Rethinking the role of sham TMS

Sham TMS approaches are widely used in basic and clinical research to ensure that observed effects are due to the intended neural manipulation instead of being caused by various possible side effects. We here critically discuss several methodological aspects of sham TMS. Importantly, we propose to carefully distinguish between the placebo versus sensory side effects of TMS. In line with this conceptual distinction, we describe current limitations of sham TMS approaches in the context of placebo effects and blinding success, followed by a short review of our own work demonstrating that the sensory side effects of sham TMS are not unspecific as often falsely assumed. Lastly, we argue that sham TMS approaches are inherently insufficient as full-fledged control conditions as they fail to demonstrate the specificity of TMS effects to a particular brain area or time point of stimulation. Sham TMS should therefore only complement alternative control strategies in TMS research

Continuous theta burst stimulation increases contralateral mu and beta rhythms with arm elevation:implications for neurorehabilitation

The study of the physiological effects underlying brain response to transcranial magnetic stimulation is important to understand its impact on neurorehabilitation. We aim to analyze the impact of a transcranial magnetic stimulation protocol, the continuous theta burst (cTBS), on human neurophysiology, particularly on contralateral motor rhythms. cTBS was applied in 20 subjects over the primary motor cortex. We recorded brain electrical activity pre- and post-cTBS with electroencephalography both at rest and while performing motor tasks, to evaluate changes in brain oscillatory patterns such as mu and beta rhythms. Moreover, we measured motor-evoked potentials before and after cTBS to assess its impact on brain's excitability. On the hemisphere contralateral to the protocol, we did observe a significant increase in mu (p = 0.027) and beta (p = 0.006) rhythms from pre- to post-cTBS, at the beginning of arm elevation. The topology of action planning and motor execution suggests that cTBS produced an inhibitory effect that propagated to the contralateral hemisphere, thereby precluding the expected/desired excitation for therapy purposes. This novel approach provides support for the notion that this protocol induces inhibitory changes in contralateral motor rhythms, by decreasing desynchronization, contradicting the ipsilateral inhibition vs. contralateral disinhibition hypothesis. Our results have implications for personalized cTBS usage as a rehabilitation intervention, suggesting that an unexpected propagation of inhibition can occur

Where Are the fMRI Correlates of Phosphene Perception?

Pulses of transcranial magnetic stimulation (TMS) over occipital cortex can induce transient visual percepts called phosphenes. Phosphenes are an interesting stimulus for the study of the human visual system, constituting conscious percepts without visual inputs, elicited by neural activation beyond retinal and subcortical processing stages in the visual hierarchy. The same TMS pulses, applied at threshold intensity phosphene threshold (PT), will prompt phosphene reports on half of all trials (“P-yes”) but not on the other half (“P-no”). Contrasting brain activity (P-yes > P-no) can provide unique information on neural mechanisms underlying conscious percepts, as has been demonstrated by published EEG studies. Yet to our knowledge no articles reporting analogous contrasts with functional magnetic resonance imaging (fMRI) have been published. Since it seems unlikely that such studies have never been performed, this straightforward and technically feasible idea may have been explored in multiple failed, and unpublished, attempts. Here, we argue why such unsuccessful attempts, even small-scale, best be shared. We also report our own failed attempt to find phosphene-related activity in fMRI. Threshold phosphenes are weak percepts, and their detection subjective and difficult. If fMRI correlates of phosphenes are obtainable with this contrast, small-scale (‘pilot’) measurements may not be sufficiently powerful to detect them. At the same time, due to the challenges and costs involved in TMS-fMRI, attempts might not often get beyond the piloting stage. We propose that the only way out of this quandary is the communication and sharing of such unsuccessful attempts and associated data

Top-down control of visual cortex by the frontal eye fields through oscillatory realignment

Voluntary allocation of visual attention is controlled by top-down signals generated within the Frontal Eye Fields (FEFs) that can change the excitability of lower-level visual areas. However, the mechanism through which this control is achieved remains elusive. Here, we emulated the generation of an attentional signal using single-pulse transcranial magnetic stimulation to activate the FEFs and tracked its consequences over the visual cortex. First, we documented changes to brain oscillations using electroencephalography and found evidence for a phase reset over occipital sites at beta frequency. We then probed for perceptual consequences of this top-down triggered phase reset and assessed its anatomical specificity. We show that FEF activation leads to cyclic modulation of visual perception and extrastriate but not primary visual cortex excitability, again at beta frequency. We conclude that top-down signals originating in FEF causally shape visual cortex activity and perception through mechanisms of oscillatory realignment

A First-in-human, Dose-escalation Study of the Methionine Aminopeptidase 2 Inhibitor M8891 in Patients with Advanced Solid Tumors

Methionine aminopeptidase 2 (MetAP2) is essential to endothelial cell growth and proliferation during tumor angiogenesis. M8891 is a novel orally bioavailable, potent, selective, reversible MetAP2 inhibitor with antiangiogenic and antitumor activity in preclinical studies. The safety, tolerability, pharmacokinetics, and pharmacodynamics of M8891 monotherapy were assessed in a phase I, first-in-human, multicenter, open-label, single-arm, dose-escalation study (NCT03138538). Patients with advanced solid tumors received 7-80 mg M8891 once daily in 21-day cycles. The primary endpoint was dose-limiting toxicity (DLT) during cycle 1, with the aim to determine the maximum tolerated dose (MTD). Twenty-seven patients were enrolled across six dose levels. Two DLTs (platelet count decrease) were reported, one each at 60 and 80 mg/once daily M8891, resolving after treatment discontinuation. MTD was not determined. The most common treatment-emergent adverse event was platelet count decrease. M8891 plasma concentration showed dose-linear increase up to 35 mg and low-to-moderate variability; dose-dependent tumor accumulation of methionylated elongation factor 1α, a MetAP2 substrate, was observed, demonstrating MetAP2 inhibition. Pharmacokinetic/pharmacodynamic response data showed that preclinically defined target levels required for in vivo efficacy were achieved at safe, tolerated doses. Seven patients (25.9%) had stable disease for 42-123 days. We conclude that M8891 demonstrates a manageable safety profile, with dose-proportional exposure and low-to-moderate interpatient variability at target pharmacokinetic/pharmacodynamic levels at ≤35 mg M8891 once daily. On the basis of the data, 35 mg M8891 once daily is the recommended phase II dose for M8891 monotherapy. This study forms the basis for future development of M8891 in monotherapy and combination studies. SIGNIFICANCE: M8891 represents a novel class of reversible MetAP2 inhibitors and has demonstrated preclinical antitumor activity. This dose-escalation study assessed M8891 treatment for patients with advanced solid tumors. M8891 demonstrated favorable pharmacokinetics, tumoral target engagement, and a manageable safety profile, and thus represents a novel antitumor strategy warranting further clinical studies

Assessing the Functional Role of Frontal Eye Fields in Voluntary and Reflexive Saccades Using Continuous Theta Burst Stimulation

The frontal eye fields (FEFs) are core nodes of the oculomotor system contributing to saccade planning, control, and execution. Here, we aimed to reveal hemispheric asymmetries between left and right FEF in both voluntary and reflexive saccades toward horizontal and vertical targets. To this end, we applied fMRI-guided continuous theta burst stimulation (cTBS) over either left or right FEF and assessed the consequences of this disruption on saccade latencies. Using a fully counterbalanced within-subject design, we measured saccade latencies before and after the application of cTBS in eighteen healthy volunteers. In general, saccade latencies on both tasks were susceptible to our experimental manipulations, that is, voluntary saccades were slower than reflexive saccades, and downward saccades were slower than upward saccades. Contrary to our expectations, we failed to reveal any TMS-related effects on saccade latencies, and Bayesian analyses provided strong support in favor of a TMS null result for both tasks. Keeping in mind the interpretative challenges of null results, we discuss possible explanations for this absence of behavioral TMS effects, focusing on methodological differences compared to previous studies (task parameters and online vs. offline TMS interventions). We also speculate about what our results might reveal about the functional role of FEF.PubMedWo

No effects of rhythmic visual stimulation on target discrimination:an online alpha entrainment experiment

Previous research established that rhythmic sensory stimulation can affect subsequent stimulus perception, possibly through 'entrainment' of oscillations in the brain. Alpha frequency is a natural target for visual entrainment, since fluctuations in posterior alpha oscillations have been linked to visual target detection or discrimination. On the other hand, alpha oscillations also relate to attentional mechanisms, such as attentional orienting or selection. Previous visual alpha entrainment studies focused on differential processing of targets presented in-phase with the preceding rhythmic stimulation relative to out-of-phase targets (an 'SOA effect'), putatively related to the phase of entrained neuronal alpha oscillations. Fewer studies probed the consequences of rhythmic alpha stimulation for attention mechanisms related to alpha power. Here we asked whether alpha-stimulation of one hemifield has similar effects on reaction times as we see for increased alpha-synchronization in M/EEG studies (i.e. more alpha means impaired processing; functional inhibition). We implemented a task inspired by attention studies, assessing reaction times to ipsilateral versus contralateral visual targets, with and without concurrent presentation of distractors. Yet, in place of any attention cues, we presented a rhythmic, versus arrhythmic, alpha-frequency train of visual flashes to one hemifield, in a large sample size (N=115) in an online experiment. We found clear evidence that flash train rhythmicity did not impact task performance. We also found that the spatial congruence between the unilateral flash train and the subsequent visual target did impact response times, but only in the presence of contralateral distractor stimuli. We discuss implications, limitations, and future directions

The effect of TMS coil position on mean reaction time.

<p>The clicking sound of a TMS pulse caused a shift of covert spatial attention to the corresponding side of space thereby facilitating target detection. Error bars show the standard error of the mean.</p