Reducing Motor Evoked Potential amplitude variability through normalization

Tese de mestrado integrado, Engenharia Biomédica e Biofísica (Sinais e Imagens Médicas), 2022, Universidade de Lisboa, Faculdade de CiênciasTranscranial Magnetic Stimulation (TMS) has several different applications, including in vivo assessment of motor cortical excitability in humans. When applied over the motor cortex, TMS single-pulses result in muscle responses that can be recorded with electromyography (EMG) as Motor Evoked Potentials (MEPs). These have been widely explored as potential biomarkers for neuropsychiatric disorders but methodological heterogeneity in their acquisition, and their inherent high variability have led to constraints in reproducibility. Normalization has been used to reduce variability of EMG measurements. Albeit being a standard practice to allow between-subject comparisons in EMG research, its effect on MEP variability has not been explored. In this study we aim to explore the impact of different normalization methods in MEP amplitude variability. After validating our in-house built EMG acquisition system, Maximal Voluntary Isometric Contractions (MVICs) and MEPs were collected from 47 healthy volunteers. Four different strategies were used in MEP normalization: two based on external references and two based on internal references. Bootstrapping was used to define distributions of coefficients of variation (CV) for each normalization method. Specifically, iterative re-sampling of 30 MEPs per subject, repeated 5000 times, was performed and a distribution of CVs per method was obtained, allowing for statistical comparison of between-subject variability. A retest session was conducted to assess the impact of normalization on within-subject variability of MEP amplitude measurements, using intra-class correlation coefficients (ICC). While normalization using external references did not reduce the CV, internal reference normalization resulted in a reduction of approximately 67% of between-subject variability. Normalization did not reduce within subject variability as measured by the ICCs. Our findings suggest that internal reference normalization reduces between-subject variability and has a minimal impact on within-subject variability. Additional research is necessary to further improve internal reference normalization methods towards potential use of MEPs as biomarkers of neuropsychiatric disorders

Replicability of motor cortex-excitability modulation by intermittent theta burst stimulation

Funding Information: GC was funded by Fundação para a Ciência e Tecnologia (FCT; Portugal) through a PhD Scholarship (SFRH/BD/130210/2017. CS, GC and AJO-M were supported by grant PTDC/MED-NEU/31331/2017. AJO-M by grant PTDC/MEC-PSQ/30302/2017-IC&DT-LISBOA-01–0145-FEDER, funded by national funds from FCT/MCTES and co-funded by FEDER, under the Partnership Agreement Lisboa 2020 - Programa Operacional Regional de Lisboa, and by a Starting Grant from the European Research Council under the European Union’s Horizon 2020 research and innovation programme (grant agreement no. 950357). The content of this study is solely the responsibility of the authors and does not necessarily represent the official views of the Fundação para a Ciência e Tecnologia or the European Research Council. Funding Information: AJO-M was national coordinator for Portugal of a non-interventional study (EDMS-ERI-143085581, 4.0) to characterize a Treatment-Resistant Depression Cohort in Europe, sponsored by Janssen-Cilag, Ltd (2019–2020), national coordinator for Portugal of trials of psilocybin therapy for treatment-resistant depression, sponsored by Compass Pathways, Ltd (EudraCT number 2017–003288-36), and of esketamine for treatment-resistant depression, sponsored by Janssen-Cilag, Ltd (EudraCT NUMBER: 2019–002992-33), and is recipient of a grant from Schuhfried GmBH for norming and validation of cognitive tests. Publisher Copyright: © 2023 International Federation of Clinical NeurophysiologyObjective: Transcranial Magnetic Stimulation (TMS) allows for cortical-excitability (CE) assessment and its modulation has been associated with neuroplasticity-like phenomena, thought to be impaired in neuropsychiatric disorders. However, the stability of these measures has been challenged, defying their potential as biomarkers. This study aimed to test the temporal stability of cortical-excitability modulation and study the impact of individual and methodological factors in determining within- and between-subject variability. Methods: We recruited healthy-subjects to assess motor cortex (MC) excitability modulation, collecting motor evoked potentials (MEP) from both hemispheres, before and after left-sided intermittent theta burst stimulation (iTBS), to obtain a measure of MEPs change (delta-MEPs). To assess stability across-time, the protocol was repeated after 6 weeks. Socio-demographic and psychological variables were collected to test association with delta-MEPs. Results: We found modulatory effects on left MC and not on right hemisphere following iTBS of left MC. Left delta-MEP was stable across-time when performed immediately after iTBS (ICC = 0.69), only when obtained first in left hemisphere. We discovered similar results in a replication cohort testing only left MC (ICC = 0.68). No meaningful associations were found between demographic and psychological factors and delta-MEPs. Conclusions: Delta-MEP is stable immediately after modulation and not impacted by different individual factors, including expectation about TMS-effect. Significance: Motor cortex excitability modulation immediately after iTBS should be further explored as a potential biomarker for neuropsychiatric diseases.publishersversionpublishe

A step-by-step guide for professional training

Funding Information: AM and GC were supported by doctoral fellowships from Fundação para a Ciência e Tecnologia (FCT, references SFRH/BD/144508/2019 and SFRH/BD/130210/2017, respectively). GC and AO-M were supported by grant PTDC/MED-NEU/31331/2017 from FCT and AO-M was supported by grant FCT-PTDC/MEC-PSQ/30302/2017-IC&DT-LISBOA-01-0145-FEDER, funded by national funds from FCT/Ministério da Ciência, Tecnologia e do Ensino Superior (MCTES) and cofounded by Fundo Europeu de Desenvolvimento Regional (FEDER), under the Partnership Agreement Lisboa 2020—Programa Operacional Regional de Lisboa. This work was supported by the Brain and Behavior Research Foundation (BBRF) through grant BBRF-27595-2018 NARSAD to AM and AO-M. FCT/MCTES, FEDER, and the BBRF did not have a role in the design and conduct of this work, in the preparation, review, or approval of the manuscript, nor in the decision to submit the manuscript for publication. Funding Information: Author AO-M was national coordinator for Portugal of a non-interventional study (EDMS-ERI-143085581, 4.0) to characterize a Treatment-Resistant Depression Cohort in Europe, sponsored by Janssen-Cilag, Ltd. (2019-2020), is recipient of a grant from Schuhfried GmBH for norming and validation of cognitive tests, and is national coordinator for Portugal of trials of psilocybin therapy for treatment-resistant depression, sponsored by Compass Pathways, Ltd. (EudraCT numbers: 2017-003288-36 and 2020-001348-25), and of esketamine for treatment-resistant depression, sponsored by Janssen-Cilag, Ltd. (EudraCT number: 2019-002992-33). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.Transcranial Magnetic Stimulation (TMS) is a non-invasive brain stimulation technique that was cleared by the Food and Drug Administration (FDA) for the treatment of Obsessive-Compulsive Disorder (OCD) in 2018. The approved protocol includes individualized symptom provocation before each stimulation session, to elicit a moderate level of obsessional distress. Although symptom provocation can be a delicate, demanding, and uncomfortable procedure, structured training methods for those who are going to apply it are not available. Here, we describe a model for training in symptom provocation for TMS technicians, developed at the Champalimaud Clinical Centre in Lisbon, Portugal. Our programme includes two-sessions dedicated to clinical communication and symptom provocation techniques from a theoretical and practical perspective. Additionally, supervision meetings are conducted during treatment of patients, allowing regular case discussion and redefinition of symptom provocation hierarchy, as needed. In addition to having a strong practical component, our training program is short and pragmatic, allowing for easy implementation and fluid transition to clinical practice. By sharing our experience, we hope to contribute to systematize training procedures required for symptom provocation in the context of TMS, and to qualitatively describe a methodology that can be used for implementation of TMS programmes for the treatment of OCD.publishersversionpublishe

Reducing motor evoked potential amplitude variability through normalization

Funding Information: The author(s) declare financial support was received for the research, authorship, and/or publication of this article. GC was funded by Fundação para a Ciência e Tecnologia (FCT; Portugal) through a PhD Scholarship (SFRH/BD/130210/2017). GC and AJO-M were supported by grant PTDC/MED-NEU/31331/2017. AJO-M was supported by grant PTDC/MEC-PSQ/30302/2017-IC\&DT-LISBOA-01-0145-FEDER, funded by national funds from FCT/MCTES and co-funded by FEDER.publishersversionpublishe

Clinical implications

Funding: GC was funded by Fundaçao para a Ciência e Tecnologia (FCT; Portugal) through a PhD Scholarship (SFRH/BD/130210/2017). AJOM was funded by FCT (Portugal) through a Junior Research and Career Development Award from the Harvard Medical School e Portugal Program (HMSP-ICJ/0020/2011). GC and AJO-M were supported by grant PTDC/MED-NEU/31331/2017, and AJO-M by grant PTDC/MED-NEU/30302/2017, funded by national funds from FCT/MCTES and co-funded by FEDER, under the Partnership Agreement Lisboa 2020 - Programa Operacional Regional de Lisboa. The content of this study is solely the responsibility of the authors and does not necessarily represent the official views of the Fundaçao para a Ciência e Tecnologia, Harvard University or its affiliated academic health care centers. AJO-M was national coordinator for Portugal of a noninterventional study (EDMS-ERI-143085581, 4.0) to characterize a Treatment-Resistant Depression Cohort in Europe, sponsored by Janssen-Cilag, Ltd (2019e2020), is recipient of a grant from Schuhfried GmBH for norming and validation of cognitive tests, and is national coordinator for Portugal of trials of psilocybin therapy for treatment-resistant depression, sponsored by Compass Pathways, Ltd (EudraCT number 2017-003288-36 and 2020-001348- 25), and of esketamine for treatment-resistant depression, sponsored by Janssen-Cilag, Ltd (EudraCT NUMBER: 2019-002992-33). AP-L is a co-founder of Linus Health and TI Solutions AG; serves on the scientific advisory boards for Starlab Neuroscience, Neuroelectrics, Magstim Inc., Nexstim, Cognito, and MedRhythms; and is listed as an inventor on several issued and pending patents on the real-time integration of noninvasive brain stimulation with electroencephalography and magnetic resonance imaging. None of the aforementioned agencies had a role in the design and conduct of the study, in the collection, management, analysis, and interpretation of the data, in the preparation, review, or approval of the manuscript, nor in the decision to submit the manuscript for publication. The remaining authors have declared that they have no potential conflicts of interest involving this work, including relevant financial activities outside the submitted work and any other relationships or activities that readers could perceive to have influenced, or that give the appearance of potentially influencing what is written.Background: When repetitive transcranial magnetic stimulation (rTMS) is used to treat medication refractory depression, the treatment pulse intensity is individualized according to motor threshold (MT). This measure is often acquired only on the first day of treatment, as per the protocol currently approved by Food and Drug Administration. Objective: Here, we aimed to assess daily MT variability across an rTMS treatment course and simulate the effects of different schedules of MT assessment on treatment intensity. Methods: We conducted a naturalistic retrospective study with 374 patients from a therapeutic rTMS program for depression that measures MT daily. Results: For each patient, in almost half the TMS sessions, MT varied on average more than 5% as compared to the baseline MT acquired in the first treatment day. Such variability was only minimally impacted by having different TMS technicians acquiring MT in different days. In a smaller cohort of healthy individuals, we confirmed that the motor hotspot localization method, a critical step for accurate MT assessment, was stable in different days, arguing that daily MT variability reflects physiological variability, rather than an artifact of measurement error. Finally, in simulations of the effect of one-time MT measurement, we found that half of sessions would have been 5% or more above or below target intensity, with almost 5% of sessions 25% above target intensity. The simulated effects of weekly MT measurements were significantly improved. Conclusions: In conclusion, MT varies significantly across days, not fully dependent on methods of MT acquisition. This finding may have important implications for therapeutic rTMS practice regarding safety and suggests that regular MT assessments, daily or at least weekly, would ameliorate the effect.publishersversionpublishe

Variability in motor threshold

Funding Information: GC was funded by Funda??o para a Ci?ncia e Tecnologia (FCT; Portugal) through a PhD Scholarship (SFRH/BD/130210/2017). AJO-M was funded by FCT (Portugal) through a Junior Research and Career Development Award from the Harvard Medical School ? Portugal Program (HMSP-ICJ/0020/2011). GC and AJO-M were supported by grant PTDC/MED-NEU/31331/2017, and AJO-M by grant PTDC/MED-NEU/30302/2017, funded by national funds from FCT/MCTES and co-funded by FEDER, under the Partnership Agreement Lisboa 2020 - Programa Operacional Regional de Lisboa. The content of this study is solely the responsibility of the authors and does not necessarily represent the official views of the Funda??o para a Ci?ncia e Tecnologia, Harvard University or its affiliated academic health care centers. Funding Information: GC was funded by Fundação para a Ciência e Tecnologia (FCT; Portugal) through a PhD Scholarship ( SFRH/BD/130210/2017 ). AJO-M was funded by FCT (Portugal) through a Junior Research and Career Development Award from the Harvard Medical School – Portugal Program ( HMSP-ICJ/0020/2011 ). GC and AJO-M were supported by grant PTDC/MED-NEU/31331/2017, and AJO-M by grant PTDC/MED-NEU/30302/2017, funded by national funds from FCT/MCTES and co-funded by FEDER , under the Partnership Agreement Lisboa 2020 - Programa Operacional Regional de Lisboa. The content of this study is solely the responsibility of the authors and does not necessarily represent the official views of the Fundação para a Ciência e Tecnologia, Harvard University or its affiliated academic health care centers. Funding Information: AJO-M was national coordinator for Portugal of a non-interventional study (EDMS-ERI-143085581, 4.0) to characterize a Treatment-Resistant Depression Cohort in Europe, sponsored by Janssen-Cilag, Ltd (2019–2020), is recipient of a grant from Schuhfried GmBH for norming and validation of cognitive tests, and is national coordinator for Portugal of trials of psilocybin therapy for treatment-resistant depression, sponsored by Compass Pathways, Ltd (EudraCT number 2017-003288-36 and 2020-001348-25), and of esketamine for treatment-resistant depression, sponsored by Janssen-Cilag, Ltd (EudraCT NUMBER: 2019-002992-33). AP-L is a co-founder of Linus Health and TI Solutions AG; serves on the scientific advisory boards for Starlab Neuroscience, Magstim Inc., Radiant Hearts, and MedRhythms; and is listed as an inventor on several issued and pending patents on the real-time integration of noninvasive brain stimulation with electroencephalography and magnetic resonance imaging. None of the aforementioned agencies or companies had a role in the design and conduct of the study, in the collection, management, analysis, and interpretation of the data, in the preparation, review, or approval of the manuscript, nor in the decision to submit the manuscript for publication. The remaining authors have declared that they have no potential conflicts of interest involving this work, including relevant financial activities outside the submitted work and any other relationships or activities that readers could perceive to have influenced, or that give the appearance of potentially influencing what is written.publishersversionpublishe

Lesion network mapping of mania using different normative connectomes

Funding GC is supported by a Doctoral Fellowship (SFRH/ BD/130210/2017) from Fundação para a Ciência e Tecnologia (FCT). AJO-M is supported by grant PTDC/MEC-PSQ/30302/2017- IC&DT-LISBOA-01-0145-FEDER, funded by Portuguese national funds from FCT and co-funded by FEDER, under the Partnership Agreement Lisboa 2020—Programa Operacional Regional de Lisboa, and by a Starting Grant from the European Research Council under the European Union’s Horizon 2020 research and innovation programme (grant agreement no. 950357). GC and AJO-M are supported by Portuguese national funds from FCT through grant PTDC/ MED-NEU/31331/2017. MDF is supported by the Sidney R. Baer, Jr. Foundation, the Nancy Lurie Marks Foundation, the Mather’s Foundation, and the National Institutes of Health (R01 MH113929, R01 MH115949, R01 AG060987). None of the funding agencies had a role in the design and conduct of the study, in the collection, management, analysis and interpretation of the data, in the preparation, review or approval of the manuscript, nor in the decision to submit the manuscript for publication.Lesion network mapping is a neuroimaging technique that explores the network of regions functionally connected to lesions causing a common syndrome. The technique uses resting state functional connectivity from large databases of healthy individuals, i.e., connectomes, and has allowed for important insight into the potential network mechanisms underlying several neuropsychiatric disorders. However, concerns regarding reproducibility have arisen, that may be due to the use of different connectomes, with variable MRI acquisition parameters and preprocessing methods. Here, we tested the impact of using different connectomes on the results of lesion network mapping for mania. We found results were reliable and consistent independent of the connectome used.publishersversionepub_ahead_of_prin