Summary: How do coordinated brain rhythms develop at the cellular level? EEGs reveal large-scale brain waves but cannot show what individual neurons and circuits are doing when rhythms go wrong in conditions such as epilepsy or autism. A new study presents a simple, scalable two-dimensional human neuron platform that connects cellular-level activity with the network rhythms seen in developing human brains.
By maturing human neurons derived from induced pluripotent stem cells (iPSCs) on sensor-equipped multi-electrode array plates, researchers recorded the onset of “nested oscillations”—slow waves containing faster, layered rhythms that match patterns observed in vivo. This high-throughput 2D model enables systematic testing of drugs and genetic variants to see how they alter network activity, offering a practical tool for neurodevelopmental research and early-stage therapeutic screening.
Key Facts
- Nested oscillations: The model reproduces layered electrical activity across delta, theta, and alpha frequency bands embedded within slow network waves, reflecting electrical maturation processes seen in human brains.
- GABAergic control: Increasing inhibitory GABAergic neurons accelerated the appearance of nested rhythms, while blocking GABA signaling reduced them, demonstrating the critical role of inhibition in organizing network activity.
- Scalable testing: Compared with complex 3D organoids, the 2D format supports large-scale, controlled dose–response studies and benchmarking across many conditions and replicates.
- Signal decomposition: Using advanced analysis to separate oscillatory peaks from broadband background activity revealed that the broadband component often carries biologically meaningful information rather than being mere noise.
- Clinical relevance: The platform can profile how potassium channel perturbations and other disease-linked mechanisms reshape network rhythms, accelerating discovery of potential interventions for epilepsy and related disorders.
Source: Sanford Burnham Prebys
What EEGs show — and what they miss: An electroencephalogram (EEG) is a noninvasive test that records electrical activity from the scalp, capturing large-scale brain waves produced by many neurons firing together. Clinicians use EEG to assess sleep stages, detect seizures, and monitor other shifts in brain state. However, EEGs provide limited insight into the cellular and circuit-level mechanisms that generate those rhythms, and they cannot directly reveal how specific cell types or molecular pathways produce or disrupt ordered oscillations.
To probe how rhythmic patterns emerge during human development, scientists at Sanford Burnham Prebys, together with collaborators at the University of California San Diego and BioMarin Pharmaceutical, developed a simplified, high-throughput human cell model. Published January 24, 2026, in Neurobiology of Disease, the study uses two-dimensional networks of iPSC-derived neurons grown on multi-electrode arrays (MEAs) to follow maturation and pharmacological responses over time.
MEAs contain many tiny sensors that record electrical activity from multiple independent networks in parallel, making them well suited for controlled, replicated experiments. Because iPSCs can be generated from accessible donor cells such as skin or blood, researchers can produce patient-specific neurons alongside controls to model disease-relevant differences in network dynamics.
As the 2D networks matured, researchers observed nested oscillations: slow baseline waves containing faster rhythms across common EEG bands (delta, theta, alpha). The team then probed mechanisms shaping those rhythms through targeted manipulations and drugs.
“This simplified 2D neuronal network captures essential features of network maturation while providing the scale and experimental control necessary for systematic testing,” said Anne Bang, PhD, the study’s senior author and director of Cell Biology at the Conrad Prebys Center for Chemical Genomics.
The authors position this 2D approach as complementary to three-dimensional brain organoids. Organoids better mimic tissue architecture and cellular diversity, but their complexity can limit throughput and consistency for experiments requiring many replicates or broad dose–response sampling. The 2D platform prioritizes reproducibility and scale, making it especially useful for benchmarking, mechanistic studies, and early-stage drug evaluation.
A central focus was inhibitory signaling via GABA. GABAergic neurons provide critical inhibition that stabilizes circuits, supports sleep rhythms, and helps prevent runaway excitation that can produce seizures. Blocking GABA-A receptors reduced nested oscillations, while increasing the fraction of GABAergic neurons caused those rhythms to appear earlier, reinforcing the role of inhibition in oscillogenesis.
The team also explored potassium channel modulation. Voltage-gated potassium channels shape neuronal excitability and firing patterns, and some channel mutations are linked to epilepsy and developmental syndromes. Different potassium channel perturbations altered nested oscillation patterns in distinct ways, indicating that specific molecular changes can leave characteristic network-level signatures rather than producing a single uniform effect on excitability.
To interpret network recordings more precisely, researchers applied an analysis framework that separates rhythmic oscillations from a broadband background component. Rather than treating the broadband signal as meaningless noise, the decomposition showed that broadband shifts sometimes track with oscillatory changes and therefore contain biologically relevant information. Assessing both oscillatory peaks and broadband background helps determine whether an intervention targets a specific rhythm, shifts overall network state, or both.
The study also compared traditional differentiation with a rapid protocol that induces neurons by expressing the transcription factor NEUROG2 (NGN2). NGN2-induced networks showed only primitive nested rhythms, suggesting accelerated differentiation methods may need further optimization to reproduce more mature rhythmic features reliably.
By combining scalable human 2D neuronal networks with analytic tools that separate rhythmic peaks from broadband background activity, this approach gives researchers a reproducible platform to study how coordinated activity emerges and to test how drugs or genetic perturbations reshape network dynamics. Over time, these controlled datasets can build reference benchmarks for comparing genetic backgrounds, disease models, and candidate therapies.
Funding: The study was supported by the National Institutes of Health, the National Institute of Mental Health, the National Institute of General Medical Sciences, BioMarin Pharmaceutical, the Viterbi Family Foundation of the Jewish Community Foundation San Diego, and the Burroughs Wellcome Fund.
Key Questions Answered:
A: 3D organoids model tissue architecture and cellular variety well, but they are more variable and harder to scale. Flat 2D networks offer consistent, high-throughput conditions that are ideal for systematic drug screening, dose–response testing, and benchmarking across many replicates.
A: Nested oscillations are slower network waves that contain faster rhythmic patterns nested inside them. They are hallmarks of circuit maturation. When these multi-layer rhythms fail to form properly, it can contribute to seizures, developmental delays, and other neurological dysfunctions. Reproducing them in vitro allows direct study of how they arise and fail.
A: Yes. Because iPSCs can be derived from patient cells, researchers can grow patient-specific neuronal networks to compare rhythmic signatures with healthy controls and test compounds that might restore balanced activity.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by staff for clarity and reproducibility emphasis.
About this neuroscience research news
Author: Greg Calhoun
Source: Sanford Burnham Prebys
Contact: Greg Calhoun – Sanford Burnham Prebys
Image: Image credit to Neuroscience News
Original Research: Open access. “Pharmacological manipulation of nested oscillations in human iPSC-derived 2D neuronal networks” by Deborah Pré, Christian Cazares, Alexander T. Wooten, Haowen Zhou, Isabel Onofre, Ashley Neil, Todd Logan, Ruilong Hu, Jan H. Lui, Bradley Voytek, and Anne G. Bang. Neurobiology of Disease
DOI: 10.1016/j.nbd.2026.107281
Abstract
Pharmacological manipulation of nested oscillations in human iPSC-derived 2D neuronal networks
Dynamically coupled neural networks underlie human cognition and behavior and are altered in many neurodevelopmental disorders. Formation and dissolution of these functional networks are driven by synchronized oscillatory bursts across large populations of neurons. The cellular and circuit mechanisms that generate these rhythms, collectively referred to as oscillogenesis, remain poorly understood in the human brain.
Using multi-electrode arrays, we examined oscillogenesis in human iPSC-derived 2D neural cultures across developmental stages and during pharmacological challenges. Cultures exhibited nested oscillations that were reduced by blocking GABAA receptors and that emerged earlier when the proportion of GABAergic neurons increased. Manipulating voltage-gated potassium channels and cholinergic receptors produced distinct changes in nested oscillatory patterns.
These findings demonstrate the potential of 2D human neuronal cultures to model oscillogenesis and highlight the importance of refining these systems to link systems-level neural network dynamics to cognition and disease.