Periodic Reporting for period 1 - UPSIDE (Focused Ultrasound Personalized Therapy for the Treatment of Depression (UPSIDE))
Reporting period: 2022-09-01 to 2023-08-31
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 objectives of the UPSIDE project during the first 12 months consisted of ramping the scientific tasks towards the first deliverables (WP1, WP2 and WP4), while setting up administrative backbone of the project (WP6 – project handbook), working on the communication, dissemination and exploitation activities (WP7 - project website, data management plan and the plan for dissemination, communication and exploitation) and participating in activities related to the portfolio of actions (WP8). On the scientific front, the integrated circuit technology and the microfabrication of ultrasound transducers has been developed as expected (WP1), while the tasks on the organic bioelectronics front also resulted in the first prototypes for in vitro and in vivo validation. Finally, WP4 started in M6 with the work on the targeting protocols using a commercial focused ultrasound transducer. Even though the activities of WP3 and WP5 were not part yet of the first year of the project, their relationship with the remaining technical WPs was carefully considered and preliminary information obtain towards the successful start of its tasks.
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 objectives of the UPSIDE project during the first 12 months consisted of ramping the scientific tasks towards the first deliverables (WP1, WP2 and WP4), while setting up administrative backbone of the project (WP6 – project handbook), working on the communication, dissemination and exploitation activities (WP7 - project website, data management plan and the plan for dissemination, communication and exploitation) and participating in activities related to the portfolio of actions (WP8). On the scientific front, the integrated circuit technology and the microfabrication of ultrasound transducers has been developed as expected (WP1), while the tasks on the organic bioelectronics front also resulted in the first prototypes for in vitro and in vivo validation. Finally, WP4 started in M6 with the work on the targeting protocols using a commercial focused ultrasound transducer. Even though the activities of WP3 and WP5 were not part yet of the first year of the project, their relationship with the remaining technical WPs was carefully considered and preliminary information obtain towards the successful start of its tasks.
• WP1
In T1.1 the CMOS interface for 2D ultrasound transducer arrays was conceptualized, validated in computer simulations, fabricated at the TSMC foundry, and experimentally validated. The circuits were optimized for power-efficiency, in close collaboration with the SG team regarding the specifications for the power management unit (T1.3) and the overall chip layout (area, thickness and form-factor) was monitored by the UF team to ensure compatibility with the implantation procedure in the rat models. In T1.2 the microfabrication procedure for integration of piezoelectric transducers in the CMOS chip was conceptualized and tested on silicon dummy chips. Furthermore, an innovative backing layer was designed and fabricated to ensure the lossless integration of piezoelectric transducers with CMOS, towards high-energy efficient ultrasound neuromodulation. In T1.3 the power management unit was specified in accordance with the requirements of the CMOS interface for piezoelectric transducers (T1.1) and the CMOS recording front-end (T1.4) and subsequently designed, validated, and sent for fabrication at the TSMC foundry. Finally, in Task 1.4 the CMOS recording interface for high-density EEG was conceptualized and is currently being validated in computer simulations prior to fabrication at the TSMC foundry, the system architecture was co-designed with UG according to specifications needed for integration with the electrode array (T3.2). A novel on-chip low power neural signal processor was developed to deal with the massive amount of raw data produced by the recording ASIC [Hoda, ISCAS’23].
• WP2
In T2.1 different designs (1st generation) of conformable neural arrays employing conductive polymer based electrodes were conceptualized, fabricated and experimentally validated. To do that we had to: i) optimize interconnection and connection strategies by means that are translatable to a later connection with our customized chip, ii) develop a microfabrication route; iii) perform quality control ; iv) validate the 1st generation probe in vivo; v) collect and analyse neural data. Every stage produced valuable data that will be used as feedback for the next generation designs and the continuation of the following tasks.
• WP4
WP4 is the preclinical/ experimental validation work-package of the multicentre UPSIDE project. During the current reporting period (M1-M12) progress in WP4 has been focused principally on T4.1 but important advances required to complete T4.4 have also been made. Work in T4.1 concentrated on i.) close collaboration with the other centres (TUD, GU) concerning the design of the eFUS/ eREC device based on the physical constraints imposed by the dimensions of the rodent skull and brain anatomy; ii.) working out the surgical protocols for the epidural implantation of the eFUS/ eREC device, for example, the required craniotomy and methods for the fixation of the device for future chronic studies (described in T4.3 – 4.5); and iii.) obtaining early experience with the use of a commercially available focussed ultrasound transducer, developing necessary accessories, and working out parameters for lesioning and stimulation. During the current reporting period, significant progress has also been made in establishing Fibre Photometry, a technique to be employed in T4.4 to monitor real-time in vivo neurotransmitter release in freely moving and behaving animals.
In T1.1 the CMOS interface for 2D ultrasound transducer arrays was conceptualized, validated in computer simulations, fabricated at the TSMC foundry, and experimentally validated. The circuits were optimized for power-efficiency, in close collaboration with the SG team regarding the specifications for the power management unit (T1.3) and the overall chip layout (area, thickness and form-factor) was monitored by the UF team to ensure compatibility with the implantation procedure in the rat models. In T1.2 the microfabrication procedure for integration of piezoelectric transducers in the CMOS chip was conceptualized and tested on silicon dummy chips. Furthermore, an innovative backing layer was designed and fabricated to ensure the lossless integration of piezoelectric transducers with CMOS, towards high-energy efficient ultrasound neuromodulation. In T1.3 the power management unit was specified in accordance with the requirements of the CMOS interface for piezoelectric transducers (T1.1) and the CMOS recording front-end (T1.4) and subsequently designed, validated, and sent for fabrication at the TSMC foundry. Finally, in Task 1.4 the CMOS recording interface for high-density EEG was conceptualized and is currently being validated in computer simulations prior to fabrication at the TSMC foundry, the system architecture was co-designed with UG according to specifications needed for integration with the electrode array (T3.2). A novel on-chip low power neural signal processor was developed to deal with the massive amount of raw data produced by the recording ASIC [Hoda, ISCAS’23].
• WP2
In T2.1 different designs (1st generation) of conformable neural arrays employing conductive polymer based electrodes were conceptualized, fabricated and experimentally validated. To do that we had to: i) optimize interconnection and connection strategies by means that are translatable to a later connection with our customized chip, ii) develop a microfabrication route; iii) perform quality control ; iv) validate the 1st generation probe in vivo; v) collect and analyse neural data. Every stage produced valuable data that will be used as feedback for the next generation designs and the continuation of the following tasks.
• WP4
WP4 is the preclinical/ experimental validation work-package of the multicentre UPSIDE project. During the current reporting period (M1-M12) progress in WP4 has been focused principally on T4.1 but important advances required to complete T4.4 have also been made. Work in T4.1 concentrated on i.) close collaboration with the other centres (TUD, GU) concerning the design of the eFUS/ eREC device based on the physical constraints imposed by the dimensions of the rodent skull and brain anatomy; ii.) working out the surgical protocols for the epidural implantation of the eFUS/ eREC device, for example, the required craniotomy and methods for the fixation of the device for future chronic studies (described in T4.3 – 4.5); and iii.) obtaining early experience with the use of a commercially available focussed ultrasound transducer, developing necessary accessories, and working out parameters for lesioning and stimulation. During the current reporting period, significant progress has also been made in establishing Fibre Photometry, a technique to be employed in T4.4 to monitor real-time in vivo neurotransmitter release in freely moving and behaving animals.
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 towards reaching its first deliverables.