How Absence Seizures Impair Sensory Perception: Insights from Awake fMRI and Simulation Studies in Rats

Reviewer #1 (Public Review):

Summary:
In this paper, the effects of two sensory stimuli (visual and somatosensory) on fMRI responsiveness during absence seizures were investigated in GEARS rats with concurrent EEG recordings. SPM analysis of fMRI showed a significant reduction in whole-brain responsiveness during the ictal period compared to the interictal period under both stimuli, and this phenomenon was replicated in a structurally constrained whole-brain computational model of rat brains.

The conclusion of this paper is that whole-brain responsiveness to both sensory stimuli is inhibited and spatially impeded during seizures.

I also suggest the manuscript should be written in a way that is more accessible to readers who are less familiar with animal experiments. In addition, the implementation and interpretation of brain simulations need to be more careful and clear.

Strengths:
1. ZTE imaging sequence was selected over traditional EPI sequence as the optimal way to perform fMRI experiments during absence seizures.

2. A detailed classification of stimulation periods is achieved based on the relative position in time of the stimulation period with respect to the brain state.

3. A whole-brain model embedded with a realistic rat connectome is simulated on the TVB platform to replicate fMRI observations.

Weaknesses:
1. The analysis in this paper does not directly answer the scientific question posed by the authors, which is to explore the mechanisms of the reduced brain responsiveness to external stimuli during absence seizures (in terms of altered information processing), but merely characterizes the spatial involvement of such reduced responsiveness. The same holds for the use of mean-field modeling, which merely reproduces experimental results without explaining them mechanistically as what the authors have claimed at the head of the paper.

2. The implementations of brain simulations need to be more specific.

Contribution:
The contribution of this paper is performing fMRI experiments under a rare condition that could provide fresh knowledge in the imaging field regarding the brain's responsiveness to environmental stimuli during absence seizures.

Reviewer #2 (Public Review):

Summary:
This study examined the possible effect of spike-wave discharges (SWDs) on the response to visual or somatosensory stimulation using fMRI and EEG. This is a significant topic because SWDs often are called seizures and because there is non-responsiveness at this time, it would be logical that responses to sensory stimulation are reduced. On the other hand, in rodents with SWDs, sensory stimulation (a noise, for example) often terminates the SWD/seizure.

In humans, these periods of SWDs are due to thalamocortical oscillations. A certain percentage of the normal population can have SWDs in response to photic stimulation at specific frequencies. Other individuals develop SWDs without stimulation. They disrupt consciousness. Individuals have an absent look, or "absence", which is called absence epilepsy.

The authors use a rat model to study the responses to stimulation of the visual or somatosensory systems during and in between SWDs. They report that the response to stimulation is reduced during the SWDs. While some data show this nicely, the authors also report on lines 396-8 "When comparing statistical responses between both states, significant changes (p<0.05, cluster-) were noticed in somatosensory auditory frontal..., with these regions being less activated in interictal state (see also Figure 4). That statement is at odds with their conclusion.

They also conclude that stimulation slows the pathways activated by the stimulus. I do not see any data proving this. It would require repeated assessments of the pathways in time.

The authors also study the hemodynamic response function (HRF) and it is not clear what conclusions can be made from the data.

Finally, the authors use a model to analyze the data. This model is novel and while that is a strength, its validation is unclear. The conclusion is that the modeling supports the conclusions of the study, which is useful.

Strengths:
Use of fMRI and EEG to study SWDs in rats.

Weaknesses:
Several aspects of the Methods and Results are unclear.

Reviewer #3 (Public Review):

Summary:
This is an interesting paper investigating fMRI changes during sensory (visual, tactile) stimulation and absence seizures in the GAERS model. The results are potentially important for the field and do suggest that sensory stimulation may not activate brain regions normally during absence seizures. However the findings are limited by substantial methodological issues that do not enable fMRI signals related to absence seizures to be fully disentangled from fMRI signals related to the sensory stimuli.

Strengths:
Investigating fMRI brain responses to sensory stimuli during absence seizures in an animal model is a novel approach with the potential to yield important insights.

The use of an awake, habituated model is a valid and potentially powerful approach.

Weaknesses:
The major difficulty with interpreting the results of this study is that the duration of the visual and auditory stimuli was 6 seconds, which is very close to the mean seizure duration per Table 1. Therefore the HRF model looking at fMRI responses to visual or auditory stimuli occurring during seizures was simultaneously weighting both seizure activity and the sensory (visual or auditory) stimuli over the same time intervals on average. The resulting maps and time courses claiming to show fMRI changes from visual or auditory stimulation during seizures will therefore in reality contain some mix of both sensory stimulation-related signals and seizure-related signals. The main claim that the sensory stimuli do not elicit the same activations during seizures as they do in the interictal period may still be true. However the attempts to localize these differences in space or time will be contaminated by the seizure-related signals.

The claims that differences were observed for example between visual cortex and superior colliculus signals with visual stim during seizures vs. interictal are unconvincing due to the above.

The maps shown in Figure 3 do not show clear changes in the areas claimed to be involved.