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Harnessing Neurophysiological Biomarkers to Accelerate Therapeutic Development in Rett Syndrome

October marks Rett Syndrome Awareness Month, a time to spotlight ongoing scientific efforts to understand and treat this devastating neurodevelopmental disorder. While much progress has been made in identifying the genetic underpinnings of Rett syndrome, translating that knowledge into effective treatments remains an ongoing challenge.

One of the emerging frontiers in this space involves neurophysiological biomarkers - objective, quantitative measures that reflect changes in brain function and can be used to evaluate treatment response earlier and more precisely than traditional clinical endpoints.

 

What is Rett Syndrome?

 

Rett syndrome (RTT) is a rare genetic neurological disorder that primarily affects girls, occurring in about 1 in 10,000 female births worldwide. Caused by mutations in the MECP2 gene on the X chromosome (with over 900 known variants), it disrupts normal brain development and leads to significant physical and cognitive impairments.

Children with Rett syndrome typically develop normally for the first 6-18 months before losing previously acquired skills such as speech, hand use, and mobility. Common features include repetitive hand movements, slowed head growth, difficulty walking, seizures, breathing irregularities, digestive issues, and problems with co-ordination and eye movement.

Although not degenerative, the condition varies in severity depending on the mutation type and X-inactivation pattern, and individuals can live into middle age or beyond.

 

Why Neurophysiological Measures Matter

 

Techniques such as electroencephalography (EEG) and transcranial magnetic stimulation (TMS) offer unique insights into synaptic activity, cortical excitability, and network plasticity - processes that are profoundly affected in Rett syndrome. Combining these modalities (TMS-EEG) enables researchers to directly measure cortical reactivity and connectivity, revealing how the brain responds to novel therapeutics targeting synaptic and neurotransmitter function.

Recent advances in electrophysiological research are helping to decode the cortical dysfunction that defines RTT and related MECP2-associated disorders. EEG studies have revealed that girls with RTT show a characteristic pattern of increased low-frequency (delta/theta) activity and reduced high-frequency (alpha/beta) power, which correlates with clinical severity and disrupted cortical organisation (Roche et al. 2019). These findings, combined with evidence from evoked potential studies, demonstrate that EEG can sensitively track changes in sensory processing and cortical connectivity, making it a powerful biomarker candidate for clinical trials (Saby et al. 2020). Building on this, TMS-EEG techniques offer a complementary and direct way to assess cortical excitability and inhibitory neurotransmission. Work by Premoli et al. (2014) has shown that specific TMS-evoked EEG potentials reflect GABAergic activity, with early components (N45) linked to GABAA receptor function and later components (N100) to GABAB receptor function. This mechanistic insight is particularly relevant to RTT, where altered GABAergic signalling is a hallmark of MECP2 dysfunction and contributes to network-level abnormalities. Together, these findings bridge molecular pathology and systems-level measurement - supporting the use of neurophysiological biomarkers such as EEG and TMS-EEG to evaluate how emerging therapeutics modulate synaptic activity, restore inhibitory balance, and improve cortical function (Collins and Neul 2022).

In the context of neuromodulator development, especially those aimed at restoring lipid composition or supporting neuronal communication, EEG-based paradigms can help establish whether a candidate compound truly enhances synaptic function and cortical plasticity. For preclinical and early clinical studies, this can provide a powerful bridge between molecular mechanisms and functional outcomes.

 

Supporting Translational Research

 

At The Science Behind, our mission is to help neuroscience-driven biopharma companies accelerate the path from mechanism to measurable impact. We provide specialised EEG and TMS-EEG services, from study design and equipment provision to data collection and analysis, tailored to the needs of preclinical and clinical-stage neuromodulation programs.

Our team works closely with Sponsors to design cognitive and resting-state paradigms that probe relevant aspects of cortical function, such as sensory processing, inhibition, and long-term potentiation-like plasticity, allowing researchers to detect neurophysiological changes even before behavioural or clinical symptoms shift.

 

A Collaborative Path Forward

 

Rett syndrome research exemplifies the importance of integrating neuroscience, technology, and translational biomarkers. By pairing innovative therapeutic strategies with advanced neurophysiological assessment, we can more effectively evaluate how interventions impact brain function and ultimately improve the outlook for individuals living with Rett syndrome and related neurodevelopmental disorders.

As we recognise Rett Syndrome Awareness Month, we also celebrate the scientific community’s growing ability to measure brain change directly - an essential step toward developing treatments that truly make a difference.

 

References

 

  1. Roche, K.J. et al. (2019). Electroencephalographic spectral power as a marker of cortical function and disease severity in girls with Rett syndrome. J Neurodev Discord 11(1): 15. DOI: 10.1186/s11689-019-9275-z
  2. Collins, B.E. and Neul, J.L. (2022). Rett syndrome and MECP2 duplication syndrome: Disorders of MeCP2 dosage. Neuropsychiatr Dis Treat 18: 2813-2835. DOI: 10.2147/NDT.S371483
  3. Premoli, I. et al. (2014). TMS-EEG signatures of GABAergic neurotransmission in the human cortex. J Neurosci 34(16): 5603-5612. DOI: 10.1523/JNEUROSCI.5089-13.2014
  4. Saby, J.N. et al. (2020). Evoked potentials and EEG analysis in Rett syndrome and related developmental encephalopathies: Towards a biomarker for translational research. Front Integr Neurosci 14: 30. DOI: 10.3389/fnint.2020.00030