Real-time brain monitoring for neurosurgery and neuroscience research of natural behaviors demands portable imaging with high spatiotemporal resolution. Current technologies cannot simultaneously achieve the resolution, mobility, and real-time performance required. Here we present a miniaturized four-dimensional functional ultrasound system capturing volumetric brain hemodynamics in real-time using 3072 transceivers controlled by custom application-specific integrated circuits. The device achieves 450 Hz volumetric imaging up to 8 cm depth while maintaining a form factor suitable for direct cortical placement and potential sub-cranial implantation. We validated this technology across three clinical scenarios: through skull prosthesis, cranial defect, and during neurosurgery. The system mapped somatotopic finger representations and achieved decoding of individual finger movements during piano playing using machine learning, demonstrating single-trial detection. This portable platform establishes a new approach for brain monitoring bridging laboratory neuroscience and clinical applications, enabling research in natural behavioral settings, providing surgeons real-time hemodynamic feedback, and advancing brain-computer interface development.

A.J.F., B.L., A.J.J., N.J.R., and M.B. work for Oldelft Ultrasound. The other authors have no competing interests to declare.

This work was supported by the NWO-Groot grant of The Dutch Organization for Scientific Research (NWO), awarded to CUBE (Center for Ultrasound and Brain-Imaging @ Erasmus MC, grant no. 175.2017.008 to S.S., and P.K.), TKI-LSH (RELAY and 4DBrain, no grant numbers available, to S.S., L.V., and P.K.), Erasmus MC - Mrace (Pilot & PhD, no grant numbers available, to A.J.P.E.V., S.S., L.V and P.K.), and the Dutch Heart Foundation (Hartstichting) as part of project number 03-004-2022-0044.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Prior to inclusion, written informed consent was obtained from all patients in line with the Dutch national medical-ethical regulations as formulated by The Central Committee on Research Involving Human Subjects (CCMO) in the Netherlands. The Erasmus Medical Center's Medical Research Ethics Committees (MREC), located in Rotterdam, the Netherlands, reviewed the three research protocols underlying the current study and ethical approval was given on all three occasions: 1. intraoperative functional Ultrasound (fUS)-imaging during awake and anesthetized neurosurgical procedures (fUS Studie), protocol number MEC-2018-037 (Ethical approval was given on 22nd of January 2020) 2. functional Ultrasound (fUS)-imaging in volunteers with a Skull Bone Defect (SBD), protocol number MEC-2019-0689 (Ethical approval was given on 29th of November 2019) 3. functional Ultrasound (fUS) and fMRI-imaging in patients with a Skull Bone Defect (SBD), protocol number MEC-2022-0087 (Ethical approval was given on 24th of May 2022) All methods in this study were carried out according to the protocols listed above. All subjects gave permission for the use and publication of their images and data.

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All data produced in the present study are available upon reasonable request to the authors.