Pharmaco-fUS in cognitive impairment: Lessons from a preclinical model.

BACKGROUND: There is an urgent need to understand and reverse cognitive impairment. The lack of appropriate animal models combined with the limited knowledge of pathophysiological mechanisms makes the development of new cognition-enhancing drugs complex. Scopolamine is a pharmacologic agent which impairs cognition and functional imaging in a wide range of animal species, similarly to what is seen in cognitive impairment in humans. METHODS: In this study, using a functional ultrasound (fUS) neuroimaging technique, we monitored the impact of donepezil (DPZ), a potent acetylcholinesterase inhibitor and first-line treatment in patients with mild to moderate Alzheimer's disease, in a scopolamine-induced mouse model. RESULTS: We demonstrated that despite its low impact on the cerebral blood volume (CBV) signal, scopolamine injection produced an overall decrease in functional connectivity between various brain areas. In addition, we revealed that DPZ induced a strong decrease in CBV signal without causing a difference in functional connectivity. CONCLUSION: Finally, our work highlighted that DPZ counteracted the impact of scopolamine on functional connectivity changes and confirmed the interest of using pharmaco-fUS imaging on cognitive disorders, both in frequent and rare neurological disorders.

Impaired Local and Long-Range Brain Connectivity and Visual Response in a Genetic Rat Model of Hyperactivity Revealed by Functional Ultrasound.

Attention-Deficit hyperactivity disorder (ADHD) is a central nervous system (CNS) disorder frequently associated with other psychiatric disorders. Pathophysiology processes at stake in ADHD are still under investigation and interestingly neuroimaging data points to modulated brain connectivity in patients. The genetic spontaneously hypertensive rat (SHR) model has been widely used to study pathophysiological underpinnings of ADHD and resting-state brain connectivity using functional magnetic resonance imaging. Here, functional ultrasound imaging, a new technique enabling fast measurement of cerebral blood volume (CBV), was used to further characterize resting-state functional connectivity - at both local and long-range - and visual response in SHR. We demonstrated that response to visual stimulation was increased in SHR in the visual cortex and the superior colliculus. They displayed altered long-range functional connectivity between spatially distinct regions. SHR also displayed modulated local connectivity, with strong increases of regional homogeneity in parts of the motor and visual cortex, along with decreases in the secondary cingulate cortex, the superior colliculus and the pretectal area. As CBV is intricately coupled to cerebral activity, these results suggest an abnormal neural activity in the SHR animal model, consistent with previous clinical studies and demonstrate the potential of functional ultrasound imaging as a translational tool in ADHD.

Inter-subject registration and application of the SIGMA rat brain atlas for regional labeling in functional ultrasound imaging.

BACKGROUND: Recent advances using functional ultrasound (fUS) imaging have opened new avenues to evaluate brain activity through the regional monitoring of cerebral blood volume (CBV) dynamics. In particular, this technology paves the way for understanding physiological or pathological cerebral processes or exploring the pharmacological profiles of new drugs targeting brain disorders. One of the main difficulties of this technology is the lack of standardized and validated tools, in particular relevant brain atlases, to help improving the accuracy, automation and reproducibility of fUS data analysis. NEW METHOD: Here, we demonstrate the possibility to use the MRI-validated SIGMA brain atlas in rat to perform fast and precise analysis of CBV changes in numerous functionally relevant regions of interest using fUS imaging. We applied this atlas to a dataset obtained in anesthetized rats evaluating the cerebral effects of atomoxetine, a norepinephrine reuptake inhibitor currently marketed in attention-deficit/hyperactivity-disorder. RESULTS: This approach enabled to show the subregional effects of atomoxetine in the rat with very few inter-individual differences in some areas, such as the dentate gyrus. CONCLUSIONS: We show the feasibility of inter-individual registration of 2D pharmaco-fUS data and subsequent detailed analysis using the SIGMA atlas.

Pharmaco-fUS for Characterizing Drugs for Alzheimer's Disease - The Case of THN201, a Drug Combination of Donepezil Plus Mefloquine.

Donepezil is a potent acetylcholinesterase inhibitor, largely used worldwide to alleviate cognitive symptoms in Alzheimer's disease (AD). Beyond the widely described neuronal impact of donepezil, it was recently shown that targeting connexins, the proteins involved in astrocyte network organization, potentiates donepezil efficacy profile using behavioral tests in AD rodent models. We herein present data demonstrating the potential of functional ultrasound imaging to monitor cerebral activity changes after pharmacological challenge in mice. As an example, we showed that although administration of donepezil or mefloquine alone at low dose had only very limited effects on the signal compared to the baseline, their combination produced marked hemodynamic effects in the hippocampus, in line with previously published behavioral data demonstrating a synergic interaction between both drugs. Thus, the present study provides new perspectives, (i) through the use of pharmaco-fUS, a new non-clinical imaging modality, to move forward drug discovery in AD and (ii) by the profiling of two drug treatments on brain dynamics, one used in AD: donepezil, and the other in development: donepezil combined with mefloquine (THN201) as a modulator of astrocyte network.

Functional ultrasound imaging to study brain dynamics: Application of pharmaco-fUS to atomoxetine.

Functional ultrasound (fUS) is a new tool enabling the imaging of brain activity through the regional monitoring of cerebral blood volume (CBV) dynamics. This innovative technique has not yet demonstrated its full potential in pharmacological applications and drug development. In the current proof-of-concept study, the impact of atomoxetine (ATX), a potent norepinephrine reuptake inhibitor and non-stimulant treatment marketed in attention-deficit/hyperactivity-disorder, was evaluated in anesthetized rat using pharmacological functional ultrasound (pharmaco-fUS) at increasing doses (0.3, 1 and 3 mg/kg). Using regions of interest (acute changes of CBV and functional connectivity) or pixel-based (general linear modeling and independent component analysis) analysis, we here demonstrated that ATX consistently displayed a hemodynamic effect in the visual cortex, the dentate gyrus and thalamus, especially visual areas such as lateral posterior thalamic nuclei and lateral geniculate nuclei (LGN). The time profile of ATX effects was dose-dependent, with fastest CBV increases at the highest dose, and longer CBV increases at the intermediate dose. Standardizing the use of pharmaco-fUS could improve our understanding of the mechanism of action of drugs active in the brain and might constitute a new step to move forward in drug development for neurological disorders.

Programa de Recursos Descentralizados na Saúde (PROREDE): consolidando a cidadania e a participação popular / Health Decentralization Resources (PROREDE): consolidating citizenship and popular participation

A gestão participativa foi um dos eixos de estruturação das políticas de saúde que orientaram a ação do governo municipal em Guarulhos, SP, no período de 2005 a 2008. Esse eixo estruturou-se em várias iniciativas, aqui destacada a que criou o Programa de Recursos Descentralizados na Saúde - PROREDE, criado pela Lei Municipal Lei 6.195 de 11 de dezembro de 2006. Com início em 2008, seu principal objetivo foi descentralizar a gestão de recursos financeiros para todas as unidades da rede municipal, a fim de serem utilizados na manutenção, conservação do imóvel e seus equipamentos, assim como para realização de atividades de promoção de saúde. A transferência de recursos financeiros próprios às unidades de saúde deu-se por meio de conta bancária específica em nome das associações de natureza civil e não lucrativa, criadas em cada equipamento da rede e compostas por usuários e trabalhadores dessas unidades. Um Plano de Ação e outro de Aplicação e controle dos recursos compunham o conjunto de documentos anexos aos convênios assinados pelas associações e pelo governo municipal. Além disso, o PROREDE objetivou descentralizar a gestão e incentivar a plena participação dos Conselhos Gestores, articulados com as associações recém-criadas, no processo de tomada de decisões, na implantação das ações planejadas, no controle e prestação de contas, e no processo de avaliação das melhorias das condições do atendimento e qualidade dos serviços prestados. Em julho de 2008, de um total de 103 Unidades Básicas de Saúde (UBS) no município, 21 tinham assinado o convênio e iniciado a gestão de recursos financeiros através do PROREDE.

Programa de Recursos Descentralizados na Saúde (PROREDE): consolidando a cidadania e a participação popular / Health Decentralization Resources (PROREDE): consolidating citizenship and popular participation

A gestão participativa foi um dos eixos de estruturação das políticas de saúde que orientaram a ação do governo municipal em Guarulhos, SP, no período de 2005 a 2008. Esse eixo estruturou-se em várias iniciativas, aqui destacada a que criou o Programa de Recursos Descentralizados na Saúde - PROREDE, criado pela Lei Municipal Lei 6.195 de 11 de dezembro de 2006. Com início em 2008, seu principal objetivo foi descentralizar a gestão de recursos financeiros para todas as unidades da rede municipal, a fim de serem utilizados na manutenção, conservação do imóvel e seus equipamentos, assim como para realização de atividades de promoção de saúde. A transferência de recursos financeiros próprios às unidades de saúde deu-se por meio de conta bancária específica em nome das associações de natureza civil e não lucrativa, criadas em cada equipamento da rede e compostas por usuários e trabalhadores dessas unidades. Um Plano de Ação e outro de Aplicação e controle dos recursos compunham o conjunto de documentos anexos aos convênios assinados pelas associações e pelo governo municipal. Além disso, o PROREDE objetivou descentralizar a gestão e incentivar a plena participação dos Conselhos Gestores, articulados com as associações recém-criadas, no processo de tomada de decisões, na implantação das ações planejadas, no controle e prestação de contas, e no processo de avaliação das melhorias das condições do atendimento e qualidade dos serviços prestados. Em julho de 2008, de um total de 103 Unidades Básicas de Saúde (UBS) no município, 21 tinham assinado o convênio e iniciado a gestão de recursos financeiros através do PROREDE.(AU)