Calcium and SOL Protease Mediate Temperature Resetting of Circadian Clocks.

Circadian clocks integrate light and temperature input to remain synchronized with the day/night cycle. Although light input to the clock is well studied, the molecular mechanisms by which circadian clocks respond to temperature remain poorly understood. We found that temperature phase shifts Drosophila circadian clocks through degradation of the pacemaker protein TIM. This degradation is mechanistically distinct from photic CRY-dependent TIM degradation. Thermal TIM degradation is triggered by cytosolic calcium increase and CALMODULIN binding to TIM and is mediated by the atypical calpain protease SOL. This thermal input pathway and CRY-dependent light input thus converge on TIM, providing a molecular mechanism for the integration of circadian light and temperature inputs. Mammals use body temperature cycles to keep peripheral clocks synchronized with their brain pacemaker. Interestingly, downregulating the mammalian SOL homolog SOLH blocks thermal mPER2 degradation and phase shifts. Thus, we propose that circadian thermosensation in insects and mammals share common principles.

Experimental Neurotherapeutics: Surfing the Tidal Wave of New Opportunities.

The subspecialty of experimental neurotherapeutics trains neurologists in discovering and developing new treatments for neurologic diseases. Based on development of exciting new treatments for genetic and inflammatory diseases, we predict that there will be many other breakthroughs. The job market has expanded rapidly in academia, the pharmaceutical industry, government, and not-for-profit sectors; many new opportunities can be anticipated. The burgeoning opportunities in the field mandate that training address the challenges of overcoming obstacles in therapeutic discovery, implementation science, and development of affordable and equitably available treatments. ANN NEUROL 2023;93:427-430.

FLUORESCE: A Pilot Randomized Clinical Trial of Fluoxetine for Vision Recovery After Acute Ischemic Stroke.

BACKGROUND: Poststroke homonymous hemianopia is disabling, and complete spontaneous recovery is rare. In this randomized, placebo-controlled, double-blind, pilot clinical trial, we tested whether fluoxetine enhances vision recovery after stroke. METHODS: We randomized 17 consecutive adults 1:1 to 90 days of fluoxetine 20 mg daily vs placebo within 10 days of an ischemic stroke causing isolated homonymous hemianopia. The primary end point was percent improvement in 24-2 automated perimetry at 6 months. Twelve participants completed the study. Clinical trial registration NCT02737930. RESULTS: Intention-to-treat analysis of the primary end point, percent improvement in perimetric mean deviation, showed a nonsignificant benefit of fluoxetine (64.4%, n = 5) compared with placebo (26.0%, n = 7, one-tailed 95% confidence interval (CI) = (-2.13, ∞), P = 0.06). The original blind field completely recovered in 60% receiving fluoxetine and 14% receiving placebo (odds ratio = 7.22, one-tailed 95% CI = (0.50, ∞)). CONCLUSION: These results suggest a trend in favor of fluoxetine for vision recovery after stroke and have the potential to inform the design of a larger multicenter trial.

Survival of retinal ganglion cells after damage to the occipital lobe in humans is activity dependent.

Damage to the optic radiations or primary visual cortex leads to blindness in all or part of the contralesional visual field. Such damage disconnects the retina from its downstream targets and, over time, leads to trans-synaptic retrograde degeneration of retinal ganglion cells. To date, visual ability is the only predictor of retinal ganglion cell degeneration that has been investigated after geniculostriate damage. Given prior findings that some patients have preserved visual cortex activity for stimuli presented in their blind field, we tested whether that activity explains variability in retinal ganglion cell degeneration over and above visual ability. We prospectively studied 15 patients (four females, mean age = 63.7 years) with homonymous visual field defects secondary to stroke, 10 of whom were tested within the first two months after stroke. Each patient completed automated Humphrey visual field testing, retinotopic mapping with functional magnetic resonance imaging, and spectral-domain optical coherence tomography of the macula. There was a positive relation between ganglion cell complex (GCC) thickness in the blind field and early visual cortex activity for stimuli presented in the blind field. Furthermore, residual visual cortex activity for stimuli presented in the blind field soon after the stroke predicted the degree of retinal GCC thinning six months later. These findings indicate that retinal ganglion cell survival after ischaemic damage to the geniculostriate pathway is activity dependent.

Thalamus segmentation based on the local diffusion direction: a group study.

Fast and accurate segmentation of deep gray matter regions in the brain is important for clinical applications such as surgical planning for the placement of deep brain stimulation implants. Mapping anatomy from stereotactic atlases to patient data is problematic because of individual differences in subject anatomy that are not accounted for by commonly used atlases. We present a segmentation method for individual subject diffusion tensor MR data that is based on local diffusion information to identify subregions of the thalamus. We show the correspondence of our segmentation results to anatomy by comparison with stereotactic atlas data. Importantly, we verify the consistency of our segmentation by evaluating the method on 63 healthy volunteers. Our method is fast, reliable, and independent of any segmentation before the classification of regions within the thalamus. It should, therefore, be useful in clinical applications.

Rehabilitation of visual perception in cortical blindness.

Blindness is a common sequela after stroke affecting the primary visual cortex, presenting as a contralesional, homonymous, visual field cut. This can occur unilaterally or, less commonly, bilaterally. While it has been widely assumed that after a brief period of spontaneous improvement, vision loss becomes stable and permanent, accumulating data show that visual training can recover some of the vision loss, even long after the stroke. Here, we review the different approaches to rehabilitation employed in adult-onset cortical blindness (CB), focusing on visual restoration methods. Most of this work was conducted in chronic stroke patients, partially restoring visual discrimination and luminance detection. However, to achieve this, patients had to train for extended periods (usually many months), and the vision restored was not entirely normal. Several adjuvants to training such as noninvasive, transcranial brain stimulation, and pharmacology are starting to be investigated for their potential to increase the efficacy of training in CB patients. However, these approaches are still exploratory and require considerably more research before being adopted. Nonetheless, having established that the adult visual system retains the capacity for restorative plasticity, attention recently turned toward the subacute poststroke period. Drawing inspiration from sensorimotor stroke rehabilitation, visual training was recently attempted for the first time in subacute poststroke patients. It improved vision faster, over larger portions of the blind field, and for a larger number of visual discrimination abilities than identical training initiated more than 6 months poststroke (i.e., in the chronic period). In conclusion, evidence now suggests that visual neuroplasticity after occipital stroke can be reliably recruited by a range of visual training approaches. In addition, it appears that poststroke visual plasticity is dynamic, with a critical window of opportunity in the early postdamage period to attain more rapid, more extensive recovery of a larger set of visual perceptual abilities.

Automatic Identification of Upper Extremity Rehabilitation Exercise Type and Dose Using Body-Worn Sensors and Machine Learning: A Pilot Study.

BACKGROUND: Prior studies suggest that participation in rehabilitation exercises improves motor function poststroke; however, studies on optimal exercise dose and timing have been limited by the technical challenge of quantifying exercise activities over multiple days. OBJECTIVES: The objectives of this study were to assess the feasibility of using body-worn sensors to track rehabilitation exercises in the inpatient setting and investigate which recording parameters and data analysis strategies are sufficient for accurately identifying and counting exercise repetitions. METHODS: MC10 BioStampRC® sensors were used to measure accelerometer and gyroscope data from upper extremities of healthy controls (n = 13) and individuals with upper extremity weakness due to recent stroke (n = 13) while the subjects performed 3 preselected arm exercises. Sensor data were then labeled by exercise type and this labeled data set was used to train a machine learning classification algorithm for identifying exercise type. The machine learning algorithm and a peak-finding algorithm were used to count exercise repetitions in non-labeled data sets. RESULTS: We achieved a repetition counting accuracy of 95.6% overall, and 95.0% in patients with upper extremity weakness due to stroke when using both accelerometer and gyroscope data. Accuracy was decreased when using fewer sensors or using accelerometer data alone. CONCLUSIONS: Our exploratory study suggests that body-worn sensor systems are technically feasible, well tolerated in subjects with recent stroke, and may ultimately be useful for developing a system to measure total exercise "dose" in poststroke patients during clinical rehabilitation or clinical trials.

Selective serotonin reuptake inhibitors for functional recovery after stroke: similarities with the critical period and the role of experience-dependent plasticity.

There has been a growing interest in the potential for plasticity-inducing pharmacological interventions to enhance post-stroke recovery. One group of drugs that continues to garner a great deal of attention in this regard is a class of antidepressants called the selective serotonin reuptake inhibitors. Here we propose a model for the mechanism by which these drugs may enhance plasticity after ischemic brain injury. First, we review the research in animal models demonstrating how selective serotonin reuptake inhibitors reopen the critical period for ocular dominance plasticity in adulthood. We then compare this period of heightened plasticity to the cellular and biochemical milieu of perilesional tissue after an ischemic event in the adult brain. We argue that selective serotonin reuptake inhibitors administered acutely after an ischemic stroke alter excitatory-inhibitory balance in perilesional tissue and reinstate a type of plasticity reminiscent of the critical period in development. Finally, we discuss opportunities for future research in this area in both the preclinical and clinical realms.

PER-TIM interactions with the photoreceptor cryptochrome mediate circadian temperature responses in Drosophila.

Drosophila cryptochrome (CRY) is a key circadian photoreceptor that interacts with the period and timeless proteins (PER and TIM) in a light-dependent manner. We show here that a heat pulse also mediates this interaction, and heat-induced phase shifts are severely reduced in the cryptochrome loss-of-function mutant cry(b). The period mutant per(L) manifests a comparable CRY dependence and dramatically enhanced temperature sensitivity of biochemical interactions and behavioral phase shifting. Remarkably, CRY is also critical for most of the abnormal temperature compensation of per(L) flies, because a per(L); cry(b) strain manifests nearly normal temperature compensation. Finally, light and temperature act together to affect rhythms in wild-type flies. The results indicate a role for CRY in circadian temperature as well as light regulation and suggest that these two features of the external 24-h cycle normally act together to dictate circadian phase.

Using Vision to Study Poststroke Recovery and Test Hypotheses About Neurorehabilitation.

Approximately one-third of stroke patients suffer visual field impairment as a result of their strokes. However, studies using the visual pathway as a paradigm for studying poststroke recovery are limited. In this article, we propose that the visual pathway has many features that make it an excellent model system for studying poststroke neuroplasticity and assessing the efficacy of therapeutic interventions. First, the functional anatomy of the visual pathway is well characterized, which makes it well suited for functional neuroimaging studies of poststroke recovery. Second, there are multiple highly standardized and clinically available diagnostic tools and outcome measures that can be used to assess visual function in stroke patients. Finally, as a sensory modality, the assessment of vision is arguably less likely to be affected by confounding factors such as functional compensation and patient motivation. Given these advantages, and the general similarities between poststroke visual field recovery and recovery in other functional domains, future neurorehabilitation studies should consider using the visual pathway to better understand the physiology of neurorecovery and test potential therapeutics.

Interactions between circadian neurons control temperature synchronization of Drosophila behavior.

Most animals rely on circadian clocks to synchronize their physiology and behavior with the day/night cycle. Light and temperature are the major physical variables that can synchronize circadian rhythms. Although the effects of light on circadian behavior have been studied in detail in Drosophila, the neuronal mechanisms underlying temperature synchronization of circadian behavior have received less attention. Here, we show that temperature cycles synchronize and durably affect circadian behavior in Drosophila in the absence of light input. This synchronization depends on the well characterized and functionally coupled circadian neurons controlling the morning and evening activity under light/dark cycles: the M cells and E cells. However, circadian neurons distinct from the M and E cells are implicated in the control of rhythmic behavior specifically under temperature cycles. These additional neurons play a dual role: they promote evening activity and negatively regulate E cell function in the middle of the day. We also demonstrate that, although temperature synchronizes circadian behavior more slowly than light, this synchronization is considerably accelerated when the M cell oscillator is absent or genetically altered. Thus, whereas the E cells show great responsiveness to temperature input, the M cells and their robust self-sustained pacemaker act as a resistance to behavioral synchronization by temperature cycles. In conclusion, the behavioral responses to temperature input are determined by both the individual properties of specific groups of circadian neurons and their organization in a neural network.

Interfacility transfers for US ischemic stroke and TIA, 2006-2014.

OBJECTIVE: To investigate changes in emergency department (ED) transfers for ischemic stroke (IS) and TIA. METHODS: We performed a retrospective observational study using the US Nationwide Emergency Department Sample to identify changes in interfacility ED transfers for IS and TIA from the perspective of the transferring ED (2006-2014). We calculated nationwide transfer rates and individual ED transfer rates for IS/TIA by diagnosis and hospital characteristics. Hospital-level fractional logistic regression examined changes in transfer rates over time. RESULTS: The population-estimated number of transfers for IS/TIA increased from 22,576 patient visits in 2006 to 54,485 patient visits in 2014 (p trend < 0.001). The rate of IS/TIA transfer increased from 3.4 (95% confidence interval [CI] 3.0-3.8) in 2006 to 7.6 (95% CI 7.2-7.9) in 2014 per 100 ED visits. Among individual EDs, mean transfer rates for IS/TIA increased from 8.2 per 100 ED visits (median 2.0, interquartile range [IQR] 0-10.2) to 19.4 per 100 ED visits (median 8.1, IQR 1.1-33.3) (2006-2014) (p trend < 0.001). Transfers were more common among IS. Transfer rates were greatest among rural (adjusted odds ratio [AOR] 3.05, 95% CI 2.56-3.64) vs urban/teaching and low-volume EDs (AOR 7.49, 95% CI 6.58-8.53, 1st vs 4th quartile). The adjusted odds of transfer for IS/TIA increased threefold (2006-2014). CONCLUSIONS: Interfacility ED transfers for IS/TIA more than doubled from 2006 to 2014. Further work should determine the necessity of IS/TIA transfers and seek to optimize the US stroke care system.

Roles of the two Drosophila CRYPTOCHROME structural domains in circadian photoreception.

CRYPTOCHROME (CRY) is the primary circadian photoreceptor in Drosophila. We show that CRY binding to TIMELESS (TIM) is light-dependent in flies and irreversibly commits TIM to proteasomal degradation. In contrast, CRY degradation is dependent on continuous light exposure, indicating that the CRY-TIM interaction is transient. A novel cry mutation (cry(m)) reveals that CRY's photolyase homology domain is sufficient for light detection and phototransduction, whereas the carboxyl-terminal domain regulates CRY stability, CRY-TIM interaction, and circadian photosensitivity. This contrasts with the function of Arabidopsis CRY domains and demonstrates that insect and plant cryptochromes use different mechanisms.