Transcranial Magnetic Stimulation Targeting Research Articles

Chronometric TMS-fMRI of personalized left dorsolateral prefrontal target reveals state-dependency of subgenual anterior cingulate cortex effects.

Transcranial magnetic stimulation (TMS) applied to a left dorsolateral prefrontal cortex (DLPFC) area with a specific connectivity profile to the subgenual anterior cingulate cortex (sgACC) has emerged as a highly effective non-invasive treatment option for depression. However, antidepressant outcomes demonstrate significant variability among therapy plans and individuals. One overlooked contributing factor is the individual brain state at the time of treatment. In this study we used interleaved TMS-fMRI to investigate the influence of brain state on acute TMS effects, both locally and remotely. TMS was performed during rest and during different phases of cognitive task processing. Twenty healthy participants were included in this study. In the first session, imaging data for TMS targeting were acquired, allowing for identification of individualized targets in the left DLPFC based on highest anti-correlation with the sgACC. The second session involved chronometric interleaved TMS-fMRI measurements, with 10 Hz triplets of TMS administered during rest and at distinct timings during an N-back task. Consistent with prior findings, interleaved TMS-fMRI revealed significant BOLD activation changes in the targeted network. The precise timing of TMS relative to the cognitive states during the task demonstrated distinct BOLD response in clinically relevant brain regions, including the sgACC. Employing a standardized timing approach for TMS using a task revealed more consistent modulation of the sgACC at the group level compared to stimulation during rest. In conclusion, our findings strongly suggest that acute local and remote effects of TMS are influenced by brain state during stimulation. This study establishes a basis for considering brain state as a significant factor in designing treatment protocols, possibly improving TMS treatment outcomes.

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.

High-frequency Repetitive Transcranial Magnetic Stimulation Targeting Left Dorsolateral Prefrontal Cortex for Depression Ameliorates Insomnia yet Triggers Excessive Daytime Sleepiness: A Catch-22 Situation

Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive brain stimulation technique that is effective and safe for the treatment of depression. We observed improvement in insomnia along with symptoms of depression following high-frequency rTMS over the left dorsolateral prefrontal cortex in a patient with treatment-resistant depression, which progressed to excessive daytime sleepiness during the treatment sessions. Causality assessment suggested a probable association of rTMS with excessive sleepiness. The implications of the effect of rTMS on sleep are discussed.

Enhancing cognitive control with transcranial magnetic stimulation in subject-specific frontoparietal networks

BackgroundCognitive control processes, including those involving frontoparietal networks, are highly variable between individuals, posing challenges to basic and clinical sciences. While distinct frontoparietal networks have been associated with specific cognitive control functions such as switching, inhibition, and working memory updating functions, there have been few basic tests of the role of these networks at the individual level. MethodsTo examine the role of cognitive control at the individual level, we conducted a within-subject excitatory transcranial magnetic stimulation (TMS) study in 19 healthy individuals that targeted intrinsic (“resting”) frontoparietal networks. Person-specific intrinsic networks were identified with resting state functional magnetic resonance imaging scans to determine TMS targets. The participants performed three cognitive control tasks: an adapted Navon figure-ground task (requiring set switching), n-back (working memory), and Stroop color-word (inhibition). ObjectiveHypothesis: We predicted that stimulating a network associated with externally oriented control [the “FPCN-B” (fronto-parietal control network)] would improve performance on the set switching and working memory task relative to a network associated with attention (the Dorsal Attention Network, DAN) and cranial vertex in a full within-subjects crossover design. ResultsWe found that set switching performance was enhanced by FPCN-B stimulation along with some evidence of enhancement in the higher-demand n-back conditions. ConclusionHigher task demands or proactive control might be a distinguishing role of the FPCN-B, and personalized intrinsic network targeting is feasible in TMS designs.

Evoked EEG Responses to TMS Targeting Regions Outside the Primary Motor Cortex and Their Test–Retest Reliability

Transcranial magnetic stimulation (TMS)–evoked electroencephalography (EEG) potentials (TEPs) provide unique insights into cortical excitability and connectivity. However, confounding EEG signals from auditory and somatosensory co-stimulation complicate TEP interpretation. Our optimized sham procedure established with TMS of primary motor cortex (Gordon in JAMA 245:118708, 2021) differentiates direct cortical EEG responses to TMS from those caused by peripheral sensory inputs. Using this approach, this study aimed to investigate TEPs and their test–retest reliability when targeting regions outside the primary motor cortex, specifically the left angular gyrus, supplementary motor area, and medial prefrontal cortex. We conducted three identical TMS–EEG sessions one week apart involving 24 healthy participants. In each session, we targeted the three areas separately using a figure-of-eight TMS coil for active TMS, while a second coil away from the head produced auditory input for sham TMS. Masking noise and electric scalp stimulation were applied in both conditions to achieve matched EEG responses to peripheral sensory inputs. High test–retest reliability was observed in both conditions. However, reliability declined for the ‘cleaned’ TEPs, resulting from the subtraction of evoked EEG response to the sham TMS from those to the active, particularly for latencies > 100 ms following the TMS pulse. Significant EEG differences were found between active and sham TMS at latencies < 90 ms for all targeted areas, exhibiting distinct spatiotemporal characteristics specific to each target. In conclusion, our optimized sham procedure effectively reveals EEG responses to direct cortical activation by TMS in brain areas outside primary motor cortex. Moreover, we demonstrate the impact of peripheral sensory inputs on test–retest reliability of TMS-EEG responses.

Fast and accurate computational E-field dosimetry for group-level transcranial magnetic stimulation targeting

Transcranial magnetic stimulation (TMS) is used to study brain function and treat mental health disorders. During TMS, a coil placed on the scalp induces an E-field in the brain that modulates its activity. TMS is known to stimulate regions that are exposed to a large E-field. Clinical TMS protocols prescribe a coil placement based on scalp landmarks. There are inter-individual variations in brain anatomy that result in variations in the TMS-induced E-field at the targeted region and its outcome. These variations across individuals could in principle be minimized by developing a large database of head subjects and determining scalp landmarks that maximize E-field at the targeted brain region while minimizing its variation using computational methods. However, this approach requires repeated execution of a computational method to determine the E-field induced in the brain for a large number of subjects and coil placements. We developed a probabilistic matrix decomposition-based approach for rapidly evaluating the E-field induced during TMS for a large number of coil placements due to a pre-defined coil model. Our approach can determine the E-field induced in over 1 Million coil placements in 9.5 h, in contrast, to over 5 years using a brute-force approach. After the initial set-up stage, the E-field can be predicted over the whole brain within 2–3 ms and to 2% accuracy. We tested our approach in over 200 subjects and achieved an error of <2% in most and <3.5% in all subjects. We will present several examples of bench-marking analysis for our tool in terms of accuracy and speed. Furthermore, we will show the methods’ applicability for group-level optimization of coil placement for illustration purposes only. The software implementation link is provided in the appendix.

Modeling the effects of transcranial magnetic stimulation on spatial attention

Objectives. Transcranial magnetic stimulation (TMS) has been widely used to modulate brain activity in healthy and diseased brains, but the underlying mechanisms are not fully understood. Previous research leveraged biophysical modeling of the induced electric field (E-field) to map causal structure–function relationships in the primary motor cortex. This study aims at transferring this localization approach to spatial attention, which helps to understand the TMS effects on cognitive functions, and may ultimately optimize stimulation schemes. Approach. Thirty right-handed healthy participants underwent a functional magnetic imaging (fMRI) experiment, and seventeen of them participated in a TMS experiment. The individual fMRI activation peak within the right inferior parietal lobule (rIPL) during a Posner-like attention task defined the center target for TMS. Thereafter, participants underwent 500 Posner task trials. During each trial, a 5-pulse burst of 10 Hz repetitive TMS (rTMS) was given over the rIPL to modulate attentional processing. The TMS-induced E-fields for every cortical target were correlated with the behavioral modulation to identify relevant cortical regions for attentional orientation and reorientation. Main results. We did not observe a robust correlation between E-field strength and behavioral outcomes, highlighting the challenges of transferring the localization method to cognitive functions with high neural response variability and complex network interactions. Nevertheless, TMS selectively inhibited attentional reorienting in five out of seventeen subjects, resulting in task-specific behavioral impairments. The BOLD-measured neuronal activity and TMS-evoked neuronal effects showed different patterns, which emphasizes the principal distinction between the neural activity being correlated with (or maybe even caused by) particular paradigms, and the activity of neural populations exerting a causal influence on the behavioral outcome. Significance. This study is the first to explore the mechanisms of TMS-induced attentional modulation through electrical field modeling. Our findings highlight the complexity of cognitive functions and provide a basis for optimizing attentional stimulation protocols.

Dissociation of Centrally and Peripherally Induced Transcranial Magnetic Stimulation Effects in Nonhuman Primates.

Transcranial magnetic stimulation (TMS) is a noninvasive brain stimulation method that is rapidly growing in popularity for studying causal brain-behavior relationships. However, its dose-dependent centrally induced neural mechanisms and peripherally induced sensory costimulation effects remain debated. Understanding how TMS stimulation parameters affect brain responses is vital for the rational design of TMS protocols. Studying these mechanisms in humans is challenging because of the limited spatiotemporal resolution of available noninvasive neuroimaging methods. Here, we leverage invasive recordings of local field potentials in a male and a female nonhuman primate (rhesus macaque) to study TMS mesoscale responses. We demonstrate that early TMS-evoked potentials show a sigmoidal dose-response curve with stimulation intensity. We further show that stimulation responses are spatially specific. We use several control conditions to dissociate centrally induced neural responses from auditory and somatosensory coactivation. These results provide crucial evidence regarding TMS neural effects at the brain circuit level. Our findings are highly relevant for interpreting human TMS studies and biomarker developments for TMS target engagement in clinical applications.SIGNIFICANCE STATEMENT Transcranial magnetic stimulation (TMS) is a widely used noninvasive brain stimulation method to stimulate the human brain. To advance its utility for clinical applications, a clear understanding of its underlying physiological mechanisms is crucial. Here, we perform invasive electrophysiological recordings in the nonhuman primate brain during TMS, achieving a spatiotemporal precision not available in human EEG experiments. We find that evoked potentials are dose dependent and spatially specific, and can be separated from peripheral stimulation effects. This means that TMS-evoked responses can indicate a direct physiological stimulation response. Our work has important implications for the interpretation of human TMS-EEG recordings and biomarker development.

Improved brain stimulation targeting by optimising image acquisition parameters

Functional connectivity analysis from rs-fMRI data has been used for determining cortical targets in therapeutic applications of non-invasive brain stimulation using transcranial magnetic stimulation (TMS). Reliable connectivity measures are therefore essential for every rs-fMRI-based TMS targeting approach. Here, we examine the effect of echo time (TE) on the reproducibility and spatial variability of resting-state connectivity measures. We acquired multiple runs of single-echo fMRI data with either short (TE = 30 ms) or long (TE = 38 ms) echo time to investigate inter-run spatial reproducibility of a clinically relevant functional connectivity map, i.e., originating from the sgACC. We find that connectivity maps obtained from TE = 38 ms rs-fMRI data are significantly more reliable than those obtained from TE = 30 ms data sets. Our results clearly show that optimizing sequence parameters can be beneficial for ensuring high-reliability resting-state acquisition protocols to be used for TMS targeting. The differences between reliability in connectivity measures for different TEs could inform future clinical research in optimising MR sequences.

Hitting the Target of Image-Guided Psychiatry?

Hitting the Target of Image-Guided Psychiatry?

Minimal scanning duration for producing individualized repetitive transcranial magnetic stimulation targets.

This study aimed to determine the minimal scanning duration of functional magnetic resonance imaging (fMRI) for producing individualized repetitive transcranial magnetic stimulation (rTMS) targets that are superior to the group-level targets. This study included 30 healthy subjects and 20 depressive patients with high-sampled fMRI data (> 69min). We computed suboptimal targets by gradually increasing the scanning duration beginning at 6min. The suboptimal target connectivity and spatial distance to the optimal target (based on the full-duration scanning data) were compared to an anatomically fixed target from a group analysis (termed as the group target). These analyses were repeated for healthy subjects and depressive patients, as well as for target masks in the dorsolateral prefrontal cortex (DLPFC) and inferior parietal lobule (IPL). As the scanning duration increased, the suboptimal targets gradually approached the optimal targets in the healthy subjects. Compared with the group targets, the suboptimal targets in the DLPFC showed higher connectivity strength after 10min of data collection and shorter spatial distance after 40min. Similar results were found in major depressive patients. In the IPL, the minimal scanning duration decreased to 6 and 8min for connectivity strength and distance, respectively. These findings provide an important reference for individualized target definition in terms of scanning duration, which may standardize connectivity-based personalized studies. Future research is needed to further validate the therapeutic effects of the approach.

Automated optimization of TMS coil placement for personalized functional network engagement

Transcranial magnetic stimulation (TMS) is used to treat multiple psychiatric and neurological conditions by manipulating activity in particular brain networks and circuits, but individual responses are highly variable. In clinical settings, TMS coil placement is typically based on either group average functional maps or scalp heuristics. Here, we found that this approach can inadvertently target different functional networks in depressed patients due to variability in their functional brain organization. More precise TMS targeting should be feasible by accounting for each patient's unique functional neuroanatomy. To this end, we developed a targeting approach, termed targeted functional network stimulation (TANS). The TANS approach improved stimulation specificity in silico in 8 highly sampled patients with depression and 6 healthy individuals and invivo when targeting somatomotor functional networks representing the upper and lower limbs. Code for implementing TANS and an example dataset are provided as a resource.

A landmark-based approach to locate symptom-specific transcranial magnetic stimulation targets of depression.

ObjectiveTwo subregions of the dorsolateral prefrontal cortex have been identified as effective repetitive transcranial magnetic stimulation (rTMS) targets for the “anxiosomatic” and “dysphoric” symptoms, respectively. We aimed to develop a convenient approach to locate these targets on the scalp.Materials and methodsIn a discovery experiment, the two personalized targets were precisely identified on 24 subjects using a neuronavigation system. Then, a localized approach was developed based on individual scalp landmarks. This “landmark-based approach” was replicated and validated in an independent cohort (N = 25). Reliability of the approach was tested by calculating the correlation of both the inter-rater and intra-rater results. Validity was tested by comparing the mean distance between the personalized and landmark-based targets to the TMS spatial resolution (i.e., 5 mm). We further conducted a total of 24 sham rTMS sessions to estimate the misplacement between the coil center and target during a 10-min stimulation without neuronavigation.ResultsThe parameters of the “landmark-based approach” in the discovery experiment were replicated well in an independent cohort. Using discovery parameters, we successfully identified the symptom-specific targets in the independent cohort. Specifically, the mean distance between the personalized and landmark-based targets on the cortex was not significantly larger than 5 mm. However, the personalized and landmark-based targets distance exceeded 5 mm in more than 50% of subjects. During the 10-min sham rTMS session, the average coil misplacement was significantly larger than 5 mm.ConclusionThe “landmark-based approach” can conveniently and reliably locate the two symptom-specific targets at group level. However, the accuracy was highly varied at individual level and further improvement is needed.

Mapping Inter-individual Functional Connectivity Variability in TMS Targets for Major Depressive Disorder.

Transcranial magnetic stimulation (TMS) is an emerging alternative to existing treatments for major depressive disorder (MDD). The effects of TMS on both brain physiology and therapeutic outcomes are known to be highly variable from subject to subject, however. Proposed reasons for this variability include individual differences in neurophysiology, in cortical geometry, and in brain connectivity. Standard approaches to TMS target site definition tend to focus on coordinates or landmarks within the individual brain regions implicated in MDD, such as the dorsolateral prefrontal cortex (dlPFC) and orbitofrontal cortex (OFC). Additionally considering the network connectivity of these sites (i.e., the wider set of brain regions that may be mono- or poly-synaptically activated by TMS stimulation) has the potential to improve subject-specificity of TMS targeting and, in turn, improve treatment outcomes. In this study, we looked at the functional connectivity (FC) of dlPFC and OFC TMS targets, based on induced electrical field (E-field) maps, estimated using the SimNIBS library. We hypothesized that individual differences in spontaneous functional brain dynamics would contribute more to downstream network engagement than individual differences in cortical geometry (i.e., E-field variability). We generated individualized E-field maps on the cortical surface for 121 subjects (67 female) from the Human Connectome Project database using tetrahedral head models generated from T1- and T2-weighted MR images. F3 and Fp1 electrode positions were used to target the left dlPFC and left OFC, respectively. We analyzed inter-subject variability in the shape and location of these TMS target E-field patterns, their FC, and the major functional networks to which they belong. Our results revealed the key differences in TMS target FC between the dlPFC and OFC, and also how this connectivity varies across subjects. Three major functional networks were targeted across the dlPFC and OFC: the ventral attention, fronto-parietal and default-mode networks in the dlPFC, and the fronto-parietal and default mode networks in the OFC. Inter-subject variability in cortical geometry and in FC was high. Our analyses showed that the use of normative neuroimaging reference data (group-average or representative FC and subject E-field) allows prediction of which networks are targeted, but fails to accurately quantify the relative loading of TMS targeting on each of the principal networks. Our results characterize the FC patterns of canonical therapeutic TMS targets, and the key dimensions of their variability across subjects. The high inter-individual variability in cortical geometry and FC, leading to high variability in distributions of targeted brain networks, may account for the high levels of variability in physiological and therapeutic TMS outcomes. These insights should, we hope, prove useful as part of the broader effort by the psychiatry, neurology, and neuroimaging communities to help improve and refine TMS therapy, through a better understanding of the technology and its neurophysiological effects.

Is There an Optimal Repetitive Transcranial Magnetic Stimulation Target to Treat Chronic Tinnitus?

Chronic tinnitus is a clinical symptom that affects 10% to 15% of the adult population. Repetitive transcranial magnetic stimulation (rTMS) is a promising treatment, but significant heterogeneity exists in the treatment outcomes and stimulation parameters. In this study, we perform a qualitative systematic review to determine if there is an optimal rTMS site to treat tinnitus. A literature search was performed by searching the MEDLINE, Embase, Web of Science, and Cochrane databases. Sham-controlled studies in adults were included that contained >10 patients with tinnitus for >3 months and utilized 10 to 20 electroencephalography coordinates. Study outcomes were considered positive if the treatment arm reported a significant reduction in the primary tinnitus score relative to sham. There were 1211 studies screened. Nineteen studies met the inclusion criteria, and 8 unique stimulation sites were reported. Studies had 53.7 ± 46.0 patients (mean ± SD). The mean duration of follow-up was 10.3 ± 9.6 weeks. Positive outcomes regarding tinnitus suppression were reported in 5 of 5 (100%) studies stimulating the temporoparietal junction midway between T3 and P3 or between T4 and P4. Tinnitus suppression at all other sites was less frequent with a combined success rate of only 8 of 14 (57.1%). Significant heterogeneity exists in the literature in regard to the optimal transcranial magnetic stimulation target. These preliminary findings suggest that the temporoparietal junction midway between T3 and P3 or T4 and P4 is a promising nonauditory rTMS target in the setting of chronic tinnitus. Future research should elucidate the effectiveness of this site for tinnitus suppression.

TAP: targeting and analysis pipeline for optimization and verification of coil placement in transcranial magnetic stimulation

Objective. Transcranial magnetic stimulation (TMS) can modulate brain function via an electric field (E-field) induced in a brain region of interest (ROI). The ROI E-field can be computationally maximized and set to match a specific reference using individualized head models to find the optimal coil placement and stimulus intensity. However, the available software lacks many practical features for prospective planning of TMS interventions and retrospective evaluation of the experimental targeting accuracy. Approach. The TMS targeting and analysis pipeline (TAP) software uses an MRI/fMRI-derived brain target to optimize coil placement considering experimental parameters such as the subject’s hair thickness and coil placement restrictions. The coil placement optimization is implemented in SimNIBS 3.2, for which an additional graphical user interface (TargetingNavigator) is provided to visualize/adjust procedural parameters. The coil optimization process also computes the E-field at the target, allowing the selection of the TMS device intensity setting to achieve specific E-field strengths. The optimized coil placement information is prepared for neuronavigation software, which supports targeting during the TMS procedure. The neuronavigation system can record the coil placement during the experiment, and these data can be processed in TAP to quantify the accuracy of the experimental TMS coil placement and induced E-field. Main results. TAP was demonstrated in a study consisting of three repetitive TMS sessions in five subjects. TMS was delivered by an experienced operator under neuronavigation with the computationally optimized coil placement. Analysis of the experimental accuracy from the recorded neuronavigation data indicated coil location and orientation deviations up to about 2 mm and 2°, respectively, resulting in an 8% median decrease in the target E-field magnitude compared to the optimal placement. Significance. TAP supports navigated TMS with a variety of features for rigorous and reproducible stimulation delivery, including planning and evaluation of coil placement and intensity selection for E-field-based dosing.

A Randomized, Sham-Controlled Trial of Repetitive Transcranial Magnetic Stimulation Targeting M1 and S2 in Central Poststroke Pain: A Pilot Trial

ObjectivesCentral poststroke pain (CPSP), a neuropathic pain condition, is difficult to treat. Repetitive transcranial magnetic stimulation (rTMS) targeted to the primary motor cortex (M1) can alleviate the condition, but not all patients respond. We aimed to assess a promising alternative rTMS target, the secondary somatosensory cortex (S2), for CPSP treatment. Materials and MethodsThis prospective, randomized, double-blind, sham-controlled three-arm crossover trial assessed navigated rTMS (nrTMS) targeted to M1 and S2 (10 sessions, 5050 pulses per session at 10 Hz). Participants were evaluated for pain, depression, anxiety, health-related quality of life, upper limb function, and three plasticity-related gene polymorphisms including Dopamine D2 Receptor (DRD2). We monitored pain intensity and interference before and during stimulations and at one month. A conditioned pain modulation test was performed using the cold pressor test. This assessed the efficacy of the descending inhibitory system, which may transmit TMS effects in pain control. ResultsWe prescreened 73 patients, screened 29, and included 21, of whom 17 completed the trial. NrTMS targeted to S2 resulted in long-term (from baseline to one-month follow-up) pain intensity reduction of ≥30% in 18% (3/17) of participants. All stimulations showed a short-term effect on pain (17–20% pain relief), with no difference between M1, S2, or sham stimulations, indicating a strong placebo effect. Only nrTMS targeted to S2 resulted in a significant long-term pain intensity reduction (15% pain relief). The cold pressor test reduced CPSP pain intensity significantly (p = 0.001), indicating functioning descending inhibitory controls. The homozygous DRD2 T/T genotype is associated with the M1 stimulation response. ConclusionsS2 is a promising nrTMS target in the treatment of CPSP. The DRD2 T/T genotype might be a biomarker for M1 nrTMS response, but this needs confirmation from a larger study.

Connectivity-Guided Theta Burst Transcranial Magnetic Stimulation Versus Repetitive Transcranial Magnetic Stimulation for Treatment-Resistant Moderate to Severe Depression: Magnetic Resonance Imaging Protocol and SARS-CoV-2–Induced Changes for a Randomized Double-blind Controlled Trial

BackgroundDepression is a substantial health and economic burden. In approximately one-third of patients, depression is resistant to first-line treatment; therefore, it is essential to find alternative treatments. Transcranial magnetic stimulation (TMS) is a neuromodulatory treatment involving the application of magnetic pulses to the brain that is approved in the United Kingdom and the United States in treatment-resistant depression. This trial aims to compare the clinical effectiveness, cost-effectiveness, and mechanism of action of standard treatment repetitive TMS (rTMS) targeted at the F3 electroencephalogram site with a newer treatment—a type of TMS called theta burst stimulation (TBS) targeted based on measures of functional brain connectivity. This protocol outlines brain imaging acquisition and analysis for the Brain Imaging Guided Transcranial Magnetic Stimulation in Depression (BRIGhTMIND) study trial that is used to create personalized TMS targets and answer the proposed mechanistic hypotheses.ObjectiveThe aims of the imaging arm of the BRIGhTMIND study are to identify functional and neurochemical brain signatures indexing the treatment mechanisms of rTMS and connectivity-guided intermittent theta burst TMS and to identify imaging-based markers predicting response to treatment.MethodsThe study is a randomized double-blind controlled trial with 1:1 allocation to either 20 sessions of TBS or standard rTMS. Multimodal magnetic resonance imaging (MRI) is acquired for each participant at baseline (before TMS treatment) with T1-weighted and task-free functional MRI during rest used to estimate TMS targets. For participants enrolled in the mechanistic substudy, additional diffusion-weighted sequences are acquired at baseline and at posttreatment follow-up 16 weeks after treatment randomization. Core data sets of T1-weighted and task-free functional MRI during rest are acquired for all participants and are used to estimate TMS targets. Additional sequences of arterial spin labeling, magnetic resonance spectroscopy, and diffusion-weighted images are acquired depending on the recruitment site for mechanistic evaluation. Standard rTMS treatment is targeted at the F3 electrode site over the left dorsolateral prefrontal cortex, whereas TBS treatment is guided using the coordinate of peak effective connectivity from the right anterior insula to the left dorsolateral prefrontal cortex. Both treatment targets benefit from the level of MRI guidance, but only TBS is provided with precision targeting based on functional brain connectivity.ResultsRecruitment began in January 2019 and is ongoing. Data collection is expected to continue until January 2023.ConclusionsThis trial will determine the impact of precision MRI guidance on rTMS treatment and assess the neural mechanisms underlying this treatment in treatment-resistant depressed patients.Trial RegistrationISRCTN Registry ISRCTN19674644; https://www.isrctn.com/ISRCTN19674644International Registered Report Identifier (IRRID)DERR1-10.2196/31925

Prehabilitation and rehabilitation using data-driven, parcel-guided transcranial magnetic stimulation treatment for brain tumor surgery: proof of concept case report

Improved knowledge of the neuroplastic potential of the brain connectome has facilitated the advancement of neuromodulatory treatments for brain tumor patients especially in the perioperative period. More recently, the idea of inducing neuroplastic changes before surgery as “prehabilitation” has been suggested in low-grade gliomas with favorable data. However, it is uncertain the degree to which this treatment with transcranial magnetic stimulation (TMS) would benefit patients with high-grade gliomas, especially with additional rehabilitation after surgery and targets defined by personalized connectomic data. The current report details a case of a patient with recurrent glioblastoma in the right motor area 2 years after previous total resection. Given the desire for a more aggressive recurrent surgery in a highly functional area, the authors decided to proceed with “prehabilitation” by stimulating the surrounding motor cortices around the lesion to turn down the motor cortex connectivity before the recurrent surgery and then completing “rehabilitation” after the surgery. Structural-functional connectomic analyses were completed using Infinitome software based on an individualized patient brain atlas using machine-learning based parcellations. Repetitive TMS was employed, specifically using continuous and intermittent theta burst stimulation protocols. Prehabilitation consisted of using continuous theta burst stimulation at the estimated surgical entry point parcel and intermittent theta burst stimulation at adjacent parcellations for a total of 10 days with 5 sessions per day per target leading up until the surgery. A gross-total resection was obtained, but the patient woke up with left-sided hemiparesis. Resting-state functional magnetic resonance imaging derived connectivity demonstrated a case of a primarily pure cingulate-motor resection causing hemiplegia with an intact corticospinal tract and supplementary motor area. Functional connectivity outliers in cingulate-motor parcels were identified and compared with connectivity matrices from a healthy control atlas. Anomalies, parcels defined as functioning significantly outside a normal range, were chosen as rehabilitation TMS targets to be similarly treated for a total of 10 days with 5 sessions per day per target approximately two weeks after surgery. By using continuous theta burst stimulation on hyperconnected parcels and intermittent theta burst stimulation on hypoconnected parcels, the patient demonstrated significant motor improvement with only 4+/5 strength in the left arm 1 month after surgery. This report demonstrates for the first time the feasibility of using TMS treatment for glioblastoma surgery near “eloquent” cortices as a means of prehabilitation before surgery and rehabilitation after surgery. This parcel-guided approach for TMS treatment based on the cortical site of entry and individualized connectivity analyses allowed for maximal tumor resection and minimal long-term neurologic deficits.

Placebo effects and neuromodulation for depression: a meta-analysis and evaluation of shared mechanisms.

There is growing evidence that placebo effects can meaningfully modulate the brain. However, there has been little consideration of whether these changes may overlap with regions/circuits targeted by depression treatments and what the implications of this overlap would be on measuring efficacy in placebo-controlled clinical trials. In this systematic review and meta-analysis, we searched PubMed/Medline and Google Scholar for functional MRI and PET neuroimaging studies of placebo effects. Studies recruiting both healthy subjects and patient populations were included. Neuroimaging coordinates were extracted and included for Activation Likelihood Estimation (ALE) meta-analysis. We then searched for interventional studies of transcranial magnetic stimulation (TMS) and deep brain stimulation (DBS) for depression and extracted target coordinates for comparative spatial analysis with the placebo effects maps. Of 1169 articles identified, 34 neuroimaging studies of placebo effects were included. There were three significant clusters of activation: left dorsolateral prefrontal cortex (DLPFC) (x = -41, y = 16, z = 34), left sub-genual anterior cingulate cortex (sgACC)/ventral striatum (x = -8, y = 18, z = -15) and the right rostral anterior cingulate cortex (rACC) (x = 4, y = 42, z = 10). There were two significant deactivation clusters: right basal ganglia (x = 20, y = 2, z = 7) and right dorsal anterior cingulate cortex (dACC) (x = 1, y = -5, z = 45). TMS and DBS targets for depression treatment overlapped with the left DLPFC cluster and sgACC cluster, respectively. Our findings identify a common set of brain regions implicated in placebo effects across healthy individuals and patient populations, and provide evidence that these regions overlap with depression treatment targets. We model the statistical impacts of this overlap and demonstrate critical implications on measurements of clinical trial efficacy for this field.