Lasting Peripheral and Central Effects of Botulinum Toxin Type A on Experimental Muscle Hypertonia in Rats.

Recent animal experiments suggested that centrally transported botulinum toxin type A (BoNT-A) might reduce an abnormal muscle tone, though with an unknown contribution to the dominant peripheral muscular effect observed clinically. Herein, we examined if late BoNT-A antispastic actions persist due to possible central toxin actions in rats. The early effect of intramuscular (i.m.) BoNT-A (5, 2 and 1 U/kg) on a reversible tetanus toxin (TeNT)-induced calf muscle spasm was examined 7 d post-TeNT and later during recovery from flaccid paralysis (TeNT reinjected on day 49 post-BoNT-A). Lumbar intrathecal (i.t.) BoNT-A-neutralizing antiserum was used to discriminate the transcytosis-dependent central toxin action of 5 U/kg BoNT-A. BoNT-A-truncated synaptosomal-associated protein 25 immunoreactivity was examined in the muscles and spinal cord at day 71 post-BoNT-A. All doses (5, 2 and 1 U/kg) induced similar antispastic actions in the early period (days 1-14) post-BoNT-A. After repeated TeNT, only the higher two doses prevented the muscle spasm and associated locomotor deficit. Central trans-synaptic activity contributed to the late antispastic effect of 5 U/kg BoNT-A. Ongoing BoNT-A enzymatic activity was present in both injected muscle and the spinal cord. These observations suggest that the treatment duration in sustained or intermittent muscular hyperactivity might be maintained by higher doses and combined peripheral and central BoNT-A action.

Review of Cerebrospinal Fluid Physiology and Dynamics: A Call for Medical Education Reform.

BACKGROUND: The flow of cerebrospinal fluid (CSF) has been described as a unidirectional system with the choroid plexus serving as the primary secretor of CSF and the arachnoid granulations as primary reabsorption site. This theory of neurosurgical forefathers has been universally adopted and taught as dogma. Many neuroscientists have found difficulty reconciling this theory with common pathologies, and recent studies have found that this "classic" hypothesis may not represent the full picture. OBJECTIVE: To review modern CSF dynamic theories and to call for medical education reform. METHODS: We reviewed the literature from January 1990 to December 2020. We searched the PubMed database using key terms "cerebrospinal fluid circulation," "cerebrospinal fluid dynamics," "cerebrospinal fluid physiology," "glymphatic system," and "glymphatic pathway." We selected articles with a primary aim to discuss either CSF dynamics and/or the glymphatic system. RESULTS: The Bulat-Klarica-Oreskovic hypothesis purports that CSF is secreted and reabsorbed throughout the craniospinal axis. CSF demonstrates similar physiology to that of water elsewhere in the body. CSF "circulates" throughout the subarachnoid space in a pulsatile to-and-fro fashion. Osmolarity plays a critical role in CSF dynamics. Aquaporin-4 and the glymphatic system contribute to CSF volume and flow by establishing osmolarity gradients and facilitating CSF movement. Multiple studies demonstrate that the choroid plexus does not play any significant role in CSF circulation. CONCLUSION: We have highlighted major studies to illustrate modern principles of CSF dynamics. Despite these, the medical education system has been slow to reform curricula and update learning resources.

Circadian Rhythm and Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative disorder with a growing epidemiological importance characterized by significant disease burden. Sleep-related pathological symptomatology often accompanies AD. The etiology and pathogenesis of disrupted circadian rhythm and AD share common factors, which also opens the perspective of viewing them as a mutually dependent process. This article focuses on the bi-directional relationship between these processes, discussing the pathophysiological links and clinical aspects. Common mechanisms linking both processes include neuroinflammation, neurodegeneration, and circadian rhythm desynchronization. Timely recognition of sleep-specific symptoms as components of AD could lead to an earlier and correct diagnosis with an opportunity of offering treatments at an earlier stage. Likewise, proper sleep hygiene and related treatments ought to be one of the priorities in the management of the patient population affected by AD. This narrative review brings a comprehensive approach to clearly demonstrate the underlying complexities linking AD and circadian rhythm disruption. Most clinical data are based on interventions including melatonin, but larger-scale research is still scarce. Following a pathophysiological reasoning backed by evidence gained from AD models, novel anti-inflammatory treatments and those targeting metabolic alterations in AD might prove useful for normalizing a disrupted circadian rhythm. By restoring it, benefits would be conferred for immunological, metabolic, and behavioral function in an affected individual. On the other hand, a balanced circadian rhythm should provide greater resilience to AD pathogenesis.