rTMS Targets Research Articles

Repetitive Transcranial Magnetic Stimulation on Individualized Spots Based on Task functional Magnetic Resonance Imaging Improves Swallowing Function in Poststroke Dysphagia.

Background: Functional magnetic resonance imaging (fMRI) has not previously been used to localize the swallowing functional area in repetitive transcranial magnetic stimulation (rTMS) treatment for poststroke dysphagia; Traditionally, the target area for rTMS is the hotspot, which is defined as the specific region of the brain identified as the optimal location for transcranial magnetic stimulation (TMS). This study aims to compare the network differences between the TMS hotspot and the saliva swallowing fMRI activation to determine the better rTMS treatment site and investigate changes in functional connectivity related to poststroke dysphagia using resting-state fMRI. Methods: Using an information-based approach, we conducted a single case study to explore neural functional connectivity in a patient with poststroke dysphagia before, immediately after rTMS, and 4 weeks after rTMS intervention. A total of 20 healthy participants underwent fMRI and TMS hotspot localization as a control group. Neural network alterations were assessed, and functional connections related to poststroke dysphagia were examined using resting-state fMRI. Results: Compared to the TMS-induced hotspots, the fMRI activation peaks were located significantly more posteriorly and exhibited stronger functional connectivity with bilateral postcentral gyri. Following rTMS treatment, this patient developed functional connection between the brainstem and the bilateral insula, caudate, anterior cingulate cortex, and cerebellum. Conclusion: The saliva swallowing fMRI activation peaks show more intense functional connectivity with bilateral postcentral gyri compared to the TMS hotspots. Activation peak-guided rTMS treatment improves swallowing function in poststroke dysphagia. This study proposes a novel and potentially more efficacious therapeutic target for rTMS, expanding its therapeutic options for treating poststroke dysphagia.

Different stimulation targets of rTMS modulate specific triple-network and hippocampal-cortex functional connectivity

BackgroundRepetitive transcranial magnetic stimulation (rTMS) is widely applied to treat Alzheimer's disease (AD). Various treatment targets are currently being explored in clinical research. However, target diversity can result in considerable heterogeneity. ObjectiveThis study aimed to investigate whether different rTMS targets can enhance cognitive domains by modulating functional connectivity (FC) of the hippocampus (HIP) and triple network, which comprises the salience network (SN), central executive network (CEN), and default mode network (DMN). MethodsWe enrolled 63 patients with AD, of whom 48 and 15 underwent rTMS targeting the left dorsolateral prefrontal cortex (dlPFC) and the bilateral angular gyrus (ANG), respectively. We examined the network-level FC differences within the triple-network before and after treatment. Additionally, we utilized HIP as a seed for voxel-level analysis. We compared the similarities and differences in the effects of dlPFC and ANG rTMS. ResultsrTMS targeting the dlPFC primarily influenced the FC of the CEN, whereas rTMS targeting the ANG primarily influenced the SN and DMN. Moreover, the right temporal lobe within the DMN exhibited reduced FC with the left HIP following both therapies. The results of least absolute shrinkage and selection operator (LASSO) analysis indicated that hippocampal-cortex FC played a dominant role in the therapeutic effect. The observed FC changes significantly correlated with improvements in multiple cognitive scales. ConclusionrTMS targeting different regions affected the FC of specific networks. Both stimulation targets modulate the FC of hippocampal-cortex to influence therapeutic outcomes. Classification of patients based on damaged networks can further inform subsequent treatment strategies.

Improvements in Sleep Quality in Patients With Major Depressive and Generalized Anxiety Disorders Treated With Individualized, Parcel-Guided Transcranial Magnetic Stimulation.

Poor quality sleep has often been cited as a cause of lowered quality of life in patients with affective disorders such as major depressive disorder (MDD) and generalized anxiety disorder (GAD). As sleep and affective disorders are affected by multi-network interactions, we hypothesize that the modulation of the central executive network (CEN), salience, and default mode networks (DMNs) through individualized repetitive transcranial magnetic stimulation (rTMS) may improve sleep and quality of life. A retrospective analysis from 2020 to 2023 was conducted in patients with affective disorders at Cingulum Health. Multiple targets were selected based on anomalies detected from individual, functional connectivity networks from a machine-learning connectivity software. rTMS was conducted with accelerated continuous or intermittent theta burst stimulation (TBS) based on the anomaly detected. Pittsburgh Sleep Quality Index (PSQI), EuroQol (EQ5D), Beck's Depression Inventory (BDI), and the General Anxiety Disorder-7 (GAD-7) questionnaires were administered prior to, after, and at follow-up of rTMS. Twenty-seven patients were identified, and the most common diagnoses were MDD (41%) or MDD with GAD (41%). All patients had at least one rTMS target in the CEN. The most common target (19 patients) was L8Av in the dorsolateral prefrontal cortex (dlPFC). Patients experienced significant improvements in sleep, quality of life, depressive, and anxiety symptoms after rTMS and during follow-up. Improvements in sleep correlated with quality of life at follow-up. This study suggests that personalized, parcel-guided rTMS is safe and may provide sustained improvements in sleep, quality of life, and affective symptoms for patients with affective disorders.

Precise Localization of the Central Left Frontal Cortex in Different Canine Skull Types: A Comparative Study of Frameless Neuronavigation and External Measurement Techniques

Repetitive Transcranial Magnetic Stimulation (rTMS), a non-invasive brain modulation technique, has been explored as an additional treatment option for behaviorally disordered dogs. For optimal effectiveness of the rTMS treatment, accurate coil positioning to the stimulation target is pivotal. Frameless stereotactic neuronavigation for the localization of intracranial regions has been established as a reliable targeting method. However, given the varying skull shape and brain structures among dog breeds, divided into mesocephalic, brachycephalic, and dolichocephalic breeds, localizing the rTMS target area, the central left frontal cortex, can be challenging. Previous neuronavigation studies have only investigated its use in mesocephalic breeds of dogs. Because this neuronavigation is based on expensive high-tesla magnetic resonance imaging data, and anesthesia needed for immobilization, a cheaper and reliable localization alternative to broaden the rTMS use in the veterinary field is needed.The objective of this study was twofold. First, the study aimed to evaluate external localization of the central left frontal cortex within the three skull types (retrospective study 1). Then, this external localization method was compared to the conventional frameless neuronavigation technique to check the consistency, focusing on mesocephalic and dolichocephalic breeds (prospective study 2). Thirty-two brachycephalic, thirty-seven mesocephalic and thirty dolichocephalic dogs were included to evaluate the external localization of the central left frontal cortex by external measurement (retrospective study 1, data obtained from previously performed MRI scans). For the second objective, thirty-eight dogs (35 mesocephalic breeds and 3 dolichocephalic breeds) were recruited to compare the external measurement localization method and the localization by neuronavigation (prospective study 2, data extracted from study 1 and former rTMS studies). The first part of this study showed the central left frontal cortex was externally located approximately two-thirds of the total skull length (sagittal length) in meso- and dolichocephalic dogs, at the center of the skull length in brachycephalic dogs, and 0.65 to 0.70 cm to the left of the cerebral midline for all skull types (retrospective study 1). Using intraclass correlation coefficient (ICC) analysis, the second part of the study showed high consistency between these two methods, for the length of the skull (0.94), the relative position of the left frontal cortex (0.84), and the distance to the cerebral midline (0.69) in mesocephalic and dolichocephalic breeds (prospective study 2). Our findings suggest that the conventional frameless neuronavigation could be replaced by the external localization method in the mesocephalic and dolichocephalic dog breeds, and therefore ultimately reduce anesthesia time and financial burden when applying non-invasive brain modulation techniques like rTMS. More research needs to be conducted for brachycephalic dogs to validate this method in this specific population of dogs.

Investigating the effects of excitatory and inhibitory somatosensory rTMS on somatosensory functioning in the acute and subacute phases of stroke: a preliminary double-blind and randomized trial.

Repetitive transcranial magnetic stimulation (rTMS) targeting the primary somatosensory cortex (S1) has a potential effect on somatosensory functioning following a stroke. However, S1-rTMS was combined with peripheral therapies in previous trials. Moreover, these studies have commonly targeted the ipsilesional S1 with excitatory rTMS paradigms. This double-blind, randomized trial (registration number: ChiCTR2200059098) investigated two forms of paradigms, that is ipsilesional excitatory and contralesional inhibitory rTMS, as a stand-alone treatment in post-stroke somatosensation. Patients in the acute and subacute phases of stroke were randomly assigned to either contralesional 1-Hz or ipsilesional 10-Hz rTMS group and received 10 daily sessions of treatment in two consecutive weeks. Results indicate that the contralesional inhibitory and ipsilesional excitatory stimulation were equally effective in improving somatosensory functioning. Moreover, this effect was most prominent in deep sensations and subjective sensations. Using single-pulse EMG recordings, our data also revealed an increased MEP amplitude in the ipsilesional motor cortex following ipsilesional excitatory treatment. This preliminary study demonstrates the primary somatosensory cortex as an effective rTMS target in somatosensory recovery following stroke. https://www.chictr.org.cn/showproj.html?proj=166474, ChiCTR2200059098.

Improving efficacy of repetitive transcranial magnetic stimulation for treatment of Parkinson disease gait disorders.

Parkinson disease (PD) is a neurodegenerative disorder that causes motor and cognitive deficits, presenting complex challenges for therapeutic interventions. Repetitive transcranial magnetic stimulation (rTMS) is a type of neuromodulation that can produce plastic changes in neural activity. rTMS has been trialed as a therapy to treat motor and non-motor symptoms in persons with Parkinson disease (PwP), particularly treatment-refractory postural instability and gait difficulties such as Freezing of Gait (FoG), but clinical outcomes have been variable. We suggest improving rTMS neuromodulation therapy for balance and gait abnormalities in PwP by targeting brain regions in cognitive-motor control networks. rTMS studies in PwP often targeted motor targets such as the primary motor cortex (M1) or supplementary motor area (SMA), overlooking network interactions involved in posture-gait control disorders. We propose a shift in focus toward alternative stimulation targets in basal ganglia-cortex-cerebellum networks involved in posture-gait control, emphasizing the dorsolateral prefrontal cortex (dlPFC), cerebellum (CB), and posterior parietal cortex (PPC) as potential targets. rTMS might also be more effective if administered during behavioral tasks designed to activate posture-gait control networks during stimulation. Optimizing stimulation parameters such as dosage and frequency as used clinically for the treatment of depression may also be useful. A network-level perspective suggests new directions for exploring optimal rTMS targets and parameters to maximize neural plasticity to treat postural instabilities and gait difficulties in PwP.

Personalized, parcel-guided non-invasive transcranial magnetic stimulation for the treatment of post-concussive syndrome: safety and proof of concept

ABSTRACT Objective To determine the safety and proof of concept of a parcel-guided, repetitive Transcranial Magnetic Stimulation (rTMS) in patients who develop a heterogeneous array of symptoms, known collectively as post-concussive syndrome (PCS), following traumatic brain injury (TBI). Methods We performed a retrospective review of off-label, individualized, parcel-guided rTMS in 19 patients from December 2020 to May 2023. Patients had at least one instance of mild, moderate, or severe TBI and developed symptoms not present prior to injury. rTMS targets were identified based on machine learning connectomic software using functional connectivity anomaly matrices compared to healthy controls. EuroQol (EQ-5D), as a measurement of quality of life, and additional questionnaires dependent on individual’s symptoms were submitted prior to, after, and during follow-up from rTMS. Results Nineteen patients showed improvement in EQ-5D and Rivermead Post Concussion Symptoms Questionnaires − 3 after treatment and follow-up. For nine patients who developed depression, five (55%) attained response and remission based on the Beck Depression Inventory after treatment. Eight of ten patients with anxiety had a clinically significant reduction in Generalized Anxiety Disorder-7 scores during follow-up. Conclusion Parcel-guided rTMS is safe and may be effective in reducing PCS symptoms following TBI and should incite further controlled studies.

Neuromodulation of the Right Motor Cortex of the Lips With Repetitive Transcranial Magnetic Stimulation to Reduce Phonological Impairment and Improve Naming in Three Persons With Aphasia: A Single-Case Experimental Design.

Repetitive transcranial magnetic stimulation (rTMS) can enhance aphasia recovery. Most studies have used inhibitory stimulation targeting the right inferior frontal gyrus. However, the motor cortex, observed to contribute to the prediction of aphasia recovery, is involved in word production and could be an appropriate target for rTMS. We aimed to observe behavioral changes in a picture naming task induced by inhibitory rTMS targeting the right motor cortex of the lips in people with poststroke aphasia. Using a single-case experimental design, we included three participants with chronic poststroke aphasia who had phonological deficits. Each participant performed a verbal picture naming task 3 times a week for 2, 3, or 4 weeks (pseudorandom across participants) to establish a baseline naming ability for each participant. These were not therapy sessions, and no feedback was provided. Then, each participant received the intervention, inhibitory continuous theta burst stimulation targeting the right motor cortex of the lips, 3 times a week for 2 weeks. Naming testing continued 3 times a week, for these latter 2 weeks. No therapy was performed at any time during the study. Visual analysis of the graphs showed a positive effect of rTMS for P2 and P3 on picture naming accuracy and a tendency toward improvement for P1. Statistical analysis showed an improvement after rTMS for P1 (τ = 0.544, p = .013, SETau = 0.288) and P2 (τ = 0.708, p = .001, SETau = 0.235). For P3, even if the intervention allowed some improvement, this was statistically nonsignificant due to a learning effect during the baseline naming testing, which lasted the longest, 4 weeks. Regarding specific language features, phonological errors significantly decreased in all patients. The motor cortex of the lips could be an appropriate target for rTMS to improve naming in people with poststroke aphasia suffering from a phonological deficit. This suggests the possibility to individualize the target for rTMS, according to the patient's linguistic impairment.

Anterior–temporal hippocampal network mechanisms of left angular gyrus-navigated rTMS for memory improvement in aMCI: A sham-controlled study

IntroductionNeuro-navigated repetitive transcranial magnetic stimulation (rTMS) of the left angular gyrus has been broadly investigated for the treatment of amnestic mild cognitive impairment (aMCI). Although abnormalities in two hippocampal networks, the anterior–temporal (AT) and posterior–medial (PM) networks, are consistent with aMCI and are potential therapeutic targets for rTMS, the underlying mechanisms of the therapeutic effects of rTMS on hippocampal network connections remain unknown. Here, we assessed the impact of left angular gyrus rTMS on activity in these networks and explored whether the treatment response was due to the distance between the clinically applied target (the group average optimal site) and the personalized target in patients with aMCI. MethodsSixty subjects clinically diagnosed with aMCI participated in this study after 20 sessions of sham-controlled rTMS targeting the left angular gyrus. Resting-state functional magnetic resonance imaging and neuropsychological assessments were performed before and after rTMS. Functional connectivity alterations in the PM and AT networks were assessed using seed-based functional connectivity analysis and two-factor repeated measures analysis of variance (ANOVA). We then computed the correlations between the functional connectivity changes and clinical rating scales. Finally, we examined whether the Euclidean distance between the clinically applied and personalized targets predicted the subsequent treatment response. ResultsCompared with the sham group, the active rTMS group showed rTMS-induced deactivation of functional connectivity within the medial temporal lobe-AT network, with a negative correlation with episodic memory score changes. Moreover, the active rTMS lowers the interdependency of changes in the PM and AT networks. Finally, the Euclidean distance between the clinically applied and personalized target distances could predict subsequent network lever responses in the active rTMS group. ConclusionsNeuro-navigated rTMS selectively modulates widespread functional connectivity abnormalities in the PM and AT hippocampal networks in aMCI patients, and the modulation of hippocampal-AT network connectivity can efficiently reverse memory deficits. The results also highlight the necessity of personalized targets for fMRI.

Placebo effects of repetitive transcranial magnetic stimulation on negative symptoms and cognition in patients with schizophrenia spectrum disorders: a systematic review and meta-analysis.

Negative symptoms and cognitive impairments are highly frequent in schizophrenia spectrum disorders (SSD), associated with adverse functional outcomes and quality of life. Repetitive transcranial magnetic stimulation (rTMS) has been considered a promising therapeutic option in SSD. However, placebo effects of rTMS on these symptoms remained unclear. To investigate placebo effects of rTMS on alleviating negative symptoms and cognitive impairment in patients with SSD and to explore potential moderators. We systematically searched five electronic databases up to 15 July 2023. Randomized, double-blind, sham-controlled trials investigating effects of rTMS on negative symptoms or cognition in patients with SSD were included. The pooled placebo effect sizes, represented by Hedges' g, were estimated using the random-effects model. Potential moderators were explored through subgroup analysis and meta-regression. Forty-four randomized controlled trials with 961 patients (mean age 37.53 years; 28.1% female) in the sham group were included. Significant low-to-moderate pooled placebo effect sizes were observed for negative symptoms (g=0.44, p<0.001), memory (g=0.31, p=0.010), executive function (g=0.35, p<0.001), working memory (g=0.26, p=0.004), and processing speed (g=0.36, p=0.004). Subgroup analysis indicated that placebo effects were affected by sham stimulation methods, rTMS targeting approaches, and stimulation frequency. Placebo effects of rTMS on negative symptoms and cognition in patients with SSD are significant in a small-to-moderate magnitude, which might be mediated by rTMS parameters. Our findings will provide new insights for practitioners to further optimize and establish standardized rTMS protocols for future RCTs tackling cardinal symptoms in SSD. https://www.crd.york.ac.uk/prospero/, identifier CRD42023390138.

Effects of parietal repetitive transcranial magnetic stimulation in prolonged disorders of consciousness: A pilot study

ObjectiveAlthough the parietal cortex is related to consciousness, the dorsolateral prefrontal and primary motor cortices are the usual targets for repetitive transcranial magnetic stimulation (rTMS) for prolonged disorders of consciousness (pDoC). Herein, we applied parietal rTMS to patients with pDoC, to verify its neurobehavioral effects and explore a new potential rTMS target. Materials and methodsTwenty-six patients with pDoC were assigned to a rTMS or sham group. The rTMS group received 10 sessions of parietal rTMS; the sham group received 10 sessions of sham stimulation. The Coma Recovery Scale-Revised (CRS-R) and event-related potential (ERP) were collected before and after the 10 sessions or sham sessions. ResultsAfter the 10 sessions, the rTMS group showed: a significant CRS-R score increase; ERP appearance of a P300 waveform and significantly increased Fz amplitudes; increased potentials on topographic mapping, especially in the left prefrontal cortex; and an increase in delta and theta band powers at Fz, Cz, and Pz. The sham group did not show such changes in CRS-R score or ERP results statistically. ConclusionParietal rTMS shows promise as a novel intervention in the recovery of consciousness in pDoC. It showed neurobehavioral enhancement of residual brain function and may promote frontal activity by enhancing frontal–parietal connections. The parietal cortex may thus be an alternative for rTMS therapy protocols.

A meta-analysis of randomized sham-controlled trials of repetitive transcranial magnetic stimulation for attention-deficit/hyperactivity disorder.

To investigate efficacy of repetitive transcranial magnetic stimulation (rTMS) on attention-deficit/hyperactivity disorder (ADHD). Randomized sham-controlled trials (RCTs) were identified from major databases from the inception date of January 1990 to January 2023. Primary outcome was improvement in total symptoms of ADHD. Subgroup analysis focused on rTMS efficacy targeting different brain regions. Secondary outcomes were associations of rTMS with improvements in different symptoms of ADHD. Outcomes were expressed as effect size (ES) based on standardized mean difference (SMD) (continuous data), and odds ratios (ORs) with 95% confidence interval (CI) (categorical data). Meta-analysis of six RCTs involving 169 participants demonstrated no difference in total ADHD symptoms between rTMS-treated participants and sham controls (SMD=-0.24,p=0.17). Subgroup analysis revealed better efficacy of rTMS than sham controls when targeting right prefrontal cortex (rPFC) (SMD=-0.49,p=0.03), but not left prefrontal cortex (lPFC) (SMD= 0.01,p=0.67). rTMS treatment correlated with better improvement in symptoms of inattention (SMD=-0.76,p=0.0002), but not hyperactivity (p=0.86), impulsivity (p=0.41), and depression (p=0.95). The apparently higher risk of dropout in the rTMS group than sham controls was not statistically significant (OR=1.65,p=0.26). Our study only supported the therapeutic efficacy of rTMS targeting rPFC for the symptoms of ADHD, especially inattention, but not that targeting lPFC. Further large-scale randomized sham-controlled trials are required to verify our findings.

Interventional clinical trial findings from targeted multiday repetitive transcranial magnetic stimulation to treat memory loss in amnestic mild cognitive impairment

AbstractBackgroundMemory loss is the hallmark cognitive symptom of Alzheimer’s disease (AD), and it affects independence, autonomy, and identity. AD‐related memory deficits are associated with pathological changes in brain structure and function, and current treatments offer limited relief. Targeted repetitive transcranial magnetic stimulation (rTMS) of AD‐vulnerable intrinsic brain networks can enhance memory abilities in healthy adults (Wang et al., 2014). To test rTMS approaches as a potential treatment for clinical memory loss, we administered a local clinical trial (ClinicalTrials.gov #alz078533) that enrolled patients with amnestic mild cognitive impairment (aMCI), a frequent precursor to AD (target enrollment of 16). Here, we report cognitive and brain findings from our trial.MethodsPatients with aMCI completed two weeklong interventions consisting of pre‐stimulation brain and cognitive measurement, rTMS for five consecutive days, and post‐stimulation brain and cognitive measurement. Brain measures included structural and resting‐state functional MRI data; cognitive assessments included measures of memory function. Interventions were identically formatted except for rTMS intensity (treatment/sham). Stimulation used β‐frequency pulse sequences which alternated 2‐sec. 20 Hz stimulation with 28‐sec. rest for 20 min (1600 pulses); stimulation location was a left lateral parietal cortex location coactive with a hippocampus‐centered functional network. Stimulation intensity varied with each participant’s resting motor threshold (treatment, 100%; sham, 10%). Condition order was counterbalanced.ResultsWe identified hippocampus‐centered networks in each participant, then localized parietal rTMS targets. Critically, we observed changes in brain and cognitive (memory) measures in the treatment‐intensity condition that were not observed in the sham‐intensity condition. Furthermore, we observed changes in intrinsic network connectivity within the stimulated hippocampus‐centered network.ConclusionsOur trial of patients with aMCI measured changes in brain and cognitive variables after rTMS of a brain network supporting memory processes. We found evidence consistent with neural plasticity, and we frequently observed memory improvement in patients with aMCI after treatment‐intensity rTMS. Our findings suggest that rTMS can improve memory in clinical populations. This is important because, counterintuitively, new disease modifying therapies for AD may increase need for symptomatic treatment of memory loss due to prolongation of prodromal/mild stages of AD. Thus, adjuvant therapies such as rTMS for memory loss could improve AD treatment outcomes.

Interventional clinical trial findings from targeted multiday repetitive transcranial magnetic stimulation to treat memory loss in amnestic mild cognitive impairment

AbstractBackgroundMemory loss is the hallmark cognitive symptom of Alzheimer’s disease (AD), and it affects independence, autonomy, and identity. AD‐related memory deficits are associated with pathological changes in brain structure and function, and current treatments offer limited relief. Targeted repetitive transcranial magnetic stimulation (rTMS) of AD‐vulnerable intrinsic brain networks can enhance memory abilities in healthy adults (Wang et al., 2014). To test rTMS approaches as a potential treatment for clinical memory loss, we administered a local clinical trial (ClinicalTrials.gov #alz081816) that enrolled patients with amnestic mild cognitive impairment (aMCI), a frequent precursor to AD (target enrollment of 16). Here, we report cognitive and brain findings from our trial.MethodPatients with aMCI completed two weeklong interventions consisting of pre‐stimulation brain and cognitive measurement, rTMS for five consecutive days, and post‐stimulation brain and cognitive measurement. Brain measures included structural and resting‐state functional MRI data; cognitive assessments included measures of memory function. Interventions were identically formatted except for rTMS intensity (treatment/sham). Stimulation used ß‐frequency pulse sequences which alternated 2‐sec. 20 Hz stimulation with 28‐sec. rest for 20 min (1600 pulses); stimulation location was a left lateral parietal cortex location coactive with a hippocampus‐centered functional network. Stimulation intensity varied with each participant’s resting motor threshold (treatment, 100%; sham, 10%). Condition order was counterbalanced.ResultWe identified hippocampus‐centered networks in each participant, then localized parietal rTMS targets. Critically, we observed changes in brain and cognitive (memory) measures in the treatment‐intensity condition that were not observed in the sham‐intensity condition. Furthermore, we observed changes in intrinsic network connectivity within the stimulated hippocampus‐centered network.ConclusionOur trial of patients with aMCI measured changes in brain and cognitive variables after rTMS of a brain network supporting memory processes. We found evidence consistent with neural plasticity, and we frequently observed memory improvement in patients with aMCI after treatment‐intensity rTMS. Our findings suggest that rTMS can improve memory in clinical populations. This is important because, counterintuitively, new disease modifying therapies for AD may increase need for symptomatic treatment of memory loss due to prolongation of prodromal/mild stages of AD. Thus, adjuvant therapies such as rTMS for memory loss could improve AD treatment outcomes.

A neuroimaging-based precision medicine framework for depression

BackgroundSymptom-based diagnostic criteria of depression leads to notorious heterogeneity and subjectivity. MethodsThe study was conducted in two stages at two sites: development of a neuroimaging-based subtyping and precise repetitive transcranial magnetic stimulation (rTMS) strategy for depression at Center 1 and its clinical application at Center 2. Center 1 identified depression subtypes and subtype-specific rTMS targets based on amplitude of low frequency fluctuation (ALFF) in a cohort of 238 major depressive disorder patients and 66 healthy controls (HC). Subtypes were identified using a Gaussian Mixture Model, and subtype-specific rTMS targets were selected based on dominant brain regions prominently differentiating depression subtypes from HC. Subsequently, one classifier was employed and 72 hospitalized, depressed youths at Center 2 received two-week precise rTMS. MRI and clinical assessments were obtained at baseline, midpoint, and treatment completion for evaluation. ResultsTwo neuroimaging subtypes of depression, archetypal and atypical depression, were identified based on distinct frontal-posterior functional imbalance patterns as measured by ALFF. The dorsomedial prefrontal cortex was identified as the rTMS target for archetypal depression, and the occipital cortex for atypical depression. Following precise rTMS, ALFF alterations were normalized in both archetypal and atypical depressed youths, corresponding with symptom response of 90.00% in archetypal depression and 70.73% in atypical depression. ConclusionsA precision medicine framework for depression was developed based on objective neurobiomarkers and implemented with promising results, actualizing a subtyping-treatment-evaluation closed loop in depression. Future randomized controlled trials are warranted.

Motor cortex repetitive transcranial magnetic stimulation in major depressive disorder - A preliminary randomized controlled clinical trial

BackgroundRepetitive transcranial magnetic stimulation (rTMS) at left dorsolateral prefrontal cortex (lDLPFC) is commonly used in major depressive disorder (MDD), even though its therapeutic efficacy is limited. Given that many MDD patients show psychomotor retardation, we aim to examine whether the left motor cortex (lMC) as a novel rTMS target would provide effective and well-tolerated treatment as being comparable to lDLPFC-rTMS. MethodsIn this prospective double-blind randomized single-center study, 131 MDD patients were randomly assigned to the lDLPFC or lMC group and were treated with 10 Hz rTMS (90 % motor threshold) applied twice daily for 4000 pulses continuously over five days. The primary endpoint was the Hamilton Depression Scale (HAMD) total score change after treatment. ResultsAfter the five-day rTMS treatment, there was no significant difference in both HAMD reduction rate (lDLPFC 59.3 % ± 20.4 %, lMC 51.3 % ± 26.3 %, P = 0.10) and adverse effects (P = 0.79) between 48 (73.8 %) lMC subjects and 51 (77.3 %) lDLPFC subjects. Furthermore, the lMC study group showed stable HAMD scores at follow-up compared to their endpoint scores (P = 0.08). LimitationsSham-control group was not included and the sample size was small. Therefore, our results should be seen as exploratory and preliminary. ConclusionsThe preliminary good therapeutic response, comparability, and tolerability of lMC-rTMS suggest lMC a potential and more easily accessible rTMS target. Together, our findings raise the possibility of symptom-specific rTMS in motor cortex (psychomotor retardation) or lDLPFC (cognitive deficits). This warrants larger clinical trials of rTMS in MDD with symptom-specific stimulation targets.

RTMS targeted to the secondary somatosensory cortex influences sleep in CRPS patients, as measured with the OURA ring.

Chronic pain associates with various sleep problems. Patients with complex regional pain syndrome (CRPS) often report impaired sleep, but objective measurements of sleep in CRPS patients are scarce. Neuromodulation with repetitive transcranial magnetic stimulation (rTMS) can alleviate pain and improve sleep. Secondary somatosensory cortex (S2) is a possible rTMS target for the treatment of chronic pain, but the effect of S2-targeted rTMS on sleep is unknown. This randomized, sham-controlled trial assessed the effect of S2-targeted rTMS on sleep in patients with CRPS. Patients (n=31) received either S2-targeted rTMS (10Hz) or sham stimulation for 3 weeks. The effect of treatment on sleep was assessed with validated questionnaires, with a sleep and pain diary, and with a consumer-grade sleep tracker, the Oura ring. In addition to an ordinary univariate analysis of the results, we conducted multivariate testing of the Oura data using linear discriminant analysis (LDA). S2-targeted rTMS decreased sleep restlessness that significantly differed between the rTMS and sham stimulation patient groups (p=.028). In the multivariate analysis of the Oura data, LDA classification accuracy to separate the rTMS and sham groups exceeded 95% confidence level in four out of the seven tested models. In the subjective evaluation of sleep, the effect of rTMS and sham did not differ. S2-targeted rTMS influenced sleep in patients with CRPS. Improved sleep may enhance CRPS symptom alleviation and be of clinical importance. A univariate analysis could separate the rTMS and sham treatments. The multivariate analysis revealed that including multiple sleep-related parameters can be beneficial when analyzing rTMS effects on sleep. As sleep is related both to pain and quality of life, and sleep rTMS can be directly affected by rTMS, objective monitoring of sleep in various future rTMS trials could be fruitful.

Auditory cortex hyperconnectivity before rTMS is correlated with tinnitus improvement

IntroductionRepetitive transcranial magnetic stimulation (rTMS) has been used as a potential treatment for tinnitus; however, its effectiveness is variable and unpredictable. We hypothesized that resting-state functional connectivity before rTMS may be correlated with rTMS treatment effectiveness. MethodsWe applied 1-Hz rTMS to the left primary auditory (A1) and dorsolateral prefrontal cortices (DLPFC) of 10 individuals with tinnitus and 10 age-matched controls. Resting-state functional magnetic resonance imaging (fMRI) studies were performed approximately one week before rTMS. Seed-based connectivity analyses were conducted for each individual, with seed regions as rTMS target areas. ResultsCompared to controls, the left superior temporal areas showed significantly increased positive connectivity with the left A1 and negative connectivity with the left DLPFC in the tinnitus group. The left frontoparietal and right cerebellar areas showed significantly increased negative connectivity with the left A1 and positive connectivity with the left DLPFC. Seed-based hyperconnectivity was correlated with tinnitus improvement (pre-rTMS vs. 2-week post-rTMS Tinnitus Handicap Inventory scores). Tinnitus improvement was significantly correlated with left A1 hyperconnectivity; however, no correlation was observed with left DLPFC connectivity. Positive rTMS outcomes were associated with significantly increased positive connectivity in bilateral superior temporal areas and significantly increased negative connectivity in bilateral frontal areas. ConclusionsOur results suggest that oversynchronisation of left A1 connectivity before rTMS of the left A1 and DLPFC is associated with treatment effectiveness.

Functional changes in the salience network of patients with amnesic mild cognitive impairment before and after repetitive transcranial magnetic stimulation.

Amnestic mild cognitive impairment (aMCI) is considered to be the prodromal stage of Alzheimer's disease (AD). The precuneus (PCUN) may be an imaging marker for monitoring the progression of AD. Meanwhile, cognitive impairment in AD patients is closely related to functional connectivity (FC) changes in the salience network (SN). We hypothesize that there are specific neuroimaging biomarkers in the SN and that FC changes in aMCI patients after repetitive transcranial magnetic stimulation (rTMS) intervention are associated with cognitive function. The purpose of this study was to first investigate the pattern of functional changes in aMCI patients and healthy controls (HCs) and then compare the functional changes in aMCI patients before and after rTMS targeting to PCUN and its correlation with cognitive function. Thirty-six HCs and 61 aMCIs were recruited for our study. Eleven people in the aMCI group received rTMS intervention 5 days a week for 4 weeks. Using the right anterior insula as the seed-of-interest, we first compared FC changes in HC and aMCI patients and then compared cognitive function in aMCI patients before and after rTMS. The above is the functional connection analysis of seed-to-voxel. Moreover, we investigated the FC changes in aMCI patients after rTMS intervention and its correlation with cognitive function. Compared with HC, the aMCI group showed altered FC in bilateral parahippocampal gyrus, bilateral inferior parietal lobule, left middle frontal gyrus, and left middle temporal gyrus. Moreover, rTMS at PCUN improved the cognitive function of aMCI patients, which was related to the altered FC in posterior cerebellar lobes (CPL). Our findings suggest that rTMS targeting PCUN is a promising, noninvasive approach to ameliorating cognitive dysfunction in aMCI patients, and that this cognitive improvement is accompanied by brain connectivity modulation.

Targeting Lower Limb, Upper Limb, and Face Representation in the Primary Motor Cortex for the Practice of Neuronavigated Transcranial Magnetic Stimulation

ObjectiveThe primary motor cortex (M1) is a usual target for therapeutic application of repetitive transcranial magnetic stimulation (rTMS), especially the region of hand motor representation. However, other M1 regions can be considered as potential rTMS targets, such as the region of lower limb or face representation. In this study, we assessed the localization of all these regions on magnetic resonance imaging (MRI) with the aim of defining three standardized M1 targets for the practice of neuronavigated rTMS. Materials and MethodsA pointing task of these targets was performed by three rTMS experts on 44 healthy brain MRI data to assess interrater reliability (including the calculation of intraclass correlation coefficients [ICCs] and coefficients of variation [CoVs] and the construction of Bland-Altman plots). In addition, two “standard” brain MRI data were randomly interspersed with the other MRI data to assess intrarater reliability. A barycenter was calculated for each target (with x-y-z coordinates provided in normalized brain coordinate systems), in addition to the geodesic distance between the scalp projection of the barycenters of these different targets. ResultsIntrarater and interrater agreement was good, according to ICCs, CoVs, or Bland-Altman plots, although interrater variability was greater for anteroposterior (y) and craniocaudal (z) coordinates, especially for the face target. The scalp projection of the barycenters between the different cortical targets ranged from 32.4 to 35.5 mm for either the lower-limb-to-upper-limb target distance or the upper-limb-to-face target distance. ConclusionsThis work clearly delineates three different targets for the application of motor cortex rTMS that correspond to lower limb, upper limb, and face motor representations. These three targets are sufficiently spaced to consider that their stimulation can act on distinct neural networks.