There is an urgent and unmet clinical need to develop nonpharmacological interventions for chronic pain management because of the critical side effects of opioids. Low-intensity transcranial focused ultrasound (tFUS) is an emerging noninvasive neuromodulation technology with high spatial specificity and deep brain penetration. Here, we developed a tightly focused 128-element ultrasound transducer to specifically target small mouse brains using dynamic focus steering. We demonstrate that tFUS stimulation at pain-processing brain circuits can significantly alter pain-associated behaviors in mouse models in vivo. Our findings indicate that a single-session focused ultrasound stimulation to the primary somatosensory cortex (S1) significantly attenuates heat pain sensitivity in wild-type mice and modulates heat and mechanical hyperalgesia in a humanized mouse model of chronic pain in sickle cell disease. Results further revealed a sustained behavioral change associated with heat hypersensitivity by targeting deeper cortical structures (eg, insula) and multisession focused ultrasound stimulation to S1 and insula. Analyses of brain electrical rhythms through electroencephalography demonstrated a significant change in noxious heat hypersensitivity-related and chronic hyperalgesia–associated neural signals after focused ultrasound treatment. Validation of efficacy was carried out through control experiments, tuning ultrasound parameters, adjusting interexperiment intervals, and investigating effects on age, sex, and genotype in a head-fixed awake model. Importantly, tFUS was found to be safe, causing no adverse effects on motor function or the brain’s neuropathology. In conclusion, the validated proof-of-principle experimental evidence demonstrates the translational potential of novel focused ultrasound neuromodulation for next-generation pain treatment without adverse effects.

Chemotherapy-induced peripheral neuropathy (CIPN) is a significant dose-limiting long-term sequela in cancer patients undergoing treatment, often leading to discontinuation of treatment. No established therapy exists to prevent and/or ameliorate CIPN. Reactive oxygen species (ROS) and mitochondrial dysregulation have been proposed to underlie the pathobiology of CIPN. However, interventions to prevent and treat CIPN are largely ineffective. Additional factors and mechanism-based targets need to be identified to develop novel strategies to target CIPN. The role of oxidative stress appears to be central, but the contribution of endoplasmic reticulum (ER) stress remains under-examined in the pathobiology of CIPN. This review describes the significance of ER stress and its contribution to CIPN, the protective role of herbal agents in countering ER stress in nervous system-associated disorders, and their possible repurposing for preventing CIPN.

Background: COVID-19 is the largest outbreak to strike humanity. The wide scale of fatalities and morbidities lead to a concurrent pandemic of uncertainty in scientific evidence. Conflicting evidences are released on daily basis about the neonatal outcomes of COVID-19-positive mothers. The aim of this study was to use the relevant case reports and series to determine the percentage of newborns who test positive for COVID-19 who are born to COVID-19-positive mothers. Secondary outcomes included examining laboratory abnormalities among COVID-19-positive neonates, and any depicted placental abnormalities in COVID-19-positive mothers. For this purpose, systematic review was performed on all studies reporting primary data on fetus-mother pairs with COVID-19. Data bases were searched for studies that met our inclusion and exclusion criteria.Results: Final screening revealed 67 studies, from which the primary data of 1787 COVID-19 mothers were identified and had their pregnancy outcome analyzed. Only 2.8% of infants born to COVID-19-positive mothers tested positive, and this finding is identical to percentages reported in former Coronaviridae outbreaks, whereas 20% manifested with intrauterine hypoxia alongside placental abnormalities suggestive of heavy placental vaso-occlusive involvement.Conclusions: These findings suggest that while vertical transmission is unlikely, there appears to be an underlying risk of placental insufficiency due to the prothrombotic tendency observed in COVID-19 infection. Guidelines for proper prophylactic anticoagulation in COVID-positive mothers need to be established.

Background: Photoreceptor (PR) enriched retinal organoid (RO) sheets (human embryonic stem cell [hESC]-derived ROs) resulted in restoration of visual acuity in immunocompromised retinal degenerate (RD) animal models after transplantation. Further assessment of their clinical potential requires evaluation in immunocompetent RD disease models with effective immune suppression. We characterized safety and efficacy profiles of both donor tissues and prospective immunosuppressive treatments in vitro; and in vivo in immunocompetent RD rats (strain SD-foxn1 Tg(S334ter)3Lav). Methods: Retinal identity of ROs was validated by histology, flow cytometry and gene expression profiling, and their immunogenicity to sensitized human immune cells was measured by mixed lymphocyte reactions (MLR). We measured the effect of RO exposure for 1–4 weeks to therapeutic concentrations of our immunosuppressant drugs of choice on gene expression and metabolic function using quantitative PCR (qPCR) and functional and structural fluorescence lifetime imaging (FLIM), respectively. Immunocompetent RD graft recipients were immunosuppressed by implanted tacrolimus (TAC) pellets and mycophenolate mofetil (MMF) in food. In vivo, LCMS aided assessments of drug pharmacodynamics. Flow cytometry immunophenotyping and assay of post-surgery cytokines were used to assess and monitor drug efficacy. Retinal transplants were imaged in situ using optical coherence tomography (OCT) at defined time points post-surgery. Visual function was assessed by optokinetic tests (OKT) and superior colliculus electrophysiology recording. At study endpoints, immune cell infiltration and donor photoreceptor engraftment into host retinal architecture was evaluated by immunohistochemistry. Results: Immunosuppressive drugs have no negative effects on RO development and metabolism in vitro; and low alloreactivity of ROs determined by MLR may be predictive to that of human graft recipients. In vivo, minimum effective dosing ranges of TAC and MMF were determined. We characterized the mechanisms and critical immune populations implicated in rejection; and subsequently demonstrated their effective suppression in our xenograft RD model. OKT measured significant visual improvement after RO transplantation. Transplants developed most retinal cell types including photoreceptors; and integrated with the host retina. However, immunosuppression induced higher sensitivity to ketamine anesthesia. Conclusions: This study proves the concept that immunosuppression is likely tolerable in retinal transplantation and human stem cell therapy for retinal degeneration patients. Graphical