Taking Sides: Asymmetries in the Evolution of Human Brain Development in Better Understanding Autism Spectrum Disorder

Round 1

Reviewer 1 Report

Taking Sides: Asymmetries in the Evolution of Hu​m​an​ ​Brain Development ​in Better Understanding Autism Spectrum Disorder

Summary

The authors review the literature on brain lateralization and autism spectrum disorder (ASD). Additionally, they give background information on lateralization from an evolutionary perspective. They present multiple instances where ASD is associated with atypical lateralization patterns.

General concept comments

The manuscript has an interesting narrative and is generally easy to follow. Additionally, the angle seems to fit the scope of the journal excellently. The English is generally good, however there are a decent number of typos, redundant words, and grammatical errors, especially in the latter half of the manuscript. A careful proofreading is recommended. The conclusion that atypical lateralization appears in individuals with ASDs is well supported by the literature. The conclusion that functional atypicality can promote structural lateralization was not as clearly supported and requires clarification.

Specific comments:

1) Sentence starting from line 95: Citation? In current formulation it’s unclear whether it also refers to reference 34.

2) Line 187: it would be beneficial to make clear which way the hemisphere dominance (typically) shifts during early life. From right dominance to left dominance?

3) Line 471: the meaning of the last part of the sentence is unclear: “…manifested as right sided sensory input and motor output and vice versa”. What does vice versa mean in this context? Also, it would be beneficial to always specify whether “right side” is referring to the brain or to the body, as they lead to opposite interpretations of hemispheric differences.

4) Line 482: acolossal should be acallosal, which may also be an unnecessarily complex term and redundant here considering that it basically means the same as split-brain. Furthermore, studying CC connections in people who lack the CC doesn’t make sense. This sentence should be rephrased to describe the previous findings more accurately.

5) Line 491: smaller size of the CC in ASD?

6) Regarding the chapter starting from line 496 (Corpus Callosum Asymmetry) generally: it isn’t clearly explained what CC asymmetry means. Difference in size of the left and right extremes of the CC? Different diffusion metrics in the white matter tracts going through the CC? Differences in activation between the hemispheres in regions connected via the CC? In addition, things that don’t seem to fit the term, such as local over-connectivity within the frontal lobes, are discussed in this chapter, making the definition of the term “CC asymmetry” even more confusing.

7) Paragraph starting on line 586: can you add references?

8) Line 655: misspelled Iain McGilchrist.

9) Line 732-734: “We have proposed that early developed structural atypicality is associated with functional atypicality which, in turn, can then promote abnormal structural lateralization”. While the authors state before that they simply do not know which came first, structure or function, this statement seems to indicate that functional atypicality can lead to or at least accentuate structural lateralization. The case for this was not made very clear in the article. It could be useful to have a subsection to specifically discuss what is known about the direction of the effects, even if it is very limited. If there is no relevant research, I suggest this statement is removed from conclusions and from the abstract.

Author Response

General concept comments

The manuscript has an interesting narrative and is generally easy to follow. Additionally, the angle seems to fit the scope of the journal excellently. The English is generally good, however, there are a decent number of typos, redundant words, and grammatical errors, especially in the latter half of the manuscript. A careful proofreading is recommended.

I thank the reviewer for the positive general impression of the ms. The typos have been corrected and a more careful rereading of the ms. has been done.

The conclusion that atypical lateralization appears in individuals with ASDs is well supported by the literature. The conclusion that functional atypicality can promote structural lateralization was not as clearly supported and requires clarification.

That functional atypicality can promote structural lateralization has been more supported by additions to the ms.

Specific comments:

1) Sentence starting from line 95: Citation? In current formulation it’s unclear whether it also refers to reference 34.

The Neubauer reference has been moved for clarity as suggested.

2) Line 187: it would be beneficial to make clear which way the hemisphere dominance (typically) shifts during early life. From right dominance to left dominance?

The qualification has been added to line 187.

3) Line 471: the meaning of the last part of the sentence is unclear: “…manifested as right-sided sensory input and motor output and vice versa”. What does vice versa mean in this context?

Thanks for pointing out the lack of clarity. The sentence on line 476 has been modified to read "right-sided sensory input and bilateral motor output."

Also, it would be beneficial to always specify whether “right side” is referring to the brain or to the body, as they lead to opposite interpretations of hemispheric differences.

Good point! This has now been done throughout.

4) Line 482: acolossal should be acallosal, which may also be an unnecessarily complex term and redundant here considering that it basically means the same as split-brain. Furthermore, studying CC connections in people who lack the CC doesn’t make sense. This sentence should be rephrased to describe the previous findings more accurately.

The sentence on 475 has been revised and hopefully makes more sense. The literature has examined the effects of those born with agenesis of the corpus callosum as distinct from individuals who have undergone split-brain later in life. The sentence now reflects that distinction and is hopefully clearer.

5) Line 491: smaller size of the CC in ASD?

Correct and the sentence has been modified accordingly now on line 495.

6) Regarding the chapter starting from line 496 (Corpus Callosum Asymmetry) generally: it isn’t clearly explained what CC asymmetry means. Difference in size of the left and right extremes of the CC? Different diffusion metrics in the white matter tracts going through the CC? Differences in activation between the hemispheres in regions connected via the CC? In addition, things that don’t seem to fit the term, such as local over-connectivity within the frontal lobes, are discussed in this chapter, making the definition of the term “CC asymmetry” even more confusing.

I think that the opening paragraph has been cleaned up. It now reads, "In attempting to explain why these clinical associations are present, Belmonte et al.[175] and Courchesne and Pierce [176] argued that fundamental deficits in ASD are associated with diminished long-range connectivities between the frontal lobes and other brain systems, and to local over-connectivity within the frontal lobes. According to these investigators, superficial white matter tracts associated with cortico-cortical fiber enlargement and CC volume are reduced. When taken together, along with deviations of cerebellar and cerebral white matter,  and cerebellar vermis size, can distinguish 95% of autistic toddlers and young children from neurotypical children, and also accurately predict whether a young child with autism will have a low or high-functioning developmental outcome.

7) Paragraph starting on line 586: can you add references?

This has been done now on line 593.

8) Line 655: misspelled Iain McGilchrist.

Whoops! Corrected.

9) Line 732-734: “We have proposed that early developed structural atypicality is associated with functional atypicality which, in turn, can then promote abnormal structural lateralization”. While the authors state before that they simply do not know which came first, structure or function, this statement seems to indicate that functional atypicality can lead to or at least accentuate structural lateralization. The case for this was not made very clear in the article. It could be useful to have a subsection to specifically discuss what is known about the direction of the effects, even if it is very limited. If there is no relevant research, I suggest this statement is removed from conclusions and from the abstract.

I have removed this from the ms and this question is presently being examined.

Author Response File: Author Response.docx

Reviewer 2 Report

The article deals with the origins of ASD - what is primary: anatomical changes or functional ones? Many approaches and theories are considered in the article, all found sources are systematized and build together one logic of presentation.

I have a few thoughts on the article revisions.

The question of brain asymmetry is well enough elaborated for the problem of the functioning and development of language functions. The authors could touch upon the aspect of asymmetry in the context of language in more detail and with references. For example, in lines 48, 77-78, and 343. Authors can cite the papers concerning brain symmetry during language acquisition.

For both language and cognitive functions (which can be affected by ASD), both brain cerebral asymmetry and functional hemispheric asymmetry (which varies with body condition and task performed) can be important. Lines 134-143 can indicate that functional asymmetry and symmetry are markers of successful language acquisition and that they are dynamic rather than static phenomena.  Language is important, as people with ASD usually have problems with communication. And here again the question arises - what is primary?

For the subject of ASD, the findings that artificial removal of asymmetry in symmetrical brain areas in some animals is detrimental both for emotional and for cognitive performance seem important.

Author Response

The question of brain asymmetry is well enough elaborated for the problem of the functioning and development of language functions. The authors could touch upon the aspect of asymmetry in the context of language in more detail and with references. For example, in lines 48, 77-78, and 343. Authors can cite the papers concerning brain symmetry during language acquisition.

This has been done and thanks for the suggestion. The connection between the corpus callosum, language, and asymmetries in ASD is now represented.  Rather than cite the myriad of papers on the subject review/structured-review papers have now been referenced and may be found in the revised marked ms. between lines 649-687.

For both language and cognitive functions (which can be affected by ASD), both brain cerebral asymmetry and functional hemispheric asymmetry (which varies with body condition and task performed) can be important. Lines 134-143 can indicate that functional asymmetry and symmetry are markers of successful language acquisition and that they are dynamic rather than static phenomena.  Language is important, as people with ASD usually have problems with communication. And here again, the question arises - what is primary?

The chicken and egg problem with language dysfunction in ASD in the context of asymmetry has been referenced in the added section referenced above.

In addition to the above, the ms. has been thoroughly revised and again double-checked for typos/spelling errors.

Author Response File: Author Response.docx

Round 2

Reviewer 2 Report

Dear authors, thanks for revisions. I agree with the current version.