Focused Ultrasound Personalized Therapy for the Treatment of Depression (UPSIDE)

Project Information

UPSIDE

Grant agreement ID: 101070931

DOI

10.3030/101070931

EC signature date 23 June 2022

Start date 1 September 2022

End date 30 November 2026

Funded under

• The European Innovation Council (EIC)

Total cost

€ 4 149 921,25

EU contribution

€ 4 149 921,00

Coordinated by

TECHNISCHE UNIVERSITEIT DELFT
Netherlands

Periodic Reporting for period 2 - UPSIDE (Focused Ultrasound Personalized Therapy for the Treatment of Depression (UPSIDE))

Reporting period: 2023-09-01 to 2025-02-28

Summary of the context and overall objectives of the project

The UPSIDE project proposes an Epidural Brain Interface (EBI) featuring a minimally invasive, responsive neural stimulation system that utilizes focused ultrasound multi-brain region stimulation (eFUS) and high spatio-temporal resolution electrical recording (eREC) to innovate the way we treat TRD (Fig.1). Epidural deployment of these devices will be enabled by the combination of state-of-the-art microelectronic devices with the latest advances in organic neuroelectronics. This massive miniaturization and the avoidance of disrupting the dura mater and brain tissue leads to a decreased device size and highly minimizes the complexity of the surgery and the implantation risk. This translates to a more favourable risk-benefit profile when compared to other invasive techniques such as deep brain stimulation.

The UPSIDE project encompasses four research objectives:
• Research and design energy-efficient CMOS circuits for interfacing with 2D arrays of ultrasound transducers and organic neural recording arrays
• Design and integrate ultrasound transducers and organic neural recording arrays with the CMOS interfaces in a biocompatible and flexible epidural system, to achieve a full EBI
• Research neural signal decoding tools to identify depression biomarkers to enable a personalized therapy for depression
• Assess safety and efficacy of the EBI in addressing depression-like symptoms in vivo, in behavioral rat models of depression

The UPSIDE project will result in an EBI that will allow, for the first time, in vivo behavioural experiments with animal models with depression-like symptoms under the stimulation of different brain regions along relevant neural pathways while simultaneously monitoring neural signals as biomarkers. While this will be researched in a pre-clinical setting with rat animal models, UPSIDE will enable designs, methods, and biocompatible materials that can be translated to humans.

The UPSIDE project is actively pursuing the development of an innovative epidural brain interface (EBI). The work encompasses the development of the device itself and the methodologies for its application. Device development is progressing, with ongoing work being done in the design and fabrication of CMOS interfaces and ultrasound transducers.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

Key achievements include the electrical and acoustic characterization of a CMOS-based ultrasound arrays and the validation of CMOS recording chip connected with passive electrode arrays, in vitro. The design of a power management unit is also underway. Different interconnect and encapsulation strategies for the device are being explored. The project is also focused on developing high-density conformable neural recording technologies, with ongoing work in the development of both passive multi-electrode arrays (MEAs) and ion-gated transistor (IGT) arrays. Progress has been made in achieving high signal-to-noise ratios and demonstrating in vitro stability. In parallel, the project is developing analytical tools to process and interpret the neural signals recorded by the device. A pipeline for offline analysis of EEG signals is being developed, incorporating methods for feature extraction and data clustering. In vivo testing to validate the technology is underway, including studies to optimize stimulation parameters and assess the feasibility of achieving the project's objectives in animal models.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

The work in WP1 will pave the way for an epidural focused ultrasound device with unprecedented volumetric spatial resolution and coverage in the context of rodent experiments. Furthermore, the chip can operate at high ultrasound frequencies (12 MHz), tailored for rat experiments, but it is also compatible with 6 MHz ultrasound, for translation into large animal models or humans. It will also enable future implantable brain-computer interfaces that can record from >1000 channels while processing information locally to reduce the cost of wireless data transfer. We anticipate that the devices and protocols developed in WP2 could result in new findings regarding the effect of the ultrasound stimulation on brain and facilitate the studies and treatment of depression that could have translation potential for use with humans subject. The continuous progress made in WP4 is expected to result in the surgical and stimulation protocols.

Fig.2

Fig.1