Treatment Of Brain Disorders Research Articles

Sonothermogenetics for noninvasive and cell-type specific deep brain neuromodulation

BackgroundCritical advances in the investigation of brain functions and treatment of brain disorders are hindered by our inability to selectively target neurons in a noninvasive manner in the deep brain. ObjectiveThis study aimed to develop sonothermogenetics for noninvasive, deep-penetrating, and cell-type-specific neuromodulation by combining a thermosensitive ion channel TRPV1 with focused ultrasound (FUS)-induced brief, non-noxious thermal effect. MethodsThe sensitivity of TRPV1 to FUS sonication was evaluated in vitro. It was followed by in vivo assessment of sonothermogenetics in the activation of genetically defined neurons in the mouse brain by two-photon calcium imaging. Behavioral response evoked by sonothermogenetic stimulation at a deep brain target was recorded in freely moving mice. Immunohistochemistry staining of ex vivo brain slices was performed to evaluate the safety of FUS sonication. ResultsTRPV1 was found to be an ultrasound-sensitive ion channel. FUS sonication at the mouse brain in vivo selectively activated neurons that were genetically modified to express TRPV1. Temporally precise activation of TRPV1-expressing neurons was achieved with its success rate linearly correlated with the peak temperature within the FUS-targeted brain region as measured by in vivo magnetic resonance thermometry. FUS stimulation of TRPV1-expressing neurons at the striatum repeatedly evoked locomotor behavior in freely moving mice. FUS sonication was confirmed to be safe based on inspection of neuronal integrity, inflammation, and apoptosis markers. ConclusionsThis noninvasive and cell-type-specific neuromodulation approach with the capability to stimulate deep brain has the promise to advance the study of the intact nervous system and uncover new ways to treat neurological disorders.

Transcranial photobiomodulation in the management of brain disorders.

High prevalence and complications of brain disorders and also side effects of neuropsychiatric medications have encouraged researchers to find alternative therapeutic techniques which tPBM can be one of them. In present review we tried to determine the existing evidence of effectiveness, useful parameters, and safety of tPBM in the management of traumatic brain injury, stroke, Alzheimer, and Parkinson's disease as common brain disorders. Four online databases, including "Cochrane", "Pub Med", "Embase", and "Google scholar" were searched. Only those articles that were published until September 2020 and designed as RCTs or animal-controlled studies were included. Search keywords were the followings: transcranial photobiomodulation" OR "transcranial low-level laser therapy" AND "stroke" OR "traumatic brain injury" OR "Alzheimer" OR "Parkinson". Several studies have confirmed effectiveness of tPBM in treatment of different brain disorders but the level of evidence of its effectiveness remain to be determined. In this study we systematically reviewed human RCTs to determine the existing evidence of tPBM effectiveness in management of four mentioned brain disorders. Since the outcomes of the reviewed RCTs were not homogeneous, further well-designed RCTs are required to decide more definitively on the evidence of this noninvasive and probably safe therapeutic intervention. We hypothesized that non-homogeneous outcomes could be due to inefficiency of PBM parameters. Controlled animal studies have the advantage of using objective tests to evaluate the results and compare them with the control group. We determined useful tPBM parameters based on these studies. This research is part of our main project of tinnitus treatment using photobiomodulation (PBM). Evidence of central nervous system involvement in tinnitus led us to believe that treatment protocol of tinnitus should also include transcranial PBM. The determined useful parameters can be helpful in designing more efficient tPBM protocols in the management of brain disorders and tinnitus as a common debilitating symptom that can be associated with these disorders.

Integration of Multimodal Data for Deciphering Brain Disorders.

The accumulation of vast amounts of multimodal data for the human brain, in both normal and disease conditions, has provided unprecedented opportunities for understanding why and how brain disorders arise. Compared with traditional analyses of single datasets, the integration of multimodal datasets covering different types of data (i.e., genomics, transcriptomics, imaging, etc.) has shed light on the mechanisms underlying brain disorders in greater detail across both the microscopic and macroscopic levels. In this review, we first briefly introduce the popular large datasets for the brain. Then, we discuss in detail how integration of multimodal human brain datasets can reveal the genetic predispositions and the abnormal molecular pathways of brain disorders. Finally, we present an outlook on how future data integration efforts may advance the diagnosis and treatment of brain disorders.

Endothelin ETB Receptor-Mediated Astrocytic Activation: Pathological Roles in Brain Disorders.

In brain disorders, reactive astrocytes, which are characterized by hypertrophy of the cell body and proliferative properties, are commonly observed. As reactive astrocytes are involved in the pathogenesis of several brain disorders, the control of astrocytic function has been proposed as a therapeutic strategy, and target molecules to effectively control astrocytic functions have been investigated. The production of brain endothelin-1 (ET-1), which increases in brain disorders, is involved in the pathophysiological response of the nervous system. Endothelin B (ETB) receptors are highly expressed in reactive astrocytes and are upregulated by brain injury. Activation of astrocyte ETB receptors promotes the induction of reactive astrocytes. In addition, the production of various astrocyte-derived factors, including neurotrophic factors and vascular permeability regulators, is regulated by ETB receptors. In animal models of Alzheimer’s disease, brain ischemia, neuropathic pain, and traumatic brain injury, ETB-receptor-mediated regulation of astrocytic activation has been reported to improve brain disorders. Therefore, the astrocytic ETB receptor is expected to be a promising drug target to improve several brain disorders. This article reviews the roles of ETB receptors in astrocytic activation and discusses its possible applications in the treatment of brain disorders.

Low-Intensity Pulsed Ultrasound Stimulation Inhibits Cortical Spreading Depression.

Cortical spreading depression (CSD), which is closely correlated with migraine aura, cerebral ischemia, seizure, and brain injury, is a spreading wave of neuronal and glial depolarization. The purpose of this study is to investigate whether low-intensity pulsed ultrasound stimulation (PUS) inhibits CSD by modulating neural activity and hemodynamics. Behavioral test, intrinsic signal optical imaging and western blot analysis were used for evaluating the inhibition effect of PUS on CSD in rat. We found that: 1) 30min of PUS can significantly improve motor activity of rat with CSD. 2) Both 30s and 30min of PUS can significantly reduce count and propagation speed of CSD in rat and the inhibitory effect was enhanced with increase of ultrasound intensity. 3) 30min of PUS significantly enhanced levels of brain-derived neurotrophic factor protein in brain tissue with CSD. These results suggest that PUS has the potential to treat brain disorders associated with CSD.

Striatal cholinergic transmission. Focus on nicotinic receptors' influence in striatal circuits.

The critical role of acetylcholine (ACh) in the basal ganglia is evident from the effect of cholinergic agents in patients suffering from several related neurological disorders, such as Parkinson's disease, Tourette syndrome, or dystonia. The striatum possesses the highest density of ACh markers in the basal ganglia underlying the importance of ACh in this structure. Striatal cholinergic interneurons (CINs) are responsible for the bulk of striatal ACh, although extrinsic cholinergic afferents from brainstem structures may also play a role. CINs are tonically active, and synchronized pause in their activity occurs following the presentation of salient stimuli during behavioral conditioning. However, the synaptic mechanisms involved are not fully understood in this physiological response. ACh modulates striatal circuits by acting on muscarinic and nicotinic receptors existing in several combinations both presynaptically and postsynaptically. While the effects of ACh in the striatum through muscarinic receptors have received particular attention, nicotinic receptors function has been less studied. Here, after briefly reviewing relevant results regarding muscarinic receptors expression and function, I will focus on striatal nicotinic receptor expressed presynaptically on glutamatergic and dopaminergic afferents and postsynaptically on diverse striatal interneurons populations. I will also review recent evidence suggesting the involvement of different GABAergic sources in two distinct nicotinic-receptor-mediated striatal circuits: the disynaptic inhibition of striatal projection neurons and the recurrent inhibition among CINs. A better understanding of striatal nicotinic receptors expression and function may help to develop targeted pharmacological interventions to treat brain disorders such as Parkinson's disease, Tourette syndrome, dystonia, or nicotine addiction.

Multiscale wavelet-based regularized reconstruction algorithm for three-dimensional compressed sensing magnetic resonance imaging

Nowadays, the most dynamic and safe imaging technique used in hospitals to diagnose is magnetic resonance imaging (MRI). In clinical applications, such as follow-up of patients with planning surgery, radiation therapy, therapy response in bone metastases assessment and treatment for brain disorders, repeated MRI scans are performed. Unfortunately, the slow acquisitions of MRI drive cost high by limiting patient throughput as well as limiting the potential indications for use. A mathematical framework called compressed sensing (CS) to accelerate MRI acquisition is used for generating undersampled measurements. Then, the iterative nonlinear numerical method is required for perfect reconstruction from highly undersampled measurements. In this work, the multiscale wavelet domain regularization prior-based iterative reconstruction algorithm is developed to address the above-mentioned reconstruction problem, in which multiscale wavelet domain generalized Gaussian mixture model is utilized for the regularization prior. The regularization-based algorithm is applied to generate three-dimensional (3D) high-quality MRI volume from multichannel k-space measurements in a compressed sensing framework. Several experiments using one synthetic and one real 3D CS multichannel k-space data were used to evaluate and validate the performance of the proposed algorithm. The total variation (TV)-based and soft-thresholding (ST) based-reconstruction methods were implemented to compare with the proposed algorithm. Extensive experimental results demonstrated that the proposed method has improved results in terms of visual quality and quantitative measurements compared to the existing methods.

All-Tissue-like Multifunctional Optoelectronic Mesh for Deep-Brain Modulation and Mapping.

The development of a multifunctional device that achieves optogenetic neuromodulation and extracellular neural mapping is crucial for understanding neural circuits and treating brain disorders. Although various devices have been explored for this purpose, it is challenging to develop biocompatible optogenetic devices that can seamlessly interface with the brain. Herein, we present a tissue-like optoelectronic mesh with a compact interface that enables not only high spatial and temporal resolutions of optical stimulation but also the sampling of optically evoked neural activities. An in vitro experiment in hydrogel showed efficient light propagation through a freestanding SU-8 waveguide that was integrated with flexible mesh electronics. Additionally, an in vivo implantation of the tissue-like optoelectronic mesh in the brain of a live transgenic mouse enabled the sampling of optically evoked neural signals. Therefore, this multifunctional device can aid the chronic modulation of neural circuits and behavior studies for developing biological and therapeutic applications.

Impacts of Drug Interactions on Pharmacokinetics and the Brain Transporters: A Recent Review of Natural Compound-Drug Interactions in Brain Disorders.

Natural compounds such as herbal medicines and/or phyto-compounds from foods, have frequently been used to exert synergistic therapeutic effects with anti-brain disorder drugs, supplement the effects of nutrients, and boost the immune system. However, co-administration of natural compounds with the drugs can cause synergistic toxicity or impeditive drug interactions due to changes in pharmacokinetic properties (e.g., absorption, metabolism, and excretion) and various drug transporters, particularly brain transporters. In this review, natural compound–drug interactions (NDIs), which can occur during the treatment of brain disorders, are emphasized from the perspective of pharmacokinetics and cellular transport. In addition, the challenges emanating from NDIs and recent approaches are discussed.

Acupoint-brain (acubrain) mapping: Common and distinct cortical language regions activated by focused ultrasound stimulation on two language-relevant acupoints

Acupuncture, taking the advantage of modality-specific neural pathways, has shown promising results in the treatment of brain disorders that affect different modalities such as pain and vision. However, the precise underlying mechanisms of within-modality neuromodulation of acupoints on human high-order cognition remain largely unknown. In the present study, we used a non-invasive and easy-operating method, focused ultrasound, to stimulate two language-relevant acupoints, namely GB39 (Xuanzhong) and SJ8 (Sanyangluo), of thirty healthy adults. The effect of focused ultrasound stimulation (FUS) on brain activation was examined by functional magnetic resonance imaging (fMRI). We found that stimulating GB39 and SJ8 by FUS evoked overlapping but distinct brain activation patterns. Our findings provide a major step toward within-modality (in this case, language) acupoint-brain (acubrain) mapping and shed light on to the potential use of FUS as a personalized treatment option for brain disorders that affect high-level cognitive functions.

Design of optimal multi-site brain stimulation protocols via neuro-inspired epilepsy models for abatement of interictal discharges

Objective. Electrical brain stimulation is recognized as a promising therapeutic approach for treating brain disorders such as epilepsy. However, the use of this technique is still largely empirical, since stimulation parameters and targets are chosen using a trial-and-error approach. Therefore, there is a pressing need to design optimal, rationale-based multi-site brain stimulation protocols to control epileptiform activity. Approach. Here, we developed biologically-inspired models of brain activity receiving stimulation at two levels of description (single- and multi-population epileptogenic networks). First, we used bifurcation analysis to determine optimal parameters able to abort epileptiform patterns. Second, we present a graph-theory based method to classify network populations in an epileptogenic network based on their contribution to seizure generation and propagation. Main results. The best therapeutic effects (i.e. reduction of epileptiform discharges duration and occurrence rate) were obtained by the specific targeting of populations with the highest eigenvector centrality values. The timing of stimulation was also found to be critical in seizure abortion impact. Significance. Overall, our results provide a proof-of-concept that using network neuroscience combined with physiology-based computational models of brain activity can provide an effective method for the rational design of brain stimulation protocols in epilepsy.

Non-invasive suppression of essential tremor via phase-locked disruption of its temporal coherence

Aberrant neural oscillations hallmark numerous brain disorders. Here, we first report a method to track the phase of neural oscillations in real-time via endpoint-corrected Hilbert transform (ecHT) that mitigates the characteristic Gibbs distortion. We then used ecHT to show that the aberrant neural oscillation that hallmarks essential tremor (ET) syndrome, the most common adult movement disorder, can be transiently suppressed via transcranial electrical stimulation of the cerebellum phase-locked to the tremor. The tremor suppression is sustained shortly after the end of the stimulation and can be phenomenologically predicted. Finally, we use feature-based statistical-learning and neurophysiological-modelling to show that the suppression of ET is mechanistically attributed to a disruption of the temporal coherence of the aberrant oscillations in the olivocerebellar loop, thus establishing its causal role. The suppression of aberrant neural oscillation via phase-locked driven disruption of temporal coherence may in the future represent a powerful neuromodulatory strategy to treat brain disorders.

Safety and Efficacy of Magnetic Resonance-Guided Focused Ultrasound Surgery With Autofocusing Echo Imaging.

ObjectiveMagnetic resonance-guided focused ultrasound surgery (MRgFUS) lesioning is a new treatment for brain disorders. However, the skull is a major barrier of ultrasound sonication in MRgFUS because it has an irregular surface and varies its size and shape among individuals. We recently developed the concept of skull density ratio (SDR) to select candidates for MRgFUS from among patients with essential tremor (ET). However, SDR is not the only factor contributing to successful MRgFUS lesioning treatment—refining the target through exact measurement of the ultrasonic echo in the transducer also improves treatment efficacy. In the present study, we carried out MRgFUS lesioning using an autofocusing echo imaging technique. We aimed to evaluate the safety and efficacy of this new approach, especially in patients with low SDR in whom previous focusing methods have failed.MethodsFrom December 2019 to March 2020, we recruited 10 patients with ET or Parkinson’s disease (PD) who had a low SDR. Two patients dropped out of the trial due to the screening failure of other medical diseases. In total, eight patients were included: six with ET who underwent MRgFUS thalamotomy and two with PD who underwent MRgFUS pallidotomy. The autofocusing echo imaging technique was used in all cases.ResultsThe mean SDR of the patients with ET was 0.34 (range: 0.29–0.39), while that of the patients with PD was 0.41 (range: 0.38–0.44). The mean skull volume of patients with ET was 280.57 cm3 (range: 227–319 cm3), while that of the patients with PD was 287.13 cm3 (range: 271–303 cm3). During MRgFUS, a mean of 15 sonications were performed, among which a mean of 5.63 used the autofocusing technique. The mean maximal temperature (Tmax) achieved was 55.88°C (range: 52–59°C), while the mean energy delivered was 34.75 kJ (range: 20–42 kJ) among all patients. No serious adverse events occurred during or after treatment. Tmax or sonication factors (skull volume, SDR, sonication number, autofocusing score, similarity score, energy range, and power) were not correlated with autofocusing technique (p > 0.05, autofocusing score showed a p-value of 0.071).ConclusionUsing autofocusing echo imaging lesioning, a safe and efficient MRgFUS treatment, is available even for patients with a low SDR. Therefore, the indications for MRgFUS lesioning could be expanded to include patients with ET who have an SDR < 0.4 and those with PD who have an SDR < 0.45.Clinical Trial Registrationclinicaltrials.gov, identifier: NCT03935581.

Physiological and pathological functions of TMEM106B: a gene associated with brain aging and multiple brain disorders.

TMEM106B, encoding a lysosome membrane protein, has been recently associated with brain aging, hypomyelinating leukodystrophy and multiple neurodegenerative diseases, such as frontotemporal lobar degeneration (FTLD) and limbic-predominant age-related TDP-43 encephalopathy (LATE). During the past decade, considerable progress has been made towards our understanding of the cellular and physiological functions of TMEM106B. TMEM106B regulates many aspects of lysosomal function, including lysosomal pH, lysosome movement, and lysosome exocytosis. Both an increase and decrease in TMEM106B levels result in lysosomal abnormalities. In mouse models,TMEM106B deficiency leads to lysosome trafficking and myelination defects and FTLD relatedpathology. In humans, alterations in TMEM106B levels or functionare intimately linked to neuronal proportions, brain aging, and brain disorders. Further elucidation of the physiological function of TMEM106B and changes inTMEM106B underpathological conditionswill facilitatetherapeutic development to treat brain disorders associated with TMEM106B.

Microglia Elimination Increases Neural Circuit Connectivity and Activity in Adult Mouse Cortex.

Microglia have crucial roles in sculpting synapses and maintaining neural circuits during development. To test the hypothesis that microglia continue to regulate neural circuit connectivity in adult brain, we have investigated the effects of chronic microglial depletion, via CSF1R inhibition, on synaptic connectivity in the visual cortex in adult mice of both sexes. We find that the absence of microglia dramatically increases both excitatory and inhibitory synaptic connections to excitatory cortical neurons assessed with functional circuit mapping experiments in acutely prepared adult brain slices. Microglia depletion leads to increased densities and intensities of perineuronal nets. Furthermore, in vivo calcium imaging across large populations of visual cortical neurons reveals enhanced neural activities of both excitatory neurons and parvalbumin-expressing interneurons in the visual cortex following microglia depletion. These changes recover following adult microglia repopulation. In summary, our new results demonstrate a prominent role of microglia in sculpting neuronal circuit connectivity and regulating subsequent functional activity in adult cortex.SIGNIFICANCE STATEMENT Microglia are the primary immune cell of the brain, but recent evidence supports that microglia play an important role in synaptic sculpting during development. However, it remains unknown whether and how microglia regulate synaptic connectivity in adult brain. Our present work shows chronic microglia depletion in adult visual cortex induces robust increases in perineuronal nets, and enhances local excitatory and inhibitory circuit connectivity to excitatory neurons. Microglia depletion increases in vivo neural activities of both excitatory neurons and parvalbumin inhibitory neurons. Our new results reveal new potential avenues to modulate adult neural plasticity by microglia manipulation to better treat brain disorders, such as Alzheimer's disease.

The Anti-Neuroinflammatory Role of Anthocyanins and Their Metabolites for the Prevention and Treatment of Brain Disorders.

Anthocyanins are naturally occurring polyphenols commonly found in fruits and vegetables. Numerous studies have described that anthocyanin-rich foods may play a crucial role in the prevention and treatment of different pathological conditions, which have encouraged their consumption around the world. Anthocyanins exhibit a significant neuroprotective role, mainly due to their well-recognized antioxidant and anti-inflammatory properties. Neuroinflammation is an intricate process relevant in both homeostatic and pathological circumstances. Since the progression of several neurological disorders relies on neuroinflammatory process, targeting brain inflammation has been considered a promising strategy in those conditions. Recent data have shown the anti-neuroinflammatory abilities of many anthocyanins and of their metabolites in the onset and development of several neurological disorders. In this review, it will be discussed the importance and the applicability of these polyphenolic compounds as neuroprotective agents and it will be also scrutinized the molecular mechanisms underlying the modulation of neuroinflammation by these natural compounds in the context of several brain diseases.

The Role of ADF/Cofilin in Synaptic Physiology and Alzheimer's Disease.

Actin-depolymerization factor (ADF)/cofilin, a family of actin-binding proteins, are critical for the regulation of actin reorganization in response to various signals. Accumulating evidence indicates that ADF/cofilin also play important roles in neuronal structure and function, including long-term potentiation and depression. These are the most extensively studied forms of long-lasting synaptic plasticity and are widely regarded as cellular mechanisms underlying learning and memory. ADF/cofilin regulate synaptic function through their effects on dendritic spines and the trafficking of glutamate receptors, the principal mediator of excitatory synaptic transmission in vertebrates. Regulation of ADF/cofilin involves various signaling pathways converging on LIM domain kinases and slingshot phosphatases, which phosphorylate/inactivate and dephosphorylate/activate ADF/cofilin, respectively. Actin-depolymerization factor/cofilin activity is also regulated by other actin-binding proteins, activity-dependent subcellular distribution and protein translation. Abnormalities in ADF/cofilin have been associated with several neurodegenerative disorders such as Alzheimer’s disease. Therefore, investigating the roles of ADF/cofilin in the brain is not only important for understanding the fundamental processes governing neuronal structure and function, but also may provide potential therapeutic strategies to treat brain disorders.

Molecular landscape of long noncoding RNAs in brain disorders.

According to current paradigms, various risk factors, such as genetic mutations, oxidative stress, neural network dysfunction, and abnormal protein degradation, contribute to the progression of brain disorders. Through the cooperation of gene transcripts in biological processes, the study of noncoding RNAs can lead to insights into the cause and treatment of brain disorders. Recently, long noncoding RNAs (lncRNAs) which are longer than 200 nucleotides in length have been suggested as key factors in various brain disorders. Accumulating evidence suggests the potential of lncRNAs as diagnostic or prognostic biomarkers and therapeutic targets. High-throughput screening-based sequencing has been instrumental in identification of lncRNAs that demand new approaches to understanding the progression of brain disorders. In this review, we discuss the recent progress in the study of lncRNAs, and addresses the pathogenesis of brain disorders that involve lncRNAs and describes the associations of lncRNAs with neurodegenerative disorders such as Alzheimer disease (AD), Parkinson disease (PD), and neurodevelopmental disorders. We also discuss potential targets of lncRNAs and their promise as novel therapeutics and biomarkers in brain disorders.

Deep learning for brain disorder diagnosis based on fMRI images

In modern neuroscience and clinical study, neuroscientists and clinicians often use non-invasive imaging techniques to validate theories and computational models, observe brain activities and diagnose brain disorders. The functional Magnetic Resonance Imaging (fMRI) is one of the commonly-used imaging modalities that can be used to understand human brain mechanisms as well as the diagnosis and treatment of brain disorders. The advances in artificial intelligence and the emergence of deep learning techniques have shown promising results to better interpret fMRI data. Deep learning techniques have rapidly become the state of the art for analyzing fMRI data sets and resulted in performance improvements in diverse fMRI applications. Deep learning is normally presented as an end-to-end learning process and can alleviate feature engineering requirements and hence reduce domain knowledge requirements to some extent. Under the framework of deep learning, fMRI data can be considered as images, time series or images series. Hence, different deep learning models such as convolutional neural networks, recurrent neural network, or a combination of both, can be developed to process fMRI data for different tasks. In this review, we discussed the basics of deep learning methods and focused on its successful implementations for brain disorder diagnosis based on fMRI images. The goal is to provide a high-level overview of brain disorder diagnosis with fMRI images from the perspective of deep learning applications.

Transcellular Model for Neutral and Charged Nanoparticles Across an In Vitro Blood-Brain Barrier.

PurposeThe therapeutic drug-loaded nanoparticles (NPs, 20–100 nm) have been widely used to treat brain disorders. To improve systemic brain delivery efficacy of these NPs, it is necessary to quantify their transport parameters across the blood–brain barrier (BBB) and understand the underlying transport mechanism.MethodsPermeability of an in vitro BBB, bEnd3 (mouse brain microvascular endothelial cells) monolayer, to three neutral NPs with the representative diameters was measured using an automated fluorometer system. To elucidate the transport mechanism of the neutral NPs across the in vitro BBB, and that of positively charged NPs whose BBB permeability was measured in a previous study, we developed a novel transcellular model, which incorporates the charge of the in vitro BBB, the mechanical property of the cell membrane, the ion concentrations of the surrounding salt solution and the size and charge of the NPs.ResultsOur model indicates that the negative charge of the surface glycocalyx and basement membrane of the BBB plays a pivotal role in the transcelluar transport of NPs with diameter 20-100 nm across the BBB. The electrostatic force between the negative charge at the in vitro BBB and the positive charge at NPs greatly enhances NP permeability. The predictions from our transcellular model fit very well with the measured BBB permeability for both neutral and charged NPs.ConclusionOur model can be used to predict the optimal size and charge of the NPs and the optimal charge of the BBB for an optimal systemic drug delivery strategy to the brain.