Silent fMRI Framework Captures Brain-Wide Networks in Behaving Mice

For decades, functional magnetic resonance imaging has offered scientists an unmatched window into the human brain, revealing whole-brain networks at work without a single incision. Yet when researchers attempt to bring that same power to bear on the smallest and most behaviorally sophisticated laboratory mammals, they run into a wall of physics and physiology. A new framework described by MacKinnon and colleagues, and highlighted in a News & Views piece by Noam Shemesh in Nature Neuroscience, promises to tear down that wall. Called SORDINO-fMRI, the approach captures global brain dynamics in mice during complex behaviors while remaining silent, motion-resistant, and compatible with simultaneous cellular or chemical validation techniques. It is, as the commentary’s title suggests, a silent leap in neuroimaging.

To appreciate why this matters, one must first understand the stubborn technical difficulties that have long constrained rodent fMRI. Mapping brain-wide networks in behaving animals remains a formidable challenge for reasons rooted in the basic mechanics of magnetic resonance. Conventional fMRI relies on echo-planar imaging sequences that generate loud acoustic noise, often exceeding one hundred decibels inside the scanner bore. For a human volunteer lying still with ear protection, that noise is an annoyance. For a mouse, an animal whose hearing is far more sensitive and whose experimental value depends on natural behavior, the acoustic barrage is a confound of the first order. It activates auditory circuits, triggers stress responses, alters arousal, and contaminates precisely those network signals researchers hope to measure.

The problem compounds when the goal is to image animals that are awake and moving. Standard echo-planar sequences are exquisitely sensitive to motion, and even the small head movements of a behaving mouse produce artifacts that can dwarf the subtle blood-oxygenation-level-dependent signals of interest. Traditional workarounds, such as anesthetizing animals or restraining their heads while training them to tolerate the scanner, solve one problem by creating another. Anesthesia suppresses consciousness and reorganizes neural dynamics, so the networks measured under it are not the networks of a behaving animal. Head fixation permits imaging during limited tasks but rules out the rich, ethologically meaningful behaviors, navigation, social interaction, foraging, that make rodents so valuable as models in the first place.

SORDINO-fMRI addresses both obstacles at once. The framework is silent, eliminating the acoustic confound that plagues conventional sequences, and it is motion-resistant by design, so that the global dynamics of freely orchestrating animals can be captured without the ghosting, blurring, and signal dropout that normally accompany movement in the magnet. According to the News & Views summary, the method captures global dynamics during complex behaviors in mice while enabling artifact-free simultaneous network-level recordings with cellular or chemical validation. That last clause deserves emphasis: SORDINO-fMRI does not operate in isolation but can be paired, in the same scanning session, with techniques that read out neural activity or neurochemistry at the cellular scale. This creates a rare multimodal platform in which whole-brain network dynamics and mechanistic ground truth can be acquired in parallel.

The significance of this convergence becomes clear when one considers how neuroscience has been pulled in two directions by its tools. On one side, techniques such as widefield calcium imaging, two-photon microscopy, and high-density electrophysiology offer cellular or near-cellular resolution, but each covers only a limited field of view. Landmark large-scale efforts, including work from the International Brain Laboratory and the population recordings of Stringer and colleagues as well as Steinmetz, Zatka-Haas, Carandini, and Harris, have shown how much can be learned from recording many neurons or many brain regions simultaneously. Yet even hundreds of targeted probes cannot deliver a truly brain-wide picture in a small rodent brain without gaps. On the other side, fMRI delivers that brain-wide coverage but has historically lacked cellular specificity and, in rodents, behavioral realism. SORDINO-fMRI aims to close this gap, bringing whole-brain functional imaging into the awake, behaving regime where modern systems neuroscience now lives.

The timing of this advance is not accidental. The past several years have seen an intensifying effort to legitimize and improve rodent fMRI as a translational bridge between human imaging and circuit neuroscience. Reviews and methodological papers by Gao and colleagues, by Mandino, Vujic, Grandjean, and Lake, and by Daley, Pan, Kaundinya, and Keilholz have catalogued both the promise and the pitfalls of preclinical fMRI, from anesthesia confounds to the challenge of interpreting blood-oxygenation signals in a brain the size of a hazelnut. Studies by Yu and colleagues, and by Bolt and colleagues, have pushed toward whole-brain imaging of neural dynamics, while Rauscher and colleagues and Pagani and colleagues have recently expanded the frontier of what functional imaging in rodents can reveal. Lake and colleagues established foundations for imaging neural activity in awake animals that have informed the field’s trajectory. Shemesh’s commentary situates SORDINO-fMRI squarely within this arc, arguing that it opens new opportunities in preclinical imaging and systems neuroscience.

What might those opportunities look like in practice? Consider a mouse navigating a virtual or physical maze while its brain is imaged silently. Because the animal is awake and behaving, the researchers can ask how distributed networks, hippocampal, cortical, subcortical, coordinate in real time as the animal makes decisions, encodes space, or responds to rewards. Because the readout is artifact-free, fluctuations in the blood-oxygenation signal can be attributed to neural dynamics rather than to head motion or acoustic startle. And because simultaneous cellular or chemical validation is possible, the researchers can anchor the macroscopic network measurements to known quantities: the firing of specific neuronal populations, or the release of specific neuromodulators. This triangulation across scales is precisely what the field has needed to translate insights about circuit mechanisms into models that can be tested against human brain imaging, and vice versa.

The preclinical implications extend into translational medicine. Rodent models are indispensable for studying neurological and psychiatric disease, from Parkinson’s and epilepsy to depression and schizophrenia, but the field has long struggled with the failure of therapies that succeed in mice and fail in humans. A significant part of that failure is measurement: preclinical readouts often do not correspond to the outcome measures used in clinical trials. A method that can image brain-wide network function in behaving disease-model mice, with the same modality, fMRI, that is used in patients, offers a more direct translational axis. Network-level phenotypes measured with SORDINO-fMRI could, in principle, be compared quantitatively with resting-state and task-based networks in human patients, enabling a more rigorous back-and-forth between bench and bedside.

None of this diminishes the substantial work that remains. Interpreting fMRI signals in rodents requires careful attention to neurovascular coupling, which may differ across species, brain regions, and behavioral states. Combining fMRI with optogenetics, electrophysiology, or pharmacology in the same session demands exquisite engineering, from radiofrequency-compatible hardware to protocols that keep animals healthy and cooperative inside a magnet. Shemesh, who directs research at the Weizmann Institute of Science and the Champalimaud Foundation and who has long championed advanced diffusion and functional MRI methods, is well placed to evaluate these challenges, and his commentary treats SORDINO-fMRI as a genuine advance rather than a finished solution. He discloses service on the scientific advisory board of Bruker Biospin, a reminder that the industrial ecosystem around preclinical imaging is actively engaged with these developments.

Still, the phrase that will linger with readers is the one Shemesh chose for his title: a silent leap. The word silent is literal, a reference to the acoustically quiet acquisition that makes natural behavior possible inside the scanner. But it also captures the way this methodological shift arrives without fanfare amid the louder headlines of AI models and brain-computer interfaces, quietly removing constraints that have shaped decades of experimental design. If SORDINO-fMRI performs as described, the neuroscience community gains something it has never had before: a way to watch entire mammalian brains orchestrate real behavior, at network scale, validated at the cellular level, all in a single experiment. For preclinical imaging and systems neuroscience alike, that is not an incremental improvement. It is a change in what questions can be asked at all, and the answers to those questions may reshape how we understand the brain in motion, in health, and in disease.

One useful way to situate the advance is through the physics of the blood-oxygenation-level-dependent signal itself. Because the hemodynamic response that fMRI measures unfolds over roughly a second or more, it is inherently slower than the millisecond-timescale spiking that electrophysiology captures, and its amplitude depends on local neurovascular mechanisms rather than on neural activity alone. This is why pairing network-level imaging with cellular or chemical readouts in the same session is so valuable: it allows investigators to calibrate what the vascular signal actually reflects under a given behavioral state, rather than assuming that coupling parameters measured in anesthetized preparations carry over unchanged.

The multimodal design also speaks to a broader trend in systems neuroscience toward convergent evidence. When a macroscopic network fluctuation can be checked against, for example, the concurrent firing of a defined neuronal population or the release of a neuromodulator, interpretations move from plausible to testable. Such cross-scale validation has historically required separate experiments in separate animals, introducing variability that complicates comparison. Acquiring the modalities simultaneously in the same animal ties them together temporally, so that a transient change in global dynamics can be linked to its cellular substrate at the very moment it occurs. For preclinical studies of disease models, where network alterations may be subtle and state-dependent, that temporal alignment could prove as consequential as the silence and motion resistance themselves.

Subject of Research: A silent, motion-resistant fMRI framework for brain-wide imaging of behaving mice

Article Title: A silent leap in neuroimaging

Article References: Shemesh, N. (2026). A silent leap in neuroimaging. Nature Neuroscience. https://doi.org/10.1038/s41593-026-02401-1

Image Credits: AI Generated

DOI: 10.1038/s41593-026-02401-1

Keywords: SORDINO-fMRI, functional MRI, neuroimaging, rodent brain imaging, awake behaving mice, brain networks, systems neuroscience, preclinical imaging, Nature Neuroscience, Noam Shemesh, MacKinnon, silent fMRI