A computational model for real-time calculation of electric field due to transcranial magnetic stimulation in clinics

The aim of this paper is to propose an approach for an accurate and fast (real-time) computation of the electric field induced inside the whole brain volume during a transcranial magnetic stimulation (TMS) procedure. The numerical solution implements the admittance method for a discretized realistic brain model derived from Magnetic Resonance Imaging (MRI). Results are in a good agreement with those obtained using commercial codes and require much less computational time. An integration of the developed codewith neuronavigation toolswill permit real-time evaluation of the stimulated brain regions during the TMSdelivery, thus improving the efficacy of clinical applications

Nanocolloids for Nanomedicine and Drug Delivery

This Special Issue highlights novel nanocolloids like magnetic nanoparticles, nanomicelles, nanoliposomes, nanocapsules, and nanoclays, stimulating novel interests and ideas in research groups involved in the development of novel nanotools within the different areas of nanomaterials. The publication of original articles contributes to scientific progress in the area of personalized medicine and further stimulates the entering into clinical praxis of such new nanosystems

cGMP Pathways as Novel Molecular Targets in the Brain for Fast Auditory Processing and Cognitive Function

Cyclic guanosine monophosphate (cGMP) signaling as the second messenger of the cGMP/cGKI cascade plays an important role in the auditory system. Particularly GC-A is suggested to be responsible for cGMP-triggered protection or recovery of cochlear components following traumatic overexposure (for review see: Marchetta, Rüttiger et al. 2021). Aiming to get insights into a potential protective role of the cGMP-producing GC-A for auditory processing, global GC-A KO mice were analyzed and shown to display impaired outer hair cell function in young animals already. They also developed a greater vulnerability of inner hair cells to noise- and age-dependent hearing loss, including temporal auditory processing deficits (Marchetta, Möhrle, et al., 2020), suggesting that the stimulation of GC-A signaling may have the potential to prevent or protect from age-dependent auditory fiber loss (cochlear synaptopathy). In the present study a cochlear synaptopathy involving a distinct auditory nerve fiber type (high-SR ANF), was shown to be critical for central compensation and temporal auditory processing. When this fast high SR ANF signaling was attenuated, the driving force to maintain inhibitory strength and to recruit BDNF in capillaries and nerve terminals of the hippocampus during auditory processing and compensation was reduced, which possibly reflected reduced vascular metabolic supply (Eckert, Marchetta et al., 2021; Marchetta et al., in preparation; Marchetta, Savitska et al., 2020). Using tamoxifen-inducible CaMKIIα-Cre mice to delete the stress receptors (mineralo- and glucocorticoid receptors) in the brain, we learned that an interplay of both receptors´ activity might link central hippocampal plasticity changes with peripheral fast auditory processing (Marchetta, Eckert et al., 2022). In conclusion, we could show the importance of development and maintenance of fast auditory processing and would like to introduce cGMP-generators, particularly GC-A, as potential new drug targets to improve auditory processing, stimulate auditory attention and learning-dependent amplification processes

Transcranial magnetic stimulation of the brain: What is stimulated? – A consensus and critical position paper

Copyright © 2022 The Author(s) and International Federation of Clinical Neurophysiology. Transcranial (electro)magnetic stimulation (TMS) is currently the method of choice to non-invasively induce neural activity in the human brain. A single transcranial stimulus induces a time-varying electric field in the brain that may evoke action potentials in cortical neurons. The spatial relationship between the locally induced electric field and the stimulated neurons determines axonal depolarization. The induced electric field is influenced by the conductive properties of the tissue compartments and is strongest in the superficial parts of the targeted cortical gyri and underlying white matter. TMS likely targets axons of both excitatory and inhibitory neurons. The propensity of individual axons to fire an action potential in response to TMS depends on their geometry, myelination and spatial relation to the imposed electric field and the physiological state of the neuron. The latter is determined by its transsynaptic dendritic and somatic inputs, intrinsic membrane potential and firing rate. Modeling work suggests that the primary target of TMS is axonal terminals in the crown top and lip regions of cortical gyri. The induced electric field may additionally excite bends of myelinated axons in the juxtacortical white matter below the gyral crown. Neuronal excitation spreads ortho- and antidromically along the stimulated axons and causes secondary excitation of connected neuronal populations within local intracortical microcircuits in the target area. Axonal and transsynaptic spread of excitation also occurs along cortico-cortical and cortico-subcortical connections, impacting on neuronal activity in the targeted network. Both local and remote neural excitation depend critically on the functional state of the stimulated target area and network. TMS also causes substantial direct co-stimulation of the peripheral nervous system. Peripheral co-excitation propagates centrally in auditory and somatosensory networks, but also produces brain responses in other networks subserving multisensory integration, orienting or arousal. The complexity of the response to TMS warrants cautious interpretation of its physiological and behavioural consequences, and a deeper understanding of the mechanistic underpinnings of TMS will be critical for advancing it as a scientific and therapeutic tool.Aman S. Aberra was supported by a U. S. A. National Science Foundation Graduate Research Fellowship (No. DGF 1106401). Andrea Antal has been supported by a grant of the Federal Ministry of Education and Research (BMBF) of Germany (Grant 01GP2124B) and by a grant of the Lower Saxony Ministry of Science and Culture (Grant 76251-12-7/19 ZN 3456). Marco Davare has been supported by a BBSRC responsive mode grant. Klaus Funke has been supported by a grant of the Federal Ministry of Education and Research (BMBF) of Germany (Grant 01EE1403B) as part of the German Center for Brain Stimulation (GCBS) and by the Deutsche Forschungsgemeinschaft (DFG) (Grants FU256/3-2; 122679504–SFB874). Mark Hallett is supported by the NINDS Intramural Program. Anke N. Karabanov holds a 4-year Sapere Aude Fellowship which is sponsored by the Independent Research Fund Denmark (Grant Nr. 0169-00027B). The sponsor had no direct involvement in the collection, analysis and interpretation of data and in the writing of the manuscript. Giacomo Koch has been supported by na EU grant H2020-EU.1.2.2. - FET Proactive (Neurotwin ID: 101017716). Sabine Meunier is Emeritus Research Director at INSERM, this has no direct involvement in the collection, analysis and interpretation of data and in the writing of the manuscript. Carlo Miniussi has been supported by a grant of the Caritro Foundation, Italy. Walter Paulus received grants from the Deutsche Forschungsgemeinschaft and BMBF. Angel V. Peterchev was supported by grants from the U. S. A. National Institutes of Health (Grants Nos. R01NS117405, R01NS088674, RF1MH114268, R01MH111865). Traian Popa has been supported by the Defitech Foundation and NIBS-iCog grant from the Swiss National Science Foundation. Hartwig R. Siebner holds a 5-year professorship in precision medicine at the Faculty of Health Sciences and Medicine, University of Copenhagen which is sponsored by the Lundbeck Foundation (Grant Nr. R186-2015-2138). The salary for Janine Kesselheim (PhD project) has been covered by a project grant “Biophysically adjusted state-informed cortex stimulation” (BASICS) funded by a synergy grant from Novo Nordisk Foundation (PI: Hartwig R Siebner, Interdisciplinary Synergy Program 2014; grant number NNF14OC001). Axel Thielscher has been supported by grants of the Lundbeck foundation (R118-A11308, R244-2017-196 and R313-2019-622). Yoshikazu Ugawa has been supported in part by grants from the Research Project Grant-in-aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology (Grants 15H05881, 16H05322, 19H01091, 20K07866). Ulf Ziemann received grants from the German Ministry of Education and Research (BMBF), European Research Council (ERC), and German Research Foundation (DFG)

Application of fMRI for action representation: decoding, aligning and modulating

Functional magnetic resonance imaging (fMRI) is an important tool for understanding neural mechanisms underlying human brain function. Understanding how the human brain responds to stimuli and how different cortical regions represent the information, and if these representational spaces are shared across brains and critical for our understanding of how the brain works. Recently, multivariate pattern analysis (MVPA) has a growing importance to predict mental states from fMRI data and to detect the coarse and fine scale neural responses. However, a major limitation of MVPA is the difficulty of aligning features across brains due to high variability in subjects’ responses and hence MVPA has been generally used as a subject specific analysis. Hyperalignment, solved this problem of feature alignment across brains by mapping neural responses into a common model to facilitate between subject classifications. Another technique of growing importance in understanding brain function is real-time fMRI Neurofeedback, which can be used to enable individuals to alter their brain activity. It facilitates people’s ability to learn control of their cognitive processes like motor control and pain by learning to modulate their brain activation in targeted regions. The aim of this PhD research is to decode and to align the motor representations of multi-joint arm actions based on different modalities of motor simulation, for instance Motor Imagery (MI) and Action Observation (AO) using functional Magnetic Resonance Imaging (fMRI) and to explore the feasibility of using a real-time fMRI neurofeedback to alter these action representations. The first experimental study of this thesis was performed on able-bodied participants to align the neural representation of multi-joint arm actions (lift, knock and throw) during MI tasks in the motor cortex using hyperalignment. Results showed that hyperalignment affords a statistically higher between-subject classification (BSC) performance compared to anatomical alignment. Also, hyperalignment is sensitive to the order in which subjects entered the hyperalignment algorithm to create the common model space. These results demonstrate the effectiveness of hyperalignment to align neural responses in motor cortex across subjects to enable BSC of motor imagery. The second study extended the use of hyperalignment to align fronto-parietal motor regions by addressing the problems of localization and cortical parcellation using cortex based alignment. Also, representational similarity analysis (RSA) was applied to investigate the shared neural code between AO+MI and MI of different actions. Results of MVPA revealed that these actions as well as their modalities can be decoded using the subject’s native or the hyperaligned neural responses. Furthermore, the RSA showed that AO+MI and MI representations formed separate clusters but that the representational organization of action types within these clusters was identical. These findings suggest that the neural representations of AO+MI and MI are neither the same nor totally distinct but exhibit a similar structural geometry with respect to different types of action. Results also showed that MI dominates in the AO+MI condition. The third study was performed on phantom limb pain (PLP) patients to explore the feasibility of using real-time fMRI neurofeedback to down-regulate the activity of premotor (PM) and anterior cingulate (ACC) cortices and whether the successful modulation will reduce the pain intensity. Results demonstrated that PLP patients were able to gain control and decrease the ACC and PM activation. Those patients reported decrease in the ongoing level of pain after training, but it was not statistically significant. The fourth study was conducted on healthy participants to study the effectiveness of fMRI neurofeedback on improving motor function by targeting Supplementary Motor Cortex (SMA). Results showed that participants learnt to up-regulate their SMA activation using MI of complex body actions as a mental strategy. In addition, behavioural changes, i.e. shortening of motor reaction time was found in those participants. These results suggest that fMRI neurofeedback can assist participants to develop greater control over motor regions involved in motor-skill learning and it can be translated into an improvement in motor function. In summary, this PhD thesis extends and validates the usefulness of hyperalignment to align the fronto-parietal motor regions and explores its ability to generalise across different levels of motor representation. Furthermore, it sheds light on the dominant role of MI in the AO+MI condition by examining the neural representational similarity of AO+MI and MI tasks. In addition, the fMRI neurofeedback studies in this thesis provide proof-of-principle of using this technology to reduce pain in clinical applications and to enhance motor functions in a healthy population, with the potential for translation into the clinical environment

The CNP signal is able to silence a supra threshold neuronal model

Several experimental results published in the literature showed that weak pulsed magnetic fields affected the response of the central nervous system. However, the specific biological mechanisms that regulate the observed behaviors are still unclear and further scientific investigation is required. In this work we performed simulations on a neuronal network model exposed to a specific pulsed magnetic field signal that seems to be very effective in modulating the brain activity: the Complex Neuroelectromagnetic Pulse (CNP). Results show that CNP can silence the neurons of a feed-forward network for signal intensities that depend on the strength of the bias current, the endogenous noise level and the specific waveforms of the pulses

Role of proteinase-activated receptor 2 in pathogeneiss of neurodegenerative diseases

This Thesis discusses the complex topic of the role of proteinase-activated receptors (PARs) in the physiology and pathophysiology of central nervous system diseases, and to some extent, the role of PARs in cancer pathobiology. Based on the results from this Thesis, we can conclude that PAR2 levels in the CSF do not track neuronal damage; therefore, PAR2 cannot be used as a marker of neuronal damage. Expression and activity of PAR2 in the brain appears to be mostly related to the activity of the disease process itself. To study the role of PAR2 in neurodegenerative diseases characterized by white matter and oligodendrocyte degeneration, a precise morphological descritption of individual diseases is essential. In the study aimed pathology of motor neuron disease we found reactive incre- ase in oligodendrocyte density in corticospinal tracts in reaction to white matter damage. In other study we confirmed the existence of a new variant of multiple system atrophy, atypical MSA (aMSA) charcterized by specific degenration of hippocampal neurons. Since the activity of kallikrein 6-PAR2 axis attenuates α-synuclein aggregation, its deficiency in hippocampus may be a prerequisite for its dominant degeneration leading to the develop- mant of α-synuclein neuronal inclusions and aMSA phenotype. Regarding the...Souhrn V předkládané práci je zpracován komplexní pohled na problematiku role proteiná- zami aktivovaných receptorů (PARs) v patogenezi nemocí CNS a částečně též nemocí nádorových. Z výsledků této práce studie vyplývá, že koncentrace PAR2 v mozkomíšním moku nelze považovat za marker neuronálního poškození ani marker typický pro jednotlivá neurode- generativní onemocnění. Exprese a aktivita PAR2 v CNS však může v případě lidských neurodegenerativních onemocnění odrážet aktivitu těchto onemocnění. Pro studium role PAR2 v patogenezi neurodegenerativních onemocnění charakterizova- ných poškozením bílé hmoty a oligodendrocytů je zásadní přesný morfologický popis pato- logie jednotlivých onemocnění. Ve studii zaměřené na patologii onemocnění motorického neuronu jsme prokázali, že s degenerací bílé hmoty kortikospinálních provazců dochází k reaktivní mobilizaci oligodendrocytů. Dále jsme potvrdili existenci nové varianty mno- hotné systémové atrofie (MSA), atypické MSA, charakterizované specifickou degenerací hipokampálních neuronů. Z hlediska PAR2 je důležitá role kallikrein 6-PAR2 systému, jehož aktivita snižuje agregaci α-synukleinu a může být v případě MSA deficientní. Lze předpokládat, že predominantní deficience aktivity kallikrein 6-PAR2 systému v hipo- kampu může být jedním z faktorů, který umožní vznik...Department of Pathology 3FM CU and UHKVÚstav patologie 3. LF UK a FNKV3. lékařská fakultaThird Faculty of Medicin