Characterizing the opioidergic mechanisms of repetitive transcranial magnetic stimulation-induced analgesia: a randomized controlled trial.

ABSTRACT: Repetitive transcranial magnetic stimulation (rTMS) is a promising technology to reduce chronic pain. Investigating the mechanisms of rTMS analgesia holds the potential to improve treatment efficacy. Using a double-blind and placebo-controlled design at both stimulation and pharmacologic ends, this study investigated the opioidergic mechanisms of rTMS analgesia by abolishing and recovering analgesia in 2 separate stages across brain regions and TMS doses. A group of 45 healthy participants were equally randomized to the primary motor cortex (M1), the dorsolateral prefrontal cortex (DLPFC), and the Sham group. In each session, participants received an intravenous infusion of naloxone or saline before the first rTMS session. Participants then received a second dose of rTMS session after the drugs were metabolized at 90 minutes. M1-rTMS-induced analgesia was abolished by naloxone compared with saline and was recovered by the second rTMS run when naloxone was metabolized. In the DLPFC, double but not the first TMS session induced significant pain reduction in the saline condition, resulting in less pain compared with the naloxone condition. In addition, TMS over the M1 or DLPFC selectively increased plasma concentrations of ß-endorphin or encephalin, respectively. Overall, we present causal evidence that opioidergic mechanisms are involved in both M1-induced and DLPFC-rTMS-induced analgesia; however, these are shaped by rTMS dosage and the release of different endogenous opioids.

Personalized and Circuit-Based Transcranial Magnetic Stimulation: Evidence, Controversies, and Opportunities.

The development of neuroimaging methodologies to map brain connectivity has transformed our understanding of psychiatric disorders, the distributed effects of brain stimulation, and how transcranial magnetic stimulation can be best employed to target and ameliorate psychiatric symptoms. In parallel, neuroimaging research has revealed that higher-order brain regions such as the prefrontal cortex, which represent the most common therapeutic brain stimulation targets for psychiatric disorders, show some of the highest levels of interindividual variation in brain connectivity. These findings provide the rationale for personalized target site selection based on person-specific brain network architecture. Recent advances have made it possible to determine reproducible personalized targets with millimeter precision in clinically tractable acquisition times. These advances enable the potential advantages of spatially personalized transcranial magnetic stimulation targeting to be evaluated and translated to basic and clinical applications. In this review, we outline the motivation for target site personalization, preliminary support (mostly in depression), convergent evidence from other brain stimulation modalities, and generalizability beyond depression and the prefrontal cortex. We end by detailing methodological recommendations, controversies, and notable alternatives. Overall, while this research area appears highly promising, the value of personalized targeting remains unclear, and dedicated large prospective randomized clinical trials using validated methodology are critical.

Comparisons of Accelerated Continuous and Intermittent Theta Burst Stimulation for Treatment-Resistant Depression and Suicidal Ideation.

BACKGROUND: Suicidal ideation is a substantial clinical challenge in treatment-resistant depression (TRD). Recent work demonstrated promising antidepressant effects in TRD patients with no or mild suicidal ideation using a specific protocol termed intermittent theta burst stimulation (iTBS). Here, we examined the clinical effects of accelerated schedules of iTBS and continuous TBS (cTBS) in patients with moderate to severe suicidal ideation. METHODS: Patients with TRD and moderate to severe suicidal ideation (n = 44) were randomly assigned to receive accelerated iTBS or cTBS treatment. Treatments were delivered in 10 daily TBS sessions (1800 pulses/session) for 5 consecutive days (total of 90,000 pulses). Neuronavigation was employed to target accelerated iTBS and cTBS to the left and right dorsolateral prefrontal cortex (DLPFC), respectively. Clinical outcomes were evaluated in a 4-week follow-up period. RESULTS: Accelerated cTBS was superior to iTBS in the management of suicidal ideation (pweek 1 = .027) and anxiety symptoms (pweek 1 = .01). Accelerated iTBS and cTBS were comparable in antidepressant effects (p < .001; accelerated cTBS: mean change at weeks 1, 3, 5 = 49.55%, 54.99%, 53.11%; accelerated iTBS: mean change at weeks 1, 3, 5 = 44.52%, 48.04%, 51.74%). No serious adverse events occurred during the trial. One patient withdrew due to hypomania. The most common adverse event was discomfort at the treatment site (22.73% in both groups). CONCLUSIONS: These findings provide the first evidence that accelerated schedules of left DLPFC iTBS and right DLPFC cTBS are comparably effective in managing antidepressant symptoms and indicate that right DLPFC cTBS is potentially superior in reducing suicidal ideation and anxiety symptoms.

Functional dysconnectivity in youth depression: Systematic review, meta-analysis, and network-based integration.

Youth depression has been associated with heterogenous patterns of aberrant brain connectivity. To make sense of these divergent findings, we conducted a systematic review encompassing 19 resting-state fMRI seed-to-whole-brain studies (1400 participants, comprising 795 youths with major depression and 605 matched healthy controls). We incorporated separate meta-analyses of connectivity abnormalities across the levels of the most commonly seeded brain networks (default-mode and limbic networks) and, based on recent additions to the literature, an updated meta-analysis of amygdala dysconnectivity in youth depression. Our findings indicated broad and distributed findings at an anatomical level, which could not be captured by conventional meta-analyses in terms of spatial convergence. However, we were able to parse the complexity of region-to-region dysconnectivity by considering constituent regions as components of distributed canonical brain networks. This integration revealed dysconnectivity centred on central executive, default mode, salience, and limbic networks, converging with findings from the adult depression literature and suggesting similar neurobiological underpinnings of youth and adult depression.

Analgesic efficacy of theta-burst stimulation for postoperative pain.

OBJECTIVE: Repetitive transcranial magnetic stimulation (rTMS) may be a relevant method to assist postoperative pain. However, studies to date have only used conventional 10 Hz rTMS and targeted the DLPFC for postoperative pain. A more recent form of rTMS, termed intermittent Theta Burst Stimulation (iTBS), enables to increase cortical excitability in a short period of time. This preliminary double-blind, randomised, sham controlled study was designed to evaluate the efficacy of iTBS in postoperative care across two distinct stimulation targets. METHODS: A group of 45 patients post laparoscopic surgery were randomised to receive a single session of iTBS over either the dorsolateral prefrontal cortex (DLPFC), primary motor cortex (M1), or Sham stimulation (1:1:1 ratio). Outcome measurements were number of pump attempts, total anaesthetic volume used, and self-rated pain experience, assessed at 1 hour, 6 hours, 24 hours, and 48 hours post stimulation. All randomised patients were analysed (n = 15 in each group). RESULTS: Compared to Sham stimulation, DLPFC-iTBS reduced pump attempts at 6 (DLPFC = 0.73 ± 0.88, Sham = 2.36 ± 1.65, P = 0.031), 24 (DLPFC = 1.40 ± 1.24, Sham = 5.03 ± 3.87, P = 0.008), and 48 (DLPFC = 1.47 ± 1.41, Sham = 5.87 ± 4.34, P = 0.014) hours post-surgery, whereby M1 stimulation had no effect. No group effect was observed on total anaesthetics, which was mainly provided through the continuous administration of opioids at a set speed for each group. There was also no group or interaction effect on pain ratings. Pump attempts were positively associated with pain ratings in the DLPFC (r = 0.59, P = 0.02) and M1 (r = 0.56, P = 0.03) stimulation. CONCLUSIONS: Our findings show that iTBS to the DLPFC reduces pump attempts for additional anaesthetics following a laparoscopic surgery. However, reduced pump attempts by DLPFC stimulation did not translate into a significantly smaller volume of total anaesthetic, due to the continuous administration of opioids at a set speed for each group. SIGNIFICANCE: Our findings therefore provide preliminary evidence for iTBS targeting the DLPFC to be used to improve postoperative pain management.

Personalized brain stimulation of memory networks.

BACKGROUND: The finding that transcranial magnetic stimulation (TMS) can enhance memory performance via stimulation of parietal sites within the Cortical-Hippocampal Network counts as one of the most exciting findings in this field in the past decade. However, the first independent effort aiming to fully replicate this finding found no discernible influence of TMS on memory performance. OBJECTIVE: We examined whether this might relate to interindividual spatial variation in brain connectivity architecture, and the capacity of personalisation methodologies to overcome the noise inherent across independent scanners and cohorts. METHODS: We implemented recently detailed personalisation methodology to retrospectively compute individual-specific parietal targets and then examined relation to TMS outcomes. RESULTS: Closer proximity between actual and novel fMRI-personalized targets associated with greater improvement in memory performance. CONCLUSION: These findings demonstrate the potential importance of aligning brain stimulation targets according to individual-specific differences in brain connectivity, and extend upon recent findings in prefrontal cortex.

Brain stimulation and brain lesions converge on common causal circuits in neuropsychiatric disease.

Damage to specific brain circuits can cause specific neuropsychiatric symptoms. Therapeutic stimulation to these same circuits may modulate these symptoms. To determine whether these circuits converge, we studied depression severity after brain lesions (n = 461, five datasets), transcranial magnetic stimulation (n = 151, four datasets) and deep brain stimulation (n = 101, five datasets). Lesions and stimulation sites most associated with depression severity were connected to a similar brain circuit across all 14 datasets (P < 0.001). Circuits derived from lesions, deep brain stimulation and transcranial magnetic stimulation were similar (P < 0.0005), as were circuits derived from patients with major depression versus other diagnoses (P < 0.001). Connectivity to this circuit predicted out-of-sample antidepressant efficacy of transcranial magnetic stimulation and deep brain stimulation sites (P < 0.0001). In an independent analysis, 29 lesions and 95 stimulation sites converged on a distinct circuit for motor symptoms of Parkinson's disease (P < 0.05). We conclude that lesions, transcranial magnetic stimulation and DBS converge on common brain circuitry that may represent improved neurostimulation targets for depression and other disorders.

High-frequency rTMS over the dorsolateral prefrontal cortex on chronic and provoked pain: A systematic review and meta-analysis.

BACKGROUND: High-frequency rTMS over the dorsolateral prefrontal cortex (DLPFC) has demonstrated mixed effects on chronic and provoked pain. OBJECTIVES/METHODS: In this study, a meta-analysis was conducted to characterise the potential analgesic effects of high-frequency rTMS over the DLPFC on both chronic and provoked pain. RESULTS: A total of 626 studies were identified in a systematic search. Twenty-six eligible studies were included for the quantitative review, among which 17 modulated chronic pain and the remaining investigated the influence on provoked pain. The left side DLPFC was uniformly targeted in the chronic pain studies. While our data identified no overall effect of TMS across chronic pain conditions, there was a significant short-term analgesia in neuropathic pain conditions only (SMD = -0.87). In terms of long-lasting analgesia, there was an overall pain reduction in the midterm (SMD = -0.53, 24.6 days average) and long term (SMD = -0.63, 3 months average) post DLPFC stimulation, although these effects were not observed within specific chronic pain conditions. Surprisingly, the number of sessions was demonstrated to have no impact on rTMS analgesia. In the analysis of provoked pain, our data also indicated a significant analgesic effect following HF-rTMS over the DLPFC (SMD = -0.73). Importantly, we identified a publication bias in the studies of provoked pain but not for chronic pain conditions. CONCLUSIONS: Overall, our findings support that HF-DLPFC stimulation is able to induce an analgesic effect in chronic pain and in response to provoked pain. These results highlight the potential of DLPFC-rTMS in the management of certain chronic pain conditions and future directions are discussed to enhance the potential long-term analgesic effects.

Personalized connectivity-guided DLPFC-TMS for depression: Advancing computational feasibility, precision and reproducibility.

Repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex (DLPFC) is an established treatment for refractory depression, however, therapeutic outcomes vary. Mounting evidence suggests that clinical response relates to functional connectivity with the subgenual cingulate cortex (SGC) at the precise DLPFC stimulation site. Critically, SGC-related network architecture shows considerable interindividual variation across the spatial extent of the DLPFC, indicating that connectivity-based target personalization could potentially be necessary to improve treatment outcomes. However, to date accurate personalization has not appeared feasible, with recent work indicating that the intraindividual reproducibility of optimal targets is limited to 3.5 cm. Here we developed reliable and accurate methodologies to compute individualized connectivity-guided stimulation targets. In resting-state functional MRI scans acquired across 1,000 healthy adults, we demonstrate that, using this approach, personalized targets can be reliably and robustly pinpointed, with a median accuracy of ~2 mm between scans repeated across separate days. These targets remained highly stable, even after 1 year, with a median intraindividual distance between coordinates of only 2.7 mm. Interindividual spatial variation in personalized targets exceeded intraindividual variation by a factor of up to 6.85, suggesting that personalized targets did not trivially converge to a group-average site. Moreover, personalized targets were heritable, suggesting that connectivity-guided rTMS personalization is stable over time and under genetic control. This computational framework provides capacity for personalized connectivity-guided TMS targets to be robustly computed with high precision and has the flexibly to advance research in other basic research and clinical applications.

Single-Pulse Transcranial Magnetic Stimulation-Evoked Potential Amplitudes and Latencies in the Motor and Dorsolateral Prefrontal Cortex among Young, Older Healthy Participants, and Schizophrenia Patients.

BACKGROUND: The combination of transcranial magnetic stimulation (TMS) with electroencephalography (EEG) allows for non-invasive investigation of cortical response and connectivity in human cortex. This study aimed to examine the amplitudes and latencies of each TMS-evoked potential (TEP) component induced by single-pulse TMS (spTMS) to the left motor (M1) and dorsolateral prefrontal cortex (DLPFC) among healthy young participants (YNG), older participants (OLD), and patients with schizophrenia (SCZ). METHODS: We compared the spatiotemporal characteristics of TEPs induced by spTMS among the groups. RESULTS: Compared to YNG, M1-spTMS induced lower amplitudes of N45 and P180 in OLD and a lower amplitude of P180 in SCZ, whereas the DLPFC-spTMS induced a lower N45 in OLD. Further, OLD demonstrated latency delays in P60 after M1-spTMS and in N45-P60 over the right central region after left DLPFC-spTMS, whereas SCZ demonstrated latency delays in N45-P60 over the midline and right central regions after DLPFC-spTMS. CONCLUSIONS: These findings suggest that inhibitory and excitatory mechanisms mediating TEPs may be altered in OLD and SCZ. The amplitude and latency changes of TEPs with spTMS may reflect underlying neurophysiological changes in OLD and SCZ, respectively. The spTMS administered to M1 and the DLPFC can probe cortical functions by examining TEPs. Thus, TMS-EEG can be used to study changes in cortical connectivity and signal propagation from healthy to pathological brains.

Using Brain Imaging to Improve Spatial Targeting of Transcranial Magnetic Stimulation for Depression.

Transcranial magnetic stimulation (TMS) is an effective treatment for depression but is limited in that the optimal therapeutic target remains unknown. Early TMS trials lacked a focal target and thus positioned the TMS coil over the prefrontal cortex using scalp measurements. Over time, it became clear that this method leads to variation in the stimulation site and that this could contribute to heterogeneity in antidepressant response. Newer methods allow for precise positioning of the TMS coil over a specific brain location, but leveraging these precise methods requires a more precise therapeutic target. We review how neuroimaging is being used to identify a more focal therapeutic target for depression. We highlight recent studies showing that more effective TMS targets in the frontal cortex are functionally connected to deep limbic regions such as the subgenual cingulate cortex. We review how connectivity might be used to identify an optimal TMS target for use in all patients and potentially even a personalized target for each individual patient. We address the clinical implications of this emerging field and highlight critical questions for future research.

Individual deviations from normative models of brain structure in a large cross-sectional schizophrenia cohort.

The heterogeneity of schizophrenia has defied efforts to derive reproducible and definitive anatomical maps of structural brain changes associated with the disorder. We aimed to map deviations from normative ranges of brain structure for individual patients and evaluate whether the loci of individual deviations recapitulated group-average brain maps of schizophrenia pathology. For each of 48 white matter tracts and 68 cortical regions, normative percentiles of variation in fractional anisotropy (FA) and cortical thickness (CT) were established using diffusion-weighted and structural MRI from healthy adults (n = 195). Individuals with schizophrenia (n = 322) were classified as either within the normative range for healthy individuals of the same age and sex (5-95% percentiles), infra-normal (<5% percentile) or supra-normal (>95% percentile). Repeating this classification for each tract and region yielded a deviation map for each individual. Compared to the healthy comparison group, the schizophrenia group showed widespread reductions in FA and CT, involving virtually all white matter tracts and cortical regions. Paradoxically, however, no more than 15-20% of patients deviated from the normative range for any single tract or region. Furthermore, 79% of patients showed infra-normal deviations for at least one locus (healthy individuals: 59 ± 2%, p < 0.001). Thus, while infra-normal deviations were common among patients, their anatomical loci were highly inconsistent between individuals. Higher polygenic risk for schizophrenia associated with a greater number of regions with infra-normal deviations in CT (r = -0.17, p = 0.006). We conclude that anatomical loci of schizophrenia-related changes are highly heterogeneous across individuals to the extent that group-consensus pathological maps are not representative of most individual patients. Normative modeling can aid in parsing schizophrenia heterogeneity and guiding personalized interventions.

A multivariate neuroimaging biomarker of individual outcome to transcranial magnetic stimulation in depression.

The neurobiology of major depressive disorder (MDD) remains incompletely understood, and many individuals fail to respond to standard treatments. Repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex (DLPFC) has emerged as a promising antidepressant therapy. However, the heterogeneity of response underscores a pressing need for biomarkers of treatment outcome. We acquired resting state functional magnetic resonance imaging (rsfMRI) data in 47 MDD individuals prior to 5-8 weeks of rTMS treatment targeted using the F3 beam approach and in 29 healthy comparison subjects. The caudate, prefrontal cortex, and thalamus showed significantly lower blood oxygenation level-dependent (BOLD) signal power in MDD individuals at baseline. Critically, individuals who responded best to treatment were associated with lower pre-treatment BOLD power in these regions. Additionally, functional connectivity (FC) in the default mode and affective networks was associated with treatment response. We leveraged these findings to train support vector machines (SVMs) to predict individual treatment responses, based on learned patterns of baseline FC, BOLD signal power and clinical features. Treatment response (responder vs. nonresponder) was predicted with 85-95% accuracy. Reduction in symptoms was predicted to within a mean error of ±16% (r = .68, p < .001). These preliminary findings suggest that therapeutic outcome to DLPFC-rTMS could be predicted at a clinically meaningful level using only a small number of core neurobiological features of MDD, warranting prospective testing to ascertain generalizability. This provides a novel, transparent and physiologically plausible multivariate approach for classification of individual response to what has become the most commonly employed rTMS treatment worldwide. This study utilizes data from a larger clinical study (Australian New Zealand Clinical Trials Registry: Investigating Predictors of Response to Transcranial Magnetic Stimulation for the Treatment of Depression; ACTRN12610001071011; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=336262).

Learning from Goal and Action Based Observations Differentially Modulates Functional Motor Cortical Plasticity.

Action observation can facilitate motor skill learning and lead to a memory trace in motor representations of action. However, it remains unclear whether the action itself or the goal of the action drive changes in motor representations after learning by observation. We performed two experiments. In Experiment 1, using serial reaction time task and transcranial magnetic stimulation, we showed that observation of right-hand actions during skill learning only increased left motor cortical excitability, leading to behavioral gains in the same hand as the observed hand. In contrast, observing a sequence of visual cue positions devoid of hand action increases motor cortical excitability in both hemispheres and facilitates motor skill learning in the right hand (Experiment 1) and left hand for a mirror-symmetric sequence (Experiment 2). We propose that the encoding of observed movements maps onto motor representations of the same action to form a limb-specific motor memory, whereas the learning of spatial goals forms memory traces in the motor representations in both hemispheres to prepare for potential action in either hand.

Involvement of different neuronal components in the induction of cortical plasticity with associative stimulation.

BACKGROUND: Paired associative stimulation (PAS), with stimulus interval of 21.5 or 25 ms, using transcranial magnetic stimulation in the posterior-anterior (PA) current direction, produces a long-term-potentiation-like effect. Stimulation with PA directed current generates both early and late indirect (I)-waves while that in anterior-posterior (AP) current predominantly elicits late I-waves. Short interval intracortical inhibition (SICI) inhibits late I-waves but not early I-waves. OBJECTIVE: To investigate how cortical inhibition modulates the effects of PAS. METHODS: PAS at stimulus interval of 21.5 ms conditioned by SICI (SICI-PAS) was compared to PAS alone with both PA and AP directed currents. RESULTS: PAS with both current directions increased cortical excitability. SICI-PAS increased cortical excitability in the PA but not the AP current direction. CONCLUSIONS: Both early and late I-waves circuits can mediate cortical PAS plasticity under different conditions. Plasticity induction with the late but not the early I-wave circuits is blocked by SICI.