Neural effects of continuous theta-burst stimulation in macaque parietal neurons
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Evaluation Summary:
The experiments reported here directly assess the impact of theta burst transcranial magnetic stimulation on neuronal activity. It will be of high potential interest to researchers using non-invasive brain stimulation. Although the results are highly intriguing, several methodological issues limit the inferences that can be drawn from the data as currently presented.
(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. The reviewers remained anonymous to the authors.)
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Abstract
Theta-burst transcranial magnetic stimulation (TBS) has become a standard non-invasive technique to induce offline changes in cortical excitability in human volunteers. Yet, TBS suffers from a high variability across subjects. A better knowledge about how TBS affects neural activity in vivo could uncover its mechanisms of action and ultimately allow its mainstream use in basic science and clinical applications. To address this issue, we applied continuous TBS (cTBS, 300 pulses) in awake behaving rhesus monkeys and quantified its after-effects on neuronal activity. Overall, we observed a pronounced, long-lasting, and highly reproducible reduction in neuronal excitability after cTBS in individual parietal neurons, with some neurons also exhibiting periods of hyperexcitability during the recovery phase. These results provide the first experimental evidence of the effects of cTBS on single neurons in awake behaving monkeys, shedding new light on the reasons underlying cTBS variability.
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Author Response:
Reviewer #1:
Authors reported here the results of two experiments. The first is about the effects of continuous theta burst transcranial magnetic stimulations on single cell responses of lateral parietal cortex of the monkey. This experiment is very challenging, requiring to obtain a stable and long-lasting signal from single cortical neurons and to stimulate constantly the same cell for an hour (they succeded also for longer periods). The paper represents a technical advance in the field and deserves attention and suggests a useful, through difficult, protocol to be replicated by other scientists.
The second experiment tests the behavioral grasp-related effects of two TMS theta burst protocols. Authors demonstrate a long-lasting increase in the grasping time after TMS.
A negative aspect is that the two …
Author Response:
Reviewer #1:
Authors reported here the results of two experiments. The first is about the effects of continuous theta burst transcranial magnetic stimulations on single cell responses of lateral parietal cortex of the monkey. This experiment is very challenging, requiring to obtain a stable and long-lasting signal from single cortical neurons and to stimulate constantly the same cell for an hour (they succeded also for longer periods). The paper represents a technical advance in the field and deserves attention and suggests a useful, through difficult, protocol to be replicated by other scientists.
The second experiment tests the behavioral grasp-related effects of two TMS theta burst protocols. Authors demonstrate a long-lasting increase in the grasping time after TMS.
A negative aspect is that the two experiments are not carried out on the same animals, and the results of the second experiment seem somehow not completely logically connected to the results of the first. Particularly important for the scientific community is the first experiment, that shows that the neural excitability is significantly reduced within the first hour after rTMS. This experiment demonstrated also a variability of effects (hyperexcitation, hypoexcitation, variable delays of recovery), that can be seen as a potential disadvantage in such TMS protocols, and an index of the different effects that may be obtained in the same experiment across subjects.
Overall, the paper represents a step forward in the neuromodulation experiments in nonhuman primates.
Reviewer #2:
Romero and colleagues designed an experiment to describe the neural and behavioral effects of continuous theta burst stimulation with the explicit aim of solving the problem of inter-subject variability of cTBS effects on human behavior. They describe two independent experiments in which cTBS was applied to the inferior parietal lobule of two monkeys per each experiment. In the first experiment the authors measure the activity of single units in response to light-on and to single-pulse TMS (spTMS). In the second experiment the authors describe the effect of cTBS on reaching time in a reach-grasp task. The results indicate a great variability on single neurons that follow different patterns of response to cTBS. In the second experiments the results show a systematic increase in reach-grasp time following cTBS. The authors provide a reasonable description of neuronal activity following their cTBS protocol but do not respond to the main issue of explaining inter-subject variability of human cTBS. The data has the merit of providing neural bases of the "delayed" effects of human cTBS.
We thank Reviewer #2 for his/her comments and for asking us to provide a possible explanation for the inter-subject variability of human cTBS. This has now been added in the Discussion (page 20). ‘The reproducibility of our results was most likely related to the very controlled conditions in which we applied cTBS in monkeys. Most importantly, the TMS coil was rigidly anchored to the head implant of the animal, so that we kept both the position and the orientation of the coil similar across sessions. However, another possibility is that monkeys become highly overtrained in the grasping task, which may partially explain the similar behavioral effects of cTBS we reported in Merken et al. (2021). It is therefore plausible to assume that the larger variability inherent to human behavior is one reason underlying the variability of cTBS effects in humans, since stimulation is applied over a brain area in subjects at different levels of learning stages and behavioral performance, ultimately impacting on the susceptibility of that brain area to cTBS and increasing inter-individual variability of the technique.’
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Evaluation Summary:
The experiments reported here directly assess the impact of theta burst transcranial magnetic stimulation on neuronal activity. It will be of high potential interest to researchers using non-invasive brain stimulation. Although the results are highly intriguing, several methodological issues limit the inferences that can be drawn from the data as currently presented.
(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. The reviewers remained anonymous to the authors.)
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Reviewer #1 (Public Review):
Authors reported here the results of two experiments. The first is about the effects of continuous theta burst transcranial magnetic stimulations on single cell responses of lateral parietal cortex of the monkey. This experiment is very challenging, requiring to obtain a stable and long-lasting signal from single cortical neurons and to stimulate constantly the same cell for an hour (they succeded also for longer periods). The paper represents a technical advance in the field and deserves attention and suggests a useful, through difficult, protocol to be replicated by other scientists.
The second experiment tests the behavioral grasp-related effects of two TMS theta burst protocols. Authors demonstrate a long-lasting increase in the grasping time after TMS.
A negative aspect is that the two experiments are …
Reviewer #1 (Public Review):
Authors reported here the results of two experiments. The first is about the effects of continuous theta burst transcranial magnetic stimulations on single cell responses of lateral parietal cortex of the monkey. This experiment is very challenging, requiring to obtain a stable and long-lasting signal from single cortical neurons and to stimulate constantly the same cell for an hour (they succeded also for longer periods). The paper represents a technical advance in the field and deserves attention and suggests a useful, through difficult, protocol to be replicated by other scientists.
The second experiment tests the behavioral grasp-related effects of two TMS theta burst protocols. Authors demonstrate a long-lasting increase in the grasping time after TMS.
A negative aspect is that the two experiments are not carried out on the same animals, and the results of the second experiment seem somehow not completely logically connected to the results of the first. Particularly important for the scientific community is the first experiment, that shows that the neural excitability is significantly reduced within the first hour after rTMS. This experiment demonstrated also a variability of effects (hyperexcitation, hypoexcitation, variable delays of recovery), that can be seen as a potential disadvantage in such TMS protocols, and an index of the different effects that may be obtained in the same experiment across subjects.
Overall, the paper represents a step forward in the neuromodulation experiments in nonhuman primates.
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Reviewer #2 (Public Review):
Romero and colleagues designed an experiment to describe the neural and behavioral effects of continuous theta burst stimulation with the explicit aim of solving the problem of inter-subject variability of cTBS effects on human behavior. They describe two independent experiments in which cTBS was applied to the inferior parietal lobule of two monkeys per each experiment. In the first experiment the authors measure the activity of single units in response to light-on and to single-pulse TMS (spTMS). In the second experiment the authors describe the effect of cTBS on reaching time in a reach-grasp task. The results indicate a great variability on single neurons that follow different patterns of response to cTBS. In the second experiments the results show a systematic increase in reach-grasp time following …
Reviewer #2 (Public Review):
Romero and colleagues designed an experiment to describe the neural and behavioral effects of continuous theta burst stimulation with the explicit aim of solving the problem of inter-subject variability of cTBS effects on human behavior. They describe two independent experiments in which cTBS was applied to the inferior parietal lobule of two monkeys per each experiment. In the first experiment the authors measure the activity of single units in response to light-on and to single-pulse TMS (spTMS). In the second experiment the authors describe the effect of cTBS on reaching time in a reach-grasp task. The results indicate a great variability on single neurons that follow different patterns of response to cTBS. In the second experiments the results show a systematic increase in reach-grasp time following cTBS. The authors provide a reasonable description of neuronal activity following their cTBS protocol but do not respond to the main issue of explaining inter-subject variability of human cTBS. The data has the merit of providing neural bases of the "delayed" effects of human cTBS.
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