A minimally invasive endovascular approach to the cerebellopontine angle cistern enables broad CNS biodistribution of scAAV9-CB-GFP.

Neurological disorders pose a challenge for targeted therapy due to restricted access of therapeutic agents to the central nervous system (CNS). Current methods are limited by procedure-related risks, invasiveness, and insufficient CNS biodistribution. A novel percutaneous transvenous technology, currently in clinical trials for communicating hydrocephalus, offers a minimally invasive approach by providing endovascular access to the cerebrospinal fluid-filled cerebellopontine angle (CPA) cistern. We hypothesized that drug delivery to the CPA cistern could yield widespread CNS distribution. Using an ovine model, we compared the biodistribution of scAAV9-CB-GFP following CPA cistern infusion with previously reported cisterna magna (CM) administration. Targeting both the CPA cistern and CM in sheep, we employed a lumbar spine-inserted microcatheter under fluoroscopy. CPA delivery of AAV9 demonstrated biodistribution and transduction in the cerebral cortices, striatum, thalamus, midbrain, cerebellum, and spinal cord, with minor liver distribution comparable to CM. The favorable safety profile in humans with hydrocephalus suggests that percutaneous endovascular injection into the CPA could offer a clinically safer and minimally invasive delivery system for CNS gene and cell-based therapies.

The substantia nigra conveys target-dependent excitatory and inhibitory outputs from the basal ganglia to the thalamus.

The basal ganglia (BG), which influence cortical activity via the thalamus, play a major role in motor activity, learning and memory, sensory processing, and many aspects of behavior. The substantia nigra (SN) consists of GABAergic neurons of the pars reticulata that inhibit thalamic neurons and provide the primary output of the BG, and dopaminergic neurons of the pars compacta that modulate thalamic excitability. Little is known about the functional properties of the SN→thalamus synapses, and anatomical characterization has been controversial. Here we use a combination of anatomical, electrophysiological, genetic, and optogenetic approaches to re-examine these synaptic connections in mice. We find that neurons in the SN inhibit neurons in the ventroposterolateral nucleus of the thalamus via GABAergic synapses, excite neurons in the thalamic nucleus reticularis, and both excite and inhibit neurons within the posterior nucleus group. Glutamatergic SN neurons express the vesicular glutamate receptor transporter vGluT2 and receive inhibitory synapses from striatal neurons, and many also express tyrosine hydroxylase, a marker of dopaminergic neurons. Thus, in addition to providing inhibitory outputs, which is consistent with the canonical circuit, the SN provides glutamatergic outputs that differentially target thalamic nuclei. This suggests that an increase in the activity of glutamatergic neurons in the SN allows the BG to directly excite neurons in specific thalamic nuclei. Elucidating an excitatory connection between the BG and the thalamus provides new insights into how the BG regulate thalamic activity, and has important implications for understanding BG function in health and disease.

Achieving high-frequency optical control of synaptic transmission.

The optogenetic tool channelrhodopsin-2 (ChR2) is widely used to excite neurons to study neural circuits. Previous optogenetic studies of synapses suggest that light-evoked synaptic responses often exhibit artificial synaptic depression, which has been attributed to either the inability of ChR2 to reliably fire presynaptic axons or to ChR2 elevating the probability of release by depolarizing presynaptic boutons. Here, we compare light-evoked and electrically evoked synaptic responses for high-frequency stimulation at three synapses in the mouse brain. At synapses from Purkinje cells to deep cerebellar nuclei neurons (PC→DCN), light- and electrically evoked synaptic currents were remarkably similar for ChR2 expressed transgenically or with adeno-associated virus (AAV) expression vectors. For hippocampal CA3→CA1 synapses, AAV expression vectors of serotype 1, 5, and 8 led to light-evoked synaptic currents that depressed much more than electrically evoked currents, even though ChR2 could fire axons reliably at up to 50 Hz. The disparity between optical and electrical stimulation was eliminated when ChR2 was expressed transgenically or with AAV9. For cerebellar granule cell to stellate cell (grc→SC) synapses, AAV1 also led to artificial synaptic depression and AAV9 provided superior performance. Artificial synaptic depression also occurred when stimulating over presynaptic boutons, rather than axons, at CA3→CA1 synapses, but not at PC→DCN synapses. These findings indicate that ChR2 expression methods and light stimulation techniques influence synaptic responses in a neuron-specific manner. They also identify pitfalls associated with using ChR2 to study synapses and suggest an approach that allows optogenetics to be applied in a manner that helps to avoid potential complications.

Endovascular Shunting for Communicating Hydrocephalus Using a Biologically Inspired Transdural Cerebrospinal Fluid Valved eShunt® Implant.

Cerebrospinal fluid (CSF) bathing the central nervous system is produced by brain and choroid plexus within the ventricles for re-absorption into the venous circulation through arachnoid granulations (AG). Communicating hydrocephalus results from disruption of the absorptive process, necessitating surgical catheter-based shunt placement to relieve excess pressure from CSF buildup. Adjustable valve designs and antibiotic impregnation have minimally impacted persistent failure rates and postoperative complications. To confront this challenge, we have developed an innovative endovascular shunt implant biologically inspired from AG function to restore the natural dynamics of CSF drainage while concurrently addressing the predominant factors contributing to conventional shunt malfunction.

Anatomical characterization of the inferior petrosal sinus and adjacent cerebellopontine angle cistern for development of an endovascular transdural cerebrospinal fluid shunt.

BACKGROUND AND PURPOSE: We evaluated the inferior petrosal sinus (IPS) and adjacent cerebellopontine angle (CPA) cistern as a potential implantation site for a novel venous endovascular transdural CSF shunt concept to treat communicating hydrocephalus. We analyzed the dimensions of the IPS, CPA cistern, and distances to adjacent neurovascular structures. MATERIALS AND METHODS: Gadolinium enhanced T1 weighted brain MRI datasets of 36 randomly selected patients, aged 20-80 years, were analyzed with three-dimensional multiplanar reconstruction to measure IPS diameter and length, CPA cistern depth, and IPS proximity to the vertebrobasilar arteries and brainstem. Statistical analysis was used to assess gender, sidedness, and age dependence. RESULTS: Mean IPS diameter ranged from 2.27 mm to 3.31 mm at three axial levels, with >90% larger than 1.46 mm. CPA cistern adjacent to the IPS exhibited a mean depth of 3.86 mm to 7.39 mm between the dura and brainstem at corresponding axial levels. There was no side dependence except for a longer distance from the IPS to the basilar artery on the left compared with the right (9.72 vs 7.28, P<0.019). Linear regression analysis showed that the distance from the IPS to the brainstem was statistically significantly increased with age (P<0.0002) and was greater in men, with little side variation (P=0.524). CONCLUSION: Our results demonstrate sufficient CSF CPA cisternal space adjacent to the IPS and support the feasibility of an endovascular catheter delivered transdural implantable shunt. Such a device could serve to mimic the function of the arachnoid granulation by establishing a regulated path for CSF flow from the intracranial subarachnoid space to the venous system and provide a treatment for communicating hydrocephalus.