Timing-dependent synergies between motor cortex and posterior spinal stimulation in humans.

Volitional movement requires descending input from the motor cortex and sensory feedback through the spinal cord. We previously developed a paired brain and spinal electrical stimulation approach in rats that relies on convergence of the descending motor and spinal sensory stimuli in the cervical cord. This approach strengthened sensorimotor circuits and improved volitional movement through associative plasticity. In humans, it is not known whether posterior epidural spinal cord stimulation targeted at the sensorimotor interface or anterior epidural spinal cord stimulation targeted within the motor system is effective at facilitating brain evoked responses. In 59 individuals undergoing elective cervical spine decompression surgery, the motor cortex was stimulated with scalp electrodes and the spinal cord was stimulated with epidural electrodes, with muscle responses being recorded in arm and leg muscles. Spinal electrodes were placed either posteriorly or anteriorly, and the interval between cortex and spinal cord stimulation was varied. Pairing stimulation between the motor cortex and spinal sensory (posterior) but not spinal motor (anterior) stimulation produced motor evoked potentials that were over five times larger than brain stimulation alone. This strong augmentation occurred only when descending motor and spinal afferent stimuli were timed to converge in the spinal cord. Paired stimulation also increased the selectivity of muscle responses relative to unpaired brain or spinal cord stimulation. Finally, clinical signs suggest that facilitation was observed in both injured and uninjured segments of the spinal cord. The large effect size of this paired stimulation makes it a promising candidate for therapeutic neuromodulation. KEY POINTS: Pairs of stimuli designed to alter nervous system function typically target the motor system, or one targets the sensory system and the other targets the motor system for convergence in cortex. In humans undergoing clinically indicated surgery, we tested paired brain and spinal cord stimulation that we developed in rats aiming to target sensorimotor convergence in the cervical cord. Arm and hand muscle responses to paired sensorimotor stimulation were more than five times larger than brain or spinal cord stimulation alone when applied to the posterior but not anterior spinal cord. Arm and hand muscle responses to paired stimulation were more selective for targeted muscles than the brain- or spinal-only conditions, especially at latencies that produced the strongest effects of paired stimulation. Measures of clinical evidence of compression were only weakly related to the paired stimulation effect, suggesting that it could be applied as therapy in people affected by disorders of the central nervous system.

CRISPR screen for protein inclusion formation uncovers a role for SRRD in the regulation of intermediate filament dynamics and aggresome assembly.

The presence of large protein inclusions is a hallmark of neurodegeneration, and yet the precise molecular factors that contribute to their formation remain poorly understood. Screens using aggregation-prone proteins have commonly relied on downstream toxicity as a readout rather than the direct formation of aggregates. Here, we combined a genome-wide CRISPR knockout screen with Pulse Shape Analysis, a FACS-based method for inclusion detection, to identify direct modifiers of TDP-43 aggregation in human cells. Our screen revealed both canonical and novel proteostasis genes, and unearthed SRRD, a poorly characterized protein, as a top regulator of protein inclusion formation. APEX biotin labeling reveals that SRRD resides in proximity to proteins that are involved in the formation and breakage of disulfide bonds and to intermediate filaments, suggesting a role in regulation of the spatial dynamics of the intermediate filament network. Indeed, loss of SRRD results in aberrant intermediate filament fibrils and the impaired formation of aggresomes, including blunted vimentin cage structure, during proteotoxic stress. Interestingly, SRRD also localizes to aggresomes and unfolded proteins, and rescues proteotoxicity in yeast whereby its N-terminal low complexity domain is sufficient to induce this affect. Altogether this suggests an unanticipated and broad role for SRRD in cytoskeletal organization and cellular proteostasis.

Spinal Epidural Abscess and Strep Pharyngitis.

Spinal epidural abscesses (SEA) require prompt diagnosis to avoid devastating consequences. Here, we discuss the case of a healthy 20-year-old college student-with a recent diagnosis of strep pharyngitis-who presented with neck pain, fever, and a neurologic deficit-the most common symptoms of SEA. Magnetic resonance imaging revealed a T1-postcontrast, peripherally enhancing epidural collection from C3-T5 with associated cord compression and T3 osteomyelitis. The patient was treated with emergent skip hemilaminectomies for abscess evacuation. Surgical cultures grew Fusobacterium necrophorum, a highly unusual pathogen in SEA. It is an oral anaerobe that translocated through the mucosa in the setting of strep pharyngitis. We treated the patient with ceftriaxone for 6 weeks. The patient had a full neurologic recovery and remains without recurrence of infection 11 months postoperatively. Healthy patients without obvious risk factors may present with SEA, highlighting the need for atypical cases such as these to be brought to clinicians' attention.

Timing dependent synergies between motor cortex and posterior spinal stimulation in humans.

Volitional movement requires descending input from motor cortex and sensory feedback through the spinal cord. We previously developed a paired brain and spinal electrical stimulation approach in rats that relies on convergence of the descending motor and spinal sensory stimuli in the cervical cord. This approach strengthened sensorimotor circuits and improved volitional movement through associative plasticity. In humans it is not known whether dorsal epidural SCS targeted at the sensorimotor interface or anterior epidural SCS targeted within the motor system is effective at facilitating brain evoked responses. In 59 individuals undergoing elective cervical spine decompression surgery, the motor cortex was stimulated with scalp electrodes and the spinal cord with epidural electrodes while muscle responses were recorded in arm and leg muscles. Spinal electrodes were placed either posteriorly or anteriorly, and the interval between cortex and spinal cord stimulation was varied. Pairing stimulation between the motor cortex and spinal sensory (posterior) but not spinal motor (anterior) stimulation produced motor evoked potentials that were over five times larger than brain stimulation alone. This strong augmentation occurred only when descending motor and spinal afferent stimuli were timed to converge in the spinal cord. Paired stimulation also increased the selectivity of muscle responses relative to unpaired brain or spinal cord stimulation. Finally, paired stimulation effects were present regardless of the severity of myelopathy as measured by clinical signs or spinal cord imaging. The large effect size of this paired stimulation makes it a promising candidate for therapeutic neuromodulation.

Successful In Vitro Fertilization in a Cisgender Female Carrier Using Oocytes Retrieved From a Transgender Man Maintained on Testosterone.

BACKGROUND: Health care providers routinely discontinue testosterone in transgender men undergoing oocyte retrieval. To date, there is little literature to support such discontinuation. The sudden drop in testosterone levels can be distressing for transgender men. The objective of this report was to describe a case study of successful reciprocal in vitro fertilization (IVF) using oocytes retrieved from a transgender man who remained on testosterone during the entire course of gonadotropin controlled ovarian stimulation and retrieval. CASE REPORT: A 33-year-old gravida 0 transgender man and his partner, a 42-year-old gravida 0 cisgender woman, presented to an outpatient clinic in 2017 seeking reciprocal IVF. Both patients were healthy with no significant past medical history. The transgender patient reported a 10-year history of testosterone hormone therapy. Both patients reported no other medication use. The transgender man underwent a 14-day course of ovarian stimulation before oocytes were retrieved. An oocyte was then fertilized and implanted into the uterus of the patient's cisgender female partner. The reciprocal IVF resulted in an uncomplicated, full-term pregnancy with vaginal delivery. The child is now 2 years old and developmentally normal. DISCUSSION: To our knowledge, this is the first report of a live birth from an oocyte retrieved from a transgender man who continued to use testosterone throughout assisted reproduction. CONCLUSION: Fertility preservation options for transmasculine people may include stimulated egg retrieval if the ovaries are left in place even when the patients remain on testosterone therapy.