New Technologies Enable Whole-Network Mapping of Human Neural Activity

A team led by scientists at Northwestern University and Shirley Ryan AbilityLab have developed a new technology that can eavesdrop on the hidden electrical dialogues unfolding inside miniature, lab-grown human brain-like tissues. The soft, three-dimensional electronic framework wraps around an organoid like a breathable, high-tech mesh, delivering near-complete, shape-conforming coverage with hundreds of miniaturized electrodes. The study was published Feb. 18 in the journal Nature Biomedical Engineering.

Scientists studying human neural organoids could only record and stimulate activity from limited regions because conventional flat electronics do not conform well to the tissues' three-dimensional, spherical structure. Rather than sampling select regions, the new technology delivers dense, three-dimensional interfacing that enables scientists to map and manipulate neural activity across almost the entire organoid.

"Human stem cell-derived organoids have become a major focus of biomedical research because they enable patient-specific studies of how tissues respond to drugs and emerging therapies," said a bioelectronic pioneer who led the device development. "Labs in academia and industry have developed these tissue constructs over the years, and the National Institutes of Health (NIH) has initiated funding streams to accelerate work in this direction. A key missing component is hardware technology that can interrogate, stimulate, and manipulate these tiny analogs to organs in the human body."

"Human neural organoids are living 3D tissues that contain active neural circuits communicating through electrical signals. However, the state-of-the-art instruments we use to study them were originally designed for flat layers of cells and do not interface well with organoids that are spherical and three dimensional," said a researcher who led the organoid development. "By creating soft, shape-matched electronics that conform to the organoid's geometry, we can now record from and stimulate hundreds of locations across its surface at once. This allows us to study neural activity at the level of whole networks rather than isolated signals."

In a complementary approach published in Neurobiology of Disease, researchers at Sanford Burnham Prebys Medical Discovery Institute, with collaborators at the University of California San Diego and BioMarin Pharmaceutical, have developed a simplified, scalable human cell model to study how coordinated rhythms emerge and how they respond when neurons are perturbed with chemical compounds.

The team's approach was to grow two-dimensional networks of human neurons derived from induced pluripotent stem cells. The scientists recorded the neurons' activity over time using multi-electrode arrays, plates embedded with tiny sensors that can monitor many independent networks in parallel. Because iPSCs can be generated in the lab from accessible donor cells such as from skin or blood samples, they make it possible to produce large numbers of human neurons from both healthy individuals and patients.

As these 2D networks matured, the researchers observed the emergence of "nested oscillations," slow waves with faster rhythmic structure layered within them. These oscillations were observed across frequency ranges commonly seen in brain recordings (delta, theta, and alpha).

"The results of these and other experiments show that this simplified 2D neuronal network model captures key features of network maturation, and gives us the scale and control needed for systematic testing," said the study's senior and co-corresponding author, an associate professor in the Center for Therapeutics Discovery at Sanford Burnham Prebys and director of Cell Biology at the Conrad Prebys Center for Chemical Genomics.

The new work positions 2D networks as complementary to three-dimensional brain organoids. Organoids, also produced from iPSCs, can recapitulate aspects of tissue architecture, cellular diversity, and network activity that are difficult to reproduce in 2D formats. At the same time, organoid complexity can make certain experiments harder to run at scale, particularly studies that require large numbers of replicates or extensive dose–response testing across many conditions.

"Organoids are invaluable for modeling aspects of brain organization," said the senior author. "What we add here is a complementary 2D platform that emphasizes experimental control and throughput, capabilities that can be especially useful for benchmarking and systematic testing in disease modeling and early-stage therapeutic evaluation."

One major focus of the team's study was inhibitory signaling mediated by GABA, a neurotransmitter produced by GABAergic neurons that helps stabilize and calm network activity. For instance, this inhibitory system helps promote sleep and prevent seizures.

The team found that nested rhythms were reduced when GABA signaling was blocked with a GABA-A receptor antagonist drug, and that increasing the proportion of GABAergic neurons in the network caused these rhythms to emerge earlier. Their findings align with prior evidence in the field and support follow-up studies on how GABA-mediated inhibition shapes the emergence and maturation of oscillations in iPSC-based models of neurodevelopmental and psychiatric disease.

The researchers also tested drugs that affect potassium channels. These proteins help set a neuron's ability to generate and transmit electrical signals, which is known as neuronal excitability. Their results suggested that different potassium channel perturbations can influence rhythmic organization in distinct ways, highlighting that excitability is not a single dial that can easily be turned up or down, and that specific mechanisms may have specific network-level signatures.

By capturing whole-network brain-like activity and drug responses in living human tissue models, the technology could accelerate disease research, therapy testing, and the development of next-generation neuroregenerative treatments. As organoids become a growing priority for NIH initiatives and for industry drug development, these advances in recording and stimulation technology provide critical tools for developing effective therapies for brain disorders.