortical inhibition), which activate different inhibitory-type receptors (GABA-A and GABA-B, respectively). In both protocols, there are signals with a single TMS-pulses (SP) or with paired-pulses (two pulses, PP). Thus, besides the characterization, the different results obtained will be compared between type of pulses, protocols and groups of study. The methodology followed is the typical one for this type of signals: removal of the TMS-pulse(s); ICA (independent component analysis) application to delete the artefactuated or noisy components; signal reconstruction with the good components and bad channel and bad trial rejection. Once the pre-processing is finished and the signal is clean, the TMS-evoked potentials are obtained. For the purpose of finding the differences between PP and SP, the former signal is subtracted from the latter and a modulation ratio is computed. The TEPs found are P25, N30, P50, N100, P140, N160 and P200. Regarding the differences between types of pulses, the observed that the TEP amplitudes for LICI PP are lower than the ones for LICI SP. However, this difference is not clearly seen in SICI protocol. As to the differences between subjects, it seems that the controls have greater inhibition than the patients. In conclusion, the results are remarkably similar to the ones expected. Due to the small sample size and the fact that it is still a poorly studied filed, some results do not match completely with the ones in the literature, but they follow the same tendencyLa combinació de la TMS (estimulació magnètica transcranial, per les seves sigles en anglès) i l’electroencefalograma permet una avaluació funcional directa de regions corticals d’una manera controlada, no invasiva i sense necessitat de realitzar una tasca per part del subjecte d’estudi. És amb la combinació d’aquestes dues tècniques que es vol caracteritzar les senyal cerebrals de persones amb esquizofrènia (16) i persones sanes (15), obtenint els potencials evocats pel TMS (TEP). S’avaluen dos protocols: SICI (short-interval intracortical inhibition) i LICI (long-interval intracortical inhibition), que activen diferents receptors de tipus inhibitori (GABA-A i GABA-B, respectivament). Dins d’aquests protocols, hi ha senyals amb un sol pols de TMS (SP) o amb dos polsos (PP). Així doncs, a part de la caracterització de la senyal, també es comparen els resultats entre els diferents tipus de polsos (1 ó 2), els protocols i els dos grups d’estudi. La metodologia seguida és la típica per aquest tipus de senyals: eliminació del pols o polsos; aplicació d’ICA (anàlisis de components independents), per tal d’eliminar aquelles components artefactuades i/o sorolloses; reconstrucció de la senyal amb les components bones i eliminació de canals i experiments sorollosos. Un cop s’ha fet el pre-processament de la senyal i aquesta està neta, es busquen els potencials evocats pel pols(os) del TMS. Per buscar les diferències entre PP i SP, es resta la primera senyal a la segona i es calcula un rati de modulació. S’han trobat els TEPs P25, N30, P50, N100, P140, N160 i P200. Referent a les diferències entre tipus de polsos, s’observa que les amplituds dels TEPs és menor en LICI PP que en LICI SP. Tanmateix, aquesta diferencia no es veu tan clara en el protocol SICI. Pel que fa les diferències entre subjectes, sembla que els controls (les persones sanes) tenen més inhibició que no pas els pacients. En conclusió, els resultats obtinguts són bastant propers als esperats. Degut a la mida reduïda de la mostra i a que es tracta d’un camp encara poc estudiat, els resultats no són exactament els de la literatura però sí que van en la mateixa líniaLa combinación de la TMS (estimulación magnética transcranial, por sus siglas en inglés) y el electroencefalograma permite una avaluación funcional directa de regiones corticales de una manera controlada, no invasiva y sin necesidad de realizar una tarea por parte del sujeto de estudio. Es con la combinación de ambas técnicas que se quiere caracterizar las señales cerebrales de personas con esquizofrenia (16) y personas sanas (15), obteniendo los potenciales evocados por el TMS (TEPs). Se evalúan dos protocolos: SICI (short-interval intracortical inhibition) y LICI (long-interval intracortical inhibition), que activan diferentes receptores de tipo inhibitorio (GABA-A y GABA-B; respectivamente). Dentro de estos protocolos, hay señales con un solo pulso de TMS (SP) o con dos pulsos (PP). Así pues, a parte de la caracterización de la señal, también se comparan los resultados entre los diferentes tipos de pulsos, los protocolos y los dos grupos de estudio. La metodología seguida es la típica para este tipo de señales: eliminación del pulso o pulsos; aplicación de ICA (análisis de componentes independientes), con el fin de eliminar las componentes artefactuadas y/o ruidosas; reconstrucción de la señal con las componentes buenas y eliminación de canales y experimentos ruidosos. Una vez hecho el pre-procesado de la señal y ésta está limpia, se buscan los TEPs. Para buscar las diferencias entre PP y SP, se resta la primera señal a la segunda y se calcula una ratio de modulación. Se han encontrado los TEPs P25, N30, P50, N100, P140, N169 y P200. Referente a las diferencias entre tipos de pulsos, se observa que las amplitudes de los TEPs son menores en LICI PP que en LICI SP. Sin embargo, esta diferencia no se ve tan clara en SICI. En cuanto a las diferencias entre sujetos, parece ser que los controles (personas sanas) tienen más inhibición que los pacientes. En conclusión, los resultados son muy similares a los esperados. Debido al tamaño reducido de la muestra y a que es un campo poco estudiado, los resultados no son exactamente iguales a los de la literatura, pero sí que van en la misma líneaObjectius de Desenvolupament Sostenible::3 - Salut i Benesta

Methods for analysis of brain connectivity : An IFCN-sponsored review

The goal of this paper is to examine existing methods to study the "Human Brain Connectome" with a specific focus on the neurophysiological ones. In recent years, a new approach has been developed to evaluate the anatomical and functional organization of the human brain: the aim of this promising multimodality effort is to identify and classify neuronal networks with a number of neurobiologically meaningful and easily computable measures to create its connectome. By defining anatomical and functional connections of brain regions on the same map through an integrated approach, comprising both modern neurophysiological and neuroimaging (i.e. flow/metabolic) brain-mapping techniques, network analysis becomes a powerful tool for exploring structural-functional connectivity mechanisms and for revealing etiological relationships that link connectivity abnormalities to neuropsychiatric disorders. Following a recent IFCN-endorsed meeting, a panel of international experts was selected to produce this current state-of-art document, which covers the available knowledge on anatomical and functional connectivity, including the most commonly used structural and functional MRI, EEG, MEG and non-invasive brain stimulation techniques and measures of local and global brain connectivity. (C) 2019 Published by Elsevier B.V. on behalf of International Federation of Clinical Neurophysiology.Peer reviewe

White Matter Integrity as a Biomarker for Stroke Recovery: Implications for TMS Treatment

White matter consists of myelinated axons which integrate information across remote brain regions. Following stroke white matter integrity is often compromised leading to functional impairment and disability. Despite its prevalence among stroke patients the role of white matter in development of post-stroke rehabilitation has been largely ignored. Rehabilitation interventions like repetitive transcranial magnetic stimulation (rTMS) are promising but reports on its efficacy have been conflicting. By understanding the role of white matter integrity in post-stroke motor recovery, brain reorganization and TMS efficacy we may be able to improve the development of future interventions. In this dissertation we set out answer these questions by investigating the relationship between white matter integrity and 1) bimanual motor performance following stroke, 2) cortical laterality following stroke and 3) TMS signal propagation (in a group of cocaine users without stroke). We identified white matter integrity of the corpus callosum as a key structure influencing bimanual performance using kinematic measures of hand symmetry (Chapter 2). Second, we found that reduced white matter integrity of corpus callosum was correlated with loss of functional laterality of the primary motor cortex during movement of the affected hand (Chapter 3). Lastly, we found that reduced white matter tract integrity from the site of stimulation to a downstream subcortical target, was correlated to the ability to modulate that target (Chapter 4). Taken together these studies support white matter integrity as a valuable biomarker for future rTMS trials in stroke. To emphasize the implications of these findings, we provide an example of how to incorporate white matter integrity at multiple levels of rTMS study design

Precision non-implantable neuromodulation therapies : a perspective for the depressed brain

Current first-line treatments for major depressive disorder (MDD) include pharmacotherapy and cognitive-behavioral therapy. However, one-third of depressed patients do not achieve remission after multiple medication trials, and psychotherapy can be costly and time-consuming. Although nonimplantable neuromodulation (NIN) techniques such as transcranial magnetic stimulation, transcranial direct current stimulation, electroconvulsive therapy, and magnetic seizure therapy are gaining momentum for treating MDD, the efficacy of non-convulsive techniques is still modest, whereas use of convulsive modalities is limited by their cognitive side effects. In this context, we propose that NIN techniques could benefit from a precision-oriented approach. In this review, we discuss the challenges and opportunities in implementing such a framework, focusing on enhancing NIN effects via a combination of individualized cognitive interventions, using closed-loop approaches, identifying multimodal biomarkers, using computer electric field modeling to guide targeting and quantify dosage, and using machine learning algorithms to integrate data collected at multiple biological levels and identify clinical responders. Though promising, this framework is currently limited, as previous studies have employed small samples and did not sufficiently explore pathophysiological mechanisms associated with NIN response and side effects. Moreover, cost-effectiveness analyses have not been performed. Nevertheless, further advancements in clinical trials of NIN could shift the field toward a more ‘‘precision-oriented’’ practice

The Acute GABAergic Effects of Mindfulness Meditation in the Motor Cortex of University Students

Background: Previous research demonstrated the cortical silent period (CSP) protocol, a measure of GABAB related cortical inhibition, reliably reflects differences between psychiatric populations and healthy controls. Furthermore, cognitive behaviour therapy (CBT) and mindfulness meditation (MM) programs have been shown to affect CSP positively. In this pilot study, we assessed acute effects of MM by measuring pre-post differences in participants with minimal experience with meditation. Methods: The CSP protocol was employed to measure cortical inhibition before and after a single 40 minute guided meditation session. Furthermore, involvement with the practice before and after the appointment was used to determine if experience affected the degree of change in cortical inhibition and whether this change could predict a participants likelihood of attending weekly meditation tutorials. Finally, increases were expected to be correlated with 5 measures of self-reports of anxiety, depression, and mindfulness. Results: Significant pre-post differences were found after 40 minutes of MM in 67 students with minimal experience with meditation (t(66) = 2.334, p = 0.011). Students who had no prior meditation experience (< 2 hours) exhibited significant increases in CSP (delta x = 0.014 s) compared to those with more experience (F(1, 1) = 5.388, p = 0.024, η2 = 0.079). Change in CSP did not predict likelihood of continued attendance (F(1, 1) = 1.242, p = 0.269). Finally, baseline CSP measures were found to be negatively correlated with self-reports of negative automatic thoughts (r = -0.303, p = 0.008, n = 63). Discussion: Findings indicated improved cortical inhibition in minimally experienced MM practitioners after 40 minutes of meditation and that experience plays a role in the effectiveness of a single guided mindfulness meditation session. Furthermore, the degree of change in CSP was predicted by the severity of self-reported automatic thoughts possibly as a result of the decreased difficulty of staying focused with fewer intrusive thoughts allowing for a more equanimous meditation session. This evidence suggests GABAergic neurotransmission may prove to be involved in a neurophysiological mode of action and that automatic thoughts may be a psychological variable involved in a cognitive mechanism underlying the health benefits associated with mindfulness meditation

Phase matters when there is power : Phasic modulation of corticospinal excitability occurs at high amplitude sensorimotor mu-oscillations

Prior studies have suggested that oscillatory activity in cortical networks can modulate stimulus-evoked responses through time-varying fluctuations in neural excitation-inhibition dynamics. Studies combining transcranial magnetic stimulation (TMS) with electromyography (EMG) and electroencephalography (EEG) can provide direct measurements to examine how instantaneous fluctuations in cortical oscillations contribute to variability in TMS-induced corticospinal responses. However, the results of these studies have been conflicting, as some reports showed consistent phase effects of sensorimotor mu-rhythms with increased excitability at the negative mu peaks, while others failed to replicate these findings or reported unspecific mu-phase effects across subjects. Given the lack of consistent results, we systematically examined the modulatory effects of instantaneous and pre-stimulus sensorimotor mu-rhythms on corticospinal responses with offline EEG-based motor evoked potential (MEP) classification analyses across five identical visits. Instantaneous sensorimotor mu-phase or pre-stimulus mu-power alone did not significantly modulate MEP responses. Instantaneous mu-power analyses showed weak effects with larger MEPs during high-power trials at the overall group level analyses, but this trend was not reproducible across visits. However, TMS delivered at the negative peak of high magnitude mu-oscillations generated the largest MEPs across all visits, with significant differences compared to other peak-phase combinations. High power effects on MEPs were only observed at the trough phase of ongoing mu oscillations originating from the stimulated region, indicating site and phase specificity, respectively. More importantly, such phase-dependent power effects on corticospinal excitability were reproducible across multiple visits. We provide further evidence that fluctuations in corticospinal excitability indexed by MEP amplitudes are partially driven by dynamic interactions between the magnitude and the phase of ongoing sensorimotor mu oscillations at the time of TMS, and suggest promising insights for (re)designing neuromodulatory TMS protocols targeted to specific cortical oscillatory states

Neuroimaging and serum biomarkers of neurodegeneration and neuroplasticity in Parkinson’s disease patients treated by intermittent theta-burst stimulation over the bilateral primary motor area: a randomized, double-blind, sham-controlled, crossover trial study

Background and objectivesIntermittent theta-burst stimulation (iTBS) is a patterned form of excitatory transcranial magnetic stimulation that has yielded encouraging results as an adjunctive therapeutic option to alleviate the emergence of clinical deficits in Parkinson’s disease (PD) patients. Although it has been demonstrated that iTBS influences dopamine-dependent corticostriatal plasticity, little research has examined the neurobiological mechanisms underlying iTBS-induced clinical enhancement. Here, our primary goal is to verify whether iTBS bilaterally delivered over the primary motor cortex (M1) is effective as an add-on treatment at reducing scores for both motor functional impairment and nonmotor symptoms in PD. We hypothesize that these clinical improvements following bilateral M1-iTBS could be driven by endogenous dopamine release, which may rebalance cortical excitability and restore compensatory striatal volume changes, resulting in increased striato-cortico-cerebellar functional connectivity and positively impacting neuroglia and neuroplasticity.MethodsA total of 24 PD patients will be assessed in a randomized, double-blind, sham-controlled crossover study involving the application of iTBS over the bilateral M1 (M1 iTBS). Patients on medication will be randomly assigned to receive real iTBS or control (sham) stimulation and will undergo 5 consecutive sessions (5 days) of iTBS over the bilateral M1 separated by a 3-month washout period. Motor evaluation will be performed at different follow-up visits along with a comprehensive neurocognitive assessment; evaluation of M1 excitability; combined structural magnetic resonance imaging (MRI), resting-state electroencephalography and functional MRI; and serum biomarker quantification of neuroaxonal damage, astrocytic reactivity, and neural plasticity prior to and after iTBS.DiscussionThe findings of this study will help to clarify the efficiency of M1 iTBS for the treatment of PD and further provide specific neurobiological insights into improvements in motor and nonmotor symptoms in these patients. This novel project aims to yield more detailed structural and functional brain evaluations than previous studies while using a noninvasive approach, with the potential to identify prognostic neuroprotective biomarkers and elucidate the structural and functional mechanisms of M1 iTBS-induced plasticity in the cortico-basal ganglia circuitry. Our approach may significantly optimize neuromodulation paradigms to ensure state-of-the-art and scalable rehabilitative treatment to alleviate motor and nonmotor symptoms of PD

Methods and models for brain connectivity assessment across levels of consciousness

The human brain is one of the most complex and fascinating systems in nature. In the last decades, two events have boosted the investigation of its functional and structural properties. Firstly, the emergence of novel noninvasive neuroimaging modalities, which helped improving the spatial and temporal resolution of the data collected from in vivo human brains. Secondly, the development of advanced mathematical tools in network science and graph theory, which has recently translated into modeling the human brain as a network, giving rise to the area of research so called Brain Connectivity or Connectomics. In brain network models, nodes correspond to gray-matter regions (based on functional or structural, atlas-based parcellations that constitute a partition), while links or edges correspond either to structural connections as modeled based on white matter fiber-tracts or to the functional coupling between brain regions by computing statistical dependencies between measured brain activity from different nodes. Indeed, the network approach for studying the brain has several advantages: 1) it eases the study of collective behaviors and interactions between regions; 2) allows to map and study quantitative properties of its anatomical pathways; 3) gives measures to quantify integration and segregation of information processes in the brain, and the flow (i.e. the interacting dynamics) between different cortical and sub-cortical regions. The main contribution of my PhD work was indeed to develop and implement new models and methods for brain connectivity assessment in the human brain, having as primary application the analysis of neuroimaging data coming from subjects at different levels of consciousness. I have here applied these methods to investigate changes in levels of consciousness, from normal wakefulness (healthy human brains) or drug-induced unconsciousness (i.e. anesthesia) to pathological (i.e. patients with disorders of consciousness)