Publications by authors named "Joel M Stein"

50 Publications

7T Epilepsy Task Force Consensus Recommendations on the Use of 7T MRI in Clinical Practice.

Neurology 2021 02 22;96(7):327-341. Epub 2020 Dec 22.

From the Neurobiology Research Unit (G.O., L.H.P.), and Epilepsy Clinic (L.H.P.), Department of Neurology, Rigshospitalet Copenhagen University Hospital; Faculty of Health and Medical Sciences (G.O.), UCPH, Denmark; Departments of Neurology and Neurosurgery (T.J.V.), UMC Utrecht Brain Center, and Department of Radiology (A.v.d.K.), University Medical Center Utrecht, Utrecht University; Department of Radiology (A.v.d.K.), Netherlands Cancer Institute Antoni van Leeuwenhoek Hospital, Amsterdam; Lund University Bioimaging Center (K.M.B.), Lund University, Sweden; Department of Neurology (A.J.C.), Neurophysiology and Neurosurgery, ACE Kempenhaeghe/MUMC, Heeze/Maastricht, the Netherlands; Department of Radiology (J.M.S.) and Penn Epilepsy Center (K.D.), Hospital of the University of Pennsylvania, Philadelphia; Department of Neurology (T.R.H.) and Center for Magnetic Resonance Research (P.-F.V.d.M., R.E.M.), University of Minnesota, Minneapolis; Department of Radiology and Nuclear Medicine (J.F.A.J.), Maastricht University Medical Center; School for Mental Health and Neuroscience (J.F.A.J.), Maastricht University; Department of Electrical Engineering (J.F.A.J.), Eindhoven University of Technology, the Netherlands; Imaging Institute (S.E.J.) and Epilepsy Center (I.W.), Cleveland Clinic, OH; Department of Neurology and Radiology (J.W.P.), University of Pittsburg, PA; Department of Neurosurgery (K.R.), Medical University of Vienna, Austria; Departments of Neurology and Clinical Sciences (M.C.S.), Lund University Hospital, Sweden; Department of Biomedical Imaging and Image Guided Therapy (S.T.), High Field MR Center, Medical University of Vienna, Austria; Neuroradiology Division, Diagnostic Unit (M.I.V.), University Hospitals and Faculty of Medicine of Geneva, Switzerland; Epileptology Department - INS (F.B.) and CRMBM - CEMEREM (J.-P.R., M.G.), Timone Hospital APHM, Aix Marseille Univ, INSERM, CNRS, France; Neuroimaging of Epilepsy Laboratory (NOEL) (N.B., A.B.), Montreal Neurological Institute (B.B.), and McConnell Brain Imaging Centre (N.B., A.B.), McGill University, Montreal, Canada; Department of Radiology (I.B.-B.), Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Sweden; Department of Translational Research and New Technologies in Medicine and Surgery (M.C.), University of Pisa, Italy; Department of Neurology (S.R.D.), University of Pennsylvania, Philadelphia; NeuroSpin (L.H.-P., A.V.), Paris-Saclay University, CEA, CNRS, BAOBAB, Gif-sur-Yvette, France; UMR 1141 (L.H.-P), University of Paris, France; EEG Section (S.I.), NINDS, NIH, Bethesda, MD; Department of Medical Imaging (M.T.J.), Children's Hospital at London Health Sciences Centre; Department of Medical Biophysics (M.T.J., A.R.K.), Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Canada; Imaging Research Laboratories (A.R.K.), Robarts Research Institute, London, ON, Canada; Functional Neurosurgery Department (S.L.), Beijing Children's Hospital of Capital Medical University, Beijing, China; Department of Radiology (S.M.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA; NYU Grossman School of Medicine (H.P.), New York; Harvard MIT Division of Health Sciences and Technology (J.R.P., S.S.), Massachusetts Institute of Technology, Cambridge; Athinoula A. Martinos Center for Biomedical Imaging (J.R.P., S.S.), Department of Radiology, Harvard Medical School, Massachusetts General Hospital, Charlestown, MA; Scannexus Ultrahigh Field MRI Research Center (E.S., C.J.W.), Maastricht; Department of Radiology and Nuclear Medicine (T.J.V.), Meander Medical Center, Amersfoort, the Netherlands; Wellcome Centre for Integrative Neuroimaging (N.V.), FMRIB Division, Nuffield Department of Clinical Neurosciences, University of Oxford, United Kingdom; EEG and Epilepsy Unit (S.V.), Neurology, Department of Clinical Neurosciences, University Hospitals and Faculty of Medicine of Geneva, Switzerland; State Key Lab of Brain and Cognitive Science (R.X.), Beijing MRI Center for Brain Research, Institute of Biophysics, Chinese Academy of Sciences, China; Neuroscience Department (R.G.), Children's Hospital A. Meyer-University of Florence; and IMAGO 7 Foundation (R.G.), Florence, Italy.

Identifying a structural brain lesion on MRI has important implications in epilepsy and is the most important factor that correlates with seizure freedom after surgery in patients with drug-resistant focal onset epilepsy. However, at conventional magnetic field strengths (1.5 and 3T), only approximately 60%-85% of MRI examinations reveal such lesions. Over the last decade, studies have demonstrated the added value of 7T MRI in patients with and without known epileptogenic lesions from 1.5 and/or 3T. However, translation of 7T MRI to clinical practice is still challenging, particularly in centers new to 7T, and there is a need for practical recommendations on targeted use of 7T MRI in the clinical management of patients with epilepsy. The 7T Epilepsy Task Force-an international group representing 21 7T MRI centers with experience from scanning over 2,000 patients with epilepsy-would hereby like to share its experience with the neurology community regarding the appropriate clinical indications, patient selection and preparation, acquisition protocols and setup, technical challenges, and radiologic guidelines for 7T MRI in patients with epilepsy. This article mainly addresses structural imaging; in addition, it presents multiple nonstructural MRI techniques that benefit from 7T and hold promise as future directions in epilepsy. Answering to the increased availability of 7T MRI as an approved tool for diagnostic purposes, this article aims to provide guidance on clinical 7T MRI epilepsy management by giving recommendations on referral, suitable 7T MRI protocols, and image interpretation.
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http://dx.doi.org/10.1212/WNL.0000000000011413DOI Listing
February 2021

Theta Synchrony Is Increased near Neural Populations That Are Active When Initiating Instructed Movement.

eNeuro 2021 Jan-Feb;8(1). Epub 2021 Feb 8.

Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.

Theta oscillations (3-8 Hz) in the human brain have been linked to perception, cognitive control, and spatial memory, but their relation to the motor system is less clear. We tested the hypothesis that theta oscillations coordinate distributed behaviorally relevant neural representations during movement using intracranial electroencephalography (iEEG) recordings from nine patients ( = 490 electrodes) as they performed a simple instructed movement task. Using high frequency activity (HFA; 70-200 Hz) as a marker of local spiking activity, we identified electrodes that were positioned near neural populations that showed increased activity during instruction and movement. We found that theta synchrony was widespread throughout the brain but was increased near regions that showed movement-related increases in neural activity. These results support the view that theta oscillations represent a general property of brain activity that may also play a specific role in coordinating widespread neural activity when initiating voluntary movement.
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http://dx.doi.org/10.1523/ENEURO.0252-20.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901148PMC
February 2021

Anatomical Variations, Mimics, and Pitfalls in Imaging of Patients with Epilepsy.

J Neuroimaging 2021 Jan 13;31(1):20-34. Epub 2020 Dec 13.

Division of Neuroradiology, Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA.

Epilepsy is among one of the most common neurologic disorders. The role of magnetic resonance imaging (MRI) in the diagnosis and management of patients with epilepsy is well established, and most patients with epilepsy are likely to undergo at least one or more MRI examinations in the course of their disease. Recent advances in high-field MRI have enabled high resolution in vivo visualization of small and intricate anatomic structures that are of great importance in the assessment of seizure disorders. Familiarity with normal anatomic variations is essential in the accurate diagnosis and image interpretation, as these variations may be mistaken for epileptogenic foci, leading to unnecessary follow-up imaging, or worse, unnecessary treatment. After a brief overview of normal imaging anatomy of the mesial temporal lobe, this article will review a few important common and uncommon anatomic variations, mimics, and pitfalls that may be encountered in the imaging evaluation of patients with epilepsy.
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http://dx.doi.org/10.1111/jon.12809DOI Listing
January 2021

A dual-genotype oligoastrocytoma with histologic, molecular, radiological and time-course features.

Acta Neuropathol Commun 2020 07 20;8(1):115. Epub 2020 Jul 20.

Division of Neuroradiology, Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA.

A case of a true dual-genotype IDH-mutant oligoastrocytoma with two different cell types within a single mass in a young woman is presented. Imaging findings of the left frontal infiltrating glioma predicted the two neoplastic components that were identified upon resection. Tissue examination demonstrated areas of tumor with contrasting histologic and molecular features, including specific IDH1, ATRX, TP53, TERT and CIC mutational profiles, consistent with oligodendroglioma and astrocytoma, respectively. The clinical and radiological course over 17 months from first diagnosis included three surgical resections with slow progression of the astrocytic component, and ultimately chemotherapy and radiation treatments were commenced. Reports of the clinical courses for these rare cases of dual-genotype oligoastrocytomas will inform therapy choices, to optimize benefit while minimizing side effects. The steadily increasing number of cases suggests that the neoplasm might be reconsidered as an official entity by the WHO.
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http://dx.doi.org/10.1186/s40478-020-00998-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7372861PMC
July 2020

Pearls & Oy-sters: Bilateral globus pallidus lesions in a patient with COVID-19.

Neurology 2020 09 25;95(10):454-457. Epub 2020 Jun 25.

From the Department of Neurology (C.V.K.-S., J.L.M., A.R., M.A.G., B.L.C., K.A.D.), Department of Radiology (R.L.W., S.M., J.M.S., J.H.M., J.W.L.), Division of Pulmonary, Allergy, and Critical Care (D.G.D., J.E.M.), and Division of Infectious Diseases (M.Z.D., R.N.E.), Perelman School of Medicine at the University of Pennsylvania; and Division of Neurology (J.L.M.), the Children's Hospital of Philadelphia, PA.

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http://dx.doi.org/10.1212/WNL.0000000000010157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7538218PMC
September 2020

The effects of direct brain stimulation in humans depend on frequency, amplitude, and white-matter proximity.

Brain Stimul 2020 Sep - Oct;13(5):1183-1195. Epub 2020 May 21.

Department of Biomedical Engineering, Columbia University, New York, 10027, USA. Electronic address:

Background: Researchers have used direct electrical brain stimulation to treat a range of neurological and psychiatric disorders. However, for brain stimulation to be maximally effective, clinicians and researchers should optimize stimulation parameters according to desired outcomes.

Objective: The goal of our large-scale study was to comprehensively evaluate the effects of stimulation at different parameters and locations on neuronal activity across the human brain.

Methods: To examine how different kinds of stimulation affect human brain activity, we compared the changes in neuronal activity that resulted from stimulation at a range of frequencies, amplitudes, and locations with direct human brain recordings. We recorded human brain activity directly with electrodes that were implanted in widespread regions across 106 neurosurgical epilepsy patients while systematically stimulating across a range of parameters and locations.

Results: Overall, stimulation most often had an inhibitory effect on neuronal activity, consistent with earlier work. When stimulation excited neuronal activity, it most often occurred from high-frequency stimulation. These effects were modulated by the location of the stimulating electrode, with stimulation sites near white matter more likely to cause excitation and sites near gray matter more likely to inhibit neuronal activity.

Conclusion: By characterizing how different stimulation parameters produced specific neuronal activity patterns on a large scale, our results provide an electrophysiological framework that clinicians and researchers may consider when designing stimulation protocols to cause precisely targeted changes in human brain activity.
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http://dx.doi.org/10.1016/j.brs.2020.05.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7494653PMC
May 2020

Functionally distinct high and low theta oscillations in the human hippocampus.

Nat Commun 2020 05 18;11(1):2469. Epub 2020 May 18.

Department of Biomedical Engineering, Columbia University, New York, NY, 10027, USA.

Based on rodent models, researchers have theorized that the hippocampus supports episodic memory and navigation via the theta oscillation, a ~4-10 Hz rhythm that coordinates brain-wide neural activity. However, recordings from humans have indicated that hippocampal theta oscillations are lower in frequency and less prevalent than in rodents, suggesting interspecies differences in theta's function. To characterize human hippocampal theta, we examine the properties of theta oscillations throughout the anterior-posterior length of the hippocampus as neurosurgical subjects performed a virtual spatial navigation task. During virtual movement, we observe hippocampal oscillations at multiple frequencies from 2 to 14 Hz. The posterior hippocampus prominently displays oscillations at ~8-Hz and the precise frequency of these oscillations correlates with the speed of movement, implicating these signals in spatial navigation. We also observe slower ~3 Hz oscillations, but these signals are more prevalent in the anterior hippocampus and their frequency does not vary with movement speed. Our results converge with recent findings to suggest an updated view of human hippocampal electrophysiology. Rather than one hippocampal theta oscillation with a single general role, high- and low-frequency theta oscillations, respectively, may reflect spatial and non-spatial cognitive processes.
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http://dx.doi.org/10.1038/s41467-020-15670-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7235253PMC
May 2020

Epilepsy Lesion Localization is not Predicted by Developmental Venous Anomaly Location or its FDG-PET Metabolic Activity.

J Neuroimaging 2020 07 8;30(4):544-550. Epub 2020 May 8.

Department of Neuroradiology, The Hospital of the University of Pennsylvania, Philadelphia, PA.

Background And Purpose: This study's purpose is to correlate location and metabolic activity of developmental venous anomalies (DVAs) in epilepsy patients to the seizure focus as determined by ictal/interictal encephaloelectrogram (EEG).

Methods: A retrospective search was performed for epilepsy patients with DVAs who underwent brain F-fluorodeoxyglucose positron emission tomography ( F-FDG-PET) and magnetic resonance imaging (MRI). MRI exams were analyzed to characterize DVA location and associated structural findings. MRI and PET images were co-registered and assessment of F-FDG uptake in the DVA territory was performed. The electronic medical record was reviewed for each subject to determine seizure semiology and site of seizure focus by ictal/interictal EEG.

Results: Twenty-eight DVAs in 25 patients were included. Twelve DVAs demonstrated regional metabolic abnormality on F-FDG-PET. There was no significant correlation between DVA site and seizure focus on EEG. DVA location was concordant with EEG seizure focus in three subjects, and all three demonstrated hypometabolism on F-FDG-PET. This significance remains indeterminate, as one of these DVAs was associated with cavernoma, which could serve as the true seizure focus, and one of the patients underwent resection of the DVA without decrease in seizure frequency. Furthermore, there was no statistically significant relationship between DVA metabolic activity and DVA-EEG lobar or laterality concordance.

Conclusions: In this sample, there is no significant correlation between location of DVA and seizure focus, and hypometabolism within the DVA territory is not predictive of EEG/DVA co-localization. As use of F-FDG-PET for evaluation of epilepsy increases, knowledge of this poor correlation is important to avoid diagnostic confusion and potentially unnecessary surgery in epilepsy patients.
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http://dx.doi.org/10.1111/jon.12722DOI Listing
July 2020

Single-Neuron Representations of Spatial Targets in Humans.

Curr Biol 2020 01 2;30(2):245-253.e4. Epub 2020 Jan 2.

Department of Biomedical Engineering, Columbia University, New York, NY 10027, USA. Electronic address:

The hippocampus and surrounding medial-temporal-lobe (MTL) structures are critical for both memory and spatial navigation, but we do not fully understand the neuronal representations used to support these behaviors. Much research has examined how the MTL neurally represents spatial information, such as with "place cells" that represent an animal's current location or "head-direction cells" that code for an animal's current heading. In addition to behaviors that require an animal to attend to the current spatial location, navigating to remote destinations is a common part of daily life. To examine the neural basis of these behaviors, we recorded single-neuron activity from neurosurgical patients playing Treasure Hunt, a virtual-reality spatial-memory task. By analyzing how the activity of these neurons related to behavior in Treasure Hunt, we found that the firing rates of many MTL neurons during navigation significantly changed depending on the position of the current spatial target. In addition, we observed neurons whose firing rates during navigation were tuned to specific heading directions in the environment, and others whose activity changed depending on the timing within the trial. By showing that neurons in our task represent remote locations rather than the subject's own position, our results suggest that the human MTL can represent remote spatial information according to task demands.
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http://dx.doi.org/10.1016/j.cub.2019.11.048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6981010PMC
January 2020

Use of Oppositely Polarized External Magnets To Improve the Accumulation and Penetration of Magnetic Nanocarriers into Solid Tumors.

ACS Nano 2020 01 23;14(1):142-152. Epub 2019 Dec 23.

Department of Bioengineering, School of Engineering and Applied Sciences , University of Pennsylvania , Philadelphia , Pennsylvania 19104 , United States.

Drug delivery to solid tumors is hindered by hydrostatic and physical barriers that limit the penetration of nanocarriers into tumor tissue. When exploiting the enhanced permeability and retention (EPR) effect for passive targeting of nanocarriers, the increased interstitial fluid pressure and dense extracellular matrix in tumors limits the distribution of the nanocarriers to perivascular regions. Previous strategies have shown that magnetophoresis enhances accumulation and penetration of nanoparticles into solid tumors. However, because magnetic fields fall off rapidly with distance from the magnet, these methods have been limited to use in superficial tumors. To overcome this problem, we have developed a system comprising two oppositely polarized magnets that enables the penetration of magnetic nanocarriers into more deeply seeded tumors. Using this method, we demonstrate a 5-fold increase in the penetration and a 3-fold increase in the accumulation of magnetic nanoparticles within solid tumors compared to EPR.
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http://dx.doi.org/10.1021/acsnano.9b05660DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7002255PMC
January 2020

Memory retrieval modulates spatial tuning of single neurons in the human entorhinal cortex.

Nat Neurosci 2019 12 11;22(12):2078-2086. Epub 2019 Nov 11.

Department of Biomedical Engineering, Columbia University, New York, NY, USA.

The medial temporal lobe is critical for both spatial navigation and memory. Although single neurons in the medial temporal lobe activate to represent locations in the environment during navigation, how this spatial tuning relates to memory for events involving those locations remains unclear. We examined memory-related changes in spatial tuning by recording single-neuron activity from neurosurgical patients performing a virtual-reality object-location memory task. We identified 'memory-trace cells' with activity that was spatially tuned to the retrieved location of the specific object that participants were cued to remember. Memory-trace cells in the entorhinal cortex, in particular, encoded discriminable representations of different memories through a memory-specific rate code. These findings indicate that single neurons in the human entorhinal cortex change their spatial tuning to target relevant memories for retrieval.
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http://dx.doi.org/10.1038/s41593-019-0523-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6897360PMC
December 2019

Virtual resection predicts surgical outcome for drug-resistant epilepsy.

Brain 2019 12;142(12):3892-3905

Department of Bioengineering, University of Pennsylvania, Philadelphia PA 19104, USA.

Patients with drug-resistant epilepsy often require surgery to become seizure-free. While laser ablation and implantable stimulation devices have lowered the morbidity of these procedures, seizure-free rates have not dramatically improved, particularly for patients without focal lesions. This is in part because it is often unclear where to intervene in these cases. To address this clinical need, several research groups have published methods to map epileptic networks but applying them to improve patient care remains a challenge. In this study we advance clinical translation of these methods by: (i) presenting and sharing a robust pipeline to rigorously quantify the boundaries of the resection zone and determining which intracranial EEG electrodes lie within it; (ii) validating a brain network model on a retrospective cohort of 28 patients with drug-resistant epilepsy implanted with intracranial electrodes prior to surgical resection; and (iii) sharing all neuroimaging, annotated electrophysiology, and clinical metadata to facilitate future collaboration. Our network methods accurately forecast whether patients are likely to benefit from surgical intervention based on synchronizability of intracranial EEG (area under the receiver operating characteristic curve of 0.89) and provide novel information that traditional electrographic features do not. We further report that removing synchronizing brain regions is associated with improved clinical outcome, and postulate that sparing desynchronizing regions may further be beneficial. Our findings suggest that data-driven network-based methods can identify patients likely to benefit from resective or ablative therapy, and perhaps prevent invasive interventions in those unlikely to do so.
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http://dx.doi.org/10.1093/brain/awz303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6885672PMC
December 2019

High interictal connectivity within the resection zone is associated with favorable post-surgical outcomes in focal epilepsy patients.

Neuroimage Clin 2019 19;23:101908. Epub 2019 Jun 19.

Department of Bioengineering, School of Engineering & Applied Science, University of Pennsylvania, Philadelphia, PA 19104, USA; Center for Neuroengineering and Therapeutics, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

Patients with drug-resistant focal epilepsy are often candidates for invasive surgical therapies. In these patients, it is necessary to accurately localize seizure generators to ensure seizure freedom following intervention. While intracranial electroencephalography (iEEG) is the gold standard for mapping networks for surgery, this approach requires inducing and recording seizures, which may cause patient morbidity. The goal of this study is to evaluate the utility of mapping interictal (non-seizure) iEEG networks to identify targets for surgical treatment. We analyze interictal iEEG recordings and neuroimaging from 27 focal epilepsy patients treated via surgical resection. We generate interictal functional networks by calculating pairwise correlation of iEEG signals across different frequency bands. Using image coregistration and segmentation, we identify electrodes falling within surgically resected tissue (i.e. the resection zone), and compute node-level and edge-level synchrony in relation to the resection zone. We further associate these metrics with post-surgical outcomes. Greater overlap between resected electrodes and highly synchronous electrodes is associated with favorable post-surgical outcomes. Additionally, good-outcome patients have significantly higher connectivity localized within the resection zone compared to those with poorer postoperative seizure control. This finding persists following normalization by a spatially-constrained null model. This study suggests that spatially-informed interictal network synchrony measures can distinguish between good and poor post-surgical outcomes. By capturing clinically-relevant information during interictal periods, our method may ultimately reduce the need for prolonged invasive implants and provide insights into the pathophysiology of an epileptic brain. We discuss next steps for translating these findings into a prospectively useful clinical tool.
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http://dx.doi.org/10.1016/j.nicl.2019.101908DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6617333PMC
August 2020

White Matter Network Architecture Guides Direct Electrical Stimulation through Optimal State Transitions.

Cell Rep 2019 Sep;28(10):2554-2566.e7

Department of Bioengineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Neurology, Hospital of the University of Pennsylvania, Philadelphia, PA 19104, USA; Penn Center for Neuroengineering and Therapeutics, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Electrical and Systems Engineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Physics and Astronomy, College of Arts & Sciences, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address:

Optimizing direct electrical stimulation for the treatment of neurological disease remains difficult due to an incomplete understanding of its physical propagation through brain tissue. Here, we use network control theory to predict how stimulation spreads through white matter to influence spatially distributed dynamics. We test the theory's predictions using a unique dataset comprising diffusion weighted imaging and electrocorticography in epilepsy patients undergoing grid stimulation. We find statistically significant shared variance between the predicted activity state transitions and the observed activity state transitions. We then use an optimal control framework to posit testable hypotheses regarding which brain states and structural properties will efficiently improve memory encoding when stimulated. Our work quantifies the role that white matter architecture plays in guiding the dynamics of direct electrical stimulation and offers empirical support for the utility of network control theory in explaining the brain's response to stimulation.
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http://dx.doi.org/10.1016/j.celrep.2019.08.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6849479PMC
September 2019

Functional control of electrophysiological network architecture using direct neurostimulation in humans.

Netw Neurosci 2019 1;3(3):848-877. Epub 2019 Jul 1.

Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA.

Chronically implantable neurostimulation devices are becoming a clinically viable option for treating patients with neurological disease and psychiatric disorders. Neurostimulation offers the ability to probe and manipulate distributed networks of interacting brain areas in dysfunctional circuits. Here, we use tools from network control theory to examine the dynamic reconfiguration of functionally interacting neuronal ensembles during targeted neurostimulation of cortical and subcortical brain structures. By integrating multimodal intracranial recordings and diffusion-weighted imaging from patients with drug-resistant epilepsy, we test hypothesized structural and functional rules that predict altered patterns of synchronized local field potentials. We demonstrate the ability to predictably reconfigure functional interactions depending on stimulation strength and location. Stimulation of areas with structurally weak connections largely modulates the functional hubness of downstream areas and concurrently propels the brain towards more difficult-to-reach dynamical states. By using focal perturbations to bridge large-scale structure, function, and markers of behavior, our findings suggest that stimulation may be tuned to influence different scales of network interactions driving cognition.
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http://dx.doi.org/10.1162/netn_a_00089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6663306PMC
July 2019

Characterizing the role of the structural connectome in seizure dynamics.

Brain 2019 07;142(7):1955-1972

Center for Neuroengineering and Therapeutics, University of Pennsylvania, Philadelphia, PA, USA.

How does the human brain's structural scaffold give rise to its intricate functional dynamics? This is a central question in translational neuroscience that is particularly relevant to epilepsy, a disorder affecting over 50 million subjects worldwide. Treatment for medication-resistant focal epilepsy is often structural-through surgery or laser ablation-but structural targets, particularly in patients without clear lesions, are largely based on functional mapping via intracranial EEG. Unfortunately, the relationship between structural and functional connectivity in the seizing brain is poorly understood. In this study, we quantify structure-function coupling, specifically between white matter connections and intracranial EEG, across pre-ictal and ictal periods in 45 seizures from nine patients with unilateral drug-resistant focal epilepsy. We use high angular resolution diffusion imaging (HARDI) tractography to construct structural connectivity networks and correlate these networks with time-varying broadband and frequency-specific functional networks derived from coregistered intracranial EEG. Across all frequency bands, we find significant increases in structure-function coupling from pre-ictal to ictal periods. We demonstrate that short-range structural connections are primarily responsible for this increase in coupling. Finally, we find that spatiotemporal patterns of structure-function coupling are highly stereotyped for each patient. These results suggest that seizures harness the underlying structural connectome as they propagate. Mapping the relationship between structural and functional connectivity in epilepsy may inform new therapies to halt seizure spread, and pave the way for targeted patient-specific interventions.
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http://dx.doi.org/10.1093/brain/awz125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6598625PMC
July 2019

Dynamic Theta Networks in the Human Medial Temporal Lobe Support Episodic Memory.

Curr Biol 2019 04 21;29(7):1100-1111.e4. Epub 2019 Mar 21.

Department of Psychology, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address:

The medial temporal lobe (MTL) is a locus of episodic memory in the human brain. It is comprised of cytologically distinct subregions that, in concert, give rise to successful encoding and retrieval of context-dependent memories. However, the functional connections between these subregions are poorly understood. To determine functional connectivity among MTL subregions, we had 131 subjects fitted with indwelling electrodes perform a verbal memory task and asked how encoding or retrieval correlated with inter-regional synchronization. Using phase-based measures of connectivity, we found that synchronous theta (4-8 Hz) activity underlies successful episodic memory. During encoding, we observed a dynamic pattern of connections converging on the left entorhinal cortex, beginning with the perirhinal cortex and shifting through hippocampal subfields. Retrieval-associated networks demonstrated enhanced involvement of the subiculum and CA1, reflecting a substantial reorganization of the encoding network. We posit that coherent theta activity within the MTL marks periods of successful memory, but distinct patterns of connectivity dissociate key stages of memory processing.
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http://dx.doi.org/10.1016/j.cub.2019.02.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6445741PMC
April 2019

Glutamate weighted imaging contrast in gliomas with 7 Tesla magnetic resonance imaging.

Neuroimage Clin 2019 29;22:101694. Epub 2019 Jan 29.

Penn Epilepsy Center, Department of Neurology, Hospital of the University of Pennsylvania, Philadelphia, PA, United States.

Introduction: Diffuse gliomas are incurable malignancies, which undergo inevitable progression and are associated with seizure in 50-90% of cases. Glutamate has the potential to be an important glioma biomarker of survival and local epileptogenicity if it can be accurately quantified noninvasively.

Methods: We applied the glutamate-weighted imaging method GluCEST (glutamate chemical exchange saturation transfer) and single voxel MRS (magnetic resonance spectroscopy) at 7 Telsa (7 T) to patients with gliomas. GluCEST contrast and MRS metabolite concentrations were quantified within the tumour region and peritumoural rim. Clinical variables of tumour aggressiveness (prior adjuvant therapy and previous radiological progression) and epilepsy (any prior seizures, seizure in last month and drug refractory epilepsy) were correlated with respective glutamate concentrations. Images were separated into post-hoc determined patterns and clinical variables were compared across patterns.

Results: Ten adult patients with a histo-molecular (n = 9) or radiological (n = 1) diagnosis of grade II-III diffuse glioma were recruited, 40.3 +/- 12.3 years. Increased tumour GluCEST contrast was associated with prior adjuvant therapy (p = .001), and increased peritumoural GluCEST contrast was associated with both recent seizures (p = .038) and drug refractory epilepsy (p = .029). We distinguished two unique GluCEST contrast patterns with distinct clinical and radiological features. MRS glutamate correlated with GluCEST contrast within the peritumoural voxel (R = 0.89, p = .003) and a positive trend existed in the tumour voxel (R = 0.65, p = .113).

Conclusion: This study supports the role of glutamate in diffuse glioma biology. It further implicates elevated peritumoural glutamate in epileptogenesis and altered tumour glutamate homeostasis in glioma aggressiveness. Given the ability to non-invasively visualise and quantify glutamate, our findings raise the prospect of 7 T GluCEST selecting patients for individualised therapies directed at the glutamate pathway. Larger studies with prospective follow-up are required.
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http://dx.doi.org/10.1016/j.nicl.2019.101694DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6396013PMC
January 2020

Chlorin e6-Coated Superparamagnetic Iron Oxide Nanoparticle (SPION) Nanoclusters as a Theranostic Agent for Dual-Mode Imaging and Photodynamic Therapy.

Sci Rep 2019 02 22;9(1):2613. Epub 2019 Feb 22.

Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, 19104, USA.

Photodynamic therapy (PDT) is an approved modality for the treatment of various types of maligancies and diseased states. However, most of the available photosensitizers (PS) are highly hydrophobic, which limits their solubility and dispersion in biological fluids and can lead to self-quenching and sub-optimal therapeutic efficacy. In this study, chlorin e6 (Ce6)-coated superparamagnetic iron oxide nanoparticle (SPION) nanoclusters (Ce6-SCs) were prepared via an oil-in-water emulsion. The physical-chemical properties of the Ce6-SCs were systematically evaluated. Dual-mode imaging and PDT was subsequently performed in tumor-bearing mice. Chlorin e6 is capable of solubilizing hydrophobic SPION into stable, water-soluble nanoclusters without the use of any additional amphiphiles or carriers. The method is reproducible and the Ce6-SCs are highly stable under physiological conditions. The Ce6-SCs have an average diameter of 92 nm and low polydispersity (average PDI < 0.2). Encapsulation efficiency of both Ce6 and SPION is ≈100%, and the total Ce6 payload can be as high as 56% of the total weight (Ce6 + Fe). The Ce6-SCs localize within tumors via enhanced permeability and retention and are detectable by magnetic resonance (MR) and optical imaging. With PDT, Ce6-SCs demonstrate high singlet oxygen generation and produce a significant delay in tumor growth in mice.
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http://dx.doi.org/10.1038/s41598-019-39036-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6385362PMC
February 2019

Structural and functional asymmetry of medial temporal subregions in unilateral temporal lobe epilepsy: A 7T MRI study.

Hum Brain Mapp 2019 06 21;40(8):2390-2398. Epub 2019 Jan 21.

Center for Neuroengineering and Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania.

Mesial temporal lobe epilepsy (TLE) is a common neurological disorder affecting the hippocampus and surrounding medial temporal lobe (MTL). Although prior studies have analyzed whole-brain network distortions in TLE patients, the functional network architecture of the MTL at the subregion level has not been examined. In this study, we utilized high-resolution 7T T2-weighted magnetic resonance imaging (MRI) and resting-state BOLD-fMRI to characterize volumetric asymmetry and functional network asymmetry of MTL subregions in unilateral medically refractory TLE patients and healthy controls. We subdivided the TLE group into mesial temporal sclerosis patients (TLE-MTS) and MRI-negative nonlesional patients (TLE-NL). Using an automated multi-atlas segmentation pipeline, we delineated 10 MTL subregions per hemisphere for each subject. We found significantly different patterns of volumetric asymmetry between the two groups, with TLE-MTS exhibiting volumetric asymmetry corresponding to decreased volumes ipsilaterally in all hippocampal subfields, and TLE-NL exhibiting no significant volumetric asymmetries other than a mild decrease in whole-hippocampal volume ipsilaterally. We also found significantly different patterns of functional network asymmetry in the CA1 subfield and whole hippocampus, with TLE-NL patients exhibiting asymmetry corresponding to increased connectivity ipsilaterally and TLE-MTS patients exhibiting asymmetry corresponding to decreased connectivity ipsilaterally. Our findings provide initial evidence that functional neuroimaging-based network properties within the MTL can distinguish between TLE subtypes. High-resolution MRI has potential to improve localization of underlying brain network disruptions in TLE patients who are candidates for surgical resection.
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http://dx.doi.org/10.1002/hbm.24530DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6497534PMC
June 2019

Hypoglossal nerve palsy due to carotid artery dissection: an uncommon presentation of a common problem.

Neuroradiol J 2019 Apr 16;32(2):123-126. Epub 2019 Jan 16.

2 Department of Radiology, University of Pennsylvania Health System, USA.

Spontaneous internal carotid artery dissection occurs in patients of all ages, rarely presenting with hypoglossal nerve palsy. The characteristic imaging findings of internal carotid artery dissection and tongue denervation are reviewed in four patients. Recognition of internal carotid artery dissection is critical for appropriate treatment and to minimise the risk of thromboembolic-ischaemic complications. Radiologists must be aware of the radiological appearance of hypoglossal nerve palsy and maintain a high index of suspicion for internal carotid artery dissection when this finding is present.
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http://dx.doi.org/10.1177/1971400918825485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6410449PMC
April 2019

Clinical validation of automated hippocampal segmentation in temporal lobe epilepsy.

Neuroimage Clin 2018 10;20:1139-1147. Epub 2018 Oct 10.

Department of Neurology, Hospital of the University of Pennsylvania, Philadelphia, PA 19104, United States. Electronic address:

Objective: To provide a multi-atlas framework for automated hippocampus segmentation in temporal lobe epilepsy (TLE) and clinically validate the results with respect to surgical lateralization and post-surgical outcome.

Methods: We retrospectively identified 47 TLE patients who underwent surgical resection and 12 healthy controls. T1-weighted 3 T MRI scans were acquired for all subjects, and patients were identified by a neuroradiologist with regards to lateralization and degree of hippocampal sclerosis (HS). Automated segmentation was implemented through the Joint Label Fusion/Corrective Learning (JLF/CL) method. Gold standard lateralization was determined from the surgically resected side in Engel I (seizure-free) patients at the two-year timepoint. ROC curves were used to identify appropriate thresholds for hippocampal asymmetry ratios, which were then used to analyze JLF/CL lateralization.

Results: The optimal template atlas based on subject images with varying appearances, from normal-appearing to severe HS, was demonstrated to be composed entirely of normal-appearing subjects, with good agreement between automated and manual segmentations. In applying this atlas to 26 surgically resected seizure-free patients at a two-year timepoint, JLF/CL lateralized seizure onset 92% of the time. In comparison, neuroradiology reads lateralized 65% of patients, but correctly lateralized seizure onset in these patients 100% of the time. When compared to lateralized neuroradiology reads, JLF/CL was in agreement and correctly lateralized all 17 patients. When compared to nonlateralized radiology reads, JLF/CL correctly lateralized 78% of the nine patients.

Significance: While a neuroradiologist's interpretation of MR imaging is a key, albeit imperfect, diagnostic tool for seizure localization in medically-refractory TLE patients, automated hippocampal segmentation may provide more efficient and accurate epileptic foci localization. These promising findings demonstrate the clinical utility of automated segmentation in the TLE MR imaging pipeline prior to surgical resection, and suggest that further investigation into JLF/CL-assisted MRI reading could improve clinical outcomes. Our JLF/CL software is publicly available at https://www.nitrc.org/projects/ashs/.
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http://dx.doi.org/10.1016/j.nicl.2018.09.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6205355PMC
February 2019

Site-Specific Labeling of Cyanine and Porphyrin Dye-Stabilized Nanoemulsions with Affibodies for Cellular Targeting.

J Am Chem Soc 2018 10 15;140(42):13550-13553. Epub 2018 Oct 15.

Department of Bioengineering, School of Engineering and Applied Sciences , University of Pennsylvania , Philadelphia , Pennsylvania 19104 , United States.

Recently, it has been shown that amphiphilic dyes such as Indocyanine Green (ICG) and Protoporphyrin IX (PpIX) can solubilize hydrophobic colloids and/or drugs by driving the formation of stable nanoemulsions. These nanoemulsions are unique in that they can be composed entirely of functional and clinically used materials; however, they lack bio-orthogonal chemical handles for the facile attachment of targeting ligands. The ability to target nanoparticles is desirable because it can lead to improved specificity and reduced side effects. Here, we describe variants of ICG and PpIX with azide handles that can be readily incorporated into dye-stabilized nanoemulsions and facilitate the attachment of targeting ligands via click-chemistry in a simple, scalable, and reproducible reaction. As a model system, an anti-Her2 affibody was site-specifically attached to both ICG and PpIX-stabilized nanoemulsions with encapsulated superparamagnetic iron oxide nanoparticles.
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http://dx.doi.org/10.1021/jacs.8b07866DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6465177PMC
October 2018

Grid-like hexadirectional modulation of human entorhinal theta oscillations.

Proc Natl Acad Sci U S A 2018 10 3;115(42):10798-10803. Epub 2018 Oct 3.

Department of Biomedical Engineering, Columbia University, New York, NY 10027;

The entorhinal cortex contains a network of grid cells that play a fundamental part in the brain's spatial system, supporting tasks such as path integration and spatial memory. In rodents, grid cells are thought to rely on network theta oscillations, but such signals are not evident in all species, challenging our understanding of the physiological basis of the grid network. We analyzed intracranial recordings from neurosurgical patients during virtual navigation to identify oscillatory characteristics of the human entorhinal grid network. The power of entorhinal theta oscillations showed six-fold modulation according to the virtual heading during navigation, which is a hypothesized signature of grid representations. Furthermore, modulation strength correlated with spatial memory performance. These results demonstrate the connection between theta oscillations and the human entorhinal grid network and show that features of grid-like neuronal representations can be identified from population electrophysiological recordings.
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http://dx.doi.org/10.1073/pnas.1805007115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6196498PMC
October 2018

An all-in-one nanoparticle (AION) contrast agent for breast cancer screening with DEM-CT-MRI-NIRF imaging.

Nanoscale 2018 Sep;10(36):17236-17248

Department of Radiology, University of Pennsylvania, 3400 Spruce St, 1 Silverstein, Philadelphia, PA 19104, USA.

Conventional X-ray mammography has low diagnostic sensitivity for women with dense breasts. As a result, alternative contrast-enhanced screening tools such as dual energy mammography (DEM), computed tomography (CT), magnetic resonance imaging (MRI), and near-infrared fluorescence (NIRF) imaging are being used or investigated for these women. However, currently available contrast agents are non-ideal, have safety issues, and each imaging technique requires a different contrast agent. We therefore sought to develop a multimodal contrast agent that is functional for each breast imaging modality to simplify the diagnosis process and address the issues of existing contrast agents. Herein, we present a novel "all-in-one" nanoparticle (AION) multimodal imaging probe that has potent DEM, CT, MRI, and NIRF contrast properties and improved biocompatibility. AION were formed by co-encapsulation of a near-infrared fluorophore (DiR), silver sulfide nanoparticles (Ag2S-NP), and iron oxide nanoparticles (IO-NP) in PEGylated micelles. AION showed negligible cytotoxicity, which was in agreement with its minimal silver ion release profiles. AION generated strong contrast with all imaging modalities as demonstrated in phantom imaging. AION allowed in vivo tumor imaging as evidenced by the increase in contrast after injection. This study indicates the potential of AION as an effective multimodal contrast agent for breast cancer diagnosis with a range of imaging methods.
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http://dx.doi.org/10.1039/c8nr03741hDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6148383PMC
September 2018

User-Guided Segmentation of Multi-modality Medical Imaging Datasets with ITK-SNAP.

Neuroinformatics 2019 01;17(1):83-102

Department of Computer Science and Engineering, NYU Tandon School of Engineering, New York, NY, USA.

ITK-SNAP is an interactive software tool for manual and semi-automatic segmentation of 3D medical images. This paper summarizes major new features added to ITK-SNAP over the last decade. The main focus of the paper is on new features that support semi-automatic segmentation of multi-modality imaging datasets, such as MRI scans acquired using different contrast mechanisms (e.g., T1, T2, FLAIR). The new functionality uses decision forest classifiers trained interactively by the user to transform multiple input image volumes into a foreground/background probability map; this map is then input as the data term to the active contour evolution algorithm, which yields regularized surface representations of the segmented objects of interest. The new functionality is evaluated in the context of high-grade and low-grade glioma segmentation by three expert neuroradiogists and a non-expert on a reference dataset from the MICCAI 2013 Multi-Modal Brain Tumor Segmentation Challenge (BRATS). The accuracy of semi-automatic segmentation is competitive with the top specialized brain tumor segmentation methods evaluated in the BRATS challenge, with most results obtained in ITK-SNAP being more accurate, relative to the BRATS reference manual segmentation, than the second-best performer in the BRATS challenge; and all results being more accurate than the fourth-best performer. Segmentation time is reduced over manual segmentation by 2.5 and 5 times, depending on the rater. Additional experiments in interactive placenta segmentation in 3D fetal ultrasound illustrate the generalizability of the new functionality to a different problem domain.
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http://dx.doi.org/10.1007/s12021-018-9385-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6310114PMC
January 2019

Lateralized hippocampal oscillations underlie distinct aspects of human spatial memory and navigation.

Nat Commun 2018 06 21;9(1):2423. Epub 2018 Jun 21.

Department of Biomedical Engineering, Columbia University, 351 Engineering Terrace, Mail Code 8904, 1210 Amsterdam Avenue, New York, NY, 10027, USA.

The hippocampus plays a vital role in various aspects of cognition including both memory and spatial navigation. To understand electrophysiologically how the hippocampus supports these processes, we recorded intracranial electroencephalographic activity from 46 neurosurgical patients as they performed a spatial memory task. We measure signals from multiple brain regions, including both left and right hippocampi, and we use spectral analysis to identify oscillatory patterns related to memory encoding and navigation. We show that in the left but not right hippocampus, the amplitude of oscillations in the 1-3-Hz "low theta" band increases when viewing subsequently remembered object-location pairs. In contrast, in the right but not left hippocampus, low-theta activity increases during periods of navigation. The frequencies of these hippocampal signals are slower than task-related signals in the neocortex. These results suggest that the human brain includes multiple lateralized oscillatory networks that support different aspects of cognition.
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http://dx.doi.org/10.1038/s41467-018-04847-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6013427PMC
June 2018

Protoporphyrin IX (PpIX)-Coated Superparamagnetic Iron Oxide Nanoparticle (SPION) Nanoclusters for Magnetic Resonance Imaging and Photodynamic Therapy.

Adv Funct Mater 2018 Apr 15;28(16). Epub 2018 Feb 15.

Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA.

The ability to produce nanotherapeutics at large-scale with high drug loading efficiency, high drug loading capacity, high stability, and high potency is critical for clinical translation. However, many nanoparticle-based therapeutics under investigation suffer from complicated synthesis, poor reproducibility, low stability, and high cost. In this work, a simple method for preparing multifunctional nanoparticles is utilized that act as both a contrast agent for magnetic resonance imaging and a photosensitizer for photodynamic therapy for the treatment of cancer. In particular, the photosensitizer protoporphyrin IX (PpIX) is used to solubilize small nanoclusters of superparamagnetic iron oxide nanoparticles (SPIONs) without the use of any additional carrier materials. These nanoclusters are characterized with a high PpIX loading efficiency; a high loading capacity, stable behavior; high potency; and a synthetic approach that is amenable to large-scale production. In vivo studies of photodynamic therapy (PDT) efficacy show that the PpIX-coated SPION nanoclusters lead to a significant reduction in the growth rate of tumors in a syngeneic murine tumor model compared to both free PpIX and PpIX-loaded poly(ethylene glycol)-polycaprolactone micelles, even when injected at 1/8th the dose. These results suggest that the nanoclusters developed in this work can be a promising nanotherapeutic for clinical translation.
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http://dx.doi.org/10.1002/adfm.201707030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5997278PMC
April 2018

Electrophysiological Signatures of Spatial Boundaries in the Human Subiculum.

J Neurosci 2018 03 21;38(13):3265-3272. Epub 2018 Feb 21.

Department of Biomedical Engineering, Columbia University, New York, New York 10027,

Environmental boundaries play a crucial role in spatial navigation and memory across a wide range of distantly related species. In rodents, boundary representations have been identified at the single-cell level in the subiculum and entorhinal cortex of the hippocampal formation. Although studies of hippocampal function and spatial behavior suggest that similar representations might exist in humans, boundary-related neural activity has not been identified electrophysiologically in humans until now. To address this gap in the literature, we analyzed intracranial recordings from the hippocampal formation of surgical epilepsy patients (of both sexes) while they performed a virtual spatial navigation task and compared the power in three frequency bands (1-4, 4-10, and 30-90 Hz) for target locations near and far from the environmental boundaries. Our results suggest that encoding locations near boundaries elicited stronger theta oscillations than for target locations near the center of the environment and that this difference cannot be explained by variables such as trial length, speed, movement, or performance. These findings provide direct evidence of boundary-dependent neural activity localized in humans to the subiculum, the homolog of the hippocampal subregion in which most boundary cells are found in rodents, and indicate that this system can represent attended locations that rather than the position of one's own body. Spatial computations using environmental boundaries are an integral part of the brain's spatial mapping system. In rodents, border/boundary cells in the subiculum and entorhinal cortex reveal boundary coding at the single-neuron level. Although there is good reason to believe that such representations also exist in humans, the evidence has thus far been limited to functional neuroimaging studies that broadly implicate the hippocampus in boundary-based navigation. By combining intracranial recordings with high-resolution imaging of hippocampal subregions, we identified a neural marker of boundary representation in the human subiculum.
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http://dx.doi.org/10.1523/JNEUROSCI.3216-17.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5884460PMC
March 2018