Thalamocortical Mechanisms Regulating the Relationship between Transient Beta Events and Human Tactile Perception.

Transient neocortical events with high spectral power in the 15-29 Hz beta band are among the most reliable predictors of sensory perception. Prestimulus beta event rates in primary somatosensory cortex correlate with sensory suppression, most effectively 100-300 ms before stimulus onset. However, the neural mechanisms underlying this perceptual association are unknown. We combined human magnetoencephalography (MEG) measurements with biophysical neural modeling to test potential cellular and circuit mechanisms that underlie observed correlations between prestimulus beta events and tactile detection. Extending prior studies, we found that simulated bursts from higher-order, nonlemniscal thalamus were sufficient to drive beta event generation and to recruit slow supragranular inhibition acting on a 300 ms timescale to suppress sensory information. Further analysis showed that the same beta-generating mechanism can lead to facilitated perception for a brief period when beta events occur simultaneously with tactile stimulation before inhibition is recruited. These findings were supported by close agreement between model-derived predictions and empirical MEG data. The postevent suppressive mechanism explains an array of studies that associate beta with decreased processing, whereas the during-event facilitatory mechanism may demand a reinterpretation of the role of beta events in the context of coincident timing.

Subthalamic-Cortical Network Reorganization during Parkinson's Tremor.

Tremor, a common and often primary symptom of Parkinson's disease, has been modeled with distinct onset and maintenance dynamics. To identify the neurophysiologic correlates of each state, we acquired intraoperative cortical and subthalamic nucleus recordings from 10 patients (9 male, 1 female) performing a naturalistic visual-motor task. From this task, we isolated short epochs of tremor onset and sustained tremor. Comparing these epochs, we found that the subthalamic nucleus was central to tremor onset, as it drove both motor cortical activity and tremor output. Once tremor became sustained, control of tremor shifted to cortex. At the same time, changes in directed functional connectivity across sensorimotor cortex further distinguished the sustained tremor state.SIGNIFICANCE STATEMENT Tremor is a common symptom of Parkinson's disease (PD). While tremor pathophysiology is thought to involve both basal ganglia and cerebello-thalamic-cortical circuits, it is unknown how these structures functionally interact to produce tremor. In this article, we analyzed intracranial recordings from the subthalamic nucleus and sensorimotor cortex in patients with PD undergoing deep brain stimulation surgery. Using an intraoperative task, we examined tremor in two separate dynamic contexts: when tremor first emerged, and when tremor was sustained. We believe that these findings reconcile several models of Parkinson's tremor, while describing the short-timescale dynamics of subcortical-cortical interactions during tremor for the first time. These findings may describe a framework for developing proactive and responsive neurostimulation models for specifically treating tremor.

Lesion location and lesion creation affect outcomes after focused ultrasound thalamotomy.

MRI-guided focused ultrasound thalamotomy has been shown to be an effective treatment for medication refractory essential tremor. Here, we report a clinical-radiological analysis of 123 cases of MRI-guided focused ultrasound thalamotomy, and explore the relationships between treatment parameters, lesion characteristics and outcomes. All patients undergoing focused ultrasound thalamotomy by a single surgeon were included. The procedure was performed as previously described, and patients were followed for up to 1 year. MRI was performed 24 h post-treatment, and lesion locations and volumes were calculated. We retrospectively evaluated 118 essential tremor patients and five tremor-dominant Parkinson's disease patients who underwent thalamotomy. At 24 h post-procedure, tremor abated completely in the treated hand in 81 essential tremor patients. Imbalance, sensory disturbances and dysarthria were the most frequent acute adverse events. Patients with any adverse event had significantly larger lesions, while inferolateral lesion margins were associated with a higher incidence of motor-related adverse events. Twenty-three lesions were identified with irregular tails, often extending into the internal capsule; 22 of these patients experienced at least one adverse event. Treatment parameters and lesion characteristics changed with increasing surgeon experience. In later cases, treatments used higher maximum power (normalized to skull density ratio), accelerated more quickly to high power, and delivered energy over fewer sonications. Larger lesions were correlated with a rapid rise in both power delivery and temperature, while increased oedema was associated with rapid rise in temperature and the maximum power delivered. Total energy and total power did not significantly affect lesion size. A support vector regression was trained to predict lesion size and confirmed the most valuable predictors of increased lesion size as higher maximum power, rapid rise to high-power delivery, and rapid rise to high tissue temperatures. These findings may relate to a decrease in the energy efficiency of the treatment, potentially due to changes in acoustic properties of skull and tissue at higher powers and temperatures. We report the largest single surgeon series of focused ultrasound thalamotomy to date, demonstrating tremor relief and adverse events consistent with reported literature. Lesion location and volume impacted adverse events, and an irregular lesion tail was strongly associated with adverse events. High-power delivery early in the treatment course, rapid temperature rise, and maximum power were dominant predictors of lesion volume, while total power, total energy, maximum energy and maximum temperature did not improve prediction of lesion volume. These findings have critical implications for treatment planning in future patients.

GABAB receptor-mediated, layer-specific synaptic plasticity reorganizes gamma-frequency neocortical response to stimulation.

Repeated presentations of sensory stimuli generate transient gamma-frequency (30-80 Hz) responses in neocortex that show plasticity in a task-dependent manner. Complex relationships between individual neuronal outputs and the mean, local field potential (population activity) accompany these changes, but little is known about the underlying mechanisms responsible. Here we show that transient stimulation of input layer 4 sufficient to generate gamma oscillations induced two different, lamina-specific plastic processes that correlated with lamina-specific changes in responses to further, repeated stimulation: Unit rates and recruitment showed overall enhancement in supragranular layers and suppression in infragranular layers associated with excitatory or inhibitory synaptic potentiation onto principal cells, respectively. Both synaptic processes were critically dependent on activation of GABAB receptors and, together, appeared to temporally segregate the cortical representation. These data suggest that adaptation to repetitive sensory input dramatically alters the spatiotemporal properties of the neocortical response in a manner that may both refine and minimize cortical output simultaneously.

Neural mechanisms of transient neocortical beta rhythms: Converging evidence from humans, computational modeling, monkeys, and mice.

Human neocortical 15-29-Hz beta oscillations are strong predictors of perceptual and motor performance. However, the mechanistic origin of beta in vivo is unknown, hindering understanding of its functional role. Combining human magnetoencephalography (MEG), computational modeling, and laminar recordings in animals, we present a new theory that accounts for the origin of spontaneous neocortical beta. In our MEG data, spontaneous beta activity from somatosensory and frontal cortex emerged as noncontinuous beta events typically lasting <150 ms with a stereotypical waveform. Computational modeling uniquely designed to infer the electrical currents underlying these signals showed that beta events could emerge from the integration of nearly synchronous bursts of excitatory synaptic drive targeting proximal and distal dendrites of pyramidal neurons, where the defining feature of a beta event was a strong distal drive that lasted one beta period (∼50 ms). This beta mechanism rigorously accounted for the beta event profiles; several other mechanisms did not. The spatial location of synaptic drive in the model to supragranular and infragranular layers was critical to the emergence of beta events and led to the prediction that beta events should be associated with a specific laminar current profile. Laminar recordings in somatosensory neocortex from anesthetized mice and awake monkeys supported these predictions, suggesting this beta mechanism is conserved across species and recording modalities. These findings make several predictions about optimal states for perceptual and motor performance and guide causal interventions to modulate beta for optimal function.

Thalamocortical control of propofol phase-amplitude coupling.

The anesthetic propofol elicits many different spectral properties on the EEG, including alpha oscillations (8-12 Hz), Slow Wave Oscillations (SWO, 0.1-1.5 Hz), and dose-dependent phase-amplitude coupling (PAC) between alpha and SWO. Propofol is known to increase GABAA inhibition and decrease H-current strength, but how it generates these rhythms and their interactions is still unknown. To investigate both generation of the alpha rhythm and its PAC to SWO, we simulate a Hodgkin-Huxley network model of a hyperpolarized thalamus and corticothalamic inputs. We find, for the first time, that the model thalamic network is capable of independently generating the sustained alpha seen in propofol, which may then be relayed to cortex and expressed on the EEG. This dose-dependent sustained alpha critically relies on propofol GABAA potentiation to alter the intrinsic spindling mechanisms of the thalamus. Furthermore, the H-current conductance and background excitation of these thalamic cells must be within specific ranges to exhibit any intrinsic oscillations, including sustained alpha. We also find that, under corticothalamic SWO UP and DOWN states, thalamocortical output can exhibit maximum alpha power at either the peak or trough of this SWO; this implies the thalamus may be the source of propofol-induced PAC. Hyperpolarization level is the main determinant of whether the thalamus exhibits trough-max PAC, which is associated with lower propofol dose, or peak-max PAC, associated with higher dose. These findings suggest: the thalamus generates a novel rhythm under GABAA potentiation such as under propofol, its hyperpolarization may determine whether a patient experiences trough-max or peak-max PAC, and the thalamus is a critical component of propofol-induced cortical spectral phenomena. Changes to the thalamus may be a critical part of how propofol accomplishes its effects, including unconsciousness.

DBStar: An Open-Source Tool Kit for Imaging Analysis with Patient-Customized Deep Brain Stimulation Platforms.

BACKGROUND/OBJECTIVES: To create an open-source method for reconstructing microelectrode recording (MER) and deep brain stimulation (DBS) electrode coordinates along multiple parallel trajectories with patient-specific DBS implantation platforms to facilitate DBS research. METHODS: We combined the surgical geometry (extracted from WayPoint Planner), pre-/intra-/postoperative computed tomography (CT) and/or magnetic resonance (MR) images, and integrated them into the Analysis of Functional NeuroImages (AFNI) neuroimaging analysis environment using functions written in Python. Electrode coordinates were calculated from image-based electrode surfaces and recording trajectory depth values. Coordinates were translated into appropriate trajectories, and were tested for proximity to patient-specific or atlas-based anatomical structures. Final DBS electrode coordinates for 3 patient populations (ventral intermediate nucleus [VIM], subthalamic nucleus [STN], and globus pallidus pars interna [GPi]) were calculated. For STN cases, MER site coordinates were then analyzed to see whether they were inside or outside the STN. RESULTS: Final DBS electrode coordinates were described for VIM, STN, and GPi patient populations. 115/169 (68%) STN MER sites were within 1 mm of the STN in AFNI's Talairach and Tournoux (TT) atlas. CONCLUSIONS: DBStar is a robust tool kit for understanding the anatomical location and context of electrode locations, and can easily be used for imaging, behavioral, or electrophysiological analyses.

Computational modeling to improve treatments for essential tremor.

Essential tremor (ET) is a neurological disorder of unknown etiology that is typically characterized by an involuntary periodic movement of the upper limbs. No longer considered monosymptomatic, ET patients often have additional motor and even cognitive impairments. Although there are several pharmacological treatments, no drugs have been developed specifically for ET [1], and 30-70% of patients are medication-refractory [2]. A subset of medication-refractory patients may benefit from electrical deep brain stimulation (DBS) of the ventral intermediate nucleus of the thalamus (VIM), which receives cerebellar inputs. Abnormal cerebellar input to VIM is presumed to be a major contributor to tremor symptoms, which is alleviated by DBS. Computational modeling of the effects of DBS in VIM has been a powerful tool to design DBS protocols to reduce tremor activity. However, far less is known about how these therapies affect non-tremor symptoms, and more experimental and computational modeling work is required to address these growing considerations. Models capable of addressing multiple facets of ET will lead to novel, more efficient treatment.

Neurosystems: brain rhythms and cognitive processing.

Neuronal rhythms are ubiquitous features of brain dynamics, and are highly correlated with cognitive processing. However, the relationship between the physiological mechanisms producing these rhythms and the functions associated with the rhythms remains mysterious. This article investigates the contributions of rhythms to basic cognitive computations (such as filtering signals by coherence and/or frequency) and to major cognitive functions (such as attention and multi-modal coordination). We offer support to the premise that the physiology underlying brain rhythms plays an essential role in how these rhythms facilitate some cognitive operations.

Frequency and clinical implications of findings on true whole-body 18F-FDG PET in the assessment of breast cancer.

INTRODUCTION: In the assessment of breast cancer using 18-F FDG PET/CT, the incremental clinical benefit in performing a true whole-body PET/CT (with a field of view (FOV) from the vertex to the toes) over a limited whole-body PET/CT (with a FOV from the base of skull to the mid-thighs) is uncertain. METHODS: Two hundred and one studies of 120 patients who underwent staging or restaging true whole body 18F-FDG PET/CT for breast cancer were retrospectively identified. Any abnormal hypermetabolic or structural focus outside the limited FOV was recorded and characterised, and referenced with the patient's known disease status and any symptomatology. RESULTS: A total of 18 (9.0%) studies had FDG avid and/or structural abnormalities detected outside the limited whole-body FOV which were identified as malignant. Seventeen out of 18 (94.4%) were skeletal and of these, 15/17 (88.2%) were located within the lower limbs. In three cases, there were de novo findings but identified in the presence of interval progression of other metastases within the limited whole-body FOV. None of these additional findings is known to have resulted in a change to staging or clinical management. CONCLUSION: In the assessment of breast cancer, a true whole-body PET/CT can reveal metastases outside the limited whole-body FOV, but these are unlikely to be encountered in isolation and therefore may have little bearing on clinical stage or management. Ultimately, while the choice of FOV should still be based on the individual patient situation, routine utilisation of the true whole-body FOV in the asymptomatic patient may not be necessary.

Flow reversal during stroke thrombectomy.

When performing mechanical thrombectomy for stroke patients, some physicians use balloon guide catheters (BGCs) in order to achieve flow reversal and thereby improve reperfusion quality. There is substantial evidence favoring the use of BGCs to improve reperfusion rates and clinical outcomes for thrombectomy patients; however, as we will outline in this review, there is also evidence that BGCs do not achieve reliable flow reversal in many circumstances. Therefore, if we are able to modify our techniques to improve the likelihood of flow reversal during thrombectomy maneuvers, we may be able to further improve reperfusion quality and clinical outcomes. This paper provides an overview of concepts on this topic and outlines some potential techniques to facilitate flow reversal more consistently, including a method to visually confirm it, with the aim of making iterative improvements towards optimal reperfusion for stroke patients.

FreeClimb 88 catheter with Tenzing 8 delivery for contact aspiration mechanical thrombectomy of anterior circulation large vessel occlusions.

PURPOSE: Contact aspiration mechanical thrombectomy (CAMT) with 0.088-inch catheters may improve first-pass success rates, but delivery of such catheters can be challenging and limit effectiveness. This study examines the initial multicenter experience using the FreeClimb 88 catheter paired with the Tenzing 8 delivery catheter. MATERIALS AND METHODS: Retrospective analysis was performed of consecutive patients with large vessel occlusion (LVO) of the internal carotid artery (ICA) or M1 segment of the middle cerebral artery treated with off-label CAMT using the FreeClimb 88 and Tenzing 8 at eight sites participating in the early limited release for these devices. Demographic and procedural variables were collected and analyzed with descriptive statistics and multivariable analysis. RESULTS: Fifty-three consecutive patients were treated. Large vessel occlusion was located in the ICA in 19/53 (35.8%) patients; 34/53 (64.2%) were in the M1 segment. FreeClimb 88 was successfully delivered to the site of occlusion in 50/53 (94.3%) of patients. First-pass TICI 2c or 3 was achieved with FreeClimb 88 delivered by Tenzing 8 in 36 (67.9%) cases. Among cases with successful FreeClimb 88 delivery 9/50 (18.0%) required additional smaller devices to perform thrombectomy of distal occlusions after recanalization of the initial LVO. No complications or symptomatic hemorrhages occurred following thrombectomy. CONCLUSION: Contact aspiration mechanical thrombectomy performed for ICA or M1 LVOs using FreeClimb 88 delivered with Tenzing 8 was safe, effective, and efficient in this early experience, with first-pass TICI 2c or 3 was achieved in 68% of patients without procedural complications occurring in any cases.

Concurrent decoding of distinct neurophysiological fingerprints of tremor and bradykinesia in Parkinson's disease.

Parkinson's disease (PD) is characterized by distinct motor phenomena that are expressed asynchronously. Understanding the neurophysiological correlates of these motor states could facilitate monitoring of disease progression and allow improved assessments of therapeutic efficacy, as well as enable optimal closed-loop neuromodulation. We examined neural activity in the basal ganglia and cortex of 31 subjects with PD during a quantitative motor task to decode tremor and bradykinesia - two cardinal motor signs of PD - and relatively asymptomatic periods of behavior. Support vector regression analysis of microelectrode and electrocorticography recordings revealed that tremor and bradykinesia had nearly opposite neural signatures, while effective motor control displayed unique, differentiating features. The neurophysiological signatures of these motor states depended on the signal type and location. Cortical decoding generally outperformed subcortical decoding. Within the subthalamic nucleus (STN), tremor and bradykinesia were better decoded from distinct subregions. These results demonstrate how to leverage neurophysiology to more precisely treat PD.

Improved catheter delivery for aspiration thrombectomy using Tenzing 7 ledge reducing catheter and FreeClimb 70.

PURPOSE: Previous comparative mechanical thrombectomy device trials reported a substantial crossover rate from first-line aspiration to stent-retriever thrombectomy. A specialized delivery catheter may help track large-bore aspiration catheters to target occlusions. We report our multicenter experience of aspiration thrombectomy of intracranial large vessel occlusions using the FreeClimbTM 70 and Tenzing® 7 delivery catheter (Route 92, San Mateo, CA). METHODS: After local Institutional Review Board approval, we retrospectively reviewed the clinical, procedural, and imaging data of patients who underwent mechanical thrombectomy with the FreeClimb 70 and Tenzing 7. RESULTS: FreeClimb 70 was successfully delivered using Tenzing 7 to target occlusion in 30/30 (100%) patients (18 M1, 6 M2, 4 ICA-terminus, and 2 basilar artery occlusions), without the use of a stent-retriever for anchoring. In 21/30 (70%) cases, a leading microwire was not needed to advance the Tenzing 7 to the target. Median (interquartile range) time from groin puncture to first pass was 12 (interquartile range 8-15) minutes. Overall first pass effect, or first pass effect (modified thrombolysis in cerebral ischemia 2C-3), was achieved 16/30 (53%). For M1 occlusions, first pass effect was 11/18 (61%). Successful reperfusion (modified thrombolysis in cerebral ischemia ≥ 2B) was achieved in 29/30 (97%) cases after a median of 1 pass (interquartile range 1-3). Median groin puncture to reperfusion time was 16 (interquartile range 12-26) minutes. There were no procedural complications or symptomatic intracranial hemorrhage. Average improvement in National Institutes of Health Stroke Scale at discharge was 6.6 ± 7.1. There were three patient deaths (renal failure, respiratory failure, and comfort care). CONCLUSIONS: Initial data support the use of Tenzing 7 with FreeClimb 70 catheter for reliable access to rapid, effective, and safe aspiration thrombectomy of large vessel occlusions.

Surgery's Rosetta Stone: Natural language processing to predict discharge and readmission after general surgery.

BACKGROUND: This study aimed to examine the accuracy with which multiple natural language processing artificial intelligence models could predict discharge and readmissions after general surgery. METHODS: Natural language processing models were derived and validated to predict discharge within the next 48 hours and 7 days and readmission within 30 days (based on daily ward round notes and discharge summaries, respectively) for general surgery inpatients at 2 South Australian hospitals. Natural language processing models included logistic regression, artificial neural networks, and Bidirectional Encoder Representations from Transformers. RESULTS: For discharge prediction analyses, 14,690 admissions were included. For readmission prediction analyses, 12,457 patients were included. For prediction of discharge within 48 hours, derivation and validation data set area under the receiver operator characteristic curves were, respectively: 0.86 and 0.86 for Bidirectional Encoder Representations from Transformers, 0.82 and 0.81 for logistic regression, and 0.82 and 0.81 for artificial neural networks. For prediction of discharge within 7 days, derivation and validation data set area under the receiver operator characteristic curves were, respectively: 0.82 and 0.81 for Bidirectional Encoder Representations from Transformers, 0.75 and 0.72 for logistic regression, and 0.68 and 0.67 for artificial neural networks. For readmission prediction within 30 days, derivation and validation data set area under the receiver operator characteristic curves were, respectively: 0.55 and 0.59 for Bidirectional Encoder Representations from Transformers and 0.77 and 0.62 for logistic regression. CONCLUSION: Modern natural language processing models, particularly Bidirectional Encoder Representations from Transformers, can effectively and accurately identify general surgery patients who will be discharged in the next 48 hours. However, these approaches are less capable of identifying general surgery patients who will be discharged within the next 7 days or who will experience readmission within 30 days of discharge.

Vital signs and medical emergency response (MER) activation predict in-hospital mortality in general surgery patients: a study of 15 969 admissions.

BACKGROUND: The applicability of the vital signs prompting medical emergency response (MER) activation has not previously been examined specifically in a large general surgical cohort. This study aimed to characterize the distribution, and predictive performance, of four vital signs selected based on Australian guidelines (oxygen saturation, respiratory rate, systolic blood pressure and heart rate); with those of the MER activation criteria. METHODS: A retrospective cohort study was conducted including patients admitted under general surgical services of two hospitals in South Australia over 2 years. Likelihood ratios for patients meeting MER activation criteria, or a vital sign in the most extreme 1% for general surgery inpatients (<0.5th percentile or > 99.5th percentile), were calculated to predict in-hospital mortality. RESULTS: 15 969 inpatient admissions were included comprising 2 254 617 total vital sign observations. The 0.5th and 99.5th centile for heart rate was 48 and 133, systolic blood pressure 85 and 184, respiratory rate 10 and 31, and oxygen saturations 89% and 100%, respectively. MER activation criteria with the highest positive likelihood ratio for in-hospital mortality were heart rate ≤ 39 (37.65, 95% CI 27.71-49.51), respiratory rate ≥ 31 (15.79, 95% CI 12.82-19.07), and respiratory rate ≤ 7 (10.53, 95% CI 6.79-14.84). These MER activation criteria likelihood ratios were similar to those derived when applying a threshold of the most extreme 1% of vital signs. CONCLUSIONS: This study demonstrated that vital signs within Australian guidelines, and escalation to MER activation, appropriately predict in-hospital mortality in a large cohort of patients admitted to general surgical services in South Australia.

Dual γ rhythm generators control interlaminar synchrony in auditory cortex.

Rhythmic activity in populations of cortical neurons accompanies, and may underlie, many aspects of primary sensory processing and short-term memory. Activity in the gamma band (30 Hz up to >100 Hz) is associated with such cognitive tasks and is thought to provide a substrate for temporal coupling of spatially separate regions of the brain. However, such coupling requires close matching of frequencies in co-active areas, and because the nominal gamma band is so spectrally broad, it may not constitute a single underlying process. Here we show that, for inhibition-based gamma rhythms in vitro in rat neocortical slices, mechanistically distinct local circuit generators exist in different laminae of rat primary auditory cortex. A persistent, 30-45 Hz, gap-junction-dependent gamma rhythm dominates rhythmic activity in supragranular layers 2/3, whereas a tonic depolarization-dependent, 50-80 Hz, pyramidal/interneuron gamma rhythm is expressed in granular layer 4 with strong glutamatergic excitation. As a consequence, altering the degree of excitation of the auditory cortex causes bifurcation in the gamma frequency spectrum and can effectively switch temporal control of layer 5 from supragranular to granular layers. Computational modeling predicts the pattern of interlaminar connections may help to stabilize this bifurcation. The data suggest that different strategies are used by primary auditory cortex to represent weak and strong inputs, with principal cell firing rate becoming increasingly important as excitation strength increases.

Aspiration thrombectomy using a novel 088 catheter and specialized delivery catheter.

BACKGROUND: We describe the first-in-human experience using the Route 92 Medical Aspiration System to perform thrombectomy in the initial 45 consecutive stroke patients enrolled in the SUMMIT NZ trial. This aspiration system includes a specifically designed delivery catheter which enables delivery of 0.070 inch and 0.088 inch aspiration catheters. METHODS: The SUMMIT NZ trial is a prospective, multicenter, single-arm study with core lab imaging adjudication. Patients presenting with acute ischemic stroke from large vessel occlusion are eligible to enrol. The study has had three phases which transitioned from use of the 0.070 inch to the 0.088 inch catheter. RESULTS: Vessel occlusions were located in the internal carotid artery (27%), M1 (60%) and M2 (13%). Median baseline National Institutes of Health Stroke Scale (NIHSS) was 16 (IQR 10). Across the three phases, the first-pass reperfusion rate of modified Thrombolysis In Cerebral Infarction (mTICI) ≥2b was 62% using the Route 92 Medical system; this rate was 29% in phase 1, 56% in phase 2, and 80% in phase 3. The first-pass reperfusion rate of mTICI ≥2c was 42% overall, 29% in phase 1, 33% in phase 2, and 55% in phase 3. A final reperfusion rate of mTICI ≥2b was achieved in 96% of cases, with 36% of cases using adjunctive devices. Patients had an average improvement of 6.7 points in NIHSS from baseline at 24 hours, and at 90 days 48% were functionally independent (modified Rankin Scale 0-2). CONCLUSIONS: In this early experience, the Route 92 Medical Aspiration System has been effective and safe. The system has design features that improve catheter deliverability and have the potential to increase first-pass reperfusion rates in aspiration thrombectomy.

A Phase I First-in-Human Study of ABBV-383, a B-Cell Maturation Antigen × CD3 Bispecific T-Cell Redirecting Antibody, in Patients With Relapsed/Refractory Multiple Myeloma.

PURPOSE: ABBV-383, a B-cell maturation antigen × CD3 T-cell engaging bispecific antibody, has demonstrated promising results in an ongoing first-in-human phase I study (ClinicalTrials.gov identifier: NCT03933735) in patients with relapsed/refractory multiple myeloma (RRMM). Herein, we report safety and efficacy outcomes of this phase I dose escalation/expansion study. METHODS: Patients with RRMM (≥ three prior lines including a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 monoclonal antibody) were eligible. ABBV-383 was administered intravenously over 1-2 hours once every 3 weeks, without any step dosing. A 3 + 3 design with backfilling for dose escalation was used (intrapatient escalation to highest safe dose permitted) followed by initiation of dose expansion. RESULTS: As of January 8, 2022, 124 patients (dose escalation [0.025-120 mg], n = 73; dose expansion [60 mg], n = 51) have received ABBV-383; median age was 68 years (range, 35-92 years). The most common hematologic treatment-emergent adverse events (TEAEs) were neutropenia (all grades: 37%) and anemia (29%). The most common nonhematologic TEAEs were cytokine release syndrome (57%) and fatigue (30%). Seven deaths from TEAEs were reported with all considered unrelated to study drug by the investigator. For all efficacy-evaluable patients (n = 122; all doses), the objective response rate (ORR) was 57% and very good partial response (VGPR) or better (≥ VGPR) rate was 43%. In the 60 mg dose expansion cohort (n = 49), the ORR and ≥ VGPR rates were 59% and 39%, respectively; and in the ≥ 40 mg dose escalation plus dose expansion cohorts (n = 79) were 68% and 54%, respectively. CONCLUSION: ABBV-383 in patients with RRMM was well tolerated with an ORR of 68% at doses ≥ 40 mg. This novel therapy's promising preliminary antitumor activity in heavily pretreated patients warrants further clinical evaluation.

Cortical gamma rhythms modulate NMDAR-mediated spike timing dependent plasticity in a biophysical model.

Spike timing dependent plasticity (STDP) has been observed experimentally in vitro and is a widely studied neural algorithm for synaptic modification. While the functional role of STDP has been investigated extensively, the effect of rhythms on the precise timing of STDP has not been characterized as well. We use a simplified biophysical model of a cortical network that generates pyramidal interneuronal gamma rhythms (PING). Plasticity via STDP is investigated at the excitatory pyramidal cell synapse from a gamma frequency (30-90 Hz) input independent of the network gamma rhythm. The input may represent a corticocortical or an information-specific thalamocortical connection. This synapse is mediated by N-methyl-D-aspartate receptor mediated (NMDAR) currents. For distinct network and input frequencies, the model shows robust frequency regimes of potentiation and depression, providing a mechanism by which responses to certain inputs can potentiate while responses to other inputs depress. For potentiating regimes, the model suggests an optimal amount and duration of plasticity that can occur, which depends on the time course for the decay of the postsynaptic NMDAR current. Prolonging the duration of the input beyond this optimal time results in depression. Inserting pauses in the input can increase the total potentiation. The optimal pause length corresponds to the decay time of the NMDAR current. Thus, STDP in this model provides a mechanism for potentiation and depression depending on input frequency and suggests that the slow NMDAR current decay helps to regulate the optimal amplitude and duration of the plasticity. The optimal pause length is comparable to the time scale of the negative phase of a modulatory theta rhythm, which may pause gamma rhythm spiking. Our pause results may suggest a novel role for this theta rhythm in plasticity. Finally, we discuss our results in the context of auditory thalamocortical plasticity.