Biology subjects

Grinband, J.

Publications and source records attributed to Grinband, J..

7 recordsLinked to original sources

bioRxiv2026

Paired Tumor Biopsies Reveal Spatiotemporal Myeloid Remodeling After Local Chemotherapy in Glioblastoma

BackgroundStandard-of-care chemotherapy for glioblastoma induces inflammation that may contribute to disease recurrence. Although recurrent tumors are enriched with myeloid cells, the early cellular response to chemotherapy and the mechanisms that initiate this inflammatory remodeling remain poorly understood. In particular, it is unknown how neoplastic and tumor-associated myeloid populations respond during the immediate post-treatment period, and whether tumor-associated myeloid cells directly experience chemotherapy-induced genotoxic stress that contributes to inflammatory state transitions. MethodsWe performed sequencing-based analysis of neoplastic and immune populations following topotecan exposure using multiple complementary model systems and time points. We first analyzed MRI-localized, paired pre- and post-treatment biopsies from a first-in-human trial of 28-day convection enhanced delivery (CED) of topotecan (n=5) using cell-type-deconvolved bulk-RNA-sequencing and immunofluorescence. We then treated syngeneic murine gliomas using an in vivo model of CED-topotecan and measured acute 3-day and 7-day treatment responses by single cell RNA-sequencing. We additionally conducted sequencing analysis of patient-derived slice cultures and in vitro human microglial and glioma cell lines following 24-hour topotecan treatment. ResultsIn paired human biopsies, CED-topotecan induced spatially restricted transcriptional remodeling within the infusion zone, characterized by suppression of proliferative tumor programs and enrichment of inflammatory, interferon, hypoxia, and mesenchymal signatures. Cell-type deconvolution and immunofluorescence linked this response to myeloid remodeling, including enrichment of monocyte-derived tumor-associated macrophage states, increased MARCO-positive myeloid populations, and pH2AX-positive genotoxic stress within Iba1-positive myeloid cells. In the murine CED model, topotecan prolonged survival and reduced tumor cellularity, while also inducing inflammatory and DNA-damage programs in tumor-associated macrophages that evolved by 7-days toward hypoxia, angiogenesis, TGF-{beta} signaling, and mesenchymal/tissue-remodeling programs. Human slice culture and in vitro microglial systems confirmed stress-coupled inflammatory and DNA-damage responses in human myeloid cells. ConclusionsChemotherapy exposure induces a spatially structured inflammatory myeloid response characterized by early genotoxic stress and inflammatory activation, with later emergence of mesenchymal and tissue-remodeling macrophage programs. Across model systems, our analysis supports a model in which chemotherapy-associated damage in both tumor and myeloid cells contributes to an evolving inflammatory microenvironment after treatment.

neuroscience↗

bioRxiv2025

Wearable, High-Density, Time-Domain Diffuse Optical Tomography Array for Functional Neuroimaging

Noninvasive functional neuroimaging techniques, such as functional magnetic resonance imaging (fMRI) and electroencephalography (EEG), are essential tools for understanding brain activity and cognition for various neurological and mental health conditions. While fMRI offers high spatial resolution, its limited temporal resolution and costly large-form-factor restricts its accessibility and practicality for many applications. In contrast, EEG is more affordable and portable but has limited spatial resolution. In the present study, we overcome the limitations of existing neuroimaging technologies with the development of Micro-DOT, a functional near-infrared spectroscopy (fNIRS) system capable of high-density, time-domain diffuse optical tomography (HD-TD-DOT). Micro-DOT tackles the tradeoff between form factor and spatial resolution that has been a longstanding issue with existing fNIRS systems through the use of a unique hardware architecture that arrays HD-TD-DOT-capable electronics directly at the tissue surface. This is made possible with complementary-metal-oxide-semiconductor (CMOS) source-detector chiplets that contain all the electronics and optics necessary for HD-TD-DOT operation, and can be mounted on flexible polyimide packaging with a very minimal footprint. Pairing these hardware innovations with an advanced volumetric reconstruction software, Micro-DOT achieves in-plane spatial resolution, depth resolution, and localization accuracy comparable to fMRI, while maintaining the wearable form factor and portability of EEG, making it a viable stand-alone system for measuring subject-specific brain activation.

neuroscience↗

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↗

bioRxiv2022

Biologically-informed deep neural networks provide quantitative assessment of intratumoral heterogeneity in post-treatment glioblastoma

Intratumoral heterogeneity poses a significant challenge to the diagnosis and treatment of glioblastoma (GBM). This heterogeneity is further exacerbated during GBM recurrence, as treatment-induced reactive changes produce additional intratumoral heterogeneity that is ambiguous to differentiate on clinical imaging. There is an urgent need to develop non-invasive approaches to map the heterogeneous landscape of histopathological alterations throughout the entire lesion for each patient. We propose to predictively fuse Magnetic Resonance Imaging (MRI) with the underlying intratumoral heterogeneity in recurrent GBM using machine learning (ML) by leveraging image-localized biopsies with their associated locoregional MRI features. To this end, we develop BioNet, a biologically-informed neural network model, to predict regional distributions of three tissue-specific gene modules: proliferating tumor, reactive/inflammatory cells, and infiltrated brain tissue. BioNet offers valuable insights into the integration of multiple implicit and qualitative biological domain knowledge, which are challenging to describe in mathematical formulations. BioNet performs significantly better than a range of existing methods on cross-validation and blind test datasets. Voxel-level prediction maps of the gene modules by BioNet help reveal intratumoral heterogeneity, which can improve surgical targeting of confirmatory biopsies and evaluation of neuro-oncological treatment effectiveness. The non-invasive nature of the approach can potentially facilitate regular monitoring of the gene modules over time, and making timely therapeutic adjustment. These results also highlight the emerging role of ML in precision medicine.

cancer biology↗

bioRxiv2021

The road not taken: disconnection of a human-unique cortical pathway in schizophrenia and its effects on naturalistic social cognition

BackgroundEfficient processing of complex and dynamic social scenes relies on intact connectivity of many underlying cortical areas and networks, but how connectivity deficits affect this functioning in social cognition remains unknown. Here we measure these relationships using functionally based localization of social cognition areas, resting-state functional connectivity, and movie-watching data. MethodsIn 42 schizophrenia participants (SzP) and 41 healthy controls (HC), we measured the functional connectivity of areas localized by face-emotion processing, theory-of-mind, and attention tasks. We quantified the weighted shortest path length between visual and medial prefrontal theory-of-mind areas in both populations to assess the impact of functional connectivity deficits on network structure. We then correlated connectivity along the shortest path in each group with movie-evoked activity in a key node of the theory-of-mind network (TPJp). ResultsSzP had pronounced connectivity deficits in temporoparietal junction/posterior superior temporal sulcus (TPJ-pSTS) areas involved in face-emotion processing (t(81)=4.4, p=0.00002). In HC the shortest path connecting visual and medial prefrontal theory-of-mind areas passed through TPJ-pSTS, whereas in SzP the shortest path passed through prefrontal cortex (PFC). While movie-evoked TPJp activity correlated with connectivity along the TPJ-pSTS pathway in both groups (r=0.43, p=0.002), it additionally correlated with connectivity along the PFC pathway only in SzP (rSzP=0.56, p=0.003). ConclusionsConnectivity along the human-unique TPJ-pSTS pathway affects both the network architecture and functioning of areas involved in processing complex dynamic social scenes. These results demonstrate how focal deficits can have widespread impacts across cortex.

neuroscience↗

bioRxiv2019

Failure to engage the TPJ-pSTS during naturalistic scene processing in schizophrenia

The ability to search for and detect social cues, such as facial expressions of emotion, is critical to the understanding of complex dynamic social situations. This ability involves the coordinated actions of multiple cognitive domains, including face-emotion processing, mentalization, and visual attention. Individuals with schizophrenia are generally impaired in social cognition, and have been shown to have deficits in all of these domains. However, the whether the neural substrates of these impairments are shared or separate remains unclear. One candidate region for a shared substrate is the right temporoparietal junction/posterior superior temporal sulcus (TPJ-pSTS), which contains areas belonging to all of the cortical networks underlying these domains. Here we use functional MRI to examine differences in cortical activity evoked by a naturalistic movie, and link these results to impaired visual scanning and social cognition. 27 schizophrenia participants and 21 healthy controls watched a 15-minute clip of the movie \"The Good, the Bad, and the Ugly\" while high resolution multiband BOLD-fMRI activity was recorded. Inter-subject correlation was used to measure the evoked activity. BOLD-fMRI activity was also correlated with motion content in the movie, with the average activity in other cortical areas, and with frequency of saccades made during the movie. Visual scanning performance was measured in a separate behavioral experiment, and social cognition measured by The Awareness of Social Inference Test (TASIT). Contrasting the groups revealed that the TPJ-pSTS has the largest engagement deficit in both cortical hemispheres in schizophrenia patients versus healthy controls. Follow-up analyses find that brain activity in this region is less correlated with the motion content of the movie, that this region is abnormally synchronized to the other cortical areas involved in the cognitive domains underlying visual scanning of social scenes, and that activity this region is less correlated with the saccades made during the movie. Lastly, schizophrenia participant visual scanning performance of this clip was impaired compared to healthy controls, and correlated across the two groups with social cognition. These results indicate that the TPJ-pSTS plays less of an integral role in the coordination of face-emotion processing, mentalization, and visual attention in schizophrenia participants versus healthy controls. This functional deficit then impacts the visual scanning of a complex dynamic visual scenes, which in turn affects the comprehension of that scene. These findings indicating that the TPJ-pSTS is potentially the shared substrate for all of these deficits will lead to new treatments targeting this region to improve social cognition in individuals with schizophrenia.

neuroscience↗

bioRxiv2019

Glioma-induced alterations in neuronal activity and neurovascular coupling during disease progression

Diffusely infiltrating gliomas are known to cause alterations in cortical function, vascular disruption and seizures. These neurological complications present major clinical challenges, yet their underlying mechanisms and causal relationships to disease progression are poorly characterized. Here, we followed glioma progression in awake Thy1-GCaMP6f mice using in-vivo wide-field optical mapping to monitor alterations in both neuronal activity and functional hemodynamics. The bilateral synchrony of spontaneous neuronal activity in glioma-infiltrated cortex gradually decreased, while neurovascular coupling was also progressively disrupted compared to uninvolved cortex. Over time, mice developed diverse patterns of high amplitude discharges and eventually generalized seizures that begin at the infiltrative margin of the tumors. Interictal and seizure events exhibited positive neurovascular coupling in uninfiltrated cortex, however glioma-infiltrated regions exhibited inverted hemodynamic responses driving seizure-evoked hypoxia. These results reveal a landscape of complex physiological interactions occurring during glioma progression and present new opportunities for exploring new biomarkers and therapeutic targets.\n\nHighlights- Glioma disrupts neural synchrony between bilateral cortical regions.\n- WFOM reveals frequent interictal discharges and seizures during glioma progression.\n- Tumor development is accompanied by local changes in neurovascular coupling.\n- Altered neurovascular coupling drives hypoperfusion of the tumor during seizures.

neuroscience↗