Herpes Simplex Oncolytic Viral Therapy for Malignant Glioma and Mechanisms of Delivery.

The authors present a comprehensive review on the history and development of oncolytic herpes simplex viral therapies for malignant glioma with a focus on mechanisms of delivery in prior and ongoing clinical trials. This review highlights the advancements made with regard to delivering these therapies to a highly complex immunologic environment in the setting of the blood brain and blood tumor barrier in a safe and effective manner.

Bidirectional regulation of motor circuits using magnetogenetic gene therapy.

Here, we report a magnetogenetic system, based on a single anti-ferritin nanobody-TRPV1 receptor fusion protein, which regulated neuronal activity when exposed to magnetic fields. Adeno-associated virus (AAV)-mediated delivery of a floxed nanobody-TRPV1 into the striatum of adenosine-2a receptor-Cre drivers resulted in motor freezing when placed in a magnetic resonance imaging machine or adjacent to a transcranial magnetic stimulation device. Functional imaging and fiber photometry confirmed activation in response to magnetic fields.

Cognitive dysfunction in animal models of human lewy-body dementia.

Cognitive impairments are a common feature of synucleinopathies such as Parkinson's Disease Dementia and Dementia with Lewy Bodies. These pathologies are characterized by accumulation of Lewy bodies and Lewy neurites as well as neuronal cell death. Alpha-synuclein is the main proteinaceous component of Lewy bodies and Lewy neurites.

Safety and Efficacy of Staged, Bilateral Focused Ultrasound Thalamotomy in Essential Tremor: An Open-Label Clinical Trial.

Importance: Unilateral magnetic resonance-guided focused ultrasound ablation of ventralis intermedius nucleus of the thalamus for essential tremor reduces tremor on 1 side, but untreated contralateral or midline symptoms remain limiting for some patients. Historically, bilateral lesioning produced unacceptable risks and was supplanted by deep brain stimulation; increasing acceptance of unilateral focused ultrasound lesioning has led to interest in a bilateral option.

Objective: To evaluate the safety and efficacy of staged, bilateral focused ultrasound thalamotomy.

Gut-Initiated Alpha Synuclein Fibrils Drive Parkinson's Disease Phenotypes: Temporal Mapping of non-Motor Symptoms and REM Sleep Behavior Disorder.

Parkinson's disease (PD) is characterized by progressive motor as well as less recognized non-motor symptoms that arise often years before motor manifestation, including sleep and gastrointestinal disturbances. Despite the heavy burden on the patient's quality of life, these non-motor manifestations are poorly understood. To elucidate the temporal dynamics of the disease, we employed a mouse model involving injection of alpha-synuclein (αSyn) pre-formed fibrils (PFF) in the duodenum and antrum as a gut-brain model of Parkinsonism.

Bidirectional Regulation of Motor Circuits Using Magnetogenetic Gene Therapy Short: Magnetogenetic Regulation of Motor Circuits.

Here we report a novel suite of magnetogenetic tools, based on a single anti-ferritin nanobody-TRPV1 receptor fusion protein, which regulated neuronal activity when exposed to magnetic fields. AAV-mediated delivery of a floxed nanobody-TRPV1 into the striatum of adenosine 2a receptor-cre driver mice resulted in motor freezing when placed in an MRI or adjacent to a transcranial magnetic stimulation (TMS) device. Functional imaging and fiber photometry both confirmed activation of the target region in response to the magnetic fields.

Cranial MRgFUS intraprocedural diffusion and T2 imaging and comparison with postablation lesion size and location.

Objective: The ability to predict final lesion characteristics during magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomy for the treatment of essential tremor remains technically challenging, yet it is essential in order to avoid off-target ablation and to ensure adequate treatment. The authors sought to evaluate the technical feasibility and utility of intraprocedural diffusion-weighted imaging (DWI) in the prediction of final lesion size and location.

Methods: Lesion diameter and distance from the midline were measured on both intraprocedural and immediate postprocedural diffusion and T2-weighted sequences.

Trial of Globus Pallidus Focused Ultrasound Ablation in Parkinson's Disease.

Background: Unilateral focused ultrasound ablation of the internal segment of globus pallidus has reduced motor symptoms of Parkinson's disease in open-label studies.

Methods: We randomly assigned, in a 3:1 ratio, patients with Parkinson's disease and dyskinesias or motor fluctuations and motor impairment in the off-medication state to undergo either focused ultrasound ablation opposite the most symptomatic side of the body or a sham procedure. The primary outcome was a response at 3 months, defined as a decrease of at least 3 points from baseline either in the score on the Movement Disorders Society-Unified Parkinson's Disease Rating Scale, part III (MDS-UPDRS III), for the treated side in the off-medication state or in the score on the Unified Dyskinesia Rating Scale (UDysRS) in the on-medication state.

Focused ultrasound-mediated blood-brain barrier opening in Alzheimer's disease: long-term safety, imaging, and cognitive outcomes.

Objective: MRI-guided low-intensity focused ultrasound (FUS) has been shown to reversibly open the blood-brain barrier (BBB), with the potential to deliver therapeutic agents noninvasively to target brain regions in patients with Alzheimer's disease (AD) and other neurodegenerative conditions. Previously, the authors reported the short-term safety and feasibility of FUS BBB opening of the hippocampus and entorhinal cortex (EC) in patients with AD. Given the need to treat larger brain regions beyond the hippocampus and EC, brain volumes and locations treated with FUS have now expanded.

Mapping and targeted viral activation of pancreatic nerves in mice reveal their roles in the regulation of glucose metabolism.

A lack of comprehensive mapping of ganglionic inputs into the pancreas and of technology for the modulation of the activity of specific pancreatic nerves has hindered the study of how they regulate metabolic processes. Here we show that the pancreas-innervating neurons in sympathetic, parasympathetic and sensory ganglia can be mapped in detail by using tissue clearing and retrograde tracing (the tracing of neural connections from the synapse to the cell body), and that genetic payloads can be delivered via intrapancreatic injection to target sites in efferent pancreatic nerves in live mice through optimized adeno-associated viruses and neural-tissue-specific promoters. We also show that, in male mice, the targeted activation of parasympathetic cholinergic intrapancreatic ganglia and neurons doubled plasma-insulin levels and improved glucose tolerance, and that tolerance was impaired by stimulating pancreas-projecting sympathetic neurons.

Monocyte-derived SDF1 supports optic nerve regeneration and alters retinal ganglion cells' response to Pten deletion.

Although mammalian retinal ganglion cells (RGCs) normally cannot regenerate axons nor survive after optic nerve injury, this failure is partially reversed by inducing sterile inflammation in the eye. Infiltrative myeloid cells express the axogenic protein oncomodulin (Ocm) but additional, as-yet-unidentified, factors are also required. We show here that infiltrative macrophages express stromal cell–derived factor 1 (SDF1, CXCL12), which plays a central role in this regard.

The Brain-Nose Interface: A Potential Cerebrospinal Fluid Clearance Site in Humans.

The human brain functions at the center of a network of systems aimed at providing a structural and immunological layer of protection. The cerebrospinal fluid (CSF) maintains a physiological homeostasis that is of paramount importance to proper neurological activity. CSF is largely produced in the choroid plexus where it is continuous with the brain extracellular fluid and circulates through the ventricles.

Disruption of mitochondrial complex I induces progressive parkinsonism.

Loss of functional mitochondrial complex I (MCI) in the dopaminergic neurons of the substantia nigra is a hallmark of Parkinson's disease. Yet, whether this change contributes to Parkinson's disease pathogenesis is unclear. Here we used intersectional genetics to disrupt the function of MCI in mouse dopaminergic neurons.

Neuromodulatory effect of interleukin 1β in the dorsal raphe nucleus on individual differences in aggression.

Heightened aggressive behavior is considered as one of the central symptoms of many neuropsychiatric disorders including autism, schizophrenia, and dementia. The consequences of aggression pose a heavy burden on patients and their families and clinicians. Unfortunately, we have limited treatment options for aggression and lack mechanistic insight into the causes of aggression needed to inform new efforts in drug discovery and development.

Innovative Applications of MR-Guided Focused Ultrasound for Neurological Disorders.

Magnetic resonance-guided focused ultrasound (MRgFUS) is a cutting-edge technology that is changing the practice of movement disorders surgery. Given the noninvasive and innovative nature of this technology, there is great interest in expanding the use of MRgFUS to additional diseases and applications. Current approved applications target the motor thalamus to treat tremor, but clinical trials are exploring or plan to study noninvasive lesions with MRgFUS to ablate tumor cells in the brain as well as novel targets for movement disorders and brain regions associated with pain and epilepsy.

Cranial MR-Guided Focused Ultrasound: Clinical Challenges and Future Directions.

Magnetic resonance-guided focused ultrasound is a powerful new technology that is enabling development of noninvasive applications for complex brain disorders. This is currently revolutionizing the treatment of tremor disorders, and a variety of experimental applications are under active investigation. To fully realize the potential of this disruptive technology, many challenges have been identified, some of which have been addressed and others remain to be solved.

Foundations of Magnetic Resonance-Guided Focused Ultrasonography.

The ability of ultrasonography to safely penetrate deeply into the brain has made it an attractive technology for neurological applications for almost 1 century. Having recognized that converging ultrasound waves could deliver high levels of energy to a target and spare the overlying and surrounding brain, early applications used craniotomies to allow transducers to contact the brain or dural surface. The development of transducer arrays that could permit the transit of sufficient numbers of ultrasound waves to deliver high energies to a target, even with the loss of energy from the skull, has now resulted in clinical systems that can permit noninvasive focused ultrasound procedures that leave the skull intact.

Slowing late infantile Batten disease by direct brain parenchymal administration of a rh.10 adeno-associated virus expressing .

Late infantile Batten disease (CLN2 disease) is an autosomal recessive, neurodegenerative lysosomal storage disease caused by mutations in the gene encoding tripeptidyl peptidase 1 (TPP1). We tested intraparenchymal delivery of AAVrh.10hCLN2, a nonhuman serotype rh.

β-Amyloid Plaque Reduction in the Hippocampus After Focused Ultrasound-Induced Blood-Brain Barrier Opening in Alzheimer's Disease.

The blood-brain barrier (BBB) limits therapeutic delivery in Alzheimer's disease (AD) and other neurological disorders. Animal models have demonstrated safe BBB opening and reduction in β-amyloid plaque with focused ultrasound (FUS). We recently demonstrated the feasibility, safety, and reversibility of FUS-induced BBB opening in the hippocampus and entorhinal cortex in six participants with early AD.

Improved targeting of the globus pallidus interna using quantitative susceptibility mapping prior to MR-guided focused ultrasound ablation in Parkinson's disease.

Purpose: Magnetic resonance guided focused ultrasound (MRgFUS) of the globus pallidus interna (GPi) has shown promise in the treatment of drug-resistant Parkinson's disease, though direct visualization of the GPi remains challenging with MRI. The purpose of this study was to compare various preoperative MR imaging techniques and to evaluate the utility of quantitative susceptibility imaging (QSM) in the depiction of the GPi prior to MRgFUS ablation.

Materials And Methods: Six patients with medication refractory advanced idiopathic Parkinson's disease were referred for preoperative MR imaging prior to MRgFUS pallidotomy.