Non-Invasive Cerebellar Stimulation in Neurodegenerative Ataxia: A Literature Review
Round 1
Reviewer 1 Report
In this article, the authors reviewed the findings of non-invasive brain stimulation, including TMS and tDCS, in patients with cerebellar ataxia. In general, the article is well written, covering most of the up-to-date findings and worth publishing.
There are some minor points that can be further tuned.
- There are a few articles that are missing in this review (e.g. Matsugi et al. NeuroReport 2018). There should be a section of which criteria (e.g. key words in Pubmed search) is used to select the papers for review, and which criteria used to exclude (if any) some of the papers (e.g. not enough information about the stimulating protocol).
- The review has a major focus on the therapeutic effect based on plasticity. Section 2.1 also introduces the general principles applicable to the cerebral cortex. However, it should be noted that the mechanism of generating cerebellar plasticity may be very different from those observed from the motor cortex. NMDA-dependent LTP and LTD plasticity changes are based on the experiments of hippocampal slices. The mechanism is very different from those in the cerebellar cortex, which should be appreciated as the first place to document LTD. 1Hz stimulation of parallel fibers (PFs, which are likely to be the stimulated target of TMS) creates NMDAR-independent LTP (e.g. De-Juan Wang et al, JNS 2014). Simultaneous activation of climbing fibers (CF, or Purkinje cell itself) and PFs actually leads to LTD, where similar protocol in the cortex (by paired associated stimulation) typically cause LTP. In general, the direction of plasticity changes by cerebellar stimulation can be very different, or even opposite to the classical view of NMDAR-dependent LTP applicable to the cerebral cortex, given the mechanisms for cerebellar plasticity could be fundamentally different.
Similarly, the plasticity changed by anodal tDCS may be very different. Depolarizing cerebral cortical neurons/dendrites facilitates NMDA-dependent cascade in the post-synaptic side and lead to LTP. However, depolarizing dendrites of the cerebellar Purkinje cells (PCs) leads to post-synaptic silencing of t-type calcium channel, which suppresses the effect of climbing fiber inputs and suppress intrinsic LTD. While anodal tDCS lead to “increased excitability” in both cerebral and cerebellar cortices, the fundamental mechanism could be very different (enhanced LTP and suppressed LTD, respectively).
Based on the mechanism-based point of view. I suggest that there should be sentences in section 2.1 to remind the readers that (r)TMS and tDCS protocols in the cerebellum may exert different effects or induce different cellular cascades from those observed in the cerebral cortex, given the fact that the fundamental mechanism of TMS/tDCS in the cerebellar cortex are not well-studied.
Based on the same concept, I would suggest to rephrase or remove the NMDAR-dependent mechanism mentioned in line 163-165. The mechanism of these plasticity changes in the cerebellum, while not directly test in human, is highly unlikely to be NMDAR-dependent.
- In addition to the function, the cerebellum can show significant structural changes in term of CF-PC and PF-PC wirings (e.g. Kuo et al. Acta Neuropathologica 2017) in cerebellar ataxia and other disorders, and some of wiring features can be rapidly changed within days and affect cerebellar synchronization (e.g. Pan et al Science Translational Medicine 2020). These structural changes may affect the effect of TMS/tDCS and should be considered in the future study. This additional factor could be mentioned in the paragraph of future studies in the discussion.
- Line 107, “…concentrations we significant…”. Please correct the typo.
- Table 1 should include additional information, such as inter-pulse interval and/or details of stimulating trains and stimulating intensity.
Author Response
We thank the Reviewer for his/her comments.
In this article, the authors reviewed the findings of non-invasive brain stimulation, including TMS and tDCS, in patients with cerebellar ataxia. In general, the article is well written, covering most of the up-to-date findings and worth publishing.
There are some minor points that can be further tuned.
There are a few articles that are missing in this review (e.g. Matsugi et al. NeuroReport 2018).
There should be a section of which criteria (e.g. key words in Pubmed search) is used to select the papers for review, and which criteria used to exclude (if any) some of the papers (e.g. not enough information about the stimulating protocol).
R: We agree with the Reviewer and included a paragraph highlighting which criteria were used to select the papers (see lines 61-64) and included the suggested reference.
The review has a major focus on the therapeutic effect based on plasticity. Section 2.1 also introduces the general principles applicable to the cerebral cortex. However, it should be noted that the mechanism of generating cerebellar plasticity may be very different from those observed from the motor cortex. NMDA-dependent LTP and LTD plasticity changes are based on the experiments of hippocampal slices. The mechanism is very different from those in the cerebellar cortex, which should be appreciated as the first place to document LTD. 1Hz stimulation of parallel fibers (PFs, which are likely to be the stimulated target of TMS) creates NMDAR-independent LTP (e.g. De-Juan Wang et al, JNS 2014). Simultaneous activation of climbing fibers (CF, or Purkinje cell itself) and PFs actually leads to LTD, where similar protocol in the cortex (by paired associated stimulation) typically cause LTP. In general, the direction of plasticity changes by cerebellar stimulation can be very different, or even opposite to the classical view of NMDAR-dependent LTP applicable to the cerebral cortex, given the mechanisms for cerebellar plasticity could be fundamentally different.
Similarly, the plasticity changed by anodal tDCS may be very different. Depolarizing cerebral cortical neurons/dendrites facilitates NMDA-dependent cascade in the post-synaptic side and lead to LTP. However, depolarizing dendrites of the cerebellar Purkinje cells (PCs) leads to post-synaptic silencing of t-type calcium channel, which suppresses the effect of climbing fiber inputs and suppress intrinsic LTD. While anodal tDCS lead to “increased excitability” in both cerebral and cerebellar cortices, the fundamental mechanism could be very different (enhanced LTP and suppressed LTD, respectively).
Based on the mechanism-based point of view. I suggest that there should be sentences in section 2.1 to remind the readers that (r)TMS and tDCS protocols in the cerebellum may exert different effects or induce different cellular cascades from those observed in the cerebral cortex, given the fact that the fundamental mechanism of TMS/tDCS in the cerebellar cortex are not well-studied.
Based on the same concept, I would suggest to rephrase or remove the NMDAR-dependent mechanism mentioned in line 163-165. The mechanism of these plasticity changes in the cerebellum, while not directly test in human, is highly unlikely to be NMDAR-dependent.
R: We thank the Reviewer for highlighting this relevant aspect regarding the differences between cerebral and cerebellar stimulation and suggesting pertinent literature to support these effects. We have amended both section 2.1 on TMS (see lines 91-99) and section 3.1 on tDCS (see lines 180-190) to include these fundamental principles.
In addition to the function, the cerebellum can show significant structural changes in term of CF-PC and PF-PC wirings (e.g. Kuo et al. Acta Neuropathologica 2017) in cerebellar ataxia and other disorders, and some of wiring features can be rapidly changed within days and affect cerebellar synchronization (e.g. Pan et al Science Translational Medicine 2020). These structural changes may affect the effect of TMS/tDCS and should be considered in the future study. This additional factor could be mentioned in the paragraph of future studies in the discussion.
R: We agree with the Reviewer and included these relevant aspects in the section on future studies (see lines 339-343).
Line 107, “…concentrations we significant…”. Please correct the typo.
R: We corrected the typo.
Table 1 should include additional information, such as inter-pulse interval and/or details of stimulating trains and stimulating intensity.
R: We included relevant information in Table 1, as suggested (inter-pulse intervals and details regarding stimulating trains and stimulating intensity).
Reviewer 2 Report
In their manuscript, Benussi et al. aim to review the literature available regarding non-invasive stimulation methods in the spinocerebellar ataxias and related disorders. Given that most of the diseases that are in the focus of the review show widespread and progressive neurodegeneration of the central nervous system, any treatment ameliorating the severe symptoms caused by these degenerative processes are more than welcome.
The basic advantage of the transcranial magnetic stimulation and direct current stimulation is their non-invasive nature, which makes them easy to apply in clinical practise. Since the methods have been established fairly recently, a concise review of the existing data ishelpful and relevant.
The review presents the data in a fairly concise manner and is easy to understand. I would recommend to accept the manuscript, with some minor revisions:
Line 32: The spinal cord is fairly frequently affected in the spinocerebellar ataxias, esp. with polyQ background. Damage is mostly done to clarke’s column and ventral motor nuclei. The statement also contradicts the statement on line 214-215, where the authors mention that the spinal cord is actually frequently affected.
Lines 235-245: Has there been any speculation or experiments that might explain the negative results of these experiments? If yes, their discussion would be a worthwhile addition to the review.
Line 253: I think the problem of sham treatment in tDCS is an interesting one. The authors could consider an expansion of this point.
Minor points:
Line 107: Should probably read: “While before rTMS ascorbate free radical concentrations were significantly higher …”
Line 225: “… after 5 sessions of tDCS …”
Author Response
We thank the Reviewer for his/her comments.
In their manuscript, Benussi et al. aim to review the literature available regarding non-invasive stimulation methods in the spinocerebellar ataxias and related disorders. Given that most of the diseases that are in the focus of the review show widespread and progressive neurodegeneration of the central nervous system, any treatment ameliorating the severe symptoms caused by these degenerative processes are more than welcome.
The basic advantage of the transcranial magnetic stimulation and direct current stimulation is their non-invasive nature, which makes them easy to apply in clinical practise. Since the methods have been established fairly recently, a concise review of the existing data is helpful and relevant.
The review presents the data in a fairly concise manner and is easy to understand. I would recommend to accept the manuscript, with some minor revisions:
Line 32: The spinal cord is fairly frequently affected in the spinocerebellar ataxias, esp. with polyQ background. Damage is mostly done to clarke’s column and ventral motor nuclei. The statement also contradicts the statement on line 214-215, where the authors mention that the spinal cord is actually frequently affected.
R: We thank the Reviewer for pointing this out. We have rephrased the sentence as suggested (see lines 32-34).
Lines 235-245: Has there been any speculation or experiments that might explain the negative results of these experiments? If yes, their discussion would be a worthwhile addition to the review.
R: We agree with the Reviewer and added several possible explanations on the negative results observed in the two studies (see lines 272-276).
Line 253: I think the problem of sham treatment in tDCS is an interesting one. The authors could consider an expansion of this point.
R: We included a paragraph on the possible problem of sham tDCS (see lines 277-285).
Minor points:
Line 107: Should probably read: “While before rTMS ascorbate free radical concentrations were significantly higher …”
Line 225: “… after 5 sessions of tDCS …”
R: We have corrected the typos.
