Reevaluating the Neural Noise Hypothesis in Dyslexia: Insights from EEG and 7T MRS Biomarkers

Reviewer #1 (Public Review):

Summary:

"Neural noise", here operationalized as an imbalance between excitatory and inhibitory neural activity, has been posited as a core cause of developmental dyslexia, a prevalent learning disability that impacts reading accuracy and fluency. This study is the first to systematically evaluate the neural noise hypothesis of dyslexia. Neural noise was measured using neurophysiological (electroencephalography [EEG]) and neurochemical (magnetic resonance spectroscopy [MRS]) in adolescents and young adults with and without dyslexia. The authors did not find evidence of elevated neural noise in the dyslexia group from EEG or MRS measures, and Bayes factors generally informed against including the grouping factor in the models. Although the comparisons between groups with and without dyslexia did not support the neural noise hypothesis, a mediation model that quantified phonological processing and reading abilities continuously revealed that EEG beta power in the left superior temporal sulcus was positively associated with reading ability via phonological awareness. This finding lends support for analysis of associations between neural excitatory/inhibitory factors and reading ability along a continuum, rather than as with a case/control approach, and indicates the relevance of phonological awareness as an intermediate trait that may provide a more proximal link between neurobiology and reading ability. Further research is needed across developmental stages and over a broader set of brain regions to more comprehensively assess the neural noise hypothesis of dyslexia, and alternative neurobiological mechanisms of this disorder should be explored.

Strengths:

The inclusion of multiple methods of assessing neural noise (neurophysiological and neurochemical) is a major advantage of this paper. MRS at 7T confers an advantage of more accurately distinguishing and quantifying glutamate, which is a primary target of this study. In addition, the subject-specific functional localization of the MRS acquisition is an innovative approach. MRS acquisition and processing details are noted in the supplementary materials according to the experts' consensus-recommended checklist (https://doi.org/10.1002/nbm.4484). Commenting on the rigor, the EEG methods is beyond my expertise as a reviewer.

Participants recruited for this study included those with a clinical diagnosis of dyslexia, which strengthens confidence in the accuracy of the diagnosis. The assessment of reading and language abilities during the study further confirms the persistently poorer performance of the dyslexia group compared to the control group.

The correlational analysis and mediation analysis provide complementary information to the main case-control analyses, and the examination of associations between EEG and MRS measures of neural noise is novel and interesting.

The authors follow good practice for open science, including data and code sharing. They also apply statistical rigor, using Bayes Factors to support conclusions of null evidence rather than relying only on non-significant findings. In the discussion, they acknowledge the limitations and generalizability of the evidence and provide directions for future research on this topic.

Weaknesses:

Though the methods employed in the paper are generally strong, there are certain aspects that are not clearly described in the Materials & Methods section, such as a description of the statistical analyses used for hypothesis testing.

With regard to metabolite quantification, it is unclear why the authors chose to analyze and report metabolite values in terms of creatine ratios rather than quantification based on a water reference given that the MRS acquisition appears to support using a water reference. GABA is typically quantified using J-editing sequences as lower field strengths (~3T), and there is some evidence that the GABA signal can be reliably measured at 7T without editing, however, the authors should discuss potential limitations, such as reliability of Glu and GABA measurements with short-TE semi-laser at 7T. In addition, MRS measurements of GABA are known to be influenced by macromolecules, and GABA is often denoted as GABA+ to indicate that other compounds contribute to the measured signal, especially at a short TE and in the absence of symmetric spectral editing. A general discussion of the strengths and limitations of unedited Glu and GABA quantification at 7T is warranted given the interest of this work to researchers who may not be experts in MRS.

Further, the single MRS voxel location is a limitation of the study as neurochemistry can vary regionally within individuals, and the putative excitatory/inhibitory imbalance in dyslexia may appear in regions outside the left temporal cortex (e.g., network-wide or in frontal regions involved in top-down executive processes). While the functional localization of the MRS voxel is a novelty and a potential advantage, it is unclear whether voxel placement based on left-lateralized reading-related neural activity may bias the experiment to be more sensitive to small, activity-related fluctuations in neurotransmitters in the CON group vs. the DYS group who may have developed an altered, compensatory reading strategy.

As the authors note in the discussion, sex could serve as a moderator of associations between neural noise and reading abilities and should be considered in future studies.

Appraisal:

The authors present a thorough evaluation of the neural noise hypothesis of developmental dyslexia in a sample of adolescents and young adults using multiple methods of measuring excitatory/inhibitory imbalances as an indicator of neural noise. The authors concluded that there was no support for the neural noise hypothesis of dyslexia in their study based on null significance and Bayes factors. This conclusion is justified, and further research is called for to more broadly evaluate the neural noise hypothesis in developmental dyslexia.

Impact:

This study provides an exemplary foundation for the evaluation of the neural noise hypothesis of dyslexia. Other researchers may adopt the model applied in this paper to examine neural noise in various populations with/without dyslexia, or across a continuum of reading abilities, to more thoroughly examine the evidence (or lack thereof) for this hypothesis. Notably, the lack of evidence here does not rule out the possibility of a role for neural noise in dyslexia, and the authors point out that presentation with co-occurring conditions, such as ADHD, may contribute to neural noise in dyslexia. Dyslexia remains a multi-faceted and heterogenous neurodevelopmental condition, and many genetic, neurobiological, and environmental factors play a role. This study demonstrates one step toward evaluating neurobiological mechanisms that may contribute to reading difficulties.

Reviewer #2 (Public Review):

Summary:

This study utilized two complementary techniques (EEG and 7T MRI/MRS) to directly test a theory of dyslexia: the neural noise hypothesis. The authors report finding no evidence to support an excitatory/inhibitory balance, as quantified by beta in EEG and Glutamate/GABA ratio in MRS. This is important work and speaks to one potential mechanism by which increased neural noise may occur in dyslexia.

Strengths:

This is a well-conceived study with in-depth analyses and publicly available data for independent review. The authors provide transparency with their statistics and display the raw data points along with the averages in figures for review and interpretation. The data suggest that an E/I balance issue may not underlie deficits in dyslexia and is a meaningful and needed test of a possible mechanism for increased neural noise.

Weaknesses:

The researchers did not include a visual print task in the EEG task, which limits analysis of reading-specific regions such as the visual word form area, which is a commonly hypoactivated region in dyslexia. This region is a common one of interest in dyslexia, yet the researchers measured the I/E balance in only one region of interest, specific to the language network. Further, this work does not consider prior studies reporting neural inconsistency; a potential consequence of increased neural noise, which has been reported in several studies and linked with candidate-dyslexia gene variants (e.g., Centanni et al., 2018, 2022; Hornickel & Kraus, 2013; Neef et al., 2017). While E/I imbalance may not be a cause of increased neural noise, other potential mechanisms remain and should be discussed.

Reviewer #3 (Public Review):

Summary:

This study by Glica and colleagues utilized EEG (i.e., Beta power, Gamma power, and aperiodic activity) and 7T MRS (i.e., MRS IE ratio, IE balance) to reevaluate the neural noise hypothesis in Dyslexia. Supported by Bayesian statistics, their results show solid 'no evidence' of EI balance differences between groups, challenging the neural noise hypothesis. The work will be of broad interest to neuroscientists, and educational and clinical psychologists.

Strengths:

Combining EEG and 7T MRS, this study utilized both the indirect (i.e., Beta power, Gamma power, and aperiodic activity) and direct (i.e., MRS IE ratio, IE balance) measures to reevaluate the neural noise hypothesis in Dyslexia.

Weaknesses:

The authors may need to provide more data to assess the quality of the MRS data.