Neural dynamics of semantic categorization in semantic variant of Primary Progressive Aphasia
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Summary: Borghesani and colleagues aimed to understand how dysfunction in the anterior temporal lobe (ATL) alters dynamic activity during semantic categorization. They contrast MEG responses between 18 patients with semantic variant Primary Progressive Aphasia (PPA) and 18 age-matched healthy controls. Both groups show similar profiles of behavioural performance on the task, and broad similarities in MEG responses. Critically, however, svPPA patients show enhanced gamma synchronization in the occipital lobe compared to controls. The authors interpret this as reflecting increased engagement of / reliance on early perceptual mechanisms for completing the task, as opposed to semantic identification of the picture.
Overall, the reviewers found the manuscript interesting. As svPPA is a rare (but scientifically informative) disorder, the sample size is impressive, and given that relatively few MEG studies exist in PPA at all, this is an interesting dataset. However, the general opinion is that the results could be more fully characterized, which would allow for more expansive interpretations and inferences.
This manuscript is in revision at eLife.
Reviewer #2 and Reviewer #3 opted to reveal their name to the authors in the decision letter after review.
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Abstract
Semantic representations are processed along a posterior-to-anterior gradient reflecting a shift from perceptual (e.g., it has eight legs ) to conceptual (e.g., venomous spiders are rare ) information. One critical region is the anterior temporal lobe (ATL): patients with semantic variant primary progressive aphasia (svPPA), a clinical syndrome associated with ATL neurodegeneration, manifest a deep loss of semantic knowledge. We test the hypothesis that svPPA patients perform semantic tasks by over-recruiting areas implicated in perceptual processing. We compared MEG recordings of svPPA patients and healthy controls during a categorization task. While behavioral performance did not differ, svPPA patients showed indications of greater activation over bilateral occipital cortices and superior temporal gyrus, and inconsistent engagement of frontal regions. These findings suggest a pervasive reorganization of brain networks in response to ATL neurodegeneration: the loss of this critical hub leads to a dysregulated (semantic) control system, and defective semantic representations are seemingly compensated via enhanced perceptual processing.
Impact Statement
Following anterior temporal lobe neurodegeneration, defective semantic representations are compensated via enhanced perceptual processing and associated with a dysregulation of the semantic control system.
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Reviewer #3:
In this interesting paper authors compare MEG recordings of svPPA patients and 44 healthy controls during living vs. non-living categorization tasks. Both patients and the control group performed this task with similar accuracy. In addition, svPPA patients showed greater activation over bilateral occipital cortices and superior temporal gyrus, and inconsistent engagement of frontal regions. The authors conclude that patients with svPPA compensate for their semantic deficit by recruiting regions involved in perceptual processing.
This is a well written study and the results are presented clearly. The findings are novel and interesting.
One question for clarification is whether the recruitment of the occipital areas in semantic PPA is truly "compensatory" - does it indicate a shift of resources due to the anterior temporal …
Reviewer #3:
In this interesting paper authors compare MEG recordings of svPPA patients and 44 healthy controls during living vs. non-living categorization tasks. Both patients and the control group performed this task with similar accuracy. In addition, svPPA patients showed greater activation over bilateral occipital cortices and superior temporal gyrus, and inconsistent engagement of frontal regions. The authors conclude that patients with svPPA compensate for their semantic deficit by recruiting regions involved in perceptual processing.
This is a well written study and the results are presented clearly. The findings are novel and interesting.
One question for clarification is whether the recruitment of the occipital areas in semantic PPA is truly "compensatory" - does it indicate a shift of resources due to the anterior temporal atrophy? Is the recruitment of the parieto-occipital regions associated with more accurate performance?
The main results concentrate on the differences between patients and controls in the low gamma range. There are also significant effects in the other frequency bands (e.g., high gamma, beta and alpha). Could the authors discuss the functional significance of these effects?
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Reviewer #2:
Borghesani and colleagues aimed to understand how dysfunction in the ATL alters the dynamic activity during semantic categorization. To achieve this, they contrast MEG responses between patients with svPPA and age-matched healthy controls. Both groups show similar profiles of behavioural performance on the task, and broad similarities in MEG responses. Critically, svPPA patients show enhanced gamma synchronization in the occipital lobe compared to controls, while gamma synchronization was correlated to task RTs.
In general, I found the manuscript interesting, and the major strength being the application of MEG analyses to a clinical population during a cognitive task. In terms of improvements, I think the results could be more fully characterized, which would allow for more expansive interpretations and inferences.
Major …
Reviewer #2:
Borghesani and colleagues aimed to understand how dysfunction in the ATL alters the dynamic activity during semantic categorization. To achieve this, they contrast MEG responses between patients with svPPA and age-matched healthy controls. Both groups show similar profiles of behavioural performance on the task, and broad similarities in MEG responses. Critically, svPPA patients show enhanced gamma synchronization in the occipital lobe compared to controls, while gamma synchronization was correlated to task RTs.
In general, I found the manuscript interesting, and the major strength being the application of MEG analyses to a clinical population during a cognitive task. In terms of improvements, I think the results could be more fully characterized, which would allow for more expansive interpretations and inferences.
Major comments:
As the paper is about 'Neural dynamics', I felt this aspect could be developed, with the timing of the effects characterized further, and considered more in relation to the conclusions. For example, the main finding is the increased occipital gamma response in svPPA compared to controls. Looking at Figure 3, there is a peak in the svPPA group near 200 ms, and very little synchronized activity in the control group. This is interesting as there are many ways we could have seen svPPA > controls, but this suggests that the gamma synchronization response associated with compensation is specific to the svPPA group (and largely absent from controls - also from Supp fig 1), and is distinguished from an initial visual evoked response (peaking ~100 ms). I would recommend discussing and characterizing the dynamics of this effect more, such as what a later occipital effect could tell us about dynamics given ATL dysfunction? Is this increase a result of a lack of top-down effects from ATL? I think these kinds of issues could be explored and discussed more.
The occipital gamma effect looks like the primary visual cortex, which might suggest the effects are not related to higher-level perceptual features (such as has eyes, teeth) as the authors suggest, but rather low-level visual effects. Do the authors perhaps think the effects could relate to enhanced processing of visual details (as related to the ideas of Hochstein and Asher's reverse hierarchy), or whether the effects relate to additional visual input following a visual saccade?
The VBM results for the svPPA patients were surprising given that all the atrophy appeared in the left hemisphere. There can be hemispheric differences in svPPA, but is this a true lateral pattern (meaning the right ATL is intact) or a product of VBM being run so that the most atrophied hemisphere is shifted to the left side? If the VBM maps are correct, and the svPPA patients are only showing left hemisphere atrophy, then what does this suggest about the role of the right ATL, and the bilateral nature of occipital increased in svPPA?
Both svPPA patients and healthy controls achieved around 80% accuracy in the categorization task. This seems surprisingly low given, (1) the task (living vs. nonliving after seeing the image for 2 seconds), (2) that all the images were pretested and had high name agreement, and (3) that items were repeated on average 2.5 times. Is there something that explains this low performance for all individuals?
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Reviewer #1:
This study examines MEG activity in a picture categorization task (decide living or non-living) in a sample of 18 patients with semantic variant PPA, compared to 18 controls. As svPPA is a rare (but scientifically informative) disorder, the sample size is impressive, and given that relatively few MEG studies exist in PPA at all, this is an interesting dataset. The authors show differences in engagement of oscillatory activity, specifically increased low-gamma ERS in occipital cortex and increased beta ERD in the superior temporal gyrus. The authors interpret this as reflecting increased engagement of / reliance on early perceptual mechanisms for completing the task, as opposed to semantic identification of the picture.
Major concerns:
My biggest methodological issue with this paper relates to a very old debate in …
Reviewer #1:
This study examines MEG activity in a picture categorization task (decide living or non-living) in a sample of 18 patients with semantic variant PPA, compared to 18 controls. As svPPA is a rare (but scientifically informative) disorder, the sample size is impressive, and given that relatively few MEG studies exist in PPA at all, this is an interesting dataset. The authors show differences in engagement of oscillatory activity, specifically increased low-gamma ERS in occipital cortex and increased beta ERD in the superior temporal gyrus. The authors interpret this as reflecting increased engagement of / reliance on early perceptual mechanisms for completing the task, as opposed to semantic identification of the picture.
Major concerns:
My biggest methodological issue with this paper relates to a very old debate in neuroimaging that still comes up all the time: the choice of statistical threshold. Using a high threshold prevents false positives, but may also lead to false negatives, and I fear that is the case here, with the high threshold contributing to an unrealistic impression of spatial specificity in MEG. It is obvious from the average responses in both groups that these oscillatory responses are widespread through the brain. Indeed the alpha and beta responses are significant in the majority of cortical voxels. This basic property of the responses should be presented clearly and prominently in the paper - I don't think it's appropriate to put it in supplementary information where only a minority of readers will even see it. The authors then use what I think is an extremely high and conservative statistical threshold to contrast differences between the two groups. P<.005 uncorrected is a highly conservative threshold already, even before cluster-thresholding is added (although with data as smooth as MEG beamforming solutions, cluster-thresholding is unlikely to change anything). Basically this makes the only the strongest part of the activation survive, and it is valid to conclude that a significant group difference exists there (protected from Type 1 error), but this can give a false impression of the difference is specific to that region. I think a more realistic characterization of the results would involve measuring differences in the strength of the responses between groups on a broader level, possibly the sensors or in large ROIs - and not ROIs pre-selected to show a dramatic difference by first searching the whole brain for the most significant effects - that is the classic "double-dipping" fallacy in neuroimaging.
Similarly, the ERD/ERS in each frequency band is treated as a separate entity, ignoring the fact that these bands are arbitrary and frequency is a continuous quantity. This matters because much is made of the fact that PPA participants exhibited greater ERS in the low-gamma range, and that this was correlated with reaction time. Supplementary figure 1 shows that both groups had strong occipital ERS in the high-gamma range, but only PPA showed it in the low gamma range as well. This suggests that the ERS in the PPA group may simply have been shifted to a lower frequency range. A more fulsome characterization of these group differences via time-frequency analysis and/or power spectral analysis would help clarify what is going on here.
It is surprising that PPA participants only exhibited increased MEG responses compared to controls - assuming that both gamma ERS and beta ERD can be interpreted as increased neural activation, which is a reasonable assumption based on the literature. No decreases in the PPA group are found, and thus the observed increases can be plausibly attributed to compensatory processes as framed by the authors. However, I am concerned about the role of certain analysis choices in producing this data pattern. In particular, the authors state (line 611): "To remove potential artifacts due to neurodegeneration or eye movement (lacking electrooculograms), we masked statistical maps using patients' ATL atrophy maps (see section MRI protocol and analyses), as well as a ventromedial frontal mask."
It is not clear whether this masking was done in group space from average atrophy maps, or on an individual level. In either case, I don't think this is well justified. I don't know any physical mechanism by which tissue undergoing neurodegeneration can be said to generate an artifactual signal. Atrophied tissue still contains living neurons with ionic currents; these are real signals not artifacts, and furthermore, atrophy is a continuous process with tissue further from the epicenter also undergoing similar neurodegenerative mechanisms. Atrophied tissue may well generate electromagnetic signals that are different from healthy tissue, and such differences should be included in this paper. I think that there may be regions of hypoactivation as well as hyperactivation in this PPA group. If the hypoactivation localizes to atrophied tissue and the hyperactivation to other regions, that will bolster the case that we are seeing compensatory processes, but it isn't certain with half the story masked. I also don't really see statistical masking of the frontal region as a valid solution to eye movement artifacts. The authors would have to present evidence that the region that they masked corresponds to the region potentially affected by eye movements. However, many studies have found that beamforming already does a pretty good job of removing ocular artifacts from estimated brain signals, except for very close to the eyes.
- The correlation with reaction time in the occipital cortex is consistent with the idea that the ERS there may reflect compensatory overreliance on perceptual information, but it isn't conclusive. The authors suggest that PPA patients are able to categorize the stimuli correctly based on visual features, but are unable to name them. What about testing for correlations with the out-of-scanner behavioural measures that established that the patients have a naming deficit? It would strengthen the case if atrophy or hypoactivation (see comment above) correlated with the naming deficit.
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Summary: Borghesani and colleagues aimed to understand how dysfunction in the anterior temporal lobe (ATL) alters dynamic activity during semantic categorization. They contrast MEG responses between 18 patients with semantic variant Primary Progressive Aphasia (PPA) and 18 age-matched healthy controls. Both groups show similar profiles of behavioural performance on the task, and broad similarities in MEG responses. Critically, however, svPPA patients show enhanced gamma synchronization in the occipital lobe compared to controls. The authors interpret this as reflecting increased engagement of / reliance on early perceptual mechanisms for completing the task, as opposed to semantic identification of the picture.
Overall, the reviewers found the manuscript interesting. As svPPA is a rare (but scientifically informative) disorder, the …
Summary: Borghesani and colleagues aimed to understand how dysfunction in the anterior temporal lobe (ATL) alters dynamic activity during semantic categorization. They contrast MEG responses between 18 patients with semantic variant Primary Progressive Aphasia (PPA) and 18 age-matched healthy controls. Both groups show similar profiles of behavioural performance on the task, and broad similarities in MEG responses. Critically, however, svPPA patients show enhanced gamma synchronization in the occipital lobe compared to controls. The authors interpret this as reflecting increased engagement of / reliance on early perceptual mechanisms for completing the task, as opposed to semantic identification of the picture.
Overall, the reviewers found the manuscript interesting. As svPPA is a rare (but scientifically informative) disorder, the sample size is impressive, and given that relatively few MEG studies exist in PPA at all, this is an interesting dataset. However, the general opinion is that the results could be more fully characterized, which would allow for more expansive interpretations and inferences.
This manuscript is in revision at eLife.
Reviewer #2 and Reviewer #3 opted to reveal their name to the authors in the decision letter after review.
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