Fragile X study uncovers brainwave biomarker bridging humans and mice

(Press-News.org) Numerous potential treatments for neurological conditions, including autism spectrum disorders, have worked well in lab mice but then disappointed in humans. What would help is a non-invasive, objective readout of treatment efficacy that is shared in both species. In a new study in Nature Communications, a team of MIT researchers backed by collaborators across the United States and in the United Kingdom identifies such a biomarker in fragile X syndrome, the most common inherited autism form. 

Led by postdoc Sara Kornfeld-Sylla and Picower Professor Mark Bear, the team measured the brainwaves of human boys and men, with or without fragile X syndrome, and comparably aged male mice, with or without the genetic alteration that models the disorder. The novel approach Kornfeld-Sylla used for analysis enabled her to uncover specific and robust patterns of differences in low-frequency brainwaves between typical and fragile X brains shared between species at each age range. In further experiments, the researchers related the brainwaves to specific inhibitory neural activity in the mice and showed that the biomarker was able to indicate the effects of even single doses of a candidate treatment for fragile X called arbaclofen, which enhances inhibition in the brain.

Both Kornfeld-Sylla and Bear praised and thanked colleagues at Boston Children’s Hospital, the Phelan-McDermid Syndrome Foundation, Cincinnati Children’s Hospital, the University of Oklahoma and King’s College London for gathering and sharing data for the study.

“This research weaves together these different datasets and finds the connection between the brainwave activity that’s happening in fragile X humans that is different from typically developed humans and in the fragile X mouse model that is different than the ‘wild-type’ mice,” said Kornfeld-Sylla, who earned her PhD in Bear’s lab in 2024 and continued the research as a FRAXA postdoctoral fellow. “The cross-species connection and the collaboration really makes this paper exciting.”

Bear, a faculty member in The Picower Institute for Learning and Memory and the Department of Brain and Cognitive Sciences at MIT, said having a way to directly compare brain waves can advance treatment studies.

“Because that is something we can measure in mice and humans minimally invasively, you can pose the question: if drug treatment X affects this signature in the mouse, at what dose does that same drug treatment change that same signature in a human?,” Bear said. “Then you have a mapping of physiological effects onto measures of behavior. And the mapping can go both ways.”

Peaks and powers

In the study, the researchers measured EEG over the occipital lobe of humans and on the surface of the visual cortex of the mice. They measured power across the frequency spectrum, replicating previous reports of altered low frequency brainwaves in adult humans with fragile X and showing for the first time how these disruptions differ in children with fragile X. 

To enable comparisons with mice, Kornfeld-Sylla subtracted out background activity to specifically isolate only “periodic” fluctuations in power (e.g., the brainwaves) at each frequency. She also disregarded the typical way brainwaves are grouped by frequency (into distinct bands with Greek letter designations delta, theta, alpha, beta and gamma) so that she could simply juxtapose the periodic power spectrums of the humans and mice without trying to match them band by band (e.g trying to compare the mouse “alpha” band to the human one). This turned out to be crucial because the significant, similar patterns exhibited by the mice actually occurred in a different low frequency band than in the humans (theta vs. alpha). Both species also had alterations in higher frequency bands in fragile X, but Kornfeld-Sylla noted that the differences in the low frequency brainwaves are easier to measure and more reliable in humans, making them a more promising biomarker. 

So what patterns constitute the biomarker? In adult men and mice alike, a peak in the power of low frequency waves is shifted to a significantly slower frequency in fragile X cases compared to in neurotypical cases. Meanwhile, in fragile X boys and juvenile mice, while the peak is somewhat shifted to a slower frequency, what is really significant is a reduced power in that same peak.

The researchers were able to identify some of these conserved age-related changes of the biomarker by looking “under the hood,” as Bear puts it, with a probe inserted inside the visual cortex of the awake mice. There they were also able to discern that the peak in question is actually made of two distinct subpeaks and that the lower frequency subpeak is the one that varies specifically with fragile X syndrome. 

Curious about the neural activity underlying the measurements, the researchers engaged in experiments in which they turned off activity of two different kinds of inhibitory neurons that are known to help produce and shape brainwave patterns: somatostatin-expressing and parvalbumin-expressing interneurons. Manipulating the somatostatin neurons specifically affected the lower-frequency subpeak that contained the newly discovered biomarker in fragile X model mice.

Drug testing

Somatostatin interneurons exert their effects on the neurons they connect to via the neurotransmitter chemical GABA and evidence from prior studies suggest that GABA receptivity is reduced in fragile X syndrome. A therapeutic approach pioneered by Bear and others has been to give the drug arbaclofen, which enhances GABA activity. In the new study, the researchers treated both control and fragile X model mice with arbaclofen to see how it affected the low frequency biomarker.

Even the lowest administered single dose made a significant difference in the neurotypical mice, which is consistent with those mice having normal GABA responsiveness. Fragile X mice needed a higher dose, but after one was administered, there was a notable increase in the power of the key subpeak, reducing the deficit exhibited by juvenile mice.

The arbaclofen experiments therefore demonstrated that the biomarker provides a significant readout of an underlying pathophysiology of fragile X: the reduced GABA responsiveness. Bear also noted that it helped to identify a dose at which arbaclofen exerted a corrective effect, even though the drug was only administered acutely rather than chronically. An arbaclofen therapy would, of course, be given over a long timeframe, not just once.

“This is a proof of concept that a drug treatment could move this phenotype acutely in a direction that makes it closer to wild-type,” Bear said. “This effort reveals that we have readouts that can be sensitive to drug treatments.”

Meanwhile, Kornfeld-Sylla noted, there is a broad spectrum of brain disorders in which human patients exhibit significant differences in low frequency (alpha) brainwaves compared to neurotypical peers. 

“Disruptions akin to the biomarker we found in this fragile X study might prove to be evident in mouse models of those other disorders, too,” she said. “Identifying this biomarker could broadly impact future translational neuroscience research.”

The paper’s other authors are Cigdem Gelegen, Jordan Norris, Francesca Chaloner, Maia Lee, Michael Khela, Maxwell Heinrich, Peter Finnie, Lauren Ethridge, Craig Erickson, Lauren Schmitt, Sam Cooke, and Carol Wilkinson.

The National Institutes of Health, the National Science Foundation, the FRAXA Foundation, the Pierce Family Fragile X Foundation, the Autism Science Foundation, the Thrasher Research Fund, Harvard University, the Simons Foundation, Wellcome, the Biotechnology and Biological Sciences Research Council and the Freedom Together Foundation provided support for the research.

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