Atlas-informed computational processing pipeline for individual targeting of brain areas for therapeutic navigated transcranial magnetic stimulation

ObjectiveNavigated transcranial magnetic stimulation (nTMS) is targeted at different cortical sites for diagnostic, therapeutic, and neuroscientific purposes. Correct identification of the cortical target areas is important for achieving desired effects, but it is challenging when no direct responses arise upon target area stimulation. We aimed at utilizing atlas-based marking of cortical areas for nTMS targeting to present a convenient, rater-independent method for overlaying the individual target sites with brain anatomy.MethodsWe developed a pipeline, which fits a brain atlas to the individual brain and enables visualization of the target areas during the nTMS session. We applied the pipeline to our previous nTMS data, focusing on depression and schizophrenia patients. Furthermore, we included examples of Tourette syndrome and tinnitus therapies, as well as neurosurgical and motor mappings.ResultsIn depression and schizophrenia patients, the visually selected dorsolateral prefrontal cortex (DLPFC) targets were close to the border between atlas areas A9/46 and A8. In the other areas, the atlas-based areas were in agreement with the treatment targets.ConclusionsThe atlas-based target areas agreed well with the cortical targets selected by experts during the treatments.SignificanceOverlaying atlas information over the navigation view is a convenient and useful add-on for improving nTMS targeting.     

D-cycloserine normalizes long-term motor plasticity after transcranial magnetic intermittent theta-burst stimulation in major depressive disorder

ObjectivesMajor Depressive Disorder (MDD) is associated with glutamatergic alterations, including the N-methyl-D-aspartate receptor (NMDA-R). The NMDA-R plays an important role in synaptic plasticity, and individuals with MDD have been shown to have impairments in repetitive Transcranial Magnetic Stimulation (rTMS) motor plasticity. Here, we test whether D-cycloserine, a NMDA-R partial agonist, can rescue TMS motor plasticity in MDD.MethodsWe conducted randomized double-blind placebo-controlled crossover studies in healthy (n = 12) and MDD (n = 12) participants. We stimulated motor cortex using TMS intermittent theta burst stimulation (iTBS) with placebo or D-cycloserine (100 mg). Motor evoked potentials (MEPs) were sampled before and after iTBS. Stimulus response curves (SRC) were characterized at baseline, +90 minutes, and the following day.ResultsAcute iTBS MEP facilitation is reduced in MDD and is not rescued by D-cycloserine. After iTBS, SRCs shift to indicate sustained decrease in excitability in healthy participants, yet increased in excitability in MDD participants. D-cycloserine normalized SRC changes from baseline to the following day in MDD participants. In both healthy and MDD participants, D-cycloserine stabilized changes in SRC.ConclusionMDD is associated with alterations in motor plasticity that are rescued and stabilized by NMDA-R agonism.SignificanceAgonism of NMDA receptors rescues iTBS motor plasticity in MDD.     

Corticospinal excitability enhancement with simultaneous transcranial near-infrared stimulation and anodal direct current stimulation of motor cortex

ObjectivesNon-invasive brain stimulation (NIBS) is beneficial to many neurological and psychiatric disorders by modulating neuroplasticity and cortical excitability. However, recent studies evidence that single type of NIBS such as transcranial direct current stimulation (tDCS) does not have meaningful clinical therapeutic responses due to their small effect size. Transcranial near-infrared stimulation (tNIRS) is a novel form of NIBS. Both tNIRS and tDCS implement its therapeutic effects by modulating cortical excitability but with different mechanisms. We hypothesized that simultaneous tNIRS and tDCS is superior to single stimulation, leading to a greater cortical excitability.MethodsSixteen healthy subjects participated in a double-blind, sham-controlled, cross-over designed study. Motor evoked potentials (MEPs) were used to measure motor cortex excitability. The changes of MEP were calculated and compared in the sham condition, tDCS stimulation condition, tNIRS condition and the simultaneous tNIRS and anodal tDCS condition.ResultstDCS alone and tNIRS alone both elicited higher MEP after stimulation, while the MEP amplitude in the simultaneous tNIRS and tDCS condition was significantly higher than either tNIRS alone or tDCS alone. The enhancement lasted up to at least 30 minutes after stimulation, indicating simultaneous 820 nm tNIRS with 2 mA anodal tDCS have a synergistic effect on cortical plasticity.ConclusionsSimultaneous application of tNIRS with tDCS produces a stronger cortical excitability effect.SignificanceThe simultaneous tNIRS and tDCS is a promising technology with exciting potential as a means of treatment, neuro-enhancement, or neuro-protection.     

Motor dysfunction in mild cognitive impairment as tested by kinematic analysis and transcranial magnetic stimulation

ObjectivePrevious studies have demonstrated voluntary movement alterations as well as motor cortex excitability and plasticity changes in patients with mild cognitive impairment (MCI). To investigate the pathophysiology of movement abnormalities in MCI, we tested possible relationships between movement abnormalities and primary motor cortex alterations in patients.MethodsFourteen amnestic MCI (aMCI) patients and 16 healthy controls were studied. Cognitive assessment was performed using clinical scales. Finger tapping was recorded by a motion analysis system. Transcranial magnetic stimulation was used to test the input/output curve of motor evoked potentials, intracortical inhibition, and short-latency afferent inhibition. Primary motor cortex plasticity was probed by theta burst stimulation. We investigated correlations between movement abnormalities, clinical scores, and cortical neurophysiological parameters.ResultsMCI patients showed less rhythmic movement but no other movement abnormalities. Cortical excitability measures were normal in patients, whereas plasticity was reduced. Movement rhythm abnormalities correlated with frontal dysfunction scores.ConclusionOur study in MCI patients demonstrated abnormal voluntary movement and plasticity changes, with no correlation between the two. Altered rhythm correlated with frontal dysfunction.SignificanceOur results contribute to the understanding of pathophysiological mechanisms of motor impairment in MCI.     

Effect of repetitive transcranial magnetic stimulation combined with robot-assisted training on wrist muscle activation post-stroke

ObjectiveTo compare the effects of active assisted wrist extension training, using a robotic exoskeleton (RW), with simultaneous 5 Hz (rTMS + RW) or Sham rTMS (Sham rTMS + RW) over the ipsilesional extensor carpi radialis motor cortical representation, on voluntary wrist muscle activation following stroke.MethodsThe two training conditions were completed at least one week apart in 13 participants >1-year post-stroke. Voluntary wrist extensor muscle activation (motor unit (MU) recruitment thresholds and firing rate modulation in a ramp-hold handgrip task), ipsilesional corticospinal excitability (motor evoked potential [MEP] amplitude) and transcallosal inhibition were measured Pre- and Post-training.ResultsFor MUs active both Pre and Post training, greater reductions in recruitment thresholds were found Post rTMS + RW training (p = 0.0001) compared to Sham rTMS + RW (p = 0.16). MU firing rate modulation increased following both training conditions (p = 0.001). Ipsilesional MEPs were elicited Pre and Post in only 5/13 participants. No significant changes were seen in ipsilesional corticospinal excitability and transcallosal inhibition measures (p > 0.05).ConclusionsFollowing a single rTMS + RW session in people >1-year post-stroke, changes were found in voluntary muscle activation of wrist extensor muscles. Alterations in ipsilesional corticospinal or interhemispheric excitability were not detected.SignificanceThe effects of rTMS + RW on muscle activation warrant further investigation as post-stroke rehabilitation strategy.     

Region-dependent bidirectional plasticity in M1 following quadripulse transcranial magnetic stimulation in the inferior parietal cortex

BackgroundThe ability to manipulate the excitability of the network between the inferior parietal lobule (IPL) and primary motor cortex (M1) may have clinical value.ObjectiveTo investigate the possibility of inducing long-lasting changes in M1 excitability by applying quadripulse transcranial magnetic stimulation (QPS) to the IPL, and to ascertain stimulus condition- and site-dependent differences in the effects.MethodsQPS was applied to M1, the primary somatosensory cortex (S1), the supramarginal gyrus (SMG) and angular gyrus (AG) IPL areas, with the inter-stimulus interval (ISI) in the train of pulses set to either 5 ms (QPS-5) or 50 ms (QPS-50). QPS was repeated at 0.2 Hz for 30 min, or not presented (sham condition). Excitability changes in the target site were examined by means of single-pulse transcranial magnetic stimulation (TMS).ResultsQPS-5 and QPS-50 at M1 increased and decreased M1 excitability, respectively. QPS at S1 induced no obvious change in M1 excitability. However, QPS at the SMG induced mainly suppressive effects in M1 for at least 30 min, regardless of the ISI length. Both QPS ISIs at the AG yielded significantly different MEP compared to those at the SMG. Thus, the direction of the plastic effect of QPS differed depending on the site, even under the same stimulation conditions.ConclusionsQPS at the IPL produced long-lasting changes in M1 excitability, which differed depending on the precise stimulation site within the IPL. These results raise the possibility of noninvasive induction of functional plasticity in M1 via input from the IPL.     

Theta-burst versus 20 Hz repetitive transcranial magnetic stimulation in neuropathic pain: A head-to-head comparison

ObjectiveHigh-frequency repetitive transcranial magnetic stimulation (rTMS) has been shown to reduce neuropathic pain, but intermittent “theta-burst” stimulation (iTBS) could be a better alternative because of shorter duration and greater ability to induce cortical plasticity. Here we compared head-to-head the pain-relieving efficacy of the two modalities when applied daily for 5 days to patients with neuropathic pain.MethodsForty-six patients received 20 Hz-rTMS and/or iTBS protocols and 39 of them underwent the full two procedures in a random cross-over design. They rated pain intensity, sleep quality, fatigue and general health status daily during 5 consecutive weeks.ResultsPain relief during the month following stimulation was superior after 20 Hz-rTMS relative to iTBS (F(1,38) = 4.645; p = 0.037). Correlation between respective levels of maximal relief showed a significant deviation toward the 20 Hz-rTMS effect. A greater proportion of individuals responded to 20 Hz-rTMS (52% vs 32%, 95 %CI[0.095–3.27]; p = 0.06), and reports of fatigue significantly improved after 20 Hz-rTMS relative to iTBS (p = 0.01). General health and sleep quality scores did not differentiate both techniques.ConclusionsHigh-frequency rTMS appeared superior to iTBS for neuropathic pain relief.SignificanceAdequate matching between the oscillatory activity of motor cortex and that of rTMS may increase synaptic efficacy, thus enhancing functional connectivity of motor cortex with distant structures involved in pain regulation.     

Probing EEG activity in the targeted cortex after focal transcranial electrical stimulation

BackgroundRecording electroencephalography (EEG) from the targeted cortex immediately before and after focal transcranial electrical stimulation (TES) remains a challenge.MethodsWe introduce a hybrid stimulation-recording approach where a single EEG electrode is inserted into the inner electrode of a double-ring montage for focal TES. The new combined electrode was placed at the C3 position of the EEG 10–20 system. Neuronal activity was recorded in two volunteers before and after 20 Hz alternating-current TES at peak-to-peak intensities of 1 and 2 mA. TES-induced electric field distributions were simulated with SIMNIBS software.ResultsUsing the hybrid stimulation-recording set-up, EEG activity was successfully recorded directly before and after TES. Simulations revealed comparable electrical fields in the stimulated cortex for the pseudomonopolar montage with and without embedded EEG electrode.ConclusionThe hybrid TES-EEG approach can be used to probe after-effects of focal TES on neuronal activity in the targeted cortex.     

Improved object recognition memory using post-encoding repetitive transcranial magnetic stimulation

BackgroundBrain stimulation is known to affect canonical pathways and proteins involved in memory. However, there are conflicting results on the ability of brain stimulation to improve to memory, which may be due to variations in timing of stimulation.HypothesisWe hypothesized that repetitive transcranial magnetic stimulation (rTMS) given following a learning task and within the time period before retrieval could help improve memory.MethodsWe implanted male B6129SF2/J mice (n = 32) with a cranial attachment to secure the rTMS coil so that the mice could be given consistent stimulation to the frontal area whilst freely moving. Mice then underwent the object recognition test sampling phase and given treatment +3, +24, +48 h following the test. Treatment consisted of 10 min 10 Hz rTMS stimulation (TMS, n = 10), sham treatment (SHAM, n = 11) or a control group which did not do the behavior test or receive rTMS (CONTROL n = 11). At +72 h mice were tested for their exploration of the novel vs familiar object.ResultsAt 72-h's, only the mice which received rTMS had greater exploration of the novel object than the familiar object. We further show that promoting synaptic GluR2 and maintaining synaptic connections in the perirhinal cortex and hippocampal CA1 are important for this effect. In addition, we found evidence that these changes were linked to CAMKII and CREB pathways in hippocampal neurons.ConclusionBy linking the known biological effects of rTMS to memory pathways we provide evidence that rTMS is effective in improving memory when given during the consolidation and maintenance phases.     

Acute effects of spaced cathodal transcranial direct current stimulation in drug resistant focal epilepsies

ObjectiveTo evaluate the safety and temporal dynamic of the antiepileptic effect of spaced transcranial direct current stimulation (tDCS) in different focal epilepsies.MethodsCathodal tDCS with individual electrode placement was performed in 15 adults with drug resistant focal epilepsy. An amplitude of 2 mA was applied twice for 9 minutes, with an interstimulation interval of 20 minutes. Tolerability was assessed via the Comfort Rating Questionnaire and the frequency of interictal epileptiform discharges (IEDs) was sequentially compared between the 24 hours before and after tDCS.ResultsTDCS led to a significant reduction in the total number of IEDs/24 h by up to 68% (mean ± SD: −30.4 ± 21.1%, p = 0.001) as well as in seizure frequency (p = 0.041). The maximum IED reduction was observed between the 3rd and 21st hour after stimulation. Favorable clinical response was associated with structural etiology and clearly circumscribed epileptogenic foci but did not differ between frontal and temporal epilepsies. Overall, the tDCS treatment was well tolerated and did not lead to severe adverse events.ConclusionsThe spaced stimulation approach proved to be safe and well-tolerated in patients with drug-resistant unifocal epilepsies, leading to sustained IED and seizure frequency reduction.SignificanceSpaced tDCS induces mediate antiepileptic effects with promising therapeutic potential.     

Prediction of postoperative motor deficits using motor evoked potential deterioration duration in intracranial aneurysm surgery

ObjectiveThe study aimed to investigate the predictive value of motor evoked potential (MEP) deterioration duration for postoperative motor deficits in patients undergoing intracranial aneurysm surgery.MethodsData from 587 patients were reviewed and 92 patients with MEP deterioration were enrolled. MEP deterioration duration was compared between patients with and without postoperative motor deficits. Receiver operating characteristic (ROC) curve analysis was performed to define the threshold value for predicting postoperative motor deficit risk. Additionally, the association between MEP deterioration duration and postoperative CT findings was explored.ResultsPatients with postoperative motor deficits had a significantly longer MEP deterioration duration (p < 0.01). An MEP deterioration duration greater than or equal to 13 min was identified as an independent predictor of immediate (p < 0.01), short-term (p < 0.01), and long-term postoperative motor deficits (p < 0.05). There was no significant association between MEP deterioration duration and new CT abnormalities.ConclusionMEP deterioration duration could be used for predicting intracranial aneurysm surgical outcome.SignificanceThe study first proposed a threshold value of MEP deterioration duration (13 min) for predicting the risk of postoperative motor deficits in patients undergoing intracranial aneurysm surgery.     

Exploring and optimizing the neuroplastic effects of anodal transcranial direct current stimulation over the primary motor cortex of older humans

BackgroundtDCS modulates cortical plasticity and has shown potential to improve cognitive/motor functions in healthy young humans. However, age-related alterations of brain structure and functions might require an adaptation of tDCS-parameters to achieve a targeted plasticity effect in older humans and conclusions obtained from young adults might not be directly transferable to older adults. Thus, our study aimed to systematically explore the association between tDCS-parameters and induced aftereffects on motor cortical excitability to determine optimal stimulation protocols for older individuals, as well as to investigate age-related differences of motor cortex plasticity in two different age groups of older adults.Methods32 healthy, volunteers from two different age groups of Young-Old (50–65 years, n = 16) and Old-Old (66–80 years, n = 16) participated in this study. Anodal tDCS was applied over the primary motor cortex, with respective combinations of three intensities (1, 2, and 3 mA) and durations (15, 20, and 30 min), in a sham-controlled cross-over design. Cortical excitability alterations were monitored by single-pulse TMS-induced MEPs until the next day morning after stimulation.ResultsAll active stimulation conditions resulted in a significant enhancement of motor cortical excitability in both age groups. The facilitatory aftereffects of anodal tDCS did not significantly differ between age groups. We observed prolonged plasticity in the late-phase range for two protocols with the highest stimulation intensity (i.e., 3 mA-20 min, 3 mA-30 min).ConclusionsOur study highlights the role of stimulation dosage in tDCS-induced neuroplastic aftereffects in the motor cortex of healthy older adults and delivers crucial information about optimized tDCS protocols in the domain of the primary motor cortex. Our findings might set the grounds for the development of optimal stimulation protocols to reinstate neuroplasticity in different cortical areas and induce long-lasting, functionally relevant plasticity in normal aging and in pathological conditions, which would require however systematic tDCS titration studies over respective target areas.     

Plastic responsiveness of motor cortex to paired associative stimulation depends on cerebellar input

ObjectiveThe extent of plastic responses of motor cortex (M1) to paired associative stimulation (PAS) varies among healthy subjects. Continuous theta-burst stimulation (cTBS) of cerebellum enhances the mean PAS-induced plasticity in groups of healthy subjects. We tested whether the initial status of Responder or Non -Responder to PAS, influenced the effect of cerebellar stimulation on PAS-induced plasticity.MethodsWe assessed in 19 young healthy volunteers (8 Responders, 11 Non-Responders to PAS), how cTBS and iTBS (intermittent TBS) applied to the cerebellum before a PAS protocol influenced the plastic responsiveness of M1 to PAS. We tested whether the PAS-induced plastic effects could be depotentiated by a short cTBS protocol applied to M1 shortly after PAS and whether cerebellar stimulation influenced GABA-ergic intracortical inhibition and M1 plasticity in parallel.ResultsCerebellar cTBS restored the M1 response to PAS in Non-Responders while cerebellar iTBS turned the potentiating response to PAS to a depressive response in both groups. The depotentiation protocol abolished both responses.ConclusionNon-Responder status to PAS is a state of M1 amenable to bidirectional plastic modulation when primed by a change in cerebello-thalamic drive.SignificanceThe meaning of lack of responsiveness to certain protocols probing plasticity should be reconsidered.     

Differentiating transcranial magnetic stimulation cortical and auditory responses via single pulse and paired pulse protocols: A TMS-EEG study

ObjectiveWe measured the neurophysiological responses of both active and sham transcranial magnetic stimulation (TMS) for both single pulse (SP) and paired pulse (PP; long interval cortical inhibition (LICI)) paradigms using TMS-EEG (electroencephalography).MethodsNineteen healthy subjects received active and sham (coil 90° tilted and touching the scalp) SP and PP TMS over the left dorsolateral prefrontal cortex (DLPFC). We measured excitability through SP TMS and inhibition (i.e., cortical inhibition (CI)) through PP TMS.ResultsCortical excitability indexed by area under the curve (AUC_(25-275ms)) was significantly higher in the active compared to sham stimulation (F(1,18) = 43.737, p < 0.001, η² = 0.708). Moreover, the amplitude of N100-P200 complex was significantly larger (F(1,18) = 9.118, p < 0.01, η² = 0.336) with active stimulation (10.38 ± 9.576 µV) compared to sham (4.295 ± 2.323 µV). Significant interaction effects were also observed between active and sham stimulation for both the SP and PP (i.e., LICI) cortical responses. Finally, only active stimulation (CI = 0.64 ± 0.23, p < 0.001) resulted in significant cortical inhibition.ConclusionThe significant differences between active and sham stimulation in both excitatory and inhibitory neurophysiological responses showed that active stimulation elicits responses from the cortex that are different from the non-specific effects of sham stimulation.SignificanceOur study reaffirms that TMS-EEG represents an effective tool to evaluate cortical neurophysiology with high fidelity.     

Paired-pulse navigated TMS is more effective than single-pulse navigated TMS for mapping upper extremity muscles in brain tumor patients

ObjectiveSingle-pulse navigated transcranial magnetic stimulation (sp-nTMS) is used for presurgical motor mapping in patients with motor-eloquent lesions. However, recently introduced paired-pulse nTMS (pp-nTMS) with biphasic pulses could improve motor mapping.MethodsThirty-four patients (mean age: 56.0 ± 12.7 years, 53.0% high-grade glioma) with motor-eloquent lesions underwent motor mapping of upper extremity representations and nTMS-based tractography of the corticospinal tract (CST) by both sp-nTMS and pp-nTMS with biphasic pulses for the tumor-affected hemisphere before resection.ResultsIn three patients (8.8%), conventional sp-nTMS did not provide motor-positive points, in contrast to pp-nTMS that was capable of generating motor maps in all patients. Good concordance between pp-nTMS and sp-nTMS in the spatial location of motor hotspots and center of gravity (CoG) as well as for CST tracking was observed, with pp-nTMS leading to similar motor map volumes (585.0 ± 667.8 vs. 586.8 ± 204.2 mm³, p = 0.9889) with considerably lower resting motor thresholds (35.0 ± 8.8 vs. 32.8 ± 7.6% of stimulator output, p = 0.0004).ConclusionsPp-nTMS with biphasic pulses may provide motor maps even in highly demanding cases with tumor-affected motor structures or edema, using lower stimulation intensity compared to sp-nTMS.SignificancePp-nTMS with biphasic pulses could replace standardly used sp-nTMS for motor mapping and may be safer due to lower stimulation intensity.     

High frequency oscillations relate to cognitive improvement after epilepsy surgery in children

ObjectiveTo investigate how high frequency oscillations (HFOs; ripples 80–250 Hz, fast ripples (FRs) 250–500 Hz) and spikes in intra-operative electrocorticography (ioECoG) relate to cognitive outcome after epilepsy surgery in children.MethodsWe retrospectively included 20 children who were seizure free after epilepsy surgery using ioECoG and determined their intelligence quotients (IQ) pre- and two years postoperatively. We analyzed whether the number of HFOs and spikes in pre- and postresection ioECoGs, and their change in the non-resected areas relate to cognitive improvement (with ≥ 5 IQ points increase considered to be clinically relevant (=IQ+ group) and < 5 IQ points as irrelevant (=IQ− group)).ResultsThe IQ+ group showed significantly more FRs in the resected tissue (p = 0.01) and less FRs in the postresection ioECoG (p = 0.045) compared to the IQ− group. Postresection decrease of ripples on spikes was correlated with postoperative cognitive improvement (correlation coefficient = −0.62 with p = 0.01).ConclusionsPostoperative cognitive improvement was related to reduction of pathological HFOs signified by removing FR generating areas with subsequently less residual FRs, and decrease of ripples on spikes in the resection edge of the non-resected area.SignificanceHFOs recorded in ioECoG could play a role as biomarkers in the prediction and understanding of cognitive outcome after epilepsy surgery.     

Navigated repetitive transcranial magnetic stimulation improves the outcome of postsurgical paresis in glioma patients – A randomized,double-blinded trial

BackgroundNavigated repetitive transcranial magnetic stimulation (nrTMS) is effective therapy for stroke patients. Neurorehabilitation could be supported by low-frequency stimulation of the non-damaged hemisphere to reduce transcallosal inhibition.ObjectiveThe present study examines the effect of postoperative nrTMS therapy of the unaffected hemisphere in glioma patients suffering from acute surgery-related paresis of the upper extremity (UE) due to subcortical ischemia.MethodsWe performed a randomized, sham-controlled, double-blinded trial on patients suffering from acute surgery-related paresis of the UE after glioma resection. Patients were randomly assigned to receive either low frequency nrTMS (1 Hz, 15 min) or sham stimulation directly before physical therapy for 7 consecutive days. We performed primary and secondary outcome measures on day 1, on day 7, and at a 3-month follow-up (FU). The primary endpoint was the change in Fugl-Meyer Assessment (FMA) at FU compared to day 1 after surgery.ResultsCompared to the sham stimulation, nrTMS significantly improved outcomes between day 1 and FU based on the FMA (mean [95% CI] +31.9 [22.6, 41.3] vs. +4.2 [-4.1, 12.5]; P = .001) and the National Institutes of Health Stroke Scale (NIHSS) (−5.6 [-7.5, −3.6] vs. −2.4 [-3.6, −1.2]; P = .02). To achieve a minimal clinically important difference of 10 points on the FMA scale, the number needed to treat is 2.19.ConclusionThe present results show that patients suffering from acute surgery-related paresis of the UE due to subcortical ischemia after glioma resection significantly benefit from low-frequency nrTMS stimulation therapy of the unaffected hemisphere.Clinical trial registrationLocal institutional registration: 12/15; ClinicalTrials.gov number: NCT03982329