Faculty Bibliography

Avalglucosidase alfa, a recombinant human GAA enzyme replacement therapy with increased mannose-6-phosphate content for increased cellular uptake, is approved in the United States for late-onset Pompe disease (LOPD) patients >=1 year of age and in Japan for all Pompe disease patients (NexviazymeTM, Sanofi Genzyme, Cambridge, MA). During the 49-week, double-blinded primary-analysis period (PAP) of the Phase 3 COMET trial (NCT02782741) comparing avalglucosidase alfa with alglucosidase alfa, avalglucosidase alfa resulted in greater improvements in forced vital capacity (FVC), 6-Minute Walk Test (6MWT), and other outcomes and a more favorable safety profile than alglucosidase alfa in treatment-naive LOPD participants. During the open-label extension-treatment period (ETP), 51/51 participants receiving avalglucosidase alfa during the PAP continued this treatment and 44/49 receiving alglucosidase alfa during the PAP switched to avalglucosidase alfa. Changes (LS mean [SE]) from Baseline at Week 97 are reported. Changes in FVC %predicted were + 2.65 (1.05) for avalglucosidase alfa PAP participants and + 0.36 (1.12) for alglucosidase alfa PAP participants. Changes in 6MWT distance (meters) were + 18.60 (12.01) for avalglucosidase alfa PAP participants versus +4.56 (12.44) for alglucosidase alfa PAP participants. Similar trends occurred in other Week-97 outcomes. Treatment-emergent adverse events (AEs) during the ETP occurred in 49 (96.1%) and 42 (95.5%) participants from the avalglucosidase alfa and alglucosidase alfa PAP groups, respectively. Five participants discontinued during the ETP by Week 97 due to AEs (ocular hyperemia, erythema, urticaria, respiratory distress, acute myocardial infarction, pancreatic adenocarcinoma). Twenty-two participants had treatment-emergent serious AEs during the ETP. Patients switched from alglucosidase alfa to avalglucosidase alfa presented no safety- or immunogenicity-related concerns. Overall results demonstrate sustained treatment effect for improvements observed with avalglucosidase alfa during the PAP and stabilization of treatment effect after switching from alglucosidase alfa to avalglucosidase alfa over 97 weeks, supporting long-term maintenance of outcomes and persistence of avalglucosidase alfa's effect.
Funding(s): Sanofi-Genzyme.
Copyright

We report an energy-efficient, cancellation-free, bit-wise time-division duplex (B-TDD) transceiver (TRX) for real-time closed-loop control of high channel count neural interfaces. The proposed B-TDD architecture consists of a duty-cycled ultra-wide band (UWB) transmitter (3.15 GHz) and a switching U-NII band (5.2 GHz) receiver. An energy-efficient duplex is realized in a single antenna without power-hungry self-interference cancellation circuits which are prevalently used in the conventional full-duplex, single antenna transceivers. To suppress the interference between up- and down-links and enhance the isolation between the two, we devised a fast-switching scheme in a low noise amplifier and used 5 oversampling with a built-in winner-take-all voting in the receiver. The B-TDD transceiver was fabricated in 65 nm CMOS RF process, achieving low energy consumption of 0.32 nJ/b at 10 Mbps in the receiver and 9.7 pJ/b at 200 Mbps in the transmitter, respectively. For validation, the B-TDD TRX has been integrated with a LED optoelectrode and a custom analog frontend integrated circuit in a prototype wireless bidirectional neural interface system. Successful in-vivo operation for simultaneously recording broadband neural signals and optical stimulation was demonstrated in a transgenic rodent.

During conversation, people take turns speaking by rapidly responding to their partners while simultaneously avoiding interruption^1,2. Such interactions display a remarkable degree of coordination, as gaps between turns are typically about 200 milliseconds³-approximately the duration of an eyeblink⁴. These latencies are considerably shorter than those observed in simple word-production tasks, which indicates that speakers often plan their responses while listening to their partners². Although a distributed network of brain regions has been implicated in speech planning^5-9, the neural dynamics underlying the specific preparatory processes that enable rapid turn-taking are poorly understood. Here we use intracranial electrocorticography to precisely measure neural activity as participants perform interactive tasks, and we observe a functionally and anatomically distinct class of planning-related cortical dynamics. We localize these responses to a frontotemporal circuit centred on the language-critical caudal inferior frontal cortex¹⁰ (Broca's region) and the caudal middle frontal gyrus-a region not normally implicated in speech planning^11-13. Using a series of motor tasks, we then show that this planning network is more active when preparing speech as opposed to non-linguistic actions. Finally, we delineate planning-related circuitry during natural conversation that is nearly identical to the network mapped with our interactive tasks, and we find this circuit to be most active before participant speech during unconstrained turn-taking. Therefore, we have identified a speech planning network that is central to natural language generation during social interaction.

Valosin-containing protein (VCP) associated multisystem proteinopathy (MSP) is a rare inherited disorder that may result in multisystem involvement of varying phenotypes including inclusion body myopathy, Paget's disease of bone (PDB), frontotemporal dementia (FTD), parkinsonism, and amyotrophic lateral sclerosis (ALS), among others. An international multidisciplinary consortium of 40+ experts in neuromuscular disease, dementia, movement disorders, psychology, cardiology, pulmonology, physical therapy, occupational therapy, speech and language pathology, nutrition, genetics, integrative medicine, and endocrinology were convened by the patient advocacy organization, Cure VCP Disease, in December 2020 to develop a standard of care for this heterogeneous and under-diagnosed disease. To achieve this goal, working groups collaborated to generate expert consensus recommendations in 10 key areas: genetic diagnosis, myopathy, FTD, PDB, ALS, Charcot Marie Tooth disease (CMT), parkinsonism, cardiomyopathy, pulmonology, supportive therapies, nutrition and supplements, and mental health. In April 2021, facilitated discussion of each working group's conclusions with consensus building techniques enabled final agreement on the proposed standard of care for VCP patients. Timely referral to a specialty neuromuscular center is recommended to aid in efficient diagnosis of VCP MSP via single-gene testing in the case of a known familial VCP variant, or multi-gene panel sequencing in undifferentiated cases. Additionally, regular and ongoing multidisciplinary team follow up is essential for proactive screening and management of secondary complications. The goal of our consortium is to raise awareness of VCP MSP, expedite the time to accurate diagnosis, define gaps and inequities in patient care, initiate appropriate pharmacotherapies and supportive therapies for optimal management, and elevate the recommended best practices guidelines for multidisciplinary care internationally.

Intrahippocampal kainic acid (IHKA) has been widely implemented to simulate temporal lobe epilepsy (TLE), but evidence of robust seizures is usually limited. To resolve this problem, we slightly modified previous methods and show robust seizures are common and frequent in both male and female mice. We employed continuous wideband video-EEG monitoring from 4 recording sites to best demonstrate the seizures. We found many more convulsive seizures than most studies have reported. Mortality was low. Analysis of convulsive seizures at 2-4 and 10-12 wks post-IHKA showed a robust frequency (2-4 per day on average) and duration (typically 20-30 s) at each time. Comparison of the two timepoints showed that seizure burden became more severe in approximately 50% of the animals. We show that almost all convulsive seizures could be characterized as either low-voltage fast or hypersynchronous onset seizures, which has not been reported in a mouse model of epilepsy and is important because these seizure types are found in humans. In addition, we report that high frequency oscillations (>250 Hz) occur, resembling findings from IHKA in rats and TLE patients. Pathology in the hippocampus at the site of IHKA injection was similar to mesial temporal lobe sclerosis and reduced contralaterally. In summary, our methods produce a model of TLE in mice with robust convulsive seizures, and there is variable progression. HFOs are robust also, and seizures have onset patterns and pathology like human TLE. SIGNIFICANCE: Although the IHKA model has been widely used in mice for epilepsy research, there is variation in outcomes, with many studies showing few robust seizures long-term, especially convulsive seizures. We present an implementation of the IHKA model with frequent convulsive seizures that are robust, meaning they are >10 s and associated with complex high frequency rhythmic activity recorded from 2 hippocampal and 2 cortical sites. Seizure onset patterns usually matched the low-voltage fast and hypersynchronous seizures in TLE. Importantly, there is low mortality, and both sexes can be used. We believe our results will advance the ability to use the IHKA model of TLE in mice. The results also have important implications for our understanding of HFOs, progression, and other topics of broad interest to the epilepsy research community. Finally, the results have implications for preclinical drug screening because seizure frequency increased in approximately half of the mice after a 6 wk. interval, suggesting that the typical 2 wk. period for monitoring seizure frequency is insufficient.

Efference copies of movement-inducing neural signals have been proposed to serve a role in gaze stabilization. Prior work has demonstrated a spino-extraocular motor circuit in the tadpole that relays copies of spinal commands to extraocular motor neurons. A recent study demonstrates the presence of this circuitry in mice, suggesting a unique method of gaze stabilization in the locomoting mouse.

The stress response to emotions elicits the release of glucocorticoids from the adrenal cortex, epinephrine from the adrenal medulla, and norepinephrine from the sympathetic nerves. The baroreflex adapts to buffer these responses to ensure that perfusion to the organs meets the demands while maintaining blood pressure within a within a narrow range. While stressor-evoked autonomic cardiovascular responses may be adaptive for the short-term, the recurrent exaggerated cardiovascular stress reactions can be maladaptive in the long-term. Prolonged stress or loss of the baroreflex's buffering capacity can predispose episodes of heightened sympathetic activity during stress leading to hypertension, tachycardia, and ventricular wall motion abnormalities. This review discusses 1) how the baroreflex responds to acute and chronic stressors, 2) how lesions in the neuronal pathways of the baroreflex alter the ability to respond or counteract the stress response, and 3) the techniques to assess baroreflex sensitivity and stress responses. Evidence suggests that loss of baroreflex sensitivity may predispose heightened autonomic responses to stress and at least in part explain the association between stress, mortality and cardiovascular diseases.

The brain must extract behaviorally relevant latent variables from the signals streamed by the sensory organs. Such latent variables are often encoded in the dynamics that generated the signal rather than in the specific realization of the waveform. Therefore, one problem faced by the brain is to segment time series based on underlying dynamics. We present two algorithms for performing this segmentation task that are biologically plausible, which we define as acting in a streaming setting and all learning rules being local. One algorithm is model based and can be derived from an optimization problem involving a mixture of autoregressive processes. This algorithm relies on feedback in the form of a prediction error and can also be used for forecasting future samples. In some brain regions, such as the retina, the feedback connections necessary to use the prediction error for learning are absent. For this case, we propose a second, model-free algorithm that uses a running estimate of the autocorrelation structure of the signal to perform the segmentation. We show that both algorithms do well when tasked with segmenting signals drawn from autoregressive models with piecewise-constant parameters. In particular, the segmentation accuracy is similar to that obtained from oracle-like methods in which the ground-truth parameters of the autoregressive models are known. We also test our methods on data sets generated by alternating snippets of voice recordings. We provide implementations of our algorithms at https://github.com/ttesileanu/bio-time-series.