Modulation of Resting Connectivity Between the Mesial Frontal Cortex and Basal Ganglia.

Background: The mesial prefrontal cortex, cingulate cortex, and the ventral striatum are key nodes of the human mesial fronto-striatal circuit involved in decision-making and executive function and pathological disorders. Here we ask whether deep wide-field repetitive transcranial magnetic stimulation (rTMS) targeting the mesial prefrontal cortex (MPFC) influences resting state functional connectivity. Methods: In Study 1, we examined functional connectivity using resting state multi-echo and independent components analysis in 154 healthy subjects to characterize default connectivity in the MPFC and mid-cingulate cortex (MCC). In Study 2, we used inhibitory, 1 Hz deep rTMS with the H7-coil targeting MPFC and dorsal anterior cingulate (dACC) in a separate group of 20 healthy volunteers and examined pre- and post-TMS functional connectivity using seed-based and independent components analysis. Results: In Study 1, we show that MPFC and MCC have distinct patterns of functional connectivity with MPFC-ventral striatum showing negative, whereas MCC-ventral striatum showing positive functional connectivity. Low-frequency rTMS decreased functional connectivity of MPFC and dACC with the ventral striatum. We further showed enhanced connectivity between MCC and ventral striatum. Conclusions: These findings emphasize how deep inhibitory rTMS using the H7-coil can influence underlying network functional connectivity by decreasing connectivity of the targeted MPFC regions, thus potentially enhancing response inhibition and decreasing drug-cue reactivity processes relevant to addictions. The unexpected finding of enhanced default connectivity between MCC and ventral striatum may be related to the decreased influence and connectivity between the MPFC and MCC. These findings are highly relevant to the treatment of disorders relying on the mesio-prefrontal-cingulo-striatal circuit

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

Variation in Reported Human Head Tissue Electrical Conductivity Values

Electromagnetic source characterisation requires accurate volume conductor models representing head geometry and the electrical conductivity field. Head tissue conductivity is often assumed from previous literature, however, despite extensive research, measurements are inconsistent. A meta-analysis of reported human head electrical conductivity values was therefore conducted to determine significant variation and subsequent influential factors. Of 3121 identified publications spanning three databases, 56 papers were included in data extraction. Conductivity values were categorised according to tissue type, and recorded alongside methodology, measurement condition, current frequency, tissue temperature, participant pathology and age. We found variation in electrical conductivity of the whole-skull, the spongiform layer of the skull, isotropic, perpendicularly- and parallelly-oriented white matter (WM) and the brain-to-skull-conductivity ratio (BSCR) could be significantly attributed to a combination of differences in methodology and demographics. This large variation should be acknowledged, and care should be taken when creating volume conductor models, ideally constructing them on an individual basis, rather than assuming them from the literature. When personalised models are unavailable, it is suggested weighted average means from the current meta-analysis are used. Assigning conductivity as: 0.41 S/m for the scalp, 0.02 S/m for the whole skull, or when better modelled as a three-layer skull 0.048 S/m for the spongiform layer, 0.007 S/m for the inner compact and 0.005 S/m for the outer compact, as well as 1.71 S/m for the CSF, 0.47 S/m for the grey matter, 0.22 S/m for WM and 50.4 for the BSCR

Novel coil designs for different neurological disorders in transcranial magnetic stimulation

Transcranial magnetic stimulation is a non-invasive, safe, painless out-patient treatment for major depressive disorder. In TMS, time varying magnetic field is used to induce electric field, in the region of interest, to stimulate the neurons. Coil design is an important aspect of TMS, as coils are used to navigate the magnetic field in the desired location. The work presented in this dissertation is regarding the use of the coil design development for the application of transcranial magnetic simulation. Two TMS coils namely the Triple Halo Coil and the Quadruple Butterfly Coil were presented, with one aiming for deep brain stimulation and other one for precise stimulation. The magnetic field due to the Triple Halo Coil is 7 times more than circular coil at 10 cm below the head. It can stimulate deep brain regions which are affected in disorders such as Parkinson’s disease and PTSD. The Quadruple Butterfly Coil has reduced volume of stimulation by around 10% at the vertex and dorsolateral prefrontal cortex when compared with the Figure-8 coil. Fifty heterogeneous MRI derived head models were used for the analysis of the induced electric field due to the Quadruple Butterfly Coil and the results were compared with the Figure-8 coil. For both the coils, first computer modelling was done on heterogeneous head models, using a finite element tool and testing using a prototype built by Jali Medicals with the help of an axial Hall probe and a gaussmeter. Furthermore, seven different coils for small animals were presented in this dissertation. These coils had varying electric field with the Slinky coil having the minimum area of stimulation and lowest electric field below 10 mm of the head, while the Animal Halo Coil had maximum area of stimulation and highest electric field at 1 mm below the head. Animal coils are important as animal testing reduces the cost and expedites the research time

Variation in reported human head tissue electrical conductivity values

Electromagnetic source characterisation requires accurate volume conductor models representing head geometry and the electrical conductivity field. Head tissue conductivity is often assumed from previous literature, however, despite extensive research, measurements are inconsistent. A meta-analysis of reported human head electrical conductivity values was therefore conducted to determine significant variation and subsequent influential factors. Of 3121 identified publications spanning three databases, 56 papers were included in data extraction. Conductivity values were categorised according to tissue type, and recorded alongside methodology, measurement condition, current frequency, tissue temperature, participant pathology and age. We found variation in electrical conductivity of the whole-skull, the spongiform layer of the skull, isotropic, perpendicularly- and parallelly-oriented white matter (WM) and the brain-to-skull-conductivity ratio (BSCR) could be significantly attributed to a combination of differences in methodology and demographics. This large variation should be acknowledged, and care should be taken when creating volume conductor models, ideally constructing them on an individual basis, rather than assuming them from the literature. When personalised models are unavailable, it is suggested weighted average means from the current meta-analysis are used. Assigning conductivity as: 0.41 S/m for the scalp, 0.02 S/m for the whole skull, or when better modelled as a three-layer skull 0.048 S/m for the spongiform layer, 0.007 S/m for the inner compact and 0.005 S/m for the outer compact, as well as 1.71 S/m for the CSF, 0.47 S/m for the grey matter, 0.22 S/m for WM and 50.4 for the BSCR

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

Non-invasive electrophysiological assessment of the corticospinal tract in health and disease

PhD ThesisTo date, no candidate markers of upper motor neuron (UMN) function have performed sufficiently well to enter widespread clinical use, and the lack of such markers impedes both the diagnostic process and clinical trials in motor neuron disease (MND). We studied 15-30Hz intermuscular coherence (IMC), a novel marker of UMN function, and central motor conduction time (CMCT), an established marker of UMN function based on transcranial magnetic stimulation (TMS), in healthy volunteers and patients newly diagnosed with MND. To clarify the relative contributions of different parts of the motor system to IMC generation, we examined IMC in patients with longstanding diagnoses of hereditary spastic paraparesis (HSP), multifocal motor neuropathy (MMN) and inclusion body myositis (IBM). Previous studies reported conflicting results for the relationship between CMCT and predictors such as age and height. We only found a significant correlation between lower limb CMCT and height. IMC did not vary significantly with age, allowing data from healthy subjects across all ages to be pooled into a single normative dataset. The variability of IMC between subjects was considerable, and within a given subject variability was greater between than within recording sessions; potential contributors are discussed. Anodal transcranial direct current stimulation (tDCS) caused a significant increase in IMC, but interindividual variability was substantial, which might hinder its future use as an adjunct to IMC. To compare individual disease groups to the normal cohort, we evaluated the area under the receiver-operating characteristic curve (AUC). IMC generally matched or exceeded the performance of CMCT in discriminating patients with MND from normal, achieving AUCs of 0.83 in the upper and 0.79 in the lower limb. Previous evidence suggests that IMC abnormalities are primarily attributable to corticospinal tract (CST) dysfunction. In line with this, most patients with HSP exhibited diminished IMC. However, patients with MMN also showed decreased IMC, suggesting either that subclinical CST involvement was present or that dysfunction of lower motor neurons (LMNs) may affect IMC; clarification through computational modelling is suggested. In iii IBM, IMC was generally increased, which might reflect that the altered motor unit discharge pattern makes synchronisation more readily detectable. IMC appears to be a promising marker of CST function. It remains to be clarified how strongly it is influenced by LMN lesions, and optimisation of methods should help to minimise the variability of results. Since IMC is non-invasive and can be measured using commonly available EMG equipment, wider dissemination should prove straightforward.Wellcome Trus