A real electro-magnetic placebo (REMP) device for sham transcranial magnetic stimulation (TMS).

ObjectiveThere is growing interest in neuropsychiatry for repetitive transcranial magnetic stimulation (rTMS) as a neuromodulatory treatment. However, there are limitations in interpreting rTMS effects as a real consequence of physiological brain changes or as placebo-mediated unspecific effects, which may be particularly strong in psychiatric patients. This is due to the fact that existing sham rTMS procedures are less than optimal. A new placebo tool is introduced here, called real electro-magnetic placebo (REMP) device, which can simulate the scalp sensation induced by the real TMS, while leaving both the visual impact and acoustic sensation of real TMS unaltered.MethodsPhysical, neurophysiological and behavioural variables of monophasic and biphasic single-pulse TMS and biphasic 1 Hz and 20 Hz rTMS procedures (at different intensities) were tested in subjects who were expert or naïve of TMS. Results of the real TMS were compared with those induced by the REMP device and with two other currently used sham procedures, namely the commercially available Magstim sham coil and tilting the real coil by 90°.ResultsThe REMP device, besides producing scalp sensations similar to the real TMS, attenuated the TMS-induced electric field (as measured by a dipole probe) to a biologically inactive level. Behaviourally, neither expert nor naïve TMS subjects identified the “coil at 90°” or the “Magstim sham coil” as a real TMS intervention, whilst naïve subjects were significantly more likely to identify the REMP-attenuated TMS as real.ConclusionsThe “goodness of sham” of the REMP device is demonstrated by physical, neurophysiological, and behavioural results.SignificanceSuch placebo TMS is superior to the available sham procedures when applied on subjects naïve to TMS, as in case of patients undergoing a clinical rTMS trial.     

A Near Infra-Red Study of Blood Oxygenation Changes Resulting From High and Low Frequency Repetitive Transcranial Magnetic Stimulation

High and low frequency repetitive transcranial magnetic stimulation (rTMS) are both used to treat major depressive disorder(MDD). However, the physiological mechanisms underlying the therapeutic benefit and the effect of the stimulation frequency are unclear. Twelve healthy participants received 1Hz, 2Hz, and 5Hz active rTMS. Twenty 5 second trains were delivered at left dorsolateral prefrontal cortex at 110% of resting motor threshold with a 25 second inter-train interval. Blood oxygenation (HbO) was significantly reduced following the 1Hz trains compared to the HbO increases observed in both the 2Hz and 5Hz conditions. There was no significant inter-hemispheric difference in response. These results suggest that short trains of high and low frequency rTMS delivered to prefrontal cortex evoke a differential HbO response and provide additional evidence that high frequency trains result in increased neural activity. The findings may provide further explanation for the improved symptoms observed in MDD patients treated with high frequency rTMS.     

Prefrontal theta phase-dependent rTMS-induced plasticity of cortical and behavioral responses in human cortex

BackgroundPrefrontal theta oscillations are involved in neuronal information transfer and retention. Phases along the theta cycle represent varied excitability states, whereby high-excitability states correspond to high-frequency neuronal activity and heightened capacity for plasticity induction, as demonstrated in animal studies. Human studies corroborate this model and suggest a core role of prefrontal theta activity in working memory (WM).Objective/Hypothesis: We aimed at modulating prefrontal neuronal excitability and WM performance in healthy humans, using real-time EEG analysis for triggering repetitive transcranial magnetic stimulation (rTMS) theta-phase synchronized to the left dorsomedial prefrontal cortex.Methods16 subjects underwent 3 different rTMS interventions on separate days, with pulses triggered according to the individual's real-time EEG activity: 400 rTMS gamma-frequency (100 Hz) triplet bursts applied during either the negative peak of the prefrontal theta oscillation, the positive peak, or at random phase. Changes in cortical excitability were assessed with EEG responses following single-pulse TMS, and behavioral effects by using a WM task.ResultsNegative-peak rTMS increased single-pulse TMS-induced prefrontal theta power and theta-gamma phase-amplitude coupling, and decreased WM response time. In contrast, positive-peak rTMS decreased prefrontal theta power, while no changes were observed after random-phase rTMS.ConclusionFindings point to the feasibility of EEG-TMS technology in a theta–gamma phase–amplitude coupling mode for effectively modifying WM networks in human prefrontal cortex, with potential for therapeutic applications.     

Current orientation induced by magnetic stimulation influences a cognitive task

The direction of the current induced by transcranial magnetic stimulation (TMS) over the motor cortex has been observed to influence the threshold and latency of evoked muscle responses. This study investigates the effect of TMS-induced current orientation (ICO) over the prefrontal cortex, on a specific cognitive task (memory-guided saccade). TMS was applied with a figure-of-eight coil, placed at one of eight different orientations over the prefrontal cortex. The most effective ICO was antero-lateral, which is a different optimal ICO from that seen over the hand area of the motor cortex. This demonstrates that ICO can alter the effect of TMS on cognitive functions and that ICO is an independent variable that should not be ignored when designing TMS studies.     

Blood oxygenation changes resulting from trains of low frequency transcranial magnetic stimulation

The evoked responses to transcranial magnetic stimulation (TMS) have been previously demonstrated to be on average greater at the beginning of a session; however the physiological reason for this remains uncertain. In order to investigate a possible hemodynamic mechanism for this phenomenon, changes in oxy-hemoglobin (HbO) following trains of single pulse TMS was investigated using near infra-red spectroscopy (NIRS). TMS was delivered in trains of two and four pulses to left pre-frontal cortex (PFC) at a typical intensity and frequency (.2 Hz) used in neuroscience research. Both trains resulted in significant drops of HbO that remained after the cessation of TMS. The changes observed imply that arterial supply drops following suprathreshold TMS and oxygen consumption outstrips supply, resulting in a net drop of HbO. This study provides evidence that at typical TMS delivery frequencies, local HbO levels remain at a sustained lower level than at the beginning of the session, potentially explaining changes in sensitivity to stimulation with repeated TMS pulses.     

Blood oxygenation changes resulting from suprathreshold transcranial magnetic stimulation

The hemodynamic response to low-intensity transcranial magnetic stimulation (TMS) has previously been demonstrated at motor cortex using near infrared spectroscopy (NIRS). To investigate the effect of TMS on oxy-hemoglobin (HbO) at prefrontal cortex, both subthreshold and suprathreshold TMS relative to resting motor threshold (rMT) were applied at typical intensities used in experimental settings. Although there was no significant change after 90% and 110% rMT TMS, there was a significant drop in HbO after 130% rMT TMS. This drop was maximal at approximately 8 seconds post-TMS. This study may have implications for determining appropriate TMS intensities when stimulating nonmotor areas.     

The Painfulness of Active,but not Sham,Transcranial Magnetic Stimulation Decreases Rapidly Over Time: Results From the Double-Blind Phase of the OPT-TMS Trial

BackgroundDaily left prefrontal repetitive transcranial magnetic stimulation (rTMS) over several weeks is an FDA approved treatment for major depression. Although rTMS is generally safe when administered using the FDA guidelines, there are a number of side effects that can make it difficult for patients to complete a course of rTMS. Many patients report that rTMS is painful, although patients appear to accommodate to the initial painfulness. The reduction in pain is hypothesized to be due to prefrontal stimulation and is not solely explained by accommodation to the stimulation.MethodsIn a recent 4 site randomized controlled trial (using an active electrical sham stimulation system) investigating the antidepressant effects of daily left dorsolateral prefrontal rTMS (Optimization of TMS, or OPT-TMS), the procedural painfulness of TMS was assessed before and after each treatment session. Computerized visual analog scale ratings were gathered before and after each TMS session in the OPT-TMS trial. Stimulation was delivered with an iron core figure-8 coil (Neuronetics) with the following parameters: 10 Hz, 120% MT (EMG-defined), 4 s pulse train, 26 s inter-train interval, 3000 pulses per session, one 37.5 min session per day. After each session, procedural pain (pain at the beginning of the TMS session, pain toward the middle, and pain toward then end of the session) ratings were collected at all 4 sites. From the 199 patients randomized, we had usable data from 142 subjects for the initial 15 TMS sessions (double-blind phase) delivered over 3 weeks (142 × 2 × 15 = 4260 rating sessions).ResultsThe painfulness of real TMS was initially higher than that of the active sham condition. Over the 15 treatment sessions, subjective reports of the painfulness of rTMS (during the beginning, middle and end of the session) decreased significantly 37% from baseline in those receiving active TMS, with no change in painfulness in those receiving sham. This reduction, although greatest in the first few days, continued steadily over the 3 weeks. Overall, there was a decay rate of 1.56 VAS points per session in subjective painfulness of the procedure in those receiving active TMS.DiscussionThe procedural pain of left, prefrontal rTMS decreases over time, independently of other emotional changes, and only in those receiving active TMS. These data suggest that actual TMS stimulation of prefrontal cortex maybe related to the reduction in pain, and that it is not a non-specific accommodation to pain. This painfulness reduction softly corresponds with later clinical outcome. Further work is needed to better understand this phenomenon and whether acute within-session or over time painfulness changes might be used as short-term biomarkers of antidepressant response.     

Unilateral left prefrontal transcranial magnetic stimulation (TMS) produces intensity-dependent bilateral effects as measured by interleaved BOLD fMRI.

Transcranial magnetic stimulation (TMS) administered over the prefrontal cortex has been shown to subtly influence neuropsychological tasks, and has antidepressant effects when applied daily for several weeks. Prefrontal TMS does not, however, produce an immediate easily observable effect, making it hard to determine if one has stimulated the cortex. Most prefrontal TMS studies have stimulated using intensity relative to the more easily determined motor threshold (MT) over motor cortex.Five healthy adults were studied in a 1.5 T MRI scanner during short trains of 1 Hz TMS delivered with a figure eight MR compatible TMS coil followed by rest epochs. In a randomized manner, left prefrontal TMS was delivered at 80%, 100% and 120% of MT interleaved with BOLD fMRI acquisition.Compared to rest, all TMS epochs activated auditory cortex, with 80% MT having no other areas of significant activation. 100% MT showed contralateral activation and 120% MT showed bilateral prefrontal activation. Higher intensity TMS, compared to lower, in general produced more activity both under the coil and contralaterally.Higher prefrontal TMS stimulation intensity produces greater local and contralateral activation. Importantly, unilateral prefrontal TMS produces bilateral effects, and TMS at 80% MT produces only minimal prefrontal cortex activation.     

A randomized, controlled trial of sequential bilateral repetitive transcranial magnetic stimulation for treatment-resistant depression

OBJECTIVE: High-frequency left-side repetitive transcranial magnetic stimulation (rTMS) and low-frequency stimulation to the right prefrontal cortex have both been shown to have antidepressant effects, but doubts remain about the magnitude of previously demonstrated treatment effects. The authors evaluated sequentially combined high-frequency left-side rTMS and low-frequency rTMS to the right prefrontal cortex for treatment-resistant depression. METHOD: The authors conducted a 6-week double-blind, randomized, sham-controlled trial in 50 patients with treatment-resistant depression. Three trains of low-frequency rTMS to the right prefrontal cortex of 140 seconds' duration at 1 Hz were applied daily, followed immediately by 15 trains of 5 seconds' duration of high-frequency left-side rTMS at 10 Hz. Sham stimulation was applied with the coil angled at 45 degrees from the scalp, resting on the side of one wing of the coil. The primary outcome variable was the score on the Montgomery-Asberg Depression Rating Scale. RESULTS: There was a significantly greater response to active than sham stimulation at 2 weeks and across the full duration of the study. A significant proportion of the study group receiving active treatment met response (11 of 25 [44%]) or remission (nine of 25 [36%]) criteria by study end compared to the sham stimulation group (two of 25 [8%] and none of 25 respectively). CONCLUSIONS: Sequentially applying both high-frequency left-side rTMS and low-frequency rTMS to the right prefrontal cortex, has substantial treatment efficacy in patients with treatment-resistant major depression. The treatment response accumulates to a clinically meaningful level over 4 to 6 weeks of active treatment.     

Stimulus Intensity for Hand Held and Robotic Transcranial Magnetic Stimulation

BackgroundTranscranial Magnetic Stimulation (TMS) is based on a changing magnetic field inducing an electric field in the brain. Conventionally, the TMS coil is mounted to a static holder and the subject is asked to avoid head motion. Additionally, head resting frames have been used. In contrast, our robotized TMS system employs active motion compensation (MC) to maintain the correct coil position.Objective/hypothesisWe study the effect of patient motion on TMS. In particular, we compare different coil positioning techniques with respect to the induced electric field.MethodsWe recorded head motion for six subjects in three scenarios: (a) avoiding head motion, (b) using a head rest, and (c) moving the head freely. Subsequently, the motion traces were replayed using a second robot to move a sensor to measure the electric field in the target region. These head movements were combined with 2 types of coil positioning: (1) using a coil holder and (2) using robotized TMS with MC.ResultsAfter 30 min the induced electric field was reduced by 32.0% and 19.7% for scenarios (1a) and (1b), respectively. For scenarios (2a)–(2c) it was reduced by only 4.9%, 1.4% and 2.0%, respectively, which is a significant improvement (P < 0.05). Furthermore, the orientation of the induced field changed by 5.5°, 7.6°, 0.4°, 0.2°, 0.2° for scenarios (1a)–(2c).ConclusionWhile none of the scenarios required rigid head fixation, using a simple holder to position a coil during TMS can lead to substantial deviations in the induced electric field. In contrast, robotic motion compensation results in clinically acceptable positioning throughout treatment.     

Neuronavigation maximizes accuracy and precision in TMS positioning: Evidence from 11,230 distance,angle, and electric field modeling measurements

BackgroundResearchers and clinicians have traditionally relied on elastic caps with markings to reposition the transcranial magnetic stimulation (TMS) coil between trains and sessions. Newer neuronavigation technology co-registers the patient's head and structural magnetic resonance imaging (MRI) scan, providing the researcher with real-time feedback about how to adjust the coil to be on-target. However, there has been no head to head comparison of accuracy and precision across treatment sessions.Objective/Hypothesis: In this two-part study, we compared elastic cap and neuronavigation targeting methodologies on distance, angle, and electric field (E-field) magnitude values.MethodsIn 42 participants receiving up to 50 total accelerated rTMS sessions in 5 days, we compared cap and neuronavigation targeting approaches in 3408 distance and 6816 angle measurements. In Experiment 1, TMS administrators saved an on-target neuronavigation location at Beam F3, which served as the landmark for all other measurements. Next, the operators placed the TMS coil based on cap markings or neuronavigation software to measure the distance and angle differences from the on-target sample. In Experiment 2, we saved each XYZ coordinate of the TMS coil from cap and neuronavigation targeting in 12 participants to compare the E-field magnitude differences at the cortical prefrontal target in 1106 cap and neuronavigation models.ResultsCap targeting was significantly off-target for distance, placing the coil an average of 10.66 mm off-target (Standard error of the mean; SEM = 0.19 mm) compared to 0.3 mm (SEM = 0.03 mm) for neuronavigation (p < 0.0001). Cap targeting also significantly deviated for angles off-target, averaging 7.79 roll/pitch degrees (SEM = 1.07°) off-target and 5.99 yaw degrees (SEM = 0.12°) off-target; in comparison, neuronavigation targeting positioned the coil 0.34 roll/pitch degrees (SEM = 0.01°) and 0.22 yaw (SEM = 0.004°) off-target (both p < 0.0001). Further analyses revealed that there were significant inter-operator differences on distance and angle positioning for F3 (all p < 0.05), but not neuronavigation. Lastly, cap targeting resulted in significantly lower E-fields at the intended prefrontal cortical target, with equivalent E-fields as 110.7% motor threshold (MT; range = 58.3–127.4%) stimulation vs. 119.9% MT (range = 115–123.3%) from neuronavigated targeting with 120% MT stimulation applied (p < 0.001).ConclusionsCap-based targeting is an inherent source of target variability compared to neuronavigation. Additionally, cap-based coil placement is more prone to differences across operators. Off-target coil placement secondary to cap-based measurements results in significantly lower amounts of stimulation reaching the cortical target, with some individuals receiving only 48.6% of the intended on-target E-field. Neuronavigation technology enables more precise and accurate TMS positioning, resulting in the intended stimulation intensities at the targeted cortical level.     

Inter-individual variability in optimal current direction for transcranial magnetic stimulation of the motor cortex

We evaluated inter-individual variability in optimal current direction for biphasic transcranial magnetic stimulation (TMS) of the motor cortex. Motor threshold for first dorsal interosseus was detected visually at eight coil orientations in 45 degrees increments. Each participant (n=13) completed two experimental sessions. One participant with low test-retest correlation (Pearson's r<0.5) was excluded. In four subjects, visual detection of motor threshold was compared to EMG detection; motor thresholds were very similar and highly correlated (0.94-0.99). Similar with previous studies, stimulation in the majority of participants was most effective when the first current pulse flowed towards postero-lateral in the brain. However, in four participants, the optimal coil orientation deviated from this pattern. A principal component analysis using all eight orientations suggests that in our sample the optimal orientation of current direction was normally distributed around the postero-lateral orientation with a range of 63 degrees (S.D.=13.70 degrees). Whenever the intensity of stimulation at the target site is calculated as a percentage from the motor threshold, in order to minimize intensity and side-effects it may be worthwhile to check whether rotating the coil 45 degrees from the traditional posterior-lateral orientation decreases motor threshold.     

Quadri-pulse stimulation induces stimulation frequency dependent cortical hemoglobin concentration changes within the ipsilateral motor cortical network

BackgroundImaging studies investigating repetitive transcranial magnetic stimulation (rTMS) mediated hemodynamic consequences revealed inconsistent results, mainly due to differences in rTMS parameters and technical difficulties with simultaneous recordings during rTMS.Objective/HypothesisQuadri-pulse rTMS (QPS) induces bidirectional long-term plasticity of the human primary motor cortex (M1). To evaluate its on-line effects, near infrared spectroscopy (NIRS) recordings were performed during QPS. We hypothesized that on-line effects during QPS are different from long-term aftereffects.MethodsUsing a novel TMS - on-line multi-channel NIRS setup we recorded hemoglobin concentration [Hb] changes at the stimulated M1 and adjacent sensory-motor areas during QPS protocols inducing oppositely directed aftereffects (QPS-5: interstimulus interval (ISI) 5 ms, potentiation; QPS-50: ISI 50 ms, depression). In two experiments we studied NIRS changes during either single or repeated QPS bursts.ResultsThe repetitive QPS-5 bursts significantly decreased oxyhemoglobin concentration ([oxy-Hb]) in the ipsilateral M1. A single QPS-5 burst decreased [oxy-Hb] in the M1 and premotor cortex. QPS-50 induced no significant NIRS changes at any sites.ConclusionsQPS can significantly alter cortical hemodynamics depending on the stimulation frequency. While bidirectional long-term aftereffects of QPS reflect synaptic efficacy changes, unidirectional on-line effects during QPS may represent pure electrophysiological property changes within the cell membrane or synapse. Since neuronal postexcitatory inhibitory postsynaptic potentials typically peak within the first 10–20 ms, only pulses delivered at higher frequencies may lead to summation of the inhibitory effects, resulting in [oxy-Hb] decrease only after QPS-5. Our new TMS-NIRS setup may be valuable to investigate TMS induced neurovascular coupling mechanisms in humans.     

TMS with fast and accurate electronic control: Measuring the orientation sensitivity of corticomotor pathways

BackgroundTranscranial magnetic stimulation (TMS) coils allow only a slow, mechanical adjustment of the stimulating electric field (E-field) orientation in the cerebral tissue. Fast E-field control is needed to synchronize the stimulation with the ongoing brain activity. Also, empirical models that fully describe the relationship between evoked responses and the stimulus orientation and intensity are still missing.ObjectiveWe aimed to (1) develop a TMS transducer for manipulating the E-field orientation electronically with high accuracy at the neuronally meaningful millisecond-level time scale and (2) devise and validate a physiologically based model describing the orientation selectivity of neuronal excitability.MethodsWe designed and manufactured a two-coil TMS transducer. The coil windings were computed with a minimum-energy optimization procedure, and the transducer was controlled with our custom-made electronics. The electronic E-field control was verified with a TMS characterizer. The motor evoked potential amplitude and latency of a hand muscle were mapped in 3° steps of the stimulus orientation in 16 healthy subjects for three stimulation intensities. We fitted a logistic model to the motor response amplitude.ResultsThe two-coil TMS transducer allows one to manipulate the pulse orientation accurately without manual coil movement. The motor response amplitude followed a logistic function of the stimulus orientation; this dependency was strongly affected by the stimulus intensity.ConclusionThe developed electronic control of the E-field orientation allows exploring new stimulation paradigms and probing neuronal mechanisms. The presented model helps to disentangle the neuronal mechanisms of brain function and guide future non-invasive stimulation protocols.     

Safety of repetitive transcranial magnetic stimulation in patients with implanted cortical electrodes. An ex-vivo study and report of a case

Objective

To evaluate the safety of repetitive transcranial magnetic stimulation (rTMS) in patients with implanted subdural cortical electrodes.

A pragmatic randomized controlled trial exploring the relationship between pulse number and response to repetitive transcranial magnetic stimulation treatment in depression

BackgroundRepetitive transcranial magnetic stimulation treatment (rTMS) is an effective treatment for depression but the optimal methods of administration have yet to be determined. In particular, it is unclear whether there is a relationship between elements of the dose of stimulation (i.e., number of pulses) and clinical response. To address one aspect of dose, we conducted a trial comparing standard and high dose versions of high frequency left sided and low frequency right sided rTMS protocols (left standard = 50 trains, left high = 125 trains, right standard = 20 min, right high = 60 min, all per day in a single session).Method300 patients with treatment resistant depression were enrolled in a four arm randomized controlled trial across a four week time period. The primary outcome assessment was a comparison of response and remission rates on data from the 17-item Hamilton Rating Scale for Depression Rating Scale (HRSD-17).ResultsThe rate of response exceeded 45% in all groups. There was no significant difference between groups on initial analysis of the primary or secondary outcome measures (response rates: standard left = 52.5%, high left = 47.3%, standard right = 49.1%, high right = 48.4%). There was a greater remission rate with high compared to moderate dose left sided treatment when controlling for illness duration. We also found significant improvements in quality of life across all treatment groups. Illness duration was weakly associated with response.ConclusionsThere was no consistent association between the antidepressant effect of rTMS and the number of TMS pulses provided across the ranges investigated in this study. Increasing TMS pulse number in individual sessions seems unlikely to be a method to substantially improve clinical outcomes, and future research should explore alternative means of improving clinical response.The study was registered on the Australian and New Zealand Clinical Trials Register (ACTRN12612000321842) https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=362063&isReview=true.     

Breaks during 5 Hz rTMS are essential for facilitatory after effects

ObjectiveStimulation frequency has been considered the most important factor in conventional repetitive transcranial magnetic stimulation (rTMS) for determining the direction of after effects on corticospinal excitability. Here, we examined the functional relevance of breaks during high-frequency subthreshold rTMS for the induction of facilitatory after effects.MethodsThe after effects on corticospinal excitability of a standard 5 Hz rTMS protocol in a block design were compared to a continuous rTMS protocol using the same number of pulses. In addition the effect of current direction both for rTMS and single pulse TMS was included in the study design.ResultsWhile 5 Hz rTMS in a standard block design induces facilitatory after effects on corticospinal excitability, the continuous protocol does not induce facilitation but rather inhibition. In our study only rTMS using an initially posterior–anterior current direction in the brain leads to significant neuroplastic effects at all.ConclusionsBreaks during conventional high-frequency rTMS are a crucial factor determining the direction of induced neuroplastic changes.SignificanceThese results contribute to the understanding of rTMS-induced neuroplasticity and are important for the design of rTMS protocols both for experimental and clinical studies.     

Significance of coil orientation for motor evoked potentials from nasalis muscle elicited by transcranial magnetic stimulation.

OBJECTIVE: In transcranial magnetic stimulation (TMS) of the motor cortex, the optimal orientation of the coil on the scalp is dependent on the muscle under investigation, but not yet known for facial muscles. METHODS: Using a figure-of-eight coil, we compared TMS induced motor evoked potentials (MEPs) from eight different coil orientations when recording from ipsi- and contralateral nasalis muscle. RESULTS: The MEPs from nasalis muscle revealed three components: The major ipsi- and contra-lateral middle latency responses of approximately 10 ms onset latency proved entirely dependent on voluntary pre-innervation. They were most easily obtained from a coil orientation with posterior inducing current direction, and in this respect resembled the intrinsic hand rather than the masseter muscles. Early short duration responses of around 6 ms onset latency were best elicited with an antero-lateral current direction and not pre-innervation dependent, and therefore most probably due to stimulation of the nerve roots. Late responses (>18 ms) could inconsistently be elicited with posterior coil orientations in pre-innervated condition. CONCLUSIONS: By using the appropriate coil orientation and both conditions relaxed and pre-innervated, cortically evoked MEP responses from nasalis muscle can reliably be separated from peripheral and reflex components and also from cross talk of masseter muscle activation.     

Opposite Optimal Current Flow Directions for Induction of Neuroplasticity and Excitation Threshold in the Human Motor Cortex

BackgroundDirectional sensitivity is relevant for the excitability threshold of the human primary motor cortex, but its importance for externally induced plasticity is unknown.ObjectiveTo study the influence of current direction on two paradigms inducing neuroplasticity by repetitive transcranial magnetic stimulation (rTMS).MethodsWe studied short-lasting after-effects induced in the human primary motor cortex of 8 healthy subjects, using 5 Hz rTMS applied in six blocks of 200 pulses each, at 90% active motor threshold. We controlled for intensity, frequency, waveform and spinal effects.ResultsOnly biphasic pulses with the effective component delivered in an anterioposterior direction (henceforth posteriorly directed) in the brain yielded an increase of motor-evoked potential (MEP) amplitudes outlasting rTMS. MEP latencies and F-wave amplitudes remained unchanged. Biphasic pulses directed posteroanterior (i.e. anteriorly) were ineffective, as were monophasic pulses from either direction. A 1 Hz study in a group of 12 healthy subjects confirmed facilitation after posteriorly directed biphasic pulses only.ConclusionsThe anisotropy of the human primary motor cortex is relevant for induction of plasticity by subtreshold rTMS, with a current flow opposite to that providing lowest excitability thresholds. This is consistent with the idea of TMS primarily targeting cortical columns of the phylogenetically new M1 in the anterior bank of the central sulcus. For these, anteriorly directed currents are soma-depolarizing, therefore optimal for low thresholds, whereas posteriorly directed currents are soma-hyperpolarizing, likely dendrite-depolarizing and bested suited for induction of plasticity. Our findings should help focus and enhance rTMS effects in experimental and clinical settings.     

Daily prefrontal closed-loop repetitive transcranial magnetic stimulation (rTMS) produces progressive EEG quasi-alpha phase entrainment in depressed adults

BackgroundTranscranial magnetic stimulation (TMS) is a non-invasive neuromodulation modality that can treat depression, obsessive-compulsive disorder, or help smoking cessation. Research suggests that timing the delivery of TMS relative to an endogenous brain state may affect efficacy and short-term brain dynamics.ObjectiveTo investigate whether, for a multi-week daily treatment of repetitive TMS (rTMS), there is an effect on brain dynamics that depends on the timing of the TMS relative to individuals’ prefrontal EEG quasi-alpha rhythm (between 6 and 13 Hz).MethodWe developed a novel closed-loop system that delivers personalized EEG-triggered rTMS to patients undergoing treatment for major depressive disorder. In a double blind study, patients received daily treatments of rTMS over a period of six weeks and were randomly assigned to either a synchronized or unsynchronized treatment group, where synchronization of rTMS was to their prefrontal EEG quasi-alpha rhythm.ResultsWhen rTMS is applied over the dorsal lateral prefrontal cortex (DLPFC) and synchronized to the patient's prefrontal quasi-alpha rhythm, patients develop strong phase entrainment over a period of weeks, both over the stimulation site as well as in a subset of areas distal to the stimulation site. In addition, at the end of the course of treatment, this group's entrainment phase shifts to be closer to the phase that optimally engages the distal target, namely the anterior cingulate cortex (ACC). These entrainment effects are not observed in the group that is given rTMS without initial EEG synchronization of each TMS train.ConclusionsThe entrainment effects build over the course of days/weeks, suggesting that these effects engage neuroplastic changes which may have clinical consequences in depression or other diseases.