CAG repeat-selective compounds reduce abundance of expanded CAG RNAs in patient cell and murine models of SCAs.

Spinocerebellar ataxias (SCAs) are a genetically heterogenous group of devastating neurodegenerative conditions for which clinical care currently focuses on managing symptoms. Across these diseases there is an unmet need for therapies that address underlying disease mechanisms. We utilised the shared CAG repeat expansion mutation causative for a large subgroup of SCAs, to develop a novel disease-gene independent and mechanism agnostic small molecule screening approach to identify compounds with therapeutic potential across multiple SCAs.

Investigation of non-invasive focused ultrasound efficacy on depressive-like behavior in hemiparkinsonian rats.

Depression is a common non-motor symptom in Parkinson's disease (PD) that includes anhedonia and impacts quality of life but is not effectively treated with conventional antidepressants clinically. Vagus nerve stimulation improves treatment-resistant depression in the general population, but research about its antidepressant efficacy in PD is limited. Here, we administered peripheral non-invasive focused ultrasound to hemiparkinsonian ('PD') and non-parkinsonian (sham) rats to mimic vagus nerve stimulation and assessed its antidepressant-like efficacy.

Widespread alternative splicing dysregulation occurs presymptomatically in CAG expansion spinocerebellar ataxias.

The spinocerebellar ataxias (SCAs) are a group of dominantly inherited neurodegenerative diseases, several of which are caused by CAG expansion mutations (SCAs 1, 2, 3, 6, 7 and 12) and more broadly belong to the large family of over 40 microsatellite expansion diseases. While dysregulation of alternative splicing is a well defined driver of disease pathogenesis across several microsatellite diseases, the contribution of alternative splicing in CAG expansion SCAs is poorly understood. Furthermore, despite extensive studies on differential gene expression, there remains a gap in our understanding of presymptomatic transcriptomic drivers of disease.

Assessing the Location, Relative Expression and Subclass of Dopamine Receptors in the Cerebellum of Hemi-Parkinsonian Rats.

Parkinson's Disease (PD) is a neurodegenerative disease with loss of dopaminergic neurons in the nigrostriatal pathway resulting in basal ganglia (BG) dysfunction. This is largely why much of the preclinical and clinical research has focused on pathophysiological changes in these brain areas in PD. The cerebellum is another motor area of the brain.

The effects of low intensity focused ultrasound on neuronal activity in pain processing regions in a rodent model of common peroneal nerve injury.

Background: Non-invasive, external low intensity focused ultrasound (liFUS) offers promise for treating neuropathic pain when applied to the dorsal root ganglion (DRG).

Objective: We examine how external liFUS treatment applied to the L5 DRG affects neuronal changes in single-unit activity from the primary somatosensory cortex (SI) and anterior cingulate cortex (ACC) in a common peroneal nerve injury (CPNI) rodent model.

Methods: Male Sprague Dawley rats were divided into two cohorts: CPNI liFUS and CPNI sham liFUS.

Stimulation of the hepatoportal nerve plexus with focused ultrasound restores glucose homoeostasis in diabetic mice, rats and swine.

Peripheral neurons that sense glucose relay signals of glucose availability to integrative clusters of neurons in the brain. However, the roles of such signalling pathways in the maintenance of glucose homoeostasis and their contribution to disease are unknown. Here we show that the selective activation of the nerve plexus of the hepatic portal system via peripheral focused ultrasound stimulation (pFUS) improves glucose homoeostasis in mice and rats with insulin-resistant diabetes and in swine subject to hyperinsulinemic-euglycaemic clamps.

Group 2 innate lymphoid cells are numerically and functionally deficient in the triple transgenic mouse model of Alzheimer's disease.

Background: The immune pathways in Alzheimer's disease (AD) remain incompletely understood. Our recent study indicates that tissue-resident group 2 innate lymphoid cells (ILC2) accumulate in the brain barriers of aged mice and that their activation alleviates aging-associated cognitive decline. The regulation and function of ILC2 in AD, however, remain unknown.

Pilot study on the effects of low intensity focused ultrasound in a swine model of neuropathic pain.

Objective: The authors' laboratory has previously demonstrated beneficial effects of noninvasive low intensity focused ultrasound (liFUS), targeted at the dorsal root ganglion (DRG), for reducing allodynia in rodent neuropathic pain models. However, in rats the DRG is 5 mm below the skin when approached laterally, while in humans the DRG is typically 5-8 cm deep. Here, using a modified liFUS probe, the authors demonstrated the feasibility of using external liFUS for modulation of antinociceptive responses in neuropathic swine.

Motor Thalamic Deep Brain Stimulation Alters Cortical Activity and Shows Therapeutic Utility for Treatment of Parkinson's Disease Symptoms in a Rat Model.

Deep brain stimulation (DBS) in Parkinson's disease (PD) alters neuronal function and network communication to improve motor symptoms. The subthalamic nucleus (STN) is the most common DBS target for PD, but some patients experience adverse effects on memory and cognition. Previously, we reported that DBS of the ventral anterior (VA) and ventrolateral (VL) nuclei of the thalamus and at the interface between the two (VA|VL), collectively VA-VL, relieved forelimb akinesia in the hemiparkinsonian 6-hydroxydopamine (6-OHDA) rat model.

Non-invasive peripheral focused ultrasound neuromodulation of the celiac plexus ameliorates symptoms in a rat model of inflammatory bowel disease.

New Findings: What is the central question of this study? Does peripheral non-invasive focused ultrasound targeted to the celiac plexus improve inflammatory bowel disease? What is the main finding and its importance? Peripheral non-invasive focused ultrasound targeted to the celiac plexus in a rat model of ulcerative colitis improved stool consistency and reduced stool bloodiness, which coincided with a longer and healthier colon than in animals without focused ultrasound treatment. The findings suggest that this novel neuromodulatory technology could serve as a plausible therapeutic approach for improving symptoms of inflammatory bowel disease.

Abstract: Individuals suffering from inflammatory bowel disease (IBD) experience significantly diminished quality of life.

Isovaline efficacy in a rat pup model of infantile spasms.

Infantile spasms, also known as epileptic spasms during infancy, is an epileptic disorder of infancy and early childhood that is associated with developmental delay or regression, high mortality rate and is difficult to treat with conventional antiseizure medication. Previously, we reported that a unique amino acid called isovaline had potent anticonvulsive efficacy in the 4-aminopyridine and pilocarpine rat models of seizures. In this study, we examined whether isovaline possess therapeutic utility in a well-established rat model of infantile spasms which involves the pretreatment of a pregnant dam with betamethasone and subsequent induction of spasms with N-methyl-D-asparate (NMDA), a glutamate receptor agonist, in 15-day old pups.

Effects of subthalamic nucleus deep brain stimulation on neuronal spiking activity in the substantia nigra pars compacta in a rat model of Parkinson's disease.

Parkinson's Disease (PD) patients undergoing subthalamic nucleus deep brain stimulation (STN-DBS) therapy can reduce levodopa equivalent daily dose (LEDD) by approximately 50 %, leading to less symptoms of dyskinesia. The underlying mechanisms contributing to this reduction remain unclear, but studies posit that STN-DBS may increase striatal dopamine levels by exciting remaining dopaminergic cells in the substantia nigra pars compacta (SNc). Yet, no direct evidence has shown how SNc neuronal activity responds during STN-DBS in PD.

Use of Functional MRI to Assess Effects of Deep Brain Stimulation Frequency Changes on Brain Activation in Parkinson Disease.

Background: Models have been developed for predicting ideal contact and amplitude for subthalamic nucleus (STN) deep brain stimulation (DBS) for Parkinson disease (PD). Pulse-width is generally varied to modulate the size of the energy field produced. Effects of varying frequency in humans have not been systematically evaluated.

Use of Functional Magnetic Resonance Imaging to Assess How Motor Phenotypes of Parkinson's Disease Respond to Deep Brain Stimulation.

Background: Deep brain stimulation (DBS) is a well-accepted treatment of Parkinson's disease (PD). Motor phenotypes include tremor-dominant (TD), akinesia-rigidity (AR), and postural instability gait disorder (PIGD). The mechanism of action in how DBS modulates motor symptom relief remains unknown.

Effects of external low intensity focused ultrasound on electrophysiological changes in vivo in a rodent model of common peroneal nerve injury.

Non-invasive treatment methods for neuropathic pain are lacking. We assess how modulatory low intensity focused ultrasound (liFUS) at the L5 dorsal root ganglion (DRG) affects behavioral responses and sensory nerve action potentials (SNAPs) in a common peroneal nerve injury (CPNI) model. Rats were assessed for mechanical and thermal responses using Von Frey filaments (VFF) and the hot plate test (HPT) following CPNI surgery.

Functional MRI Signature of Chronic Pain Relief From Deep Brain Stimulation in Parkinson Disease Patients.

Background: Chronic pain occurs in 83% of Parkinson disease (PD) patients and deep brain stimulation (DBS) has shown to result in pain relief in a subset of patients, though the mechanism is unclear.

Objective: To compare functional magnetic resonance imaging (MRI) data in PD patients with chronic pain without DBS, those whose pain was relieved (PR) with DBS and those whose pain was not relieved (PNR) with DBS.

Methods: Functional MRI (fMRI) with blood oxygen level-dependent activation data was obtained in 15 patients in control, PR, and PNR patients.

Effects of subthalamic deep brain stimulation with gabapentin and morphine on mechanical and thermal thresholds in 6-hydroxydopamine lesioned rats.

Chronic pain is the most common non-motor symptom among Parkinson's disease (PD) patients, with 1.85 million estimated to be in debilitating pain by 2030. Subthalamic deep brain stimulation (STN DBS) programmed for treating PD motor symptoms has also been shown to significantly improve pain scores.

Deep brain stimulation of the ventroanterior and ventrolateral thalamus improves motor function in a rat model of Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disease with affected individuals exhibiting motor symptoms of bradykinesia, muscle rigidity, tremor, postural instability and gait dysfunction. The current gold standard treatment is pharmacotherapy with levodopa, but long-term use is associated with motor response fluctuations and can cause abnormal movements called dyskinesias. An alternative treatment option is deep brain stimulation (DBS) with the two FDA-approved brain targets for PD situated in the basal ganglia; specifically, in the subthalamic nucleus (STN) and globus pallidus pars interna (GPi).

The use of focused ultrasound for the treatment of cutaneous allodynia associated with chronic migraine.

Chronic migraines (CM) are the third most common disease and are refractory to medical treatment in 15% of patients. Currently, temporary relief is achieved with steroid blocks or pulsed radiofrequency ablation, which have short-term benefits. Our project aims to develop a non-invasive treatment for medically refractory chronic migraine, which does not require a permanent implant.

Pallidal deep brain stimulation and intraoperative neurophysiology for treatment of poststroke hemiballism.

Deep brain stimulation is a recognized and effective treatment for several movement disorders. Nevertheless, the efficacy of this intervention on abnormal movements secondary to structural brain pathologies is less consistent. In this report, we describe a case of hemiballism-hemichorea due to a peripartum ischemic stroke-treated with deep brain stimulation of the globus pallidus internus.

Ventral pallidum deep brain stimulation attenuates acute partial, generalized and tonic-clonic seizures in two rat models.

Approximately 30% of individuals with epilepsy are refractory to antiepileptic drugs and currently approved neuromodulatory approaches fall short of providing seizure freedom for many individuals with limited utility for generalized seizures. Here, we expand on previous findings and investigate whether ventral pallidum deep brain stimulation (VP-DBS) can be efficacious for various acute seizure phenotypes. For rats administered pilocarpine, we found that VP-DBS (50 Hz) decreased generalized stage 4/5 seizure median frequency from 9 to 6 and total duration from 1667 to 264 s even after generalized seizures emerged.

Effect of Eye Opening on Single-Unit Activity and Local Field Potentials in the Subthalamic Nucleus.

Background: Subthalamic nucleus deep brain stimulation (STN DBS) is an established treatment in Parkinson's disease (PD). We investigate the effect of eye opening on neuronal activity and local field potentials (LFPs) in the STN.

Methods: We prospectively enrolled 25 PD patients undergoing STN DBS in our institution.

Occipital Nerve Stimulation Attenuates Neuronal Firing Response to Mechanical Stimuli in the Ventral Posteromedial Thalamus of a Rodent Model of Chronic Migraine.

Background: Chronic migraine (CM) is a highly debilitating disease, and many patients remain refractory to medicinal therapy. Given the convergent nature of neuronal networks in the ventral posteromedial nucleus (VPM) and the evidence of sensitization of pain circuitry in this disease, we hypothesize CM rats will have increased VPM neuronal firing, which can be attenuated using occipital nerve stimulation (ONS).

Objective: To determine whether VPM firing frequency differs between CM and sham rats, and whether ONS significantly alters firing rates during the application of mechanical stimuli.

Effect of diazepam and yohimbine on neuronal activity in sham and hemiparkinsonian rats.

The prefrontal cortex and the amygdala are critical for the emotional guidance of behavior and are believed to be a site of action for many anxiolytics and anxiogenics. Despite extensive studies examining how these drugs affect behavior, there is little information regarding their effects on neuronal activity. Additionally, with recent recognition of anxiety as a non-motor symptom of Parkinson's disease, it is unknown if activity in the cortex and the amygdala is altered.