Biology subjects

Konofagou, E.

Publications and source records attributed to Konofagou, E..

12 recordsLinked to original sources

bioRxiv2026

A Fully Endovascular Neural Interface

Electrical stimulation of neural circuits is expanding therapeutic strategies to modulate brain, autonomic, and immune functions. Devices delivered endovascularly offer a less invasive alternative to conventional implanted electrodes, while delivering spatio-temporal specificity superior to noninvasive techniques. We demonstrate a fully endovascular sub-1-mm3 implant, utilizing ultrasound for wireless power delivery and data telemetry in a fashion invariant to device orientation. The implant consists of piezoelectric transducers, an energy storage capacitor, an application-specific integrated circuit, and electrodes packaged on a 7-{micro}m-thick polyimide scaffold. The implant can be delivered through a microcatheter in a manner analogous to conventional neurovascular stents, and self-expands upon deployment to appose the vessel walls. We demonstrate intravascular stimulation of the autonomic nervous system from the carotid artery, achieving modulation of blood pressure in rabbits. This approach establishes a broadly applicable platform for neural interfaces enabling both stimulation and recording.

neuroscience↗

bioRxiv2025

Transcranial Focused Ultrasound of the Human Subgenual Anterior Cingulate Reconfigures Resting State Connectivity: A Sham-Controlled fMRI Study

Transcranial focused ultrasound stimulation (tFUS) can modulate human brain activity, but its impact on large-scale functional connectivity (FC) in vivo remains incompletely characterized. Here we asked whether brief tFUS to the subgenual anterior cingulate cortex (sgACC) modulates its FC with other brain regions. In a sham-controlled, within-subject study of healthy adults (N = 16), we measured resting-state blood-oxygen-level dependent (BOLD) activity with functional magnetic resonance imaging (fMRI) before, during, and after five minutes of tFUS (i.e., five 20-second sonications followed by 40 second pauses). Subject-level sgACC-whole-brain FC was analyzed with a linear mixed-effects model (fixed: time, condition, timexcondition; random: subject). tFUS increased sgACC-whole brain connectivity after sonication relative to sham. A smaller, non-significant trend was observed during sonication. Baseline-controlled analyses were employed to rule out the possibility that the observed increase in FC was due to a "regression to the mean" effect. Interestingly, network-level analysis revealed a clear disassociation in the evolution of resting-state FC across the 15 minute recordings: during sham sessions, the sgACCs connectivity with the default mode network (DMN) increased, while FC with other networks was largely unchanged. On the other hand, active tFUS led to a notable increase in FC with non-DMN networks (especially the cognitive control network), while connectivity with the DMN was stable. These results provide whole-brain evidence that tFUS reconfigures network dynamics in the human brain, motivating clinical applications to disorders characterized by dysregulated brain activity.

neuroscience↗

bioRxiv2025

Alteration of Water Exchange Rates Following Focused Ultrasound-Mediated BBB Opening in the Dorsal Striatum of Non-Human Primates: A Diffusion-Prepared pCASL Study

This study applied diffusion-prepared pseudo-continuous arterial spin labeling (DP-pCASL) to quantify cerebral blood flow (CBF), arterial transit time (ATT), and blood-brain barrier (BBB) water exchange rate (Kw) before and after focused ultrasound (FUS)-mediated blood-brain barrier opening (BBBO) in the dorsal striatum of four non-human primates. Six baseline and seven BBBO sessions were performed. DP-pCASL was acquired approximately 45 minutes after FUS sonication combined with intravenous microbubbles, and contrast-enhanced T1-weighted imaging was subsequently used to confirm the BBBO region. Whole-brain analyses revealed no significant changes in CBF or ATT following BBBO (permutation p > 0.05). Region-of-interest analysis within the sonicated caudate demonstrated a significant localized decrease in Kw, with median (IQR) values of 45.0 (40.6 - 55.6) min-1 at the BBBO site versus 61.6 (58.3 - 70.4) min-1 in the contralateral control region (p < 0.05), confirming spatially specific suppression of transendothelial water flux. In contrast, whole-brain Kw increased significantly following BBBO, with median (IQR) values of 49.8 (46.3 - 55.9) min-1 in non-BBBO sessions versus 59.4 (56.6 - 66.3) min-1 in BBBO sessions (p < 0.01), indicating a diffuse enhancement of water exchange across the brain. These findings establish DP-pCASL-derived Kw as a sensitive, non-contrast biomarker for both local and global BBB permeability changes induced by focused ultrasound, supporting its potential for longitudinal monitoring in preclinical and clinical neurotherapeutic applications.

neuroscience↗

bioRxiv2025

Mechanical Artifacts During Transcranial Focused Ultrasound Mimic Biologically Evoked Responses

Low-intensity transcranial focused ultrasound stimulation (tFUS) has emerged as a promising technique for non-invasive neuromodulation, offering deep brain penetration and high spatial precision. However, the electrophysiological effects of tFUS remain poorly understood, in part due to challenges distinguishing genuine neural responses from mechanical artifacts. Here we investigated the electrophysiological signatures captured during tFUS of the anesthetized rat hippocampus using silicon microelectrodes. We observed a strong, stereotyped local field potential (LFP) response that was time-locked to the onset and offset of sonication and resembled sensory-evoked potentials. Critically, the same waveform was observed in euthanized animals, confirming a non-biological, artifact-driven origin. The artifact scaled with acoustic intensity and was most pronounced under continuous-wave sonication. These findings suggest that electrode movement induced by ultrasound can generate artifactual LFP signals that closely mimic authentic neural responses. Our results underscore the need for caution when interpreting in situ electrophysiological recordings during tFUS and advocate for alternative, artifact-resistant readouts such as fiber photometry to unambiguously detect neuromodulatory effects.

neuroscience↗

bioRxiv2024

Automated Tumor and FUS Lesion Quantification on Multi-frequency Harmonic Motion and B-mode Imaging Using a Multi-modality Neural Network

Harmonic Motion Imaging (HMI) is an ultrasound elasticity imaging method that measures the mechanical properties of tissue using amplitude-modulated acoustic radiation force (AM-ARF). By estimating tissues on-axis oscillatory motion, HMI-derived displacement images represent localized relative stiffness and can predict the tumor response to neoadjuvant chemotherapy (NACT) and monitor focused ultrasound (FUS) ablation therapy. Multi-frequency HMI (MF-HMI) excites tissue at various AM frequencies simultaneously, which allows for image optimization without prior knowledge of inclusion size and stiffness. However, challenges remain in size estimation as inconsistent boundary effects result in different perceived sizes across AM frequencies. Herein, we developed an automated tumor and FUS lesion quantification method using a transformer-based multi-modality neural network, HMINet. It was trained on 380 pairs of MF-HMI and B-mode images of phantoms and in vivo orthotopic breast cancer mice (4T1). Test datasets included phantoms (n = 32), in vivo 4T1 mice (n = 24), breast cancer patients (n = 16), and a FUS-induced lesion, with average segmentation accuracy (Dice Similarity Score) of 0.95, 0.86, 0.82, and 0.87, respectively. To increase the generalizability of HMINet, we applied a transfer learning strategy, i.e., fine-tuning the model using patient data. For NACT patients, the displacement ratios (DR) between the tumor and surrounding tissue were calculated based on HMINet-segmented boundaries to predict tumor response based on stiffness changes.

bioengineering↗

bioRxiv2024

Focused ultrasound enhanced antibody delivery for the treatment of Parkinson's Disease

Treatment of neurological disorders is partly impeded by the size of large pharmacological agents which are thereby unable to bypass the blood-brain barrier (BBB). Focused ultrasound (FUS) in conjunction with systemically administered microbubbles has been shown to safely, non-invasively and transiently open the BBB, allowing the passage of large biomolecules to the brain parenchyma through the otherwise impermeable barrier. This pilot study assessed the feasibility of FUS-mediated delivery of an anti-alpha-synuclein (-syn) monoclonal antibody (mAb) in Parkinsons disease (PD) mouse models that exhibit -syn aggregates. Mice (n=21) underwent FUS on a weekly basis over the course of 2-3 weeks, followed by a one-month survival period. MRI and microscopy were performed to confirm BBB opening with FUS and visualize antibody delivery. Safety was assessed in vivo using passive cavitation detection and immunohistochemistry to evaluate microglial and astrocyte activity ex vivo. It was found that treatment sessions for multiple FUS sessions of targeted antibody delivery was feasible in alpha-synuclein models facilitating immunotherapeutics for PD.

neuroscience↗

bioRxiv2024

Low hemoglobin causes hematoma expansion and poor intracerebral hemorrhage outcomes

ObjectivesAlthough lower hemoglobin levels associate with worse intracerebral hemorrhage (ICH) outcomes, causal drivers for this relationship remain unclear. We investigated the hypothesis that lower hemoglobin relates to increased hematoma expansion (HE) risk and poor outcomes using human observational data and assessed causal relationships using a translational murine model of anemia and ICH. MethodsICH patients with baseline hemoglobin measurements and serial CT neuroimaging enrolled between 2010-2016 to a multicenter, prospective observational cohort study were studied. Patients with systemic evidence of coagulopathy were excluded. Separate regression models assessed relationships of baseline hemoglobin with HE ([≥]33% and/or [≥]6mL growth) and poor long-term neurological outcomes (modified Rankin Scale 4-6) after adjusting for relevant covariates. Using a murine collagenase ICH model with serial neuroimaging in anemic vs. non-anemic C57/BL6 mice, intergroup differences in ICH lesion volume, ICH volume changes, and early mortality were assessed. ResultsAmong 1190 ICH patients analyzed, lower baseline hemoglobin levels associated with increased odds of HE (adjusted OR per -1g/dL hemoglobin decrement: 1.10 [1.02-1.19]) and poor 3-month clinical outcomes (adjusted OR per -1g/dL hemoglobin decrement: 1.11 [1.03-1.21]). Similar relationships were seen with poor 6 and 12-month outcomes. In our animal model, anemic mice had significantly greater ICH lesion expansion, final lesion volumes, and greater mortality, as compared to non-anemic mice. ConclusionsThese results, in a human cohort and a mouse model, provide novel evidence suggesting that anemia has causal roles in HE and poor ICH outcomes. Additional studies are required to clarify whether correcting anemia can improve these outcomes.

pathology↗

bioRxiv2024

Functional ultrasound (fUS) imaging of displacement-guided focused ultrasound (FUS) neuromodulation in mice

Focused ultrasound (FUS) stimulation is a promising neuromodulation technique with the merits of non-invasiveness, high spatial resolution, and deep penetration depth. However, simultaneous imaging of FUS-induced brain tissue displacement and the subsequent effect of FUS stimulation on brain hemodynamics has proven challenging thus far. In addition, earlier studies lack in situ confirmation of targeting except for the magnetic resonance imaging-guided FUS system-based studies. The purpose of this study is 1) to introduce a fully ultrasonic approach to in situ target, modulate neuronal activity, and monitor the resultant neuromodulation effect by respectively leveraging displacement imaging, FUS, and functional ultrasound (fUS) imaging, and 2) to investigate FUS-evoked cerebral blood volume (CBV) response and the relationship between CBV and displacement. We performed displacement imaging on craniotomized mice to confirm the in targeting for neuromodulation site. We recorded hemodynamic responses evoked by FUS and fUS revealed an ipsilateral CBV increase that peaks at 4 s post-FUS. We saw a stronger hemodynamic activation in the subcortical region than cortical, showing good agreement with the brain elasticity map that can also be obtained using a similar methodology. We observed dose-dependent CBV response with peak CBV, activated area, and correlation coefficient increasing with ultrasonic dose. Furthermore, by mapping displacement and hemodynamic activation, we found that displacement colocalizes and linearly correlates with CBV increase. The findings presented herein demonstrated that FUS evokes ipsilateral hemodynamic activation in cortical and subcortical depths and the evoked hemodynamic responses colocalized and correlate with FUS-induced displacement. We anticipate that our findings will help consolidate accurate targeting as well as an understanding of how FUS displaces brain tissue and affects cerebral hemodynamics.

bioengineering↗

bioRxiv2023

Alteration of functional connectivity in the cortex and major brain networks of non-human primates following focused ultrasound exposure

Focused ultrasound (FUS) is a non-invasive neuromodulation technology that is being investigated for potential treatment of neurological and psychiatric disorders. Focused ultrasound combined with microbubbles can temporarily open the intact blood-brain barrier (BBB) of animals and humans, and facilitate drug delivery. FUS exposure, either with or without microbubbles, has been demonstrated to alter the behavior of non-human primates, and previous work has demonstrated transient and long-term effects of FUS neuromodulation on functional connectivity using resting state functional MRI. However, it is unknown whether opening the BBB affects functional connectivity differently than FUS alone. Thus we applied FUS alone (neuromodulation) and FUS with microbubbles (BBB opening) in the dorsal striatum of lightly anesthetized non-human primates, and compared changes in functional connectivity in major brain networks. We found different alteration patterns between FUS neuromodulation and FUS-mediated BBB opening in several cortical areas, and we also found that applying FUS to a deep brain structure can alter functional connectivity in the default mode network and frontotemporal network.

neuroscience↗

bioRxiv2021

Neuronal responses to focused ultrasound are gated by pre-stimulation brain rhythms

BackgroundOwing to its high spatial resolution and penetration depth, transcranial focused ultrasound stimulation (tFUS) is one of the most promising approaches to non-invasive neuromodulation. Identifying the impact of the stimulation waveform and endogenous neural activity on neuromodulation outcome is critical to harnessing the potential of tFUS. ObjectiveHere we tested a new form of tFUS where the amplitude of the ultrasonic waveform is modulated at a rate much slower than the operating frequency. Moreover, we sought to identify the relationship between pre-stimulation neural activity and the neuronal response to tFUS. MethodsWe applied three minutes of amplitude modulated (AM) tFUS at 40 Hz to the rat hippocampus while recording local field potentials (LFP) and multi-unit activity (MUA)from the sonicated region. To assess the role of AM, we also tested continuous-wave (CW) stimulation. ResultsAM tFUS reduced firing rate during and immediately after stimulation. On the other hand, CW tFUS produced an acute firing rate increase that was abolished after sonication. For both waveforms, firing rate changes were stronger in units exhibiting high baseline LFP power, particularly in the gamma band (30-250 Hz). The neuromodulatory effect was also influenced by the prevalence of sharp wave ripples (SWR) during the pre-stimulation period, with firing rates modulated by up to 33% at units showing frequent baseline SWR. ConclusionOur findings suggest that AM and CW tFUS produce qualitatively different neuronal outcomes, and that baseline rhythms may effectively "gate" the response to tFUS.

neuroscience↗

bioRxiv2020

Differential effects of amplitude-modulated transcranial focused ultrasound on excitatory and inhibitory neurons

Although stimulation with ultrasound has been shown to modulate brain activity at multiple scales, it remains unclear whether transcranial focused ultrasound stimulation (tFUS) exerts its influence on specific cell types. Here we propose a novel form of tFUS where a continuous waveform is amplitude modulated (AM) at a slow rate (i.e., 40 Hz) targeting the temporal range of electrophysiological activity: AM-tFUS. We stimulated the rat hippocampus while recording multi-unit activity (MUA) followed by classification of spike waveforms into putative excitatory pyramidal cells and inhibitory interneurons. At low acoustic intensity, AM-tFUS selectively reduced firing rates of inhibitory interneurons. On the other hand, higher intensity AM-tFUS increased firing of putative excitatory neurons with no effect on inhibitory firing. Interestingly, firing rate was unchanged during AM-tFUS at intermediate intensity. Consistent with the observed changes in firing rate, power in the theta band (3-10 Hz) of the local field potential (LFP) decreased at low-intensity, was unchanged at intermediate intensity, and increased at higher intensity. Temperature increases at the AM-tFUS target were limited to 0.2{degrees}C. Our findings indicate that inhibitory interneurons exhibit greater sensitivity to ultrasound, and that cell-type specific neuromodulation may be achieved by calibrating the intensity of AM-tFUS.

neuroscience↗

bioRxiv2020

Atrophy associated with tau pathology precedes overt cell death in a mouse model of progressive tauopathy

In the early stages of Alzheimers disease (AD), tau pathology first develops in the entorhinal cortex (EC), then spreads to the hippocampus and at later stages, to the neocortex. Pathology in the neocortex correlates with impaired cognitive performance. Overall, tau pathology correlates well with neurodegeneration but the spatial and temporal association between tau pathology and overt volume loss is unclear. Using in vivo magnetic resonance imaging (MRI) with tensor-based morphometry (TBM) we mapped the spatio-temporal pattern of structural changes in a mouse model of AD-like progressive tauopathy. A novel, co-registered in vivo MRI atlas identified particular regions in the medial temporal lobe (MTL) that had significant volume reduction. The medial entorhinal cortex (MEC) and pre-/para-subiculum (PPS) had the most significant atrophy at the early stage, but atrophy then spread into the hippocampus, most notably, the CA1, dentate gyrus (DG) and subiculum (Sub). TBM-related atrophy in the DG and Sub preceded overt cell loss that has been reported in ex vivo studies in the same mouse model. By unifying an ex vivo 3D reconstruction of tau pathology with the TBM-MRI results we mapped the progression of atrophy in the MTL with the corresponding spread of tau pathology. Our study shows that there is an association between the spread of tau pathology and TBM-related atrophy from the EC to the hippocampus, but atrophy in the DG and Sub preceded overt cell loss. One Sentence SummarySpread of tau pathology in a mouse model of Alzheimers disease assessed by MRI was associated with reduced brain tissue volume but not neuronal loss.

neuroscience↗