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  1. Evaluation Summary:

    This manuscript presents a novel EEG-based, real-time feedback approach that enables healthy participants to independently self-regulate excitability of the left versus the right hemisphere. Using this unique approach, the authors demonstrate that their paradigm could have the potential to modulate the neural interplay between both hemispheres which is relevant for the field of neurorehabilitation.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #2 agreed to share their name with the authors.)

  2. Reviewer #1 (Public Review):

    The authors aimed to develop a new method for modulating interhemispheric inhibition (IHI) between the sensorimotor cortices. They present and validate a highly sophisticated neurofeedback approach that has a strong neuromodulatory effect on IHI. I'm not aware that such strong effects can be obtained with any other neuromodulatory tool that is currently available.

    This study is well powered, very thoroughly executed and it reveals interesting new insights into how interhemispheric inhibition changes as a function of self-regulating unilateral sensorimotor activity. As such it provides an interesting new approach for neuromodulation which might provide new treatment opportunities, for example, in patients suffering from a unilateral stroke.

    One weakness is that the authors did not yet test whether changes in interhemispheric inhibition and changes in corticomotor excitability are independent phenomena. This does not allow them to dissociate whether the participants learned to specifically modulate neural circuits regulating interhemispheric inhibition (as claimed by the authors) or rather unilateral excitability in general. Thus, while the authors achieved their aim at the phenomenological level, their interpretation regarding the specific neurobiological underpinnings is rather speculative. This is, however, important for designing evidence-based interventions for stroke recovery.

    The manuscript would further benefit from editing the results section and modifying some of the figures to make it more accessible for the reader.

  3. Reviewer #2 (Public Review):

    The study by Ushiba et al. directly demonstrates that volitional control of motor cortical activation patterns using a brain-computer interface influences the strength of interhemispheric interaction in the motor system. Specifically, using non-invasive EEG, Ushiba et al. recorded electrical activity from neurons in the sensorimotor cortex in real-time, and provided information about the bilateral activation of the motor cortex to users on a computer screen, a process known as "neurofeedback". This allowed users to learn to modify the motor cortex activation patterns using their own volition, during states of high and low activation (relative to the contralateral hemisphere). By concurrently stimulating the motor cortex using magnetic pulses (TMS), Ushiba et al were able to show that states of higher relative ipsilateral cortical activation were associated with significantly lower levels of inhibition between the bilateral motor cortices.

    The authors use common neuroscience techniques such as TMS and EEG, but they are deployed in combination and in real-time, making this study a technical masterwork. Moreover, statistically significant effects were achieved compared to rigorous control conditions, by analysing random trials when TMS stimuli were triggered without provision of neurofeedback and/or independent of successful neurofeedback control.

    Nevertheless, even though the study clearly demonstrates that interhemispheric inhibition (IHI) may be influenced by neurofeedback, it does so only in the direction for decreasing IHI relative to baseline. Future studies will be needed to ascertain if a similar setup may also be used to successfully upregulate (i.e. increase) IHI.

    Finally, although a number of previous studies indicate that IHI may be a relevant prognostic marker of motor recovery in clinical populations (e.g. patients with stroke), future work will need to explore more directly the links between IHI self-regulation and its impact, if any, on motor rehabilitation outcomes.

  4. Reviewer #3 (Public Review):

    In this study, healthy participants imagine moving their right index finger and receive neurofeedback of their oscillatory brain activity. They learn to up-and down-regulate the oscillations in the right motor cortex, and thereby its responsiveness to transcranial magnetic stimulation (TMS). Whenever the brain activity in the right motor cortex is desynchronized, i.e., more responsive, TMS to the right motor cortex induces a stronger effect on the left motor cortex, which is probed by TMS as well. In those participants who can better regulate the oscillations in the right motor cortex during the task, TMS of the right hemisphere induces a stronger effect on the left motor cortex already before the task at rest.

    This study successfully demonstrates that human subjects can volitionally control ipsilateral sensorimotor excitability (measured as sensorimotor rhythm event-related desynchronization or SMR-ERD) with the aid of brain computer interface (BCI)-based neurofeedback. The approach is innovative since it provides neurofeedback with regard to brain activity in both hemispheres independently. Furthermore, this study shows that the participants learn to both up-and down-regulate the ipsilateral brain activity; this modifies the ipsilateral hemisphere's responsiveness to a TMS pulse, which in turn changes also the responsiveness of the opposite brain hemisphere to a second TMS pulse (thereby applying a classical dual-coil paired-pulse protocol). It is important that another measure of interhemispheric interactions is applied as well, namely an oscillatory coherence measure. Interestingly, the paired-pulse TMS effects before the task at rest correspond to the interhemispheric coherence at rest, and to the paired-pulse TMS effects and the ipsilateral SMR-ERD during the task.

    Up- and down-regulating the oscillations in the right motor cortex has not led to a corresponding change in interhemispheric coherence (Figure 5D). Therefore, no conclusions with regard to interhemispheric "rebalancing" can be drawn. Moreover, "rebalancing" would indicate an "unbalanced" starting point, which is not the case in the examined healthy participants. The paired-pulse TMS effects can be explained by the modulated responsiveness of the right motor cortex: The more excitable the right motor cortex (i.e., the more SMR-ERD), the stronger its responsiveness to TMS, the stronger the impact of this first (conditioning) TMS pulse on the opposite hemisphere, the less responsive is the opposite hemisphere to the second (test) TMS pulse. This observation is in line with the well-established finding in the literature that this interhemispheric inhibition (IHI) is a stimulation intensity-dependent phenomenon of the first (conditioning) TMS pulse, which is also demonstrated in this study (Figure 2B); the neurofeedback task is achieving a similar effect (Figure 3 suppl 1; Figure 5B) without the necessity to modify the stimulation intensity of the conditioning pulse. This effect is however not achieved by changing the interhemispheric coherence (Figure 5D).

    Moreover, the statistical analysis should only compare the latter three conditions (high, middle, low) that have been randomized, to avoid order effects due to cumulative TMS pulses.

    It remains an open question, whether the more sophisticated neurofeedback approach (of modulating both hemispheres separately) was indeed necessary to achieve the findings of this work.

    The supplementary findings (Figure 6 Suppl 1) underline the necessity to investigate other frequency bands as well with regard to the ERD findings/correlation (Figure 4, 5, 6) to confirm the frequency-specificity of the neurofeedback task.