Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics

Cognitive impairment remains a persistent challenge in people living with HIV (PWLH) despite antiretroviral therapy (ART) due to ART's inability to eliminate brain HIV. HIV-induced cognitive dysfunction results from immune dysregulation, ongoing neuroinflammation, and the continuous virus presence, collectively contributing to cognitive deficits. Therefore, adjunctive therapies are needed to reduce cerebral HIV reservoirs, mitigate neuroinflammation, and impede cognitive dysfunction progression. Our study focused on Honokiol, known for its anti-inflammatory and neuroprotective properties, in an experimental mouse model simulating HIV-induced cognitive dysfunction...

Stroke is one of the most common and debilitating neurological conditions worldwide. Those who survive experience motor, sensory, speech, vision, and/or cognitive deficits that severely limit remaining quality of life. While rehabilitation programs can help improve patients' symptoms, recovery is often limited, and patients frequently continue to experience impairments in functional status. In this review, invasive neuromodulation techniques to augment the effects of conventional rehabilitation methods are described, including vagus nerve stimulation (VNS), deep brain stimulation (DBS) and brain-computer interfaces (BCIs)...

There is currently no disease-modifying therapy for Huntington's disease (HD). We recently described a small molecule, MK-28, which restored homeostasis in HD models by specifically activating PKR-like ER kinase (PERK). This activation boosts the unfolded protein response (UPR), thereby reducing endoplasmic reticulum (ER) stress, a central cytotoxic mechanism in HD and other neurodegenerative diseases. Here, we have tested the long-term effects of MK-28 in HD model mice. R6/2 CAG (160) mice were treated by lifetime intraperitoneal injections 3 times a week...

A challenging complication in patients with peripheral compressive neuropathy is neuropathic pain. Excessive neuroinflammation at the injury site worsens neuropathic pain and impairs function. Currently, non-invasive modulation techniques like transcutaneous electrical nerve stimulation (TENS) have shown therapeutic promise with positive results. However, the underlying regulatory molecular mechanism for pain relief remains complex and unexplored. This study aimed to validate the therapeutic effect of ultrahigh frequency (UHF)-TENS in chronic constriction injury of the rat sciatic nerve...

Psychosis in Parkinson's disease is a common phenomenon associated with poor outcomes. To clarify the pathophysiology of this condition and the mechanisms of antipsychotic treatments, we have here characterized the neurophysiological brain states induced by clozapine, pimavanserin, and the novel prospective antipsychotic mesdopetam in a rodent model of Parkinson's disease psychosis, based on chronic dopaminergic denervation by 6-OHDA lesions, levodopa priming, and the acute administration of an NMDA antagonist...

We report results of a large multisite double-blind randomized trial investigating the short and long-term efficacy of repetitive transcranial magnetic stimulation (rTMS) applied to patients with Alzheimer's disease (AD) at mild to moderate stages, in doses of either 2 or 4 weeks of treatment (5 days/week), whilst compared with 4 weeks of sham rTMS. Randomization to treatment group was stratified based on age and severity. The objectives of this study were to: 1) investigate the efficacy of active rTMS versus sham, 2) investigate the effect of dose of treatment (2 or 4 weeks), and 3) investigate the length of benefits from treatment...

Methamphetamine (MA) use disorder poses significant challenges to both the affected individuals and society. Current non-drug therapies like transcranial direct-current stimulation and transcranial magnetic stimulation have limitations due to their invasive nature and limited reach to deeper brain areas. Transcranial focused ultrasound (FUS) is gaining attention as a noninvasive option with precise spatial targeting, able to affect deeper areas of the brain. This research focused on assessing the effectiveness of FUS in influencing the infralimbic cortex (IL) to prevent the recurrence of MA-seeking behavior, using the conditioned place preference (CPP) method in rats...

Over the past 30 years, the field of neuromodulation has witnessed remarkable advancements. These developments encompass a spectrum of techniques, both non-invasive and invasive, that possess the ability to both probe and influence the central nervous system. In many cases neuromodulation therapies have been adopted into standard care treatments. Transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), and transcranial ultrasound stimulation (TUS) are the most common non-invasive methods in use today...

Thromboembolism is a possible consequence of underlying atrial cardiopathy, which can occur even before the onset of atrial fibrillation. Our objective was to examine the association between biomarkers of atrial cardiopathy and outcomes of acute ischemic stroke (AIS) following endovascular treatment (EVT). We conducted a retrospective study that collected data from patients with AIS who underwent EVT and compared the outcomes between those with and without atrial cardiopathy. Neurological function was assessed using the modified Rankin Scale (mRS), with an mRS score >2 indicating poor function at day 90...

Intraventricular hemorrhage (IVH) is an important cause of long-term disability in extremely preterm infants, with no current treatment. This study assessed the potential neuroprotective effects of cannabidiol (CBD) in an IVH model using immature rats. IVH was induced in 1-day-old (P1) Wistar rats by left periventricular injection of Clostridial collagenase. Some rats received CBD prenatally (10 ​mg/kg i.p. to the dam) and then 5 ​mg/kg i.p. 6, 30 and 54 ​h after IVH (IVH+CBD, n ​= ​30)...

The tauopathies encompass over 20 adult neurodegenerative diseases and are characterized by the dysfunction and accumulation of insoluble tau protein. Among them, Alzheimer's disease, frontotemporal dementia, and progressive supranuclear palsy collectively impact millions of patients and their families worldwide. Despite years of drug development using a variety of mechanisms of action, no therapeutic directed against tau has been approved for clinical use. This raises important questions about our current model of tau pathology and invites thoughtful consideration of our approach to nonclinical models and clinical trial design...

In recent years, psychedelics have generated considerable excitement and interest as potential novel therapeutics for an array of conditions, with the most advanced evidence base in the treatment of certain severe and/or treatment-resistant psychiatric disorders. An array of clinical and pre-clinical evidence has informed our current understanding of how psychedelics produce profound alterations in consciousness. Mechanisms of psychedelic action include receptor binding and downstream cellular and transcriptional pathways, with long-term impacts on brain structure and function-from the level of single neurons to large-scale circuits...

Pink1 (PTEN-induced putative kinase 1) is a protein associated with maintaining mitochondrial function and integrity and has been reported to mediate neurodegeneration and neuroinflammation. While the role of Pink1 in intracerebral hemorrhage (ICH)-related neurological deficits and inflammatory responses is not deciphered. Congenic blood was transfused into the left corpus striatum to construct the ICH model in C57/BL6 wild-type (WT) and Pink1-/- mice. The relative expression of Pink1, monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein (MIP)-2, tumor necrosis factor (TNF)-α, interleukin (IL)-1β, Cd86, nitric oxide synthase 2 (Nos2), Cd206, arginase 1 (Arg-1), and IL-10 was detected with qRT-PCR, Western blotting, or ELISA...

Mirror therapy (MT) has been proposed to promote motor recovery post-stroke through activation of mirror neuron system, recruitment of ipsilateral motor pathways, or/and increasing attention toward the affected limb. However, neuroimaging evidence for these mechanisms is still lacking. To uncover the underlying mechanisms, we designed a randomized controlled study and used a voxel-based whole-brain analysis of resting-state fMRI to explore the brain reorganizations induced by MT. Thirty-five stroke patients were randomized to an MT group (n ​= ​16) and a conventional therapy (CT) group (n ​= ​19) for a 4-week intervention...

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the death of upper and lower motor neurons (MNs). Excessive neuronal excitability has been implicated in MN degeneration; thus, modulation of hyperexcitability appears as a promising therapeutic strategy. Potassium channels are attractive targets since they can be activated at subthreshold voltages and can regulate neuronal excitability. In this study, we assayed the effects of N-(6-Chloro-pyridin-3-yl)-3,4-difluorobenzamide compound, known as ICA-27243, as a potential treatment for ALS...

Signal transduction at the neuromuscular junction (NMJ) is compromised in a diverse array of diseases including congenital myasthenic syndromes (CMS). Germline mutations in CHRNE encoding the acetylcholine receptor (AChR) ε subunit are the most common cause of CMS. An active form of vitamin D, calcitriol, binds to vitamin D receptor (VDR) and regulates gene expressions. We found that calcitriol enhanced MuSK phosphorylation, AChR clustering, and myotube twitching in co-cultured C2C12 myotubes and NSC34 motor neurons...

No abstract text is available yet for this article.

The advent of next-generation technology has significantly advanced the implementation and delivery of Deep Brain Stimulation (DBS) for Essential Tremor (ET), yet controversies persist regarding optimal targets and networks responsible for tremor genesis and suppression. This review consolidates key insights from anatomy, neurology, electrophysiology, and radiology to summarize the current state-of-the-art in DBS for ET. We explore the role of the thalamus in motor function and describe how differences in parcellations and nomenclature have shaped our understanding of the neuroanatomical substrates associated with optimal outcomes...

Neuropathic pain is a chronic condition representing a significant burden for society. It is estimated 1 out of 10 people over the age of 30 that in the US have been diagnosed with neuropathic pain. Most of the available treatments for neuropathic pain have moderate efficacy over time which limit their use; therefore, other therapeutic approaches are needed for patients. Spinal cord stimulation is an established and cost-effective modality for treating severe chronic pain. In this article we will review the current approved indications for the use of spinal cord stimulation in the US and the novel therapeutic options which are now available using this therapy...

Epilepsy is a common and debilitating neurological disorder, and approximately one-third of affected individuals have ongoing seizures despite appropriate trials of two anti-seizure medications. This population with drug-resistant epilepsy (DRE) may benefit from neurostimulation approaches, such as vagus nerve stimulation (VNS), deep brain stimulation (DBS) and responsive neurostimulation (RNS). In some patient populations, these techniques are FDA-approved for treating DRE. VNS is used as adjuvant therapy for children and adults...