AutisM Spectrum
Disorder
The Growing Burden of Fragile X Syndrome,
Affecting the Rare Diseases Landscape
The prevalence of Fragile X Syndrome (FXS) is approximately 1 in 3,600 for males and 1 in 4,000-6,000 for females(1), making it one of the most prevalent rare neurological conditions worldwide (Orphanet). Additionally, FXS is also recognized as the most common cause of inherited intellectual disability as well as the most commonly known cause of autism spectrum disorders.
FXS is a genetic condition caused by a lengthening of the Fragile X messenger Ribonucleoprotein (FMR1) gene on the X chromosome.
Considering these facts, Fragile X Syndrome, as several other types of rare CNS conditions, is being more and more investigated by drug developers. Despite the existence of relatively efficient therapeutic strategies, there is still a lack of efficacy that the CNS community needs to fill in. In that way, having a look at the electroencephalography method is a game changer that could be brought to help the scientific community thanks to its well-known ability to bridge the preclinical to clinical gap.
The FMR1-KO Rat, a Translational Model of Fragile X Syndrome
Fragile X patients show a significant decrease of the evoked response to auditory stimulations. A second endpoint seems relevant: resting state qEEG. Indeed, patients show an increase of high frequencies (between 40 and 120Hz) as well as a decrease of low frequency bands (between 10 and 20Hz).
Building on our years of research and development efforts, we characterized a translational model of Fragile X Syndrome, the FMR1-KO rat, mimicking with great prediction the evoked responses from auditory stimuli that have been evidenced in the clinic.
*Erthridge et al, 2017
The FMR1-KO Rat, a Reference Model in the Field of ASD
The FMR1-KO rat model show deficits in information processing, increased baseline gamma power, and decreased alpha power. These data are linked to the observations made in patients, which reveal reduced local circuit inhibition, leading to sensory hypersensitivity and neuro excitability.
A Robust and Translational EEG Biomarker
ASSR abnormalities are associated with conditions like Autism Spectrum Disorders (ASD).
Thanks to the highly translational properties of EEG, coupled with our proprietary analysis platform Cue®, we have identified a relevant EEG biomarker, the 40Hz-ASSR. This EEG biomarker is found in humans and rodents, and evaluates auditory cortex function and neural synchronization.
Paving the Way for New Predictive Models
Besides our efficacy models, SynapCell can also help to identify abnormal brain wave patterns in animal models using EEG phenotyping. By focusing on Auditory Evoked Potentials (AEPs) protocols, we bring a predicting approach and expand our efficacy programs for drug discovery.
Key Features
of the FMR1-KO Rat Model
The FMR1-KO rat model is considered a gold standard for drug discovery in FXS disease:
- Gamma synchronization of ITC and ERP reduction in FRMR1-KO rats
- Deficits on information processing are highlighted in FMR1-KO rats
- Significant increase in epsilon power after qEEG analysis
- Involvement of GABAergic inhibitory neurons in rats
Cue®, SynapCell’s platform, is a reliable solution for evaluating potential Autism’s treatments in preclinical research.
Correlation between gamma power and sensory hypersensitivities in FXS patients converge with FXS animal model findings of altered local inhibitory networks, making the model relevant to help you identify the most promising compounds in terms of their functional ability to reverse deficits.
Drug Discovery Assays
with the FMR1-KO Rat Model
The stability of the model and its endpoints over time allow the possibility to perform different types of experimental protocols. In acute conditions, each animals can be used as their own control during a crossover protocol, powering the statistical analysis.
In a few words, this model is suited to identify, optimize and test promising compounds in terms of efficacy and pharmacological properties to determine their potential as drug candidates.
Assess how a compound’s effect changes with varying doses and analyze the relationship between dose and magnitude of the response, dose and duration of the effect and examine efficacy, safety, and biological effects across different concentrations to determine optimal dosing strategies.
POSTER
EEG Phenotyping of a Rat Model of Fragile X
In this Poster, we took advantage of quantitative electroencephalography (qEEG) and related methodologies (auditory evoked potentials) to characterize a humanized rat model of Fragile X. The implantation of cortical EEG electrodes over the frontal and parietal cortices allows the resting EEG monitoring and the achievement of 40Hz ASSR. This gives inputs into the total evoked power at 40Hz for each structure as well as on the inter-trial coherence.
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POSTER
POSTER
Alteration in Spontaneous and Auditory Evoked Electro-physiological Activities in a Rat Model of Fragile X Syndrome
In this study, we see that the sensitivity of EEG allows a dynamic characterization and differentiation of translational humanized models of brain disorders. The combination of translational preclinical models with EEG represents the next step for loop translating preclinical trials into clinical practice, opening the era of precision medicine for patients.
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POSTER
AUDITORY EVOKED
POTENTIAL
APPLICATION NOTE
40Hz-Auditory Steady State Response (40Hz-ASSR)
The main challenge in preclinical research is finding biomarkers that can be applied across both clinical and preclinical settings. The 40Hz-ASSR is a non-invasive EEG biomarker detectable in both humans and rodents. It measures how well the auditory cortex processes information and generates synchronous activity at a specific frequency. Disruptions in ASSR are linked to disorders such as autism spectrum disorder.
Powered by Cue®, SynapCell's Predictive In Vivo EEG Platform
SynapCell’s FMR1-KO rat model and its associated 40Hz-ASSR EEG biomarker are processed on Cue®, our innovative translational in vivo EEG platform, which is designed to predict the in-human efficacy of your drug candidates during the preclinical step. Cue® is the result of decades of R&D, combining SynapCell’s know-how, expertise and scientific excellence in the fields of brain surgery and EEG signal recording, processing, and analysis.
Using Cue®, we transform preclinical data into actionable insights, offering end-to-end support for informed decision-making in CNS drug discovery.
THE SCIENCE CORNER
Insight into the 40Hz ASSR Paradigm
The 40Hz ASSR is of interest because it reflects synchronous neural oscillations in the auditory cortex and is thought to be associated with cognitive processes like attention and sensory integration. This frequency range is significant in neuroscience and clinical settings, as abnormalities in 40Hz ASSR have been linked to various neurological and psychiatric conditions, including schizophrenia and autism.
SynapCell uses a specific paradigm in house which consists of a train of 80 auditory stimulations in two seconds, repeated 360 times. One auditory stimulation is a 5ms white noise click. By measuring the coherence (inter-trial coherence, ITC) between the 360 trials, we can collect information on how the brain filters redundant information and its capability to have some kind of entrainment.
A Glimpse of the Translational Readouts
Provided by our Experts
The figure below elicits a nice comparison of the evoked responses to the 40Hz ASSR paradigm seen in wild-type animals (WT) and FMR1-hemi-KO rats. We can clearly observe a reduction in the average response in FMR1-KO rats as compared with WT.
Furthermore, in Figure 2, we are able to identify a significant decrease of the evoked power in FMR1-KO rats comparison to WT rats. Regarding the evaluation of the ITC, in Figure 3, we also detect a significant decrease in FMR1-KO rats. These observations suggest that FMR1-KO rats have a deficit in information processing as compared to WT littermate.
Overall, the sensitivity of EEG allows a dynamic characterization and differentiation of translational humanized models of brain disorders. The combination of translational preclinical models with EEG represents the next step for loop translating preclinical trials into clinical practice, opening the era of precision medicine for patients.
Let's Talk About Your Research Project!
More than a CRO, a team of collaborators – we are your dream neuroscience team specialized in preclinical EEG! We don’t just produce data, we are your partners from conceptualization to conclusion. We translate raw EEG data into meaningful, clinically-relevant endpoints, delivering clear insights to allow data-based decision-making. Choose SynapCell, a leading preclinical CNS-specialized CRO for cutting-edge EEG expertise combined with an irresistible touch of fun.
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