Allegra Conti

RESEARCH OUTPUT

Selected publications

1. A new in silico model to precisely design focused ultrasound brain therapies.Medical physics · 2026
   BACKGROUND: Focused ultrasound (FUS) combined with microbubbles enables transient and noninvasive blood-brain barrier (BBB) opening, facilitating targeted drug delivery. However, accurate treatment planning remains difficult due to inter-patient anatomical variability and the common assumption in simulations that brain tissues behave like water. PURPOSE: To develop and evaluate MODFUS ( M O D e l t o p r e c i s e l y d e s i g n F o c u s e d U l t r a S o u n d e x p e r i m e n t s ), an in silico acoustic simulation framework that integrates a high-resolution anatomical head model to quantify the impact of intracranial tissue heterogeneity and probe alignment on transmitted acoustic pressure, supporting treatment planning for BBB opening. METHODS: MODFUS integrates an anatomical head model comprising 115 tissue types and Computed Tomography (CT)-derived skull properties. FUS simulations were conducted using a 250 kHz single-element transducer at 13 distinct skull entry locations. Two modeling approaches were evaluated: a classical model, in which the skull was embedded in water and brain tissues were homogenized as water, and an heterogeneous anatomical model. To further assess robustness, an additional set of 50 simulations introduced controlled perturbations in probe positioning, consisting of angular deviations ( ± 18 ∘ ) and translational offsets ( ± 7 mm) relative to the reference configuration. Model- and configuration-dependent differences were quantified using peak positive pressure (PPP), peak negative pressure (PNP), and potential therapeutic volume. Statistical significance was assessed using Wilcoxon rank-sum or Wilcoxon signed-rank tests ( α = 0.05). For Classical vs Realistic models, Wilcoxon rank-sum tests were applied to PPP, PNP, and BBB exposure volume, and Levene's test assessed variance differences across 13 positions. Multiple testing was controlled using the Holm-Bonferroni procedure ( α = 0.05) across all tests. Effect sizes were quantified using Cohen's d with 95% confidence intervals. RESULTS: Compared to the classical "skull+water" benchmark model, the heterogeneous model predicted up to 11% lower PPP, slightly lower PNP ( ∼ -5%), and 35% smaller potential BBB exposure volumes across the 13 paired sonication positions. After Bonferroni correction, Paired statistical testing (Wilcoxon signed-rank, two-sided) showed significant differences for PPP (p = 0.0270) and potential BBB exposure volume (p = 0.0015), while differences in PNP were not statistically significant (p = 0.8286). Levene's test for variance confirmed significant heteroscedasticity for PPP (p = 0.027) and PNP (p = 3.2 × 10), but not for BBB exposure volume (p = 0.2680). Cohen's d effect sizes indicated a large positive effect for PPP, a small negative effect for PNP, and a very large positive effect for BBB exposure volume. CONCLUSIONS: MODFUS demonstrates the influence of incorporating detailed tissue heterogeneity on simulation outcomes, including pressure distribution and potential BBB exposure volume. These results highlight the importance of realistic soft tissue modeling and stereotaxic probe alignment for safe and effective FUS treatment planning. The study serves as a preliminary proof-of-concept. Future studies incorporating in vivo experiments will be required to quantify the accuracy of this approach.

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2. Ex vivo localization of wireless implantable microdevice using high-resolution 3D imaging techniques.Frontiers in bioengineering and biotechnology · 2026
   The CROSSBRAIN EU project aims to address the heterogeneous nature of brain pathologies by developing wireless implantable microbots (µBots, planned dimensions 100 × 100 × 100 μm3) for highly localized neuromodulation. These devices are designed to precisely modulate brain activity with minimal invasiveness, enabling targeted resolution of specific spatiotemporal events, capabilities not currently achieved by existing neuromodulation technologies. A crucial step involves visualizing and ensuring the optimal placement of the µBots in the brain tissue, to study their functionality after implantation. In this preliminary ex vivo study, we used non-functional µBot silicon (Si) dummies matching the lateral dimensions of the intended µBots, with reduced thickness (100 × 100 × 50 μm3) to simplify fabrication and handling. Due to the intrinsic MRI incompatibility of the µBot platform, encompassing both the dummies used in this study and the future functional devices under development, and the limitations of standard histological approaches in reliably identifying and preserving the implant site during processing, we developed an integrated imaging workflow combining 2D and 3D techniques. While standard histological methods and tissue clearing presented substantial limitations in preserving the position of the dummies within the brain tissue, combining histological techniques with 3D X-ray tomography provided a robust strategy. In particular, synchrotron radiation-based X-ray Phase Contrast Tomography (XPCT), with its intrinsic high contrast and resolution, enabled detailed visualization of dummies within the surrounding vascular and cellular architecture. In contrast, conventional micro-Computed Tomography (micro-CT), although more widely accessible, enabled non-destructive guidance for targeted sectioning. Importantly, and in line with the scope of a Brief Research Report, this study presents a preliminary but technically robust investigation conducted within the CROSSBRAIN project, aimed at identifying and establishing an optimized imaging strategy for the visualization of implanted µBots in brain tissue. This methodological framework is intended as an initial step toward future in vivo studies, in which the validated imaging pipeline will be applied to track both dummy and functional devices and to enable subsequent evaluation of foreign body response under physiologically relevant conditions. This ex vivo workflow therefore provides the essential technical foundation for such future investigations and supports the clear positioning of this work as a feasibility and optimization study. This approach could be particularly valuable for new generations of implantable technologies incompatible with MRI and could support future development of personalized neuromodulation therapies by enabling precise device localization and structural tissue assessment.

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3. Ultrasound-Assisted multimodal neuromodulation via nanosystems.Journal of nanobiotechnology · 2026
   Neuromodulation techniques have emerged as transformative tools for treating several neurological and psychiatric disorders, offering alternatives to traditional pharmacological approaches often hindered by the blood-brain barrier and off-target effects. While conventional modalities like deep brain stimulation, transcranial magnetic stimulation, and optogenetics have shown promise, they each face limitations in invasiveness, spatial resolution, or clinical applicability. In recent years, low-intensity ultrasound has gained attention as a noninvasive, deep-penetrating modality capable of modulating brain circuits with millimeter-sized spatial precision. This review explores the synergistic integration of ultrasound with engineered nanosystems to achieve multimodal neuromodulation such as electrical, mechanical, optical, and chemical via acoustic energy. We describe how nanoscale materials can transduce ultrasound into localized bioelectric signals, mechanical stress, light emission, or controlled drug release. These interactions enable precise, on-demand stimulation or inhibition of neuronal activity, including in deep brain regions. Experimental studies have demonstrated neuromodulatory effects across a variety of models, with applications ranging from optogenetics and drug delivery to behavioral modulation in rodents and primates. The review concludes with a critical assessment of the translational challenges such as nanoparticle delivery, biocompatibility, long-term clearance, and safety thresholds for human use while outlining promising strategies like cell-based delivery, biodegradable materials, and closed-loop control systems. These innovations highlight the potential of ultrasound-assisted nanosystems as transformative tools for precise neuromodulation in both experimental neuroscience and clinical applications.

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4. Therapeutic ultrasound for the treatment of demyelinating diseases.Progress in neurobiology · 2026
   Demyelinating diseases, such as multiple sclerosis, result from the progressive loss of myelin sheaths in the central and peripheral nervous systems, leading to impaired neural conduction and disability. Current disease-modifying therapies focus on immunosuppression to limit inflammation but fail to restore lost myelin. This lack of regenerative capacity underscores the need for strategies that actively promote remyelination. Recent advances highlight neuromodulation, and in particular low-intensity ultrasound (US), as a promising approach to stimulate both neuronal activity and glial responses essential for myelin repair. Ultrasound noninvasively promotes remyelination through complementary mechanisms: indirectly, by enhancing activity-dependent myelination via neuronal firing, and directly, by exerting mechanical bioeffects on oligodendrocyte precursor cells, oligodendrocytes, astrocytes, microglia, and Schwann cells. Experimental studies show US activation of key signaling cascades (PI3K/Akt, MAPK/ERK, NF-κB, TGF-β1), promoting oligodendrocyte survival, differentiation, and myelin repair, alongside microglial polarization, astrocytic neurotrophic support, and functional recovery in central and peripheral models. Converging data from neuromodulation research indicate that activation of cholinergic and noradrenergic circuits-such as those engaged by vagus nerve stimulation-can enhance OPC differentiation, attenuate neuroinflammation, and support remyelination, raising the possibility that ultrasound-based stimulation of these pathways may synergistically amplify regenerative outcomes while avoiding the need for implanted devices. Ultrasound holds transformative potential for central nervous system repair and can also promote regenerative processes in the peripheral nervous system. Cutting-edge ultrasound technologies enable noninvasive penetration of the skull, precise modulation of deep brain circuits with millimeter accuracy, and fine temporal control without inducing systemic side effects. When combined with advanced imaging techniques (e.g., MR-guided US), ultrasound achieves increasingly effective therapeutic outcomes by enhancing beam-targeting precision and enabling real-time monitoring. Moreover, emerging approaches such as sonogenetics and magneto-acoustic stimulation further expand its specificity and therapeutic potential. Collectively, current evidence establishes therapeutic ultrasound as a transformative, noninvasive strategy for treating demyelinating diseases.

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5. Magnetite nanodiscs as vortex-enhanced MRI contrast agents: a novel approach in medical imaging.Nanoscale advances · 2026
   Magnetic nanodiscs (MNDs) represent a transformative class of anisotropic magnetic nanoparticles with intrinsic vortex magnetization, enabling multifunctional applications in biomedical imaging and therapy. Here, we demonstrate their potential as dual-mode magnetic resonance (MR) contrast agents, a unique feature which is enabled by the high longitudinal relaxivity (r 1 ≈ 40 mM-1 s-1) at ultralow magnetic fields (<70 µT) in combination with strong transverse relaxivity (r 2 > 150 mM-1 s-1) at ultrahigh fields (>7 T). This field-dependent relaxivity profile uniquely positions MNDs as versatile T 1/T 2 agents compatible with emerging low-field MRI platforms and high-resolution clinical systems. Ex vivo and in vivo assessments confirmed clear anatomical localization and preferential hepatic accumulation, suggesting prolonged circulation times due to surface-mediated immune evasion. These properties highlight MNDs as promising candidates for next-generation theranostics, with tunable magnetic responses, high contrast efficiency, and the ability to synergize imaging and neurostimulation.

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