Reliability of transcranial magnetic stimulation evoked potentials to detect the effects of theta-burst stimulation of the prefrontal cortex

Background: Transcranial magnetic stimulation (TMS) with simultaneous electroencephalography (EEG) is a novel method for assessing cortical properties outside the motor region. Theta burst stimulation (TBS), a form of repetitive TMS, can non-invasively modulate cortical excitability and has been increasingly used to treat psychiatric disorders by targetting the dorsolateral prefrontal cortex (DLPFC). The TMS-evoked potentials (TEPs) and local mean field power (LMFP) analyses have been used to evaluate local cortical excitability changes after TBS. However, it remains unclear whether TEPs can detect the neuromodulatory effects of TBS. Objectives: To confirm the reliability of TEP components and LMFP within and between sessions and to measure changes in neural excitability induced by intermittent (iTBS) and continuous TBS (cTBS) applied to the left DLPFC. Methods: Test-retest reliability of TEPs/LMFP and TBS-induced changes in cortical excitability were assessed in twenty-four healthy participants by stimulating the DLPFC in five separate sessions, once with sham and twice with iTBS and cTBS. EEG responses were recorded of 100 single TMS pulses before and after TBS, and the reproducibility measures were quantified with the concordance correlation coefficient (CCC). Results: The N100 and P200 components presented substantial reliability within the baseline block (CCCs>0.8) and moderate concordance between sessions (CCCmax> 0.6). Both N40 and P60 TEP amplitudes showed little concordance between sessions. Similar results were achieved using LMFP responses. Changes in TEP amplitudes after iTBS were marginally reliable for N100 (CCCmax = 0.52), P200 (CCCmax = 0.47) and P60 (CCCmax = 0.40), presenting only fair levels of concordance at specific time points. LMFP changes showed poor reproducibility after iTBS and cTBS. Conclusions: The present findings show that only the N100 and P200 components had good concordance between sessions. The reliability of earlier TEP components and LMF responses may have been affected by a sub-optimal removal of TMS-related artefacts. The poor reliability in detecting changes in neural excitability induced by TBS indicates that TEPs/LMFP do not provide a precise estimate of the changes in excitability in the DLPFC or, alternatively, that TBS did not induce consistent changes in neural excitability

Neuromodulatory effects of theta burst stimulation to the prefrontal cortex

Theta burst stimulation (TBS) is a new form of repetitive transcranial magnetic stimulation (TMS) capable of non-invasively modulating cortical excitability. In recent years TBS has been increasingly used as a neuroscientific investigative tool and therapeutic intervention for psychiatric disorders, in which the dorsolateral prefrontal cortex (DLPFC) is often the primary target. However, the neuromodulatory effects of TBS on prefrontal regions remain unclear. Here we share EEG and ECG recordings and structural MRI scans, including high-resolution DTI, from twenty-four healthy participants who received intermittent TBS (two sessions), continuous TBS (two sessions), and sham stimulation (one session) applied to the left DLPFC using a single-blinded crossover design. Each session includes eyes-open resting-state EEG and single-pulse TMS-EEG obtained before TBS and 2−, 15−, and 30-minutes post-stimulation. This dataset enables foundational basic science investigations into the neuromodulatory effects of TBS on the DLPFC

Individualised Transcranial Magnetic Stimulation Targeting of the Left Dorsolateral Prefrontal Cortex for Enhancing Cognition: A Randomised Controlled Trial

Repetitive transcranial magnetic stimulation (rTMS) has been demonstrated to produce cognitive enhancing effects across different neuropsychiatric disorders; however, so far, these effects have been limited. This trial investigated the efficacy of using a novel individualised approach to target the left dorsolateral prefrontal cortex (L-DLPFC) for enhancing cognitive flexibility based on performance on a cognitive task. First, forty healthy participants had their single target site at the L-DLPFC determined based on each individual’s performance on a random letter generation task. Participants then received, in a cross-over single-blinded experimental design, a single session of intermittent theta burst stimulation (iTBS) to their individualised DLPFC target site, an active control site and sham iTBS. Following each treatment condition, participants completed the Task Switching task and Colour–Word Stroop test. There was no significant main effect of treatment condition on the primary outcome measure of switch reaction times from the Task Switching task [F = 1.16 (2, 21.6), p = 0.33] or for any of the secondary cognitive outcome measures. The current results do not support the use of our novel individualised targeting methodology for enhancing cognitive flexibility in healthy participants. Research into alternative methodological targeting approaches is required to further improve rTMS’s cognitive enhancing effects

Familial hypercholesterolaemia in children and adolescents from 48 countries: a cross-sectional study

Background Approximately 450 000 children are born with familial hypercholesterolaemia worldwide every year, yet only 2·1% of adults with familial hypercholesterolaemia were diagnosed before age 18 years via current diagnostic approaches, which are derived from observations in adults. We aimed to characterise children and adolescents with heterozygous familial hypercholesterolaemia (HeFH) and understand current approaches to the identification and management of familial hypercholesterolaemia to inform future public health strategies. Methods For this cross-sectional study, we assessed children and adolescents younger than 18 years with a clinical or genetic diagnosis of HeFH at the time of entry into the Familial Hypercholesterolaemia Studies Collaboration (FHSC) registry between Oct 1, 2015, and Jan 31, 2021. Data in the registry were collected from 55 regional or national registries in 48 countries. Diagnoses relying on self-reported history of familial hypercholesterolaemia and suspected secondary hypercholesterolaemia were excluded from the registry; people with untreated LDL cholesterol (LDL-C) of at least 13·0 mmol/L were excluded from this study. Data were assessed overall and by WHO region, World Bank country income status, age, diagnostic criteria, and index-case status. The main outcome of this study was to assess current identification and management of children and adolescents with familial hypercholesterolaemia. Findings Of 63 093 individuals in the FHSC registry, 11 848 (18·8%) were children or adolescents younger than 18 years with HeFH and were included in this study; 5756 (50·2%) of 11 476 included individuals were female and 5720 (49·8%) were male. Sex data were missing for 372 (3·1%) of 11 848 individuals. Median age at registry entry was 9·6 years (IQR 5·8–13·2). 10 099 (89·9%) of 11 235 included individuals had a final genetically confirmed diagnosis of familial hypercholesterolaemia and 1136 (10·1%) had a clinical diagnosis. Genetically confirmed diagnosis data or clinical diagnosis data were missing for 613 (5·2%) of 11 848 individuals. Genetic diagnosis was more common in children and adolescents from high-income countries (9427 [92·4%] of 10 202) than in children and adolescents from non-high-income countries (199 [48·0%] of 415). 3414 (31·6%) of 10 804 children or adolescents were index cases. Familial-hypercholesterolaemia-related physical signs, cardiovascular risk factors, and cardiovascular disease were uncommon, but were more common in non-high-income countries. 7557 (72·4%) of 10 428 included children or adolescents were not taking lipid-lowering medication (LLM) and had a median LDL-C of 5·00 mmol/L (IQR 4·05–6·08). Compared with genetic diagnosis, the use of unadapted clinical criteria intended for use in adults and reliant on more extreme phenotypes could result in 50–75% of children and adolescents with familial hypercholesterolaemia not being identified. Interpretation Clinical characteristics observed in adults with familial hypercholesterolaemia are uncommon in children and adolescents with familial hypercholesterolaemia, hence detection in this age group relies on measurement of LDL-C and genetic confirmation. Where genetic testing is unavailable, increased availability and use of LDL-C measurements in the first few years of life could help reduce the current gap between prevalence and detection, enabling increased use of combination LLM to reach recommended LDL-C targets early in life. Funding Pfizer, Amgen, Merck Sharp & Dohme, Sanofi–Aventis, Daiichi Sankyo, and Regeneron

Treatment-emergent mania/hypomania during antidepressant treatment with transcranial direct current stimulation (tDCS): A systematic review and meta-analysis

Background Treatment-emergent mania/hypomania (TEM) is a possible adverse effect of pharmacological and non-pharmacological antidepressant treatments. Objective We performed a systematic review and meta-analysis to evaluate the risk of TEM in depressed patients during randomized, sham-controlled trials (RCTs). Data sources Medline database, from the first date available to August 12, 2016. Results From 283 references, 10 RCTs were identified. Only 3 of them described TEM. In active and sham groups, respectively, only 8 of 226 (3.5%) and 1 of 190 (0.5%) participants presented TEM. This difference was not statistically significant (OR = 1.79, 95% CI = 0.6 to 5.32). There were also five additional reports of TEM in participants not on RCTs. No risk factors for TEM were identified. Limitations Low number of studies and TEM reports. Conclusion Despite previous reports, active vs. sham tDCS was not associated with a significantly greater number of TEM episodes

Noninvasive brain stimulation in psychiatric disorders: A primer

Objective: Noninvasive brain stimulation (NIBS) techniques, such as transcranial direct current stimulation (tDCS) and repetitive transcranial magnetic stimulation (rTMS), are increasingly being used to treat mental disorders, particularly major depression. The aim of this comprehensive review is to summarize the main advances, limitations, and perspectives of the field. Methods: We searched PubMed and other databases from inception to July 2017 for articles, particularly systematic reviews and meta-analyses, evaluating the use of NIBS in psychiatric disorders. Results: We reviewed the mechanisms of action, safety, tolerability, efficacy, and relevant clinical parameters of NIBS. Repetitive TMS is already an established technique for the treatment of depression, and there is theoretically room for further methodological development towards a high-end therapeutic intervention. In contrast, tDCS is a technically easier method and therefore potentially suitable for wider clinical use. However the evidence of its antidepressant efficacy is less sound, and a recent study found tDCS to be inferior to antidepressant pharmacotherapy. Clinical trials using rTMS for other mental disorders produced mixed findings, whereas tDCS use has not been sufficiently appraised. Conclusion: The most promising results of NIBS have been obtained for depression. These techniques excel in safety and tolerability, although their efficacy still warrants improvement