Clinical Research Directory

The Underlying Neural Mechanism of TMS in Improving the Imbalance of "Microbiota-brain-gut Axis" in Alzheimer 's Disease Population

What is this study about? This study focuses on Alzheimer's Disease (AD), a common neurodegenerative disease that affects memory, thinking, and daily life. We aim to explore whether a non-invasive treatment called Repetitive Transcranial Magnetic Stimulation (rTMS) can improve AD symptoms by regulating the "gut-brain-intestine axis" - a connection between gut bacteria, the brain, and the intestines. Who can participate? * \*\*AD patients\*\*: Aged 50-80, diagnosed with mild to moderate AD (MMSE score 18-27, MoCA score 10-26), with stable condition for at least 6 months, and able to cooperate with tests and treatment. * \*\*Healthy controls\*\*: Aged 50-80, with normal cognitive function (MMSE ≥28, MoCA ≥27), no AD family history, and matched in age and gender with AD patients. Those with epilepsy, severe mental illness, recent use of antibiotics/probiotics, or inability to complete MRI scans are not eligible. What will participants experience? * \*\*AD patients\*\*: Will be randomly divided into two groups. Both groups will receive 4 weeks of treatment (5 days/week) with a helmet-like device. One group gets real rTMS (safe magnetic stimulation to the brain), and the other gets sham stimulation (no effective magnetic field, but same sound/feel). * \*\*Healthy controls\*\*: No treatment, but will complete the same tests as AD patients. * \*\*Tests during the study\*\*: Cognitive assessments (memory, thinking skills via questionnaires), stool/blood sample collection (to check gut bacteria and body markers), and MRI scans (to look at brain structure/function) at baseline, 1 month, 3 months, 6 months, and 1 year. What are the potential benefits? * Free rTMS treatment (for AD patients), free MRI scans (valued at 700 RMB), and a 200 RMB subsidy. * Free health checks (gut bacteria analysis, metabolic tests) and cognitive evaluations to understand personal health status. * Contribution to developing new AD treatments that may help future patients. Is it safe? rTMS is a clinically proven safe technique. Possible mild side effects (headache, scalp irritation) usually go away on their own. Sample collection (stool/blood) and MRI scans are non-invasive or minimally invasive. A professional team will monitor participants throughout to handle any issues. For healthcare providers This is a multicenter, randomized, double-blind sham-controlled study (200 AD patients, 200 healthy controls). The primary goal is to explore rTMS's mechanism via the gut-brain-intestine axis, with MoCA score changes (6 months post-treatment) as the main outcome. It integrates multi-omics and neuroimaging data to provide evidence for AD's non-drug treatment.

Study of the Correlation Between Cortical Excitability and Cytoarchitectonics of Prefrontal Cortex in Healthy Adult Participants, Using Transcranial Magnetic Stimulation Coupled to EEG and High-field MRI

Repeated transcranial magnetic stimulation (rTMS) is mainly used to treat mood disorders by addressing differences in brain function, particularly in the dorsolateral prefrontal cortex (DLPFC), which affects emotions and executive functions. The therapy aims to enhance the left DLPFC or suppress the right. It has been approved for severe major depression in several countries (Canada and Israel since 2002, USA since 2008) and is in the process of being validated in Europe but is not yet reimbursed in France. due to variable results from one study to another and lack of standardization issues. In a previous study, by recording electroencephalographic (EEG) rhythms before and after rTMS treatment of the DLPFC, the investigators showed on a small cohort of patients (n=17) with major or bipolar depression, that the responder patients showed higher EEG theta rhythms in the DLPFC but also and especially in parietal regions. This suggests that the DLPFC is part of the fronto-parietal central executive network (CEN), which is important for working memory and cognitive control. The CEN is not well connected in severe resistant depression, possibly leading to negative emotional bias. The rTMS cure of DLPFC can be interpreted as improving depressive symptoms through the normalization of the CEN by increasing DLPFC excitability and its downward connectivity. However experimental and clinical evidence for this mechanism, among others, is still to be demonstrated, and remission rates of rTMS from DLPFC in drug-resistant depression are still low (20-40%). To improve these response rates to rTMS in DLPFC, it is essential to continue research aimed at improving clinical practices through a better knowledge of the functional neuroanatomy and mechanisms of action of rTMS. This will require the definition of biomarkers allowing in particular to better target the DLPFC, this structure beeing indeed relatively poorly defined on the neuroanatomical level (large portion of the medial frontal gyrus). To this end, the investigators have set up a collaborative research program with Dr. Corey Keller, psychiatrist at Stanford University USA, which was jointly funded in 2022 by the Agence Nationale pour la Recherche (ANR) and the National Institute of Health (NIH) - FrontalProbe project "Probing the dorsolateral prefrontal cortex and central executive network for improving neuromodulation in depression". The ultimate aim of this project is to develop and test different strategies for targeting the DLPFC in the rTMS treatment of pharmaco-resistant depressive patients, following the fundamental neuroanatomical and pathophysiological hypothesis that patients will respond better to therapy if their CEN network is better modulated. This clinical trial will take place in Stanford, USA, in the years 2025-2026. Previously, the investigators are working on the development of methodological strategies aimed at preferentially activating, in a personalized way, the part of the DLPFC that projects onto the PPC. This is the subject of the present protocol, which aims to identify this subpart of the DLPFC to be targeted as a priority for modulating the CEN, through neuroanatomical measurements with high-field MRI and cortical excitability by TMS-EEG in healthy subjects. To this end, the investigators will use a small cohort of healthy subjects who will have one multimodal MRI acquisition session of at 7T and one TMS-EEG session. The 7T MRI data, acquired at the Centre de Résonance Magnétique en Biologie et Médecine (CRMBM), will be used to obtain anatomical markers of the DLPFC. TMS-EEG data, acquired at the Institut de Neurosciences de Systèmes (INS), will be used for cortical excitability measurements of the DLPFC and its projection sites, notably the PPC. At this stage, no data exchange is planned with our American partners. Firstly, the processing of MRI data will include segmentation of gray and white matter, reconstruction of the cortical surface and estimation of the different cortical layers, mainly by monitoring variations in the T1 parameter along the cortical mantle. Other MRI parameters will also be acquired to maximize the specificity of the segmentation of the DLPFC into sub-regions, firstly by identifying the part of the DLPFC that connects preferentially to the PPC using the reconstruction of fiber bundles from diffusion MRI and functional resting MRI. Secondly, during TMS-EEG acquisitions, participants will be stimulated in 3 sub-regions of the DLPFC. For each target, the analyses of the EEG data will focus on quantifying connectivity with the PPC as well as their spectral signature, which is possibly an indirect reflection of the neuronal composition of the stimulated regions. Correlation of 7T MRI and TMS-EEG data will help set optimal DLPFC targeting criteria for PPC activation. The aim is to create an MRI-based targeting procedure for clinical practice. In this sense, TMS-EEG will serve as validation of MRI markers.

Novel Brain Stimulation Treatment for Neuropsychiatric Symptoms in Alzheimer's Disease

The goal of this pilot study is to test a combination of two non-invasive brain stimulation methods, called iTBS (intermittent theta burst stimulation) and tDCS (transcranial direct current stimulation), in people with Alzheimer's Disease (AD) and related dementias (ADRD). This study will also explore whether the combined treatment shows promise for reducing neuropsychiatric symptoms like mood swings, apathy, and agitation, and will evaluate the impact of the treatment on caregivers. The main questions the study aims to answer are: 1. Is the combined brain stimulation treatment practical and well-tolerated? 2. Do preliminary results suggest that this treatment could help manage neuropsychiatric symptoms and support a larger study? Participants will: * Attend nine in-person visits over three months. * Complete one week of in-clinic brain stimulation sessions (iTBS) followed by four weeks of daily at-home brain stimulation sessions (tDCS). * Take part in brain scans, questionnaires, and brain activity tests before and after the treatment. This pilot study is a first step to assess whether this combined treatment approach is practical and whether it has potential to improve symptoms, laying the groundwork for larger studies in the future.

Repetitive Transcranial Magnetic Stimulation Primed Self-controlled Practice on Motor Learning

This study aims to investigate the additive effects of combining self-controlled practice with repetitive transcranial magnetic stimulation (rTMS) pretreatment on motivation enhancement and motor learning performance in healthy young adults. According to the "Optimizing Performance Through Intrinsic Motivation and Attention for Learning" (OPTIMAL) theory, numerous studies have demonstrated that providing learners with autonomy during practice can facilitate intrinsic motivation and motor learning. However, self-controlled practice alone may have limited effects, and further interventions may be required to amplify learning outcomes. In recent years, non-invasive brain stimulation techniques-particularly high-frequency (facilitatory) rTMS applied to the dorsolateral prefrontal cortex (DLPFC)-have been shown to enhance motivational drive and explicit learning performance by strengthening the connectivity of the DLPFC-midbrain dopamine pathway. For example, 10 Hz high-frequency stimulation can significantly improve learners' accuracy and motivation. Interestingly, several sequence learning studies have found that low-frequency (inhibitory) rTMS, when used as a priming intervention, can instead enhance implicit procedural learning. This effect may occur because inhibiting the lateral prefrontal cortex reduces its top-down suppression of implicit learning systems, thereby releasing procedural learning potential. Based on the theory of metaplasticity, applying facilitatory or inhibitory stimulation beforehand can alter the threshold of synaptic plasticity, thus influencing subsequent learning outcomes. Therefore, this study designed two DLPFC pretreatments-facilitatory and inhibitory-and combined them with self-controlled practice to systematically examine the interaction between different stimulation protocols on motivation and motor learning. This cross-sectional experiment plans to recruit 72 healthy participants aged 20 or older, randomly assigned to one of six groups: (1) facilitatory rTMS + self-controlled practice, (2) facilitatory rTMS + yoked control, (3) inhibitory rTMS + self-controlled practice, (4) inhibitory rTMS + yoked control, (5) sham rTMS + self-controlled practice, and (6) sham rTMS + yoked control. The experiment will last for seven days. On Day 1, participants will complete baseline testing, followed by facilitatory rTMS, inhibitory rTMS, or sham stimulation over the DLPFC. Immediately afterward, they will engage in a trajectory-tracking learning task (manipulating a joystick to reproduce a sine-wave pattern). After practice, participants will complete a motivation assessment. During the trajectory-tracking task, the self-controlled group can choose when to receive feedback to adjust their learning, whereas the yoked control group will receive feedback at time points matched to their paired counterpart. On Day 2, participants will again receive the assigned rTMS (facilitatory, inhibitory, or sham), complete the trajectory-tracking task, and undergo a motivation assessment. After a five-minute rest, they will perform retention and transfer tests, followed by TMS measurement of cortical excitability. On Day 7, participants will return to the laboratory to complete another retention and transfer test, along with cortical excitability measurement via TMS. The primary behavioral outcomes are the root mean square error (RMSE) and error estimation (EE) in the trajectory-tracking task. Motivation will be assessed using the Intrinsic Motivation Inventory (IMI). As there have been no prior studies combining DLPFC rTMS pretreatment with practice autonomy, the results of this experimental design are expected to provide new insights and references for enhancing motor learning ability in healthy adults.

Efficacy of Non-Invasive Neuromodulation on Pain in Migraine

This is a prospective clinical study evaluating the analgesic efficacy of a non-medicated treatment: repeated transcranial magnetic stimulation (rTMS) of the primary motor cortex in chronic migraine (\> 7 headache days per month and failure of at least 3 drug treatments). To this end, the study involves a double-blind, randomized, comparative experimental protocol against a sham control condition via 2 parallel groups comprising 60 patients each (N= 120 in total). Randomized block design with stratification by center and type of migraine (episodic or chronic). 5 rTMS sessions will be performed, with one stimulation session every 2 weeks. One group will receive active stimulation at each session (high-frequency stimulation of the left primary motor cortex, 2000 pulses per session, 80% of resting motor threshold) and the other group placebo stimulation (sham). Depending on the randomization group, rTMS sessions will be carried out by trained experimenters in the investigating center where the patient has been included. The study is multicentric, with five centers, four of which are in the Auvergne-Rhône-Alpes region. Data will be centralized at the Clermont-Ferrand University Hospital, and statistical analysis will be carried out by the Clermont-Ferrand University Hospital's Clinical Research and Innovation Department. Principal difference analysis (active vs sham) performed in ITT; missing data processed by multiple imputation.

Effects of Repetitive Transcranial Magnetic Stimulations in Patients With Amphetamine Use Disorders

Amphetamine Use Disorder (AUD) is a major public health issue in Taiwan, where it is the most commonly abused illegal drug. There are currently no effective approved medications to treat it, which makes finding new treatment options urgent. Repetitive Transcranial Magnetic Stimulation (rTMS), a non-invasive brain stimulation method, has shown promise in reducing cravings and drug use in people with addiction, but its effects on AUD are not well studied. To explore this, the investigators plan to conduct a double-blind, sham-controlled study with 20 people diagnosed with AUD. Half will receive real rTMS treatment, and half will receive a placebo-like sham treatment. The treatment targets a specific brain area (the left dorsolateral prefrontal cortex) and will be given 10 times over two weeks. The investigators will assess the effectiveness of rTMS by tracking drug cravings, urine test results, and side effects with follow-up over 12 weeks. The investigators also include brain imaging using near-infrared spectroscopy (NIRS) after the treatment. The study aims to better understand how rTMS might help reduce amphetamine cravings and improve outcomes, potentially leading to new treatment options for AUD.

Effectiveness of High-frequency rTMS in Reducing Alcohol Consumption in Non-abstinent Patients With an Alcohol Use Disorder

The fight against alcoholism is a public health priority. Around 15 million Europeans and 10 million North Americans are alcohol dependent. Worldwide, 1 death out of 25 is thought to be attributed to alcohol. In France, the latest published data on alcohol-related mortality indicates that there were 49,000 alcohol-related deaths in 2009. Alcohol is thought to be the leading cause of hospitalisation for French people, and its social cost is estimated at 37.4 billion euros. However, few patients with an alcohol use disorder are treated: less than 8% in Europe and less than 10.5% in the USA receive appropriate treatment for their alcohol problem. This low rate of treatment is mainly due to the fact that these patients are not ready to stop drinking. They are therefore not attracted by the goal of abstinence that is required by most current therapies and drug treatments. The arrival of new treatments aimed at reducing consumption (rather than abstinence) should make treatment more attractive. To date, nalmefen is the only treatment marketed for this indication. Baclofen should be marketed in 2020, but with restrictive prescription criteria. In this new strategy to reduce consumption, brain stimulation could play a predominant role as an alternative or complementary therapy. Indeed, functional brain imaging techniques have made it possible to visualise the cortical regions involved in craving, in particular the dorsolateral prefrontal cortex (DLPFC). Craving, i.e. the irrepressible desire to consume, is often at the origin of consumption and relapse. Stimulation of the dorsolateral prefrontal cortex with non-invasive cerebral stimulation techniques, such as repeated transcranial magnetic stimulation (rTMS), has provided encouraging results for the reduction of cravings in all addictive behaviours (alcohol, tobacco, cocaine, food). Furthermore, stimulation of the DLPFC seems to modulate decision-making processes: it may thus reduce impulsivity and strengthen inhibitory control, leading to a reduction in substance use. The hypothesis to be tested is that repeated transcranial magnetic stimulation allows a reduction in alcohol consumption in patients with an alcohol use disorder.

Prospective Exploratory Study on rTMS for Migraine Under the Guidance of MEG

Using magnetoencephalography to locate and regulate targets in migraine patients, repeating transcranial magnetic stimulation to physically regulate targets, and evaluating the safety and effectiveness of this treatment method through headache related scales. Using whole genome data and scale scores for correlation analysis, and conducting randomized controls with traditional drugs to explore new approaches for migraine.