The use of noninvasive transcranial brain stimulation methods, such as transcranial electrical stimulation (tES), transcranial magnetic stimulation (TMS), transcranial focused ultrasound stimulation (tFUS), and electroconvulsive therapy (ECT), has grown significantly over the past two decades. Evidence indicates that the dose-response relationship in brain stimulation is neither straightforward nor monotonic, with outcomes influenced by factors such as the brain state, anatomical variability, and neurophysiological mechanisms. Despite advancements in the field, there is still no consensus on standards for estimating and reporting delivered and received stimulation doses or defining dose-response relationships. This paper addresses these gaps by discussing four key areas: (1) factors influencing the delivered dose (stimulation parameters applied at the scalp), (2) quantification of the received dose (electric or acoustic fields delivered to brain tissue), (3) characterization of physiological, behavioral, and molecular responses to specific delivered/received doses, and (4) the dose-response relationship, which describes how variations in dose modulate brain function and behavior. Drawing on evidence from human and animal studies conducted in silico, in vitro, and in vivo, we outline challenges, propose solutions, and summarize current consensus standards. By promoting rigorous methodologies and transparent reporting, this paper aims to advance the reproducibility, safety, and efficacy of research on dose-response assessment in transcranial brain stimulation and its clinical applications.

Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive brain stimulation technique used in the treatment of several psychiatric disorders. However, its clinical efficacy remains limited in some cases, in part due to the lack of control over ongoing brain state during stimulation. Although some studies have combined rTMS with psychotherapy to engage the brain state during stimulation, brain state is still not objectively measured in such studies. Real-time functional magnetic resonance imaging neurofeedback (rt-fMRI-nf) offers a promising approach to objectively monitor and modulate brain state during rTMS. Here, we report the first study to investigate the feasibility of combining connectivity-based rTMS with rt-fMRI-nf to modulate amygdala activity. First, participants completed an fMRI emotion-matching task to identify an individualized medial prefrontal cortex (mPFC) target showing the strongest negative functional connectivity with the right amygdala. Across four subsequent visits, participants received active rTMS to either a mPFC target or to the vertex (control site) while engaged in rt-fMRI-nf. During rt-fMRI-nf, participants were presented with aversive images and were instructed either to passively look at them or to downregulate the height of a visual gauge representing their amygdala activity. We expected that rTMS during this downregulation would decrease amygdala activation even more than during downregulation alone. Feasibility, signal quality, rTMS-induced artifacts, and participant experience were systematically evaluated. We demonstrate that while concurrent connectivity-based rTMS and rt-fMRI-nf is feasible, the integration presents substantial technical and methodological challenges. These include limitations related to RF coil selection, signal-to-noise ratio in deep brain structures, prolonged rTMS-induced artifacts, and inter-individual variability in amygdala engagement. Despite these challenges, this work establishes a methodological foundation for future studies integrating real-time neuroimaging and neuromodulation. Continued advances in hardware, acquisition strategies, and individualized targeting may enable more precise state-dependent stimulation of emotion-related circuits, with potential implications for precision interventions in psychiatric disorders.

Evidence-based psychotherapies are first-line treatments for psychiatric disorders, yet response rates remain suboptimal. Noninvasive brain stimulation (NIBS) may augment psychotherapy by modulating treatment-engaged circuits. We conducted a systematic review and meta-analysis of randomized controlled trials comparing active NIBS plus evidence-based psychotherapy versus sham NIBS plus psychotherapy. We searched six databases through February 2025, screening 1017 records. Twenty-eight trials (31 treatment arms; 1506 participants) met inclusion criteria. Active NIBS combined with psychotherapy produced significantly greater symptom improvement than sham NIBS with psychotherapy (SMD = -0.38, 95% CI [-0.68, -0.08]), with substantial heterogeneity. Moderator analyses revealed critical implementation parameters: repetitive transcranial magnetic stimulation (rTMS) showed significant benefit while transcranial direct current stimulation did not. Non-concurrent delivery showed significant effects; concurrent delivery did not. Cognitive behavioral therapy (CBT) combined with NIBS showed significant benefit; other psychotherapy modalities did not. Human-delivered psychotherapy significantly enhanced outcomes; computerized formats did not. Significant effects were observed only for anxiety disorders (SMD = -0.70, 95% CI [-1.26, -0.14]). While there was a null finding for depression, it likely reflects insufficient statistical power rather than true ineffectiveness. Secondary analyses found no significant effects on executive functioning or quality of life. Treatment integrity was under-reported: only 39.3% of studies used fully manualized protocols and 10.7% documented therapist adherence. Timing and modality are largely confounded in the current evidence base, and priming versus consolidation effects cannot be distinguished. These findings provide an evidence-based framework for optimizing combined treatment protocols and highlight the need for standardized psychotherapy fidelity monitoring.

Military service members (SMs) and veterans who have sustained one or more concussions during their service have significantly higher rates of persistent depressive symptoms and suicidality compared to non-injured peers. Despite over 500,000 SMs who have sustained concussions, there are currently no Level I evidence-based treatments for improving depressive symptoms associated with concussion. Accelerated intermittent theta burst stimulation (aiTBS), a specific repetitive transcranial magnetic stimulation (rTMS) protocol, targeted at the dorsolateral prefrontal cortex (DLPFC) has demonstrated efficacy and is cleared for the treatment of Major Depressive Disorder (MDD) by the United States Food and Drug Administration (FDA). The mechanism of action of aiTBS is thought to be via the modulation of functional networks. Herein we outline the design of a multisite, double-blind, randomized, sham-controlled trial of aiTBS for the treatment of depressive symptoms in SMs and veterans with a history of concussion. We present the rationale for this specific design and highlight the potential for personalized neuroimaging-informed parameter determination in this population where brain injuries have resulted in variable structural and functional brain circuitry disruptions. If successful, this project will accelerate solutions to improve the health, well-being, and healthcare of SMs and veterans with depressive symptoms following concussion.Clinical trial registrationClinicaltrials.gov, NCT05426967.

Background:Electroconvulsive therapy (ECT) and magnetic seizure therapy (MST) are effective in the treatment of medication-resistant depression. Determining the stimulus frequency that results in the lowest seizure threshold could produce fewer adverse effects by reducing the overall stimulus intensity. Methods:To determine the optimal frequency for seizure induction, 4 male rhesus macaques were titrated with an increasing number of pulses at fixed frequencies ranging from 5 to 240 pulses per second (pps) using ultrabrief pulse right-unilateral ECT and circular-coil-on-vertex MST. Bilateral electroencephalography was recorded to characterize the seizure expression. Results:The seizure threshold dependence on stimulus frequency was similar for ECT and MST. While higher frequencies required progressively shorter trains to induce a seizure, the middle frequency range was associated with the fewest pulses (and therefore the least charge and energy), with a minimum at 16 pps and similarly low thresholds for 10 and 25 pps. The number of pulses at seizure threshold increased markedly at lower and higher frequencies. The lowest stimulus frequencies, 5 and 10 pps, were associated with the greatest ictal power measured by electroencephalography. Conclusions:While neither efficacy nor side effects were assessed in this study, the results highlight the significance of stimulus frequency for seizure induction, suggest efficient titration schedules that minimize exposure to the electrical stimulus, and can inform studies to assess the impact on clinical outcomes. These data can also support safety guidelines for interventions such as transcranial magnetic stimulation that must avoid seizure induction.

NIMH’s mission is to transform the understanding and treatment of mental illnesses through basic and clinical research, paving the way for prevention, recovery, and cure. New imaging techniques hold great promise for improving our understanding of the pathophysiology of mental illnesses, stratifying patients for treatment selection, and developing a personalized medicine approach. Here, we highlight emerging and promising new technologies that are likely to be vital in helping NIMH accomplish its mission, the potential for utilizing multimodal approaches to study mental illness, and considerations for data analytics and data sharing.

Neurostimulation devices that use rotating permanent magnets are being explored for their potential therapeutic benefits in patients with psychiatric and neurological disorders. This study aims to characterize the electric field (E-field) for ten configurations of rotating magnets using finite element analysis and phantom measurements. Various configurations were modeled, including single or multiple magnets, and bipolar or multipolar magnets, rotated at 10, 13.3, and 350 revolutions per second (rps). E-field strengths were also measured using a hollow sphere (r=9.2 cm) filled with a 0.9% sodium chloride solution and with a dipole probe. The E-field spatial distribution is determined by the magnets’ dimensions, number of poles, direction of the magnetization, and axis of rotation, while the E-field strength is determined by the magnets’ rotational frequency and magnetic field strength. The induced E-field strength on the surface of the head ranged between 0.0092 and 0.52 V/m. In the range of rotational frequencies applied, the induced E-field strengths were approximately an order or two of magnitude lower than those delivered by conventional transcranial magnetic stimulation. The impact of rotational frequency on E-field strength represents a confound in clinical trials that seek to tailor rotational frequency to individual neural oscillations. This factor could explain some of the variability observed in clinical trial outcomes.

The Stroop task is a well-established tool to investigate the influence of competing visual categories on decision making. Neuroimaging as well as rTMS studies have demonstrated the involvement of parietal structures, particularly the intraparietal sulcus (IPS), in this task. Given its reliability, the numerical Stroop task was used to compare the effects of different TMS targeting approaches by Sack and colleagues (Sack AT 2009), who elegantly demonstrated the superiority of individualized fMRI targeting. We performed the present study to test whether fMRI-guided rTMS effects on numerical Stroop task performance could still be observed while using more advanced techniques that have emerged in the last decade (e.g., electrical sham, robotic coil holder system, etc.). To do so we used a traditional reaction time analysis and we performed, post-hoc, a more advanced comprehensive drift diffusion modeling approach. Fifteen participants performed the numerical Stroop task while active or sham 10 Hz rTMS was applied over the region of the right intraparietal sulcus (IPS) showing the strongest functional activation in the Incongruent > Congruent contrast. This target was determined based on individualized fMRI data collected during a separate session. Contrary to our assumption, the classical reaction time analysis did not show any superiority of active rTMS over sham, probably due to confounds such as potential cumulative rTMS effects, and the effect of practice. However, the modeling approach revealed a robust effect of rTMS on the drift rate variable, suggesting differential processing of congruent and incongruent properties in perceptual decision-making, and more generally, illustrating that more advanced computational analysis of performance can elucidate the effects of rTMS on the brain where simpler methods may not.

In this study, repetitive transcranial magnetic stimulation was applied to either the right inferior frontal junction or the right inferior parietal cortex during a difficult aerial reconnaissance search task to test its capacity to improve search performance. Two stimulation strategies previously found to enhance cognitive performance were tested: The first is called "addition by subtraction," and the second condition utilizes a direct excitatory approach by applying brief trains of high-frequency repetitive transcranial magnetic stimulation immediately before task trials. In a within-subjects design, participants were given active or sham repetitive transcranial magnetic stimulation at either 1 Hz or at 1 Hz above their individual peak alpha frequency (IAF + 1, mean 11.5 Hz), delivered to either the right inferior frontal junction or the right inferior parietal cortex, both defined with individualized peak functional magnetic resonance imaging (fMRI) activation obtained during the visual search task. Results indicated that among the 13 participants who completed the protocol, only active IAF + 1 stimulation to inferior frontal junction resulted in significant speeding of reaction time compared to sham. This site- and frequency-specific enhancement of performance with IAF + 1 repetitive transcranial magnetic stimulation applied immediately prior to task trials provides evidence for the involvement of inferior frontal junction in guiding difficult visual search, and more generally for the use of online repetitive transcranial magnetic stimulation directed at specific functional networks to enhance visual search performance.

OBJECTIVES:This study aimed to describe current US electroconvulsive therapy (ECT) practice, identify practice changes over time, and inform discussion of practice. METHOD:Our anonymous survey was open on SurveyMonkey.com from January to June 2022. We sent invitations to providers identified using a Medicare provider database, an advanced PubMed search function, and professional group listservs. Participants were instructed to submit 1 survey per ECT site. We examined frequency of responses, tabulated individual comments, and grouped data for comparison. RESULTS:We received responses from 74 US practice sites encompassing 283 providers. Forty-nine percent (n = 36) of respondents practiced at general academic medical centers, 23% (n = 17) at general medical centers, 16% (n = 12) at freestanding psychiatric hospitals, and 7% (n = 5) at Veterans Affairs medical centers. Proportions of female (29%) and Black or African American (AA) (1%) ECT providers were markedly lower than proportions of female (60%) and Black or African American ECT patients (10%). The median number of treatments for a major depressive episode was 10. The preferred electrode placement was right unilateral (66%, n = 45). The favored dosing strategy was seizure threshold titration. Quantitative outcome measures were used by 89% (n = 66) of sites for depressive symptoms and 84% (n = 62) for cognitive adverse effects. CONCLUSIONS:This survey is the first nationwide survey of ECT practice in nearly 40 years. Our results describe changes in practice over time and highlight the need to increase the number of female and Black or African American ECT providers. A comprehensive network of ECT sites could facilitate more frequent nationwide surveys.

ABSTRACT:Attempts to dissociate electroconvulsive therapy (ECT) therapeutic efficacy from cognitive side effects of ECT include modifying electrode placement, but traditional electrode placements employing 2 large electrodes are inherently nonfocal, limiting the ability to selectively engage targets associated with clinical benefit while avoiding nontargets associated with adverse side effects. Limited focality represents a technical limitation of conventional ECT, and there is growing evidence that the spatial distribution of the ECT electric fields induced in the brain drives efficacy and side effects. Computational models can be used to predict brain current flow patterns for existing and novel ECT montages. Using finite element method simulations (under quasi-static, nonadaptive assumptions, 800-mA total current), the electric fields generated in the superficial cortex and subcortical structures were predicted for the following traditional ECT montages (bilateral temporal, bifrontal, right unilateral) and experimental montages (focal electrically administered seizure therapy, lateralized high-definition [HD]-ECT, unilateral 4 × 1-ring HD-ECT, bilateral 4 × 1-ring HD-ECT, and a multipolar HD-ECT). Peak brain current density in regions of interest was quantified. Conventional montages (bilateral bifrontal, right unilateral) each produce distinct but diffuse and deep current flow. Focal electrically administered seizure therapy and lateralized HD-ECT produce unique, lateralized current flow, also impacting specific deep regions. A 4 × 1-ring HD-ECT restricts current flow to 1 (unilateral) or 2 (bilateral) cortical regions. Multipolar HD-ECT shows optimization to a specific target set. Future clinical trials are needed to determine whether enhanced control over current distribution is achieved with these experimental montages, and the resultant seizures, improve the risk/benefit ratio of ECT.

The history of transcranial magnetic stimulation (TMS) in psychiatry spans disciplines, continents, and decades, and it upended prevailing dogma. Initially developed as a tool to probe the motor system in neurology, TMS induces electricity in the brain without inducing a seizure (when given within safety limits). TMS made its debut in 1985 in the United Kingdom when the prevailing dogma in psychiatry was that a seizure is necessary for the therapeutic effects of electroconvulsive therapy (ECT). The idea of treating depression with electricity alone without inducing a seizure was viewed with skepticism. Fortunately, a group of pioneering researchers across several countries in the early 1990s saw TMS as a promising means of treating severe depression without the cognitive side effects of ECT. Borrowing methods used to study the motor system (a large round coil positioned on the vertex) and the fastest repetition rate available to them in 1993 (0.25–0.5 Hz), a team in Germany treated 2 patients with treatment-resistant depression, one of whom showed benefit ( 1 Höflich G. Kasper S. Hufnagel A. Ruhrmann S. Möller H.-J. Application of transcranial magnetic stimulation in treatment of drug-resistant major depression—A report of 2 cases. Hum Psychopharmacol. 1993; 8: 361-365 Crossref Scopus (223) Google Scholar ). In 1994, a group in Israel took a similar approach in 10 patients with depression and 10 patients with schizophrenia ( 2 Grisaru N. Yarovslavsky U. Abarbanel J. Lamberg T. Belmaker R.H. Transcranial magnetic stimulation in depression and schizophrenia. Eur Neuropsychopharmacol. 1994; 4: 287-288 Crossref Scopus (134) Google Scholar ). In 1995, a team from Germany and Austria reported significant antidepressant effects of this approach in a randomized controlled trial ( 3 Kolbinger H.M. Höflich G. Hufnagel A. Müller H.-J. Kasper S. Transcranial magnetic stimulation (TMS) in the treatment of major depression—A pilot study. Hum Psychopharmacol. 1995; 10: 305-310 Crossref Scopus (176) Google Scholar ). That same year, researchers in the United States took a different approach—informed by neuroimaging findings in depression, they used the more focal figure-8 coil to target the left dorsolateral prefrontal cortex using the higher repetition rate that was available then (20 Hz repetitive TMS) and reported significant antidepressant effects in an open-label trial ( 4 George M.S. Wassermann E.M. Williams W.A. Callahan A. Ketter T.A. Basser P. et al. Daily repetitive transcranial magnetic stimulation (rTMS) improves mood in depression. Neuroreport. 1995; 6: 1853-1856 Crossref PubMed Scopus (792) Google Scholar ). In 1996, a team in Spain reported the first randomized controlled trial of repetitive TMS targeting the dorsolateral prefrontal cortex for depression ( 5 Pascual-Leone A. Rubio B. Pallardo F. Catala M.D. Rapid-rate transcranial magnetic stimulation of left dorsolateral prefrontal cortex in drug-resistant depression. Lancet. 1996; 348: 233-237 Abstract Full Text Full Text PDF PubMed Scopus (1030) Google Scholar ). Numerous randomized controlled trials, meta-analyses, and an industry-sponsored pivotal trial later, the U.S. Food and Drug Administration cleared TMS for the treatment of depression in adults in 2008. Subsequent clearances followed, for presurgical mapping in 2009, migraine with aura in 2013, obsessive-compulsive disorder in 2019, smoking cessation in 2020, and comorbid anxiety in major depressive disorder in 2021. How did we get here, and what have we learned along the way? This commentary touches on a few lessons from the past that may be useful to reflect on as TMS reaches its fifteenth year after U.S. Food and Drug Administration clearance.

Purpose of Review Sleep deprivation is a global health issue, and the resultant cognitive deficits can be debilitating. A series of studies reported success with individually neuronavigated transcranial magnetic stimulation (TMS), coupled with online task performance, in substantially reducing performance deficits in working memory in healthy adults caused by 2 days of total sleep depression. This paradigm of coupling TMS with online task performance has been referred to as Cognitive Paired Associative Stimulation (C-PAS). This review describes those studies and the research since using various TMS paradigms to remediate working memory deficits in sleep deprivation. Recent Findings Three such studies were found, but none replicated the earlier findings. However, in each case, there were differences in study design that might explain the negative findings and inform future methodological choices and to underline the need to combine TMS with brain imaging guidance. Summary Online task performance during TMS, as done in the C-PAS paradigm, appears to be essential to demonstrating lasting remediation of working memory deficits induced by sleep deprivation. This observation highlights the importance of state-dependency in determining the effects of TMS. Further work needs to be done to clarify the potential role of C-PAS in alleviating the effects of sleep deprivation and studying cognitive processes affected by sleep.

BACKGROUND:Magnetic seizure therapy (MST) is under investigation as a treatment for adults with major depression. Previous research has suggested that MST has antidepressant efficacy comparable to that of electroconvulsive therapy (ECT), but with greater cognitive safety. The objective of the study was to compare the neurocognitive outcomes of patients receiving an acute course of MST with the outcomes of those receiving ECT for the treatment of major depressive episode. METHODS:This was a between-subjects, double-masked, randomized, multicenter clinical trial. Seventy-three participants with a severe major depressive episode were enrolled and randomly assigned to treatment with MST (n = 35) or ultra-brief pulse right unilateral ECT (n = 38). The main outcome was change in performance from baseline to the end of acute treatment on multiple neurocognitive measures. RESULTS:Compared with patients who received ECT, patients who received MST had superior cognitive outcomes up to 72 hours posttreatment. Specifically, following MST treatment, there was significant improvement in fine motor dexterity (p = .017) and no significant change in cognitive domains of attention, verbal fluency, executive function, or verbal learning and memory. In contrast, following treatment with ECT, patients demonstrated significantly worse performance on measures of verbal fluency (p < .001), executive function (p = .038), and verbal memory retention (p < .001). Autobiographical memory consistency decreased significantly following treatment with both ECT (p < .001) and MST, although the magnitude of change was greater for ECT. CONCLUSIONS:The study findings confirm previous work and provide new evidence supporting the enhanced cognitive safety of MST relative to ECT. Future research on MST is warranted to optimize its application to individuals with neuropsychiatric illnesses across the life span.

It has been suggested that aberrant excitation/inhibition (E/I) balance and dysfunctional structure and function of relevant brain networks may underlie the symptoms of autism spectrum disorder (ASD). However, the nomological network linking these constructs to quantifiable measures and mechanistically relating these constructs to behavioral symptoms of ASD is lacking. Herein we describe a within-subject, controlled, proof-of-mechanism study investigating the pathophysiology of auditory/language processing in adolescents with ASD. We utilize neurophysiological and neuroimaging techniques including magnetic resonance spectroscopy (MRS), diffusion-weighted imaging (DWI), functional magnetic resonance imaging (fMRI), and magnetoencephalography (MEG) metrics of language network structure and function. Additionally, we apply a single, individually targeted session of continuous theta burst stimulation (cTBS) as an experimental probe of the impact of perturbation of the system on these neurophysiological and neuroimaging outcomes. MRS, fMRI, and MEG measures are evaluated at baseline and immediately prior to and following cTBS over the posterior superior temporal cortex (pSTC), a region involved in auditory and language processing deficits in ASD. Also, behavioral measures of ASD and language processing and DWI measures of auditory/language network structures are obtained at baseline to characterize the relationship between the neuroimaging and neurophysiological measures and baseline symptom presentation. We hypothesize that local gamma-aminobutyric acid (GABA) and glutamate concentrations (measured with MRS), and structural and functional activity and network connectivity (measured with DWI and fMRI), will significantly predict MEG indices of auditory/language processing and behavioral deficits in ASD. Furthermore, a single session of cTBS over left pSTC is hypothesized to lead to significant, acute changes in local glutamate and GABA concentration, functional activity and network connectivity, and MEG indices of auditory/language processing. We have completed the pilot phase of the study (n=20 Healthy Volunteer adults) and have begun enrollment for the main phase with adolescents with ASD (n=86; age 14-17). If successful, this study will establish a nomological network linking local E/I balance measures to functional and structural connectivity within relevant brain networks, ultimately connecting them to ASD symptoms. Furthermore, this study will inform future therapeutic trials using cTBS to treat the symptoms of ASD.