Clinical depression is associated with dysfunctional neural networks that regulate mood, emotion and reward-orientated behaviours. Neuromodulation is a therapeutic strategy aiming to correct the activity of the pathological pathways that underpin the key symptoms. The current project aims to produce an implantable epidural brain interface (EBI) with low-intensity focused ultrasound and cortical recording capability that can regulate neural activity in a spatial and temporal defined fashion via focused acoustic pressure waves. The EBI will combine the CMOS Integrated focused ultrasound stimulation chip and the CMOS integrated ion gated transistor neural recording arrays (henceforth referred to as “eREC”).
The objectives leading into D4.1 were to procure and test the commercially available FUS on diverse media to verify its technical characteristics (e.g. focal length). The media used were temperature sensitive film, an agar-based tissue phantom, post-mortem 4% PFA fixed brains, or in unfixed ex vivo brains. Furthermore, the preliminary studies were to identify appropriate stimulation parameters – in terms of intensity and targeting – that could serve as the basis for future deliverables. Targeting in the brain of freshly sacrificed animals was confirmed with a histological staining. An additional important commitment (and component of D4.1) was to design together with our consortium partners a prototype for the EBI (including both eFUS and eREC), and generate the appropriate consequent surgical method and protocol for the implantation of the EBI on the rodent’s head/ skull. The surgical protocol needed to take into account both physical constraints on the rat’s head, such as the skull’s thickness or its anterior-posterior or lateral dimensions, as well all the physical characteristics of the EBI. Throughout the protocol refinement consideration had to be given to animal welfare, particularly in view of optimizing craniotomy size and EBI fixation options. At this stage, the two components of the implantable EBI, the eREC array and the eFUS chip, along with their PCBs and connections, are developed separately but in consultation across the consortium members. On these grounds, the prototype EBI for which we have developed the implantation protocol could evolve over time.
The document describes the effort leading up to the completion of Deliverable D4.1, work carried out in the context of WP4 Tasks 4.1. Deliverable D4.1 concerns i.) the implantation protocol for the (EBI) on the rodent’s head/ skull and ii.) targeting the focused ultrasound (FUS) in a rat brain using a commercially available transducer.
Using the commercial transducer, we performed the planned in vitro and ex vivo tests. With the use of a power amplifier the maximum focal pressure was sufficient to cause a lesion in an explanted fixed rat brain. It was not possible to form a lesion in the mfb in unfixed tissue with the same parameters, instead a larger area of the tissue was heated. While further tests will be conducted and the temperature of the brain at the time of stimulation has to be taken into account as well as shorter stimulation times, at this
point the commercial transducer does not seem to be the ideal tool to target the mfb in vivo. The large necessary craniotomy and focal spot size seem to make it difficult to target deep structures reliably and accurately. Therefore the Task 4.2 will be achieved by looking at brain slice cultures of the mfb and shallower targets using histological methods and electrophysiological recordings. As soon as the first generation of the chip is ready, the mfb can be targeted and the parameters confirmed. In the second part of Task 4.1 an implantation protocol was established for the eFUS chip and eREC electrode on their own, as well as the integrated EBI. Since the design and development is an ongoing process, especially for the used PCB boards, exact craniotomy sizes and PCB dimensions might change in the future. The general method, as well as the size constrictions for both the craniotomies and PCBs have been successfully tested. With the use of two layered PCB boards, sufficient pressure can be applied to assure the FUS Chip is in constant contact with the brain surface. We will need to confirm whether the angle of the chip can be kept perpendicular to the target during fixation. The gap between the 7 mm craniotomy and 5 mm chip would allow for additional electrodes surrounding the chip although for the recording of potential biomarkers the extension of the electrode onto the prefrontal cortex is essential.
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