CITRUS is committed to actively collaborating with other projects funded under the 2021 EIC Pathfinder challenge call "Tools to measure and stimulate activity in brain tissue". We strongly believe in the importance of partnerships to harness collective expertise and resources, thus maximizing the impact of our research and development endeavours.
Major depressive disorder (MDD) is the leading cause of disability worldwide, affecting 300 million people with a lifetime prevalence of 15%. Approximately one third of all MDD patients fail to respond to currently established treatments based on medication and psychotherapy, thus falling into the category of Treatment-Resistant Depression (TRD) patients. Electroconvulsive therapy (ECT), repetitive Transcranial Magnetic Stimulation (tRMS), Vagus nerve stimulation, deep brain stimulation (DBS) and transcranial focused ultrasound (tFUS) still show poor spatial resolution (ECT, tRMS, tFUS) or low network coverage (VNS, DBS), with average remission rates in clinical trials still lower than 30 %. Apart from the existing stimulation hurdles, reliable biomarkers for depression are needed as a diagnostic tool, and, in the case of NT, to determine the stimulation efficacy and allow for personalized treatment. The UPSIDE project proposes a minimally invasive, high spatial resolution and multi-brain region stimulation and recording system to largely exceed the capabilities of existing NT for depression. Our objective is to research and validate in vivo an hybrid neurotechnology consisting of an epidural focused ultrasound (eFUS) stimulator employing three-dimensional beamforming, and a high-density epidural EEG recording system. Epidural deployment of these devices will be enabled by novel methods for massive integration and miniaturization of high-performing piezoelectric ultrasound materials and high-fidelity organic bioelectronic materials with high energy-efficient complementary metal-oxide semiconductor (CMOS) technology in a biocompatible manner. The UPSIDE project will result in a demonstrator which will allow, for the first time, network stimulation and simultaneous biomarker readout in behavioral experiments with animal models featuring depression-like symptoms. This technological breakthrough will pave the way towards a personalized treatment for TRD.
Obtaining functional information on living organs non-invasively across different size scales is a tremendous challenge in medical imaging research, as diseases start locally at the cellular level deep into organs before expressing large-scale and observable symptoms. The unique complexity of the human brain adds another level of difficulty for neuroimaging. The cerebrovascular system consists of a multiscale network of blood vessels. Interaction between neurons and this vascular system, the so-called neurovascular coupling, is a major foundation of brain function leading to constant adaptation of the local cerebral blood flow to local metabolic demand. Its alteration is intimately linked to cerebral dysfunction. Current brain imaging modalities are essential for evaluating cerebrovascular diseases in patients but are restricted to millimetric resolution and fail to capture most of blood flow dynamics. Here, we propose to revolutionize the field of neuroimaging by introducing a groundbreaking technology called functional Ultrasound Localization Microscopy (fULM) capable of monitoring transcranially the whole human brain vasculature and function down to microscopic resolution. Beyond opening a complete paradigm shift in brain angiography (at least two orders of magnitude increase in spatial resolution), fULM will also be able to map the functional brain response during task-evoked and spontaneous activity at microscopic levels. We will address major technical challenges of ultrasound imaging, develop advanced neurocomputational analysis methods, validate our methods in preclinical models of cerebrovascular diseases and perform a First-In-Human study. Fundamental understanding of brain hemodynamics and neurovascular coupling as well as early clinical diagnosis of neurovascular abnormalities and evaluation of drug efficacy would tremendously benefit from such capabilities revealing both the brain vasculature and neurofunctional activity down to microscopic resolutions.
A vast number of pathological brain conditions directly involve aberrant electrical activity of the brain. CROSSBRAIN centres its technological revolution on the convergence of novel nanoactuation modalities, bleeding-edge nano-electronics, and miniaturized wireless energy harvesting and communication. Combining extreme edge computing with advanced nanomaterials featuring tailored physical properties, biocompatible coatings, and material modifications to prevent glial scarring, CROSSBRAIN will enable individualized, adaptive and highly spatiotemporally localized actuation of brain tissue. It will leverage sensing electric local field potentials, multiunit neuronal activity, and cross-modal nanomaterial-based modulation (electrical, mechanical, thermal, ionic concentration, optogenetics) of neuronal excitability with on-board intelligence. The CROSSBRAIN platform comprises a swarm of wireless, implantable, MRI-compatible microbots for in vivo electrophysiology and cross-modal neuromodulation at the cell- and microcircuit levels, in freely moving rodents. CROSSBRAIN delivers a multiplicity of stimulation modalities, involving electro-mechano-magneto-thermo-optical principles for modulation of nerve cell excitability. The microbots will feature both sensing and actuation electrodes, engineered with nanomaterials and viral vectors coatings. They will be implanted endovascularly, deliver genetic material upon command, and operate in federation under the networked control and wireless power supply by a tiny central unit, which can be worn like an internet of things device. CROSSBRAIN will deliver autonomous or manual, closed-loop sensing, prediction, and actuation through combining multiple neuromodulation mechanisms, which will act in a synergistic and dynamic manner to optimally shape stimulation according to individual neuronal firing patterns or clinician’s needs. As case studies, we will explore CROSSBRAIN action in animal models of Parkinson’s Disease and Epilepsy.