Breaching the Blood-Brain Barrier as a Gate to Psychiatric Disorder

The mechanisms underlying the development and progression of psychiatric illnesses are only partially known. Clinical data suggest blood-brain barrier (BBB) breakdown and inflammation are involved in some patients groups. Here we put forward the “BBB hypothesis” and abnormal blood-brain communication as key mechanisms leading to neuronal dysfunction underlying disturbed cognition, mood, and behavior. Based on accumulating clinical data and animal experiments, we propose that events within the “neurovascular unit” are initiated by a focal BBB breakdown, and are associated with dysfunction of brain astrocytes, a local inflammatory response, pathological synaptic plasticity, and increased network connectivity. Our hypothesis should be validated in animal models of psychiatric diseases and BBB breakdown. Recently developed imaging approaches open the opportunity to challenge our hypothesis in patients. We propose that molecular mechanisms controlling BBB permeability, astrocytic functions, and inflammation may become novel targets for the prevention and treatment of psychiatric disorders

Vascular Pathology and Blood-Brain Barrier Disruption in Cognitive and Psychiatric Complications of Type 2 Diabetes Mellitus

Vascular pathology is recognized as a principle insult in type 2 diabetes mellitus (T2DM). Co-morbidities such as structural brain abnormalities, cognitive, learning and memory deficits are also prevailing in T2DM patients. We previously suggested that microvascular pathologies involving blood-brain barrier (BBB) breakdown results in leakage of serum-derived components into the brain parenchyma, leading to neuronal dysfunction manifested as psychiatric illnesses. The current postulate focuses on the molecular mechanisms controlling BBB permeability in T2DM, as key contributors to the pathogenesis of mental disorders in patients. Revealing the mechanisms underlying BBB dysfunction and inflammatory response in T2DM and their role in metabolic disturbances, abnormal neurovascular coupling and neuronal plasticity, would contribute to the understanding of the mechanisms underlying psychopathologies in diabetic patients. Establishing this link would offer new targets for future therapeutic interventions

Stimulation of the Sphenopalatine Ganglion Induces Reperfusion and Blood-Brain Barrier Protection in the Photothrombotic Stroke Model

The treatment of stroke remains a challenge. Animal studies showing that electrical stimulation of the sphenopalatine ganglion (SPG) exerts beneficial effects in the treatment of stroke have led to the initiation of clinical studies. However, the detailed effects of SPG stimulation on the injured brain are not known.The effect of acute SPG stimulation was studied by direct vascular imaging, fluorescent angiography and laser Doppler flowmetry in the sensory motor cortex of the anaesthetized rat. Focal cerebral ischemia was induced by the rose bengal (RB) photothrombosis method. In chronic experiments, SPG stimulation, starting 15 min or 24 h after photothrombosis, was given for 3 h per day on four consecutive days. Structural damage was assessed using histological and immunohistochemical methods. Cortical functions were assessed by quantitative analysis of epidural electro-corticographic (ECoG) activity continuously recorded in behaving animals.Stimulation induced intensity- and duration-dependent vasodilation and increased cerebral blood flow in both healthy and photothrombotic brains. In SPG-stimulated rats both blood brain-barrier (BBB) opening, pathological brain activity and lesion volume were attenuated compared to untreated stroke animals, with no apparent difference in the glial response surrounding the necrotic lesion.SPG-stimulation in rats induces vasodilation of cortical arterioles, partial reperfusion of the ischemic lesion, and normalization of brain functions with reduced BBB dysfunction and stroke volume. These findings support the potential therapeutic effect of SPG stimulation in focal cerebral ischemia even when applied 24 h after stroke onset and thus may extend the therapeutic window of currently administered stroke medications

Mechanisms of blood-retinal barrier disruption related to intraocular inflammation and malignancy

Blood-retinal barrier (BRB) disruption is a common accompaniment of intermediate, posterior and panuveitis causing leakage into the retina and macular oedema resulting in vision loss. It is much less common in anterior uveitis or in patients with intraocular lymphoma who may have marked signs of intraocular inflammation. New drugs used for chemotherapy (cytarabine, immune checkpoint inhibitors, BRAF inhibitors, EGFR inhibitors, bispecific anti-EGFR inhibitors, MET receptor inhibitors and Bruton tyrosine kinase inhibitors) can also cause different types of uveitis and BRB disruption. As malignant disease itself can cause uveitis, particularly from breast, lung and gastrointestinal tract cancers, it can be clinically difficult to sort out the cause of BRB disruption. Immunosuppression due to malignant disease and/or chemotherapy can lead to infection which can also cause BRB disruption and intraocular infection. In this paper we address the pathophysiology of BRB disruption related to intraocular inflammation and malignancy, methods for estimating the extent and effect of the disruption and examine why some types of intraocular inflammation and malignancy cause BRB disruption and others do not. Understanding this may help sort and manage these patients, as well as devise future therapeutic approaches

Novel fluorescein angiography-based computer-aided algorithm for assessment of retinal vessel permeability.

PURPOSE: To present a novel method for quantitative assessment of retinal vessel permeability using a fluorescein angiography-based computer algorithm. METHODS: Twenty-one subjects (13 with diabetic retinopathy, 8 healthy volunteers) underwent fluorescein angiography (FA). Image pre-processing included removal of non-retinal and noisy images and registration to achieve spatial and temporal pixel-based analysis. Permeability was assessed for each pixel by computing intensity kinetics normalized to arterial values. A linear curve was fitted and the slope value was assigned, color-coded and displayed. The initial FA studies and the computed permeability maps were interpreted in a masked and randomized manner by three experienced ophthalmologists for statistical validation of diagnosis accuracy and efficacy. RESULTS: Permeability maps were successfully generated for all subjects. For healthy volunteers permeability values showed a normal distribution with a comparable range between subjects. Based on the mean cumulative histogram for the healthy population a threshold (99.5%) for pathological permeability was determined. Clear differences were found between patients and healthy subjects in the number and spatial distribution of pixels with pathological vascular leakage. The computed maps improved the discrimination between patients and healthy subjects, achieved sensitivity and specificity of 0.974 and 0.833 respectively, and significantly improved the consensus among raters for the localization of pathological regions. CONCLUSION: The new algorithm allows quantification of retinal vessel permeability and provides objective, more sensitive and accurate evaluation than the present subjective clinical diagnosis. Future studies with a larger patients' cohort and different retinal pathologies are awaited to further validate this new approach and its role in diagnosis and treatment follow-up. Successful evaluation of vasculature permeability may be used for the early diagnosis of brain microvascular pathology and potentially predict associated neurological sequelae. Finally, the algorithm could be implemented for intraoperative evaluation of micovascular integrity in other organs or during animal experiments

Fluorescent angiography during SPG stimulation A, Two representative angiographic images of cortical surface vessels under control conditions (left) and during SPG stimulation (3 mA, 500 µs, right, white bar represents 0.1 mm).

<p>B, Intensity curves (in arbitrary intensity units, iu) for the venous (blue) and arterial (red) compartments for the venous (blue) and arterial (red) compartments (marked in (A)) during control injection (left) and SPG stimulation (right). C, % change in diameter (black) and peak-to-peak (arterial-venous) interval (red) at different stimulation intensities (1–5 mA, 500 µs).</p

BBB breakdown, astroglial response and brain damage after SPG stimulation A, Two brain surface images after injection of Evans blue indicates BBB breakdown of RB-treated (left) and RB-SPG-15 min (right) rat brains.

<p>Images below display EB (blue color) intensity, color coded. Both the size of the area with increased EB and the intensity were decreased in SPG-treated rats compared to non-stimulated animals (right graph). B, Immunostaining against the astrocytic marker, GFAP (upper panels) and the microglial marker, Iba-1 (lower panel) in RB-treated (left) and the contra-lateral control hemisphere (right). Bar graphs show area measured with intracellular staining (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0039636#s2" target="_blank">Methods</a>). C, Coronal sections of brains from RB (left) and RB-SPG-15 min (right) animals. Bar graphs show change in cortical volume after photothrombosis. *p<0.05.</p

SPG stimulation in the RB-treated cortex.

<p>A, Brain surface images in a typical experiment before (left), and after (middle) photothrombosis and during SPG stimulation (2 mA, 500 µs, right). Note vasodilation and reperfusion of the thrombosed vessels (circled). B, Laser-Doppler recording in the same experiment as in (A), showing reduced rCBF during photothrombosis, which was partially reversible during SPG stimulation. C, Fluorescent angiography from a different rat before (left), after photothrombosis (middle) and during SPG stimulation (2 mA, 500 µs, right).</p

A working hypothesis on SPG-induced brain protection after stroke: The ischemic core is surrounded by a peri-ischemic region which is susceptible for an irreversible injury (AKA “stroke progression”).

<p>The peri-ischemic lesion is characterized by dysfunction of the blood-brain barrier (BBB) which induces neuronal hyper-excitability, spreading depolarizations and seizures, inflammation and cellular damage <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0039636#pone.0039636-Shlosberg1" target="_blank">[4]</a>. SPG stimulation at an early, post-insult therapeutic time window induces vasodilation and increased rCBF, sufficient to re-perfuse the ischemic core and to reduce lesion size. When stimulation is initiated at a delayed post-insult therapeutic window (24 h), vasodilation in the peri-ischemic lesion attenuates BBB injury and the associated neuronal hyper-excitability, thus preventing progression of the primary lesion.</p