Replay, the default mode network and the cascaded memory systems model.

The spontaneous replay of patterns of activity related to past experiences and memories is a striking feature of brain activity, as is the coherent activation of sets of brain areas - particularly those comprising the default mode network (DMN) - during rest. We propose that these two phenomena are strongly intertwined and that their potential functions overlap. In the 'cascaded memory systems model' that we outline here, we hypothesize that the DMN forms the backbone for the propagation of replay, mediating interactions between the hippocampus and the neocortex that enable the consolidation of new memories. The DMN may also independently ignite replay cascades, which support reactivation of older memories or high-level semantic representations. We suggest that transient cortical activations, inducing long-range correlations across the neocortex, are a key mechanism supporting a hierarchy of representations that progresses from simple percepts to semantic representations of causes and, finally, to whole episodes.

Hippocampal ripples coincide with "up-state" and spindles in retrosplenial cortex.

During NREM sleep, hippocampal sharp-wave ripple (SWR) events are thought to stabilize memory traces for long-term storage in downstream neocortical structures. Within the neocortex, a set of distributed networks organized around retrosplenial cortex (RS-network) interact preferentially with the hippocampus purportedly to consolidate those traces. Transient bouts of slow oscillations and sleep spindles in this RS-network are often observed around SWRs, suggesting that these two activities are related and that their interplay possibly contributes to memory consolidation. To investigate how SWRs interact with the RS-network and spindles, we combined cortical wide-field voltage imaging, Electrocorticography, and hippocampal LFP recordings in anesthetized and sleeping mice. Here, we show that, during SWR, "up-states" and spindles reliably co-occur in a cortical subnetwork centered around the retrosplenial cortex. Furthermore, retrosplenial transient activations and spindles predict slow gamma oscillations in CA1 during SWRs. Together, our results suggest that retrosplenial-hippocampal interaction may be a critical pathway of information exchange between the cortex and hippocampus.

Hippocampal gamma and sharp wave/ripples mediate bidirectional interactions with cortical networks during sleep.

Hippocampus-neocortex interactions during sleep are critical for memory processes: Hippocampally initiated replay contributes to memory consolidation in the neocortex and hippocampal sharp wave/ripples modulate cortical activity. Yet, the spatial and temporal patterns of this interaction are unknown. With voltage imaging, electrocorticography, and laminarly resolved hippocampal potentials, we characterized cortico-hippocampal signaling during anesthesia and nonrapid eye movement sleep. We observed neocortical activation transients, with statistics suggesting a quasi-critical regime, may be helpful for communication across remote brain areas. From activity transients, we identified, in a data-driven fashion, three functional networks. A network overlapping with the default mode network and centered on retrosplenial cortex was the most associated with hippocampal activity. Hippocampal slow gamma rhythms were strongly associated to neocortical transients, even more than ripples. In fact, neocortical activity predicted hippocampal slow gamma and followed ripples, suggesting that consolidation processes rely on bidirectional signaling between hippocampus and neocortex.

Post-exercise cardiac autonomic and cardiovascular responses to heart rate-matched and work rate-matched hypoxic exercise.

PURPOSE: This study investigated the effect of performing hypoxic exercise at the same heart rate (HR) or work rate (WR) as normoxic exercise on post-exercise autonomic and cardiovascular responses. METHODS: Thirteen men performed three interval-type exercise sessions (5 × 5-min; 1-min recovery): normoxic exercise at 80% of the WR at the first ventilatory threshold (N), hypoxic exercise (FiO2 = 14.2%) at the same WR as N (H-WR) and hypoxic exercise at the same HR as N (H-HR). Autonomic and cardiovascular assessments were conducted before and after exercise, both at rest and during active squat-stand manoeuvres (SS). RESULTS: Compared to N, H-WR elicited a higher HR response (≈ 83% vs ≈ 75%HRmax, p < 0.001) and H-HR a reduced exercise WR (- 21.1 ± 9.3%, p < 0.001). Cardiac parasympathetic indices were reduced 15 min after exercise and recovered within 60 min in N and H-HR, but not after H-WR (p < 0.05). H-WR altered cardiac baroreflex sensitivity (cBRS) both at rest and during SS (specifically in the control of blood pressure fall during standing phases) in the first 60 min after the exercise bout (p < 0.05). Post-exercise hypotension (PEH) did not occur in H-HR (p > 0.05) but lasted longer in H-WR than in N (p < 0.05). CONCLUSIONS: Moderate HR-matched hypoxic exercise mimicked post-exercise autonomic responses of normoxic exercise without resulting in significant PEH. This may relate to the reduced WR and the limited associated mechanical/metabolic strain. Conversely, WR-matched hypoxic exercise impacted upon post-exercise autonomic and cardiovascular responses, delaying cardiac autonomic recovery, temporarily decreasing cBRS and evoking prolonged PEH.

Effects of three-exercise sessions in the heat on endurance cycling performance.

PURPOSE: To investigate the effects of a very short-term acclimation protocol (VSTAP) on performance, physiological and perceptual responses to exercise in the heat. METHODS: 12 trained male cyclists (age 31.2 ± 7; weight 71.3 ± 7 kg, VO2max: 58.4 ± 3.7 mL/kg/min) randomly performed two Time to Exhaustion Tests (TTE) at 75% of normothermic peak power output (PPO), one in normothermia (N,18°C-50% RH) and one in the heat (H,35°C-50% RH), before and after a VSTAP intervention, consisting of 3 days-90 min exercise (10min at 30% of PPO+80 min at 50% of PPO) in H (≈4.5h of heat exposure). Performance time of TTEs and physiological and perceptual variables of both TTEs and training sessions (T1, T2 and T3) were evaluated. RESULTS: Magnitude Based Inferences (MBI) revealed 92/6/1% and 62/27/11% chances of positive/trivial/negative effects of VSTAP of improving performance in H (+17%) and in N (+9%), respectively. Heart Rate (HR) decreased from T1 to T3 (p < 0.001) and T2 to T3 (p < 0.001), whereas Tympanic Temperature (TyT) decreased from T1 to T2 (p = 0.047) and from T1 to T3 (p = 0.007). Furthermore, despite the increased tolerance to target Power Output (PO) throughout training sessions, RPE decreased from T1 to T3 (p = 0.032). CONCLUSIONS: The VSTAP determined meaningful physiological (i.e. decreased HR and TyT) and perceptual (i.e. decreased RPE) adaptations to submaximal exercise. Furthermore, showing good chances to improve performance in the heat, it represents a valid acclimation strategy to be implemented when no longer acclimation period is possible. Finally, no cross-over effect of the VSTAP on performance in temperate conditions was detected.

Partial coherence and frustration in self-organizing spherical grids.

Nearby grid cells have been observed to express a remarkable degree of long-range order, which is often idealized as extending potentially to infinity. Yet their strict periodic firing and ensemble coherence are theoretically possible only in flat environments, much unlike the burrows which rodents usually live in. Are the symmetrical, coherent grid maps inferred in the lab relevant to chart their way in their natural habitat? We consider spheres as simple models of curved environments and waiting for the appropriate experiments to be performed, we use our adaptation model to predict what grid maps would emerge in a network with the same type of recurrent connections, which on the plane produce coherence among the units. We find that on the sphere such connections distort the maps that single grid units would express on their own, and aggregate them into clusters. When remapping to a different spherical environment, units in each cluster maintain only partial coherence, similar to what is observed in disordered materials, such as spin glasses.

Coherence between Rat Sensorimotor System and Hippocampus Is Enhanced during Tactile Discrimination.

Rhythms with time scales of multiple cycles per second permeate the mammalian brain, yet neuroscientists are not certain of their functional roles. One leading idea is that coherent oscillation between two brain regions facilitates the exchange of information between them. In rats, the hippocampus and the vibrissal sensorimotor system both are characterized by rhythmic oscillation in the theta range, 5-12 Hz. Previous work has been divided as to whether the two rhythms are independent or coherent. To resolve this question, we acquired three measures from rats--whisker motion, hippocampal local field potential (LFP), and barrel cortex unit firing--during a whisker-mediated texture discrimination task and during control conditions (not engaged in a whisker-mediated memory task). Compared to control conditions, the theta band of hippocampal LFP showed a marked increase in power as the rats approached and then palpated the texture. Phase synchronization between whisking and hippocampal LFP increased by almost 50% during approach and texture palpation. In addition, a greater proportion of barrel cortex neurons showed firing that was phase-locked to hippocampal theta while rats were engaged in the discrimination task. Consistent with a behavioral consequence of phase synchronization, the rats identified the texture more rapidly and with lower error likelihood on trials in which there was an increase in theta-whisking coherence at the moment of texture palpation. These results suggest that coherence between the whisking rhythm, barrel cortex firing, and hippocampal LFP is augmented selectively during epochs in which the rat collects sensory information and that such coherence enhances the efficiency of integration of stimulus information into memory and decision-making centers.

Cardiac Autonomic and Physiological Responses to Moderate- intensity Exercise in Hypoxia.

Exercise physiological responses can be markedly affected by acute hypoxia. We investigated cardiac autonomic and physiological responses to different hypoxic training protocols. Thirteen men performed three exercise sessions (5×5-min; 1-min passive recovery): normoxic exercise at 80% of the power output (PO) at the first ventilatory threshold (N), hypoxic exercise (FiO2=14.2%) with the same PO as N (HPO) and hypoxic exercise at the same heart rate (HR) as N (HHR). PO was lower in HHR (21.1±9.3%) compared to N and HPO. Mean HR was higher in HPO (154±11 bpm, p<0.01) than N and HHR (139±10 vs. 138±9 bpm; p=0.80). SpO2 was reduced (p<0.01) to a similar extent (p>0.05) in HPO and HHR compared to N. HR recovery (HRR) and HR variability indices were similar in N and HHR (p>0.05) but reduced in HPO (p<0.05), mirroring a delayed parasympathetic reactivation. Blood lactate and ventilation were similar in N and HHR (p>0.05) and increased in HPO (p<0.001). During recovery oxygen consumption and ventilation were similar in N and HHR (p>0.05) and increased in HPO (p<0.01). Moderate HR-matched hypoxic exercise triggers similar cardiac autonomic and physiological responses to normoxic exercise with a reduced mechanical load. On the contrary, the same absolute intensity exercise in hypoxia is associated with increased exercise-induced metabolic stress and delayed cardiac autonomic recovery.

Delayed parasympathetic reactivation and sympathetic withdrawal following maximal cardiopulmonary exercise testing (CPET) in hypoxia.

PURPOSE: This study investigated the effects of acute hypoxic exposure on post-exercise cardiac autonomic modulation following maximal cardiopulmonary exercise testing (CPET). METHODS: Thirteen healthy men performed CPET and recovery in normoxia (N) and normobaric hypoxia (H) (FiO2 = 13.4%, ≈ 3500 m). Post-exercise cardiac autonomic modulation was assessed during recovery (300 s) through the analysis of fast-phase and slow-phase heart rate recovery (HRR) and heart rate variability (HRV) indices. RESULTS: Both short-term, T30 (mean difference (MD) 60.0 s, 95% CI 18.2-101.8, p = 0.009, ES 1.01), and long-term, HRRt (MD 21.7 s, 95% CI 4.1-39.3, p = 0.020, ES 0.64), time constants of HRR were higher in H. Fast-phase (30 and 60 s) and slow-phase (300 s) HRR indices were reduced in H either when expressed in bpm or in percentage of HRpeak (p < 0.05). Chronotropic reserve recovery was lower in H than in N at 30 s (MD - 3.77%, 95% CI - 7.06 to - 0.49, p = 0.028, ES - 0.80) and at 60 s (MD - 7.23%, 95% CI - 11.45 to - 3.01, p = 0.003, ES - 0.81), but not at 300 s (p = 0.436). Concurrently, Ln-RMSSD was reduced in H at 60 and 90 s (p < 0.01) but not at other time points during recovery (p > 0.05). CONCLUSIONS: Affected fast-phase, slow-phase HRR and HRV indices suggested delayed parasympathetic reactivation and sympathetic withdrawal after maximal exercise in hypoxia. However, a similar cardiac autonomic recovery was re-established within 5 min after exercise cessation. These findings have several implications in cardiac autonomic recovery interpretation and in HR assessment in response to high-intensity hypoxic exercise.

Monocytes in leukapheresis products affect the outcome of CD19-targeted CAR T-cell therapy in patients with lymphoma.

ABSTRACT: CD19-directed chimeric antigen receptor (CAR) T cells can induce durable remissions in relapsed/refractory large B-cell lymphomas (R/R LBCLs), but 60% of patients do not respond or relapse. Biological mechanisms explaining lack of response are emerging, but they are largely unsuccessful in predicting disease response at the patient level. Additionally, to maximize the cost-effectiveness of CAR T-cell therapy, biomarkers able to predict response and survival before CAR T-cell manufacturing would be desirable. We performed transcriptomic and functional evaluations of leukapheresis products in 95 patients with R/R LBCL enrolled in a prospective observational study, to identify correlates of response and survival to tisagenlecleucel and axicabtagene ciloleucel. A signature composed of 4 myeloid genes expressed by T cells isolated from leukapheresis products is able to identify patients with a very short progression-free survival (PFS), highlighting the impact of monocytes in CAR T-cell therapy response. Accordingly, response and PFS were also negatively influenced by high circulating absolute monocyte counts at the time of leukapheresis. The combined evaluation of peripheral blood monocytes at the time of leukapheresis and the 4-gene signature represents a novel tool to identify patients with R/R LBCL at very high risk of progression after CAR T-cell therapy and could be used to plan trials evaluating CAR T cells vs other novel treatments or allogeneic CAR T cells. However, it also highlights the need to incorporate monocyte depletion strategies for better CAR T production.

A multi-center real-life prospective study of axicabtagene ciloleucel versus tisagenlecleucel toxicity and outcomes in Large B-Cell Lymphomas.

This real-world prospective observational study across 21 Italian centers (CART-SIE) compares axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) outcomes in 485 relapsed-refractory large B-cell lymphoma patients with baseline characteristics matched by Stabilized Inverse Propensity-Score Weighting. Axi-cel versus tisa-cel had higher all-grade cytokine release syndrome (78.6% vs 89.3%, p=0.0017) and neurotoxicity (9.9% vs 32.2%, p<0.0001), but also superior progression-free survival (PFS) at one year (46.5% vs 34.1%, p=0.0009). Even among patients who failed bridging therapy, axi-cel PFS was superior to tisa-cel (37.5% vs 22.7%, p=0.0059). Differences in overall survival (OS) and high-grade immune toxicities were not significant. The CAR-HEMATOTOX score not only predicted hematologic toxicity but also 1-year survival outcomes (51.5% in CAR-HEMATOTOX high vs. 77.2% in CAR-HEMATOTOX low, p<0.0001). Twenty patients developed second primary malignancies, including two cases of T-cell neoplasms. These findings enable more informed selection of anti-CD19 CAR T-cell therapy balancing bridging, safety and efficacy considerations for individual patients.

Grid maps for spaceflight, anyone? They are for free!

We show that, given extensive exploration of a three-dimensional volume, grid units can form with the approximate periodicity of a face-centered cubic crystal, as the spontaneous product of a self-organizing process at the single unit level, driven solely by firing rate adaptation.

Heterogeneity of network and coding states in mouse CA1 place cells.

Theta sequences and phase precession shape hippocampal activity and are considered key underpinnings of memory formation. Theta sequences are sweeps of spikes from multiple cells, tracing trajectories from past to future. Phase precession is the correlation between theta firing phase and animal position. Here, we reconsider these temporal processes in CA1 and the computational principles that they are thought to obey. We find stronger heterogeneity than previously described: we identify cells that do not phase precess but reliably express theta sequences. Other cells phase precess only when medium gamma (linked to entorhinal inputs) is strongest. The same cells express more sequences, but not precession, when slow gamma (linked to CA3 inputs) dominates. Moreover, sequences occur independently in distinct cell groups. Our results challenge the view that phase precession is the mechanism underlying the emergence of theta sequences, suggesting a role for CA1 cells in multiplexing diverse computational processes.

Theta oscillations as a substrate for medial prefrontal-hippocampal assembly interactions.

The execution of cognitive functions requires coordinated circuit activity across different brain areas that involves the associated firing of neuronal assemblies. Here, we tested the circuit mechanism behind assembly interactions between the hippocampus and the medial prefrontal cortex (mPFC) of adult rats by recording neuronal populations during a rule-switching task. We identified functionally coupled CA1-mPFC cells that synchronized their activity beyond that expected from common spatial coding or oscillatory firing. When such cell pairs fired together, the mPFC cell strongly phase locked to CA1 theta oscillations and maintained consistent theta firing phases, independent of the theta timing of their CA1 counterpart. These functionally connected CA1-mPFC cells formed interconnected assemblies. While firing together with their CA1 assembly partners, mPFC cells fired along specific theta sequences. Our results suggest that upregulated theta oscillatory firing of mPFC cells can signal transient interactions with specific CA1 assemblies, thus enabling distributed computations.

State-dependent coupling of hippocampal oscillations.

Oscillations occurring simultaneously in a given area represent a physiological unit of brain states. They allow for temporal segmentation of spikes and support distinct behaviors. To establish how multiple oscillatory components co-vary simultaneously and influence neuronal firing during sleep and wakefulness in mice, we describe a multivariate analytical framework for constructing the state space of hippocampal oscillations. Examining the co-occurrence patterns of oscillations on the state space, across species, uncovered the presence of network constraints and distinct set of cross-frequency interactions during wakefulness compared to sleep. We demonstrated how the state space can be used as a canvas to map the neural firing and found that distinct neurons during navigation were tuned to different sets of simultaneously occurring oscillations during sleep. This multivariate analytical framework provides a window to move beyond classical bivariate pipelines for investigating oscillations and neuronal firing, thereby allowing to factor-in the complexity of oscillation-population interactions.

Nonrestrictive diet does not increase infections during post-HSCT neutropenia: data from a multicenter randomized trial.

Infections are a major cause of morbidity and mortality during neutropenia after hematopoietic stem cell transplantation (HSCT). The use of a low-microbial protective diet (PD) in the peritransplantation period is a standard of care, although its efficacy has never been tested prospectively. We conducted a multicenter, randomized, noninferiority trial, enrolling all consecutive adult patients undergoing high-dose induction chemotherapy or HSCT with the objective to compare nonrestrictive diet (NRD) vs PD. Overall, 222 patients were enrolled, randomly assigned, and analyzed. One hundred seventy-five subjects (79%) received autologous HSCT (auto-HSCT), 41 (18%) received allogeneic HSCT (allo-HSCT), and 6 (3%) patients received high-dose induction chemotherapy. There was no significant difference in terms of incidence of grade ≥2 infections and death during neutropenia in the 2 arms. In multivariable analysis, only multiple myeloma diagnosis, fluoroquinolone prophylaxis, and the absence of mucositis were associated with a lower incidence of grade ≥2 infections. We did not report any significant variation in terms of hospitalization length, incidence of mucositis and gastrointestinal infections, body weight, and serum albumin variations in the 2 arms. In allo-HSCT recipients, the incidence of acute graft-versus-host disease grade ≥3 was similar. NRD was associated with higher patient-reported satisfaction. In conclusion, NRD is not inferior to a traditional PD during neutropenia after HSCT, and our results demonstrated that implementing a restrictive diet unnecessary burdens patients' quality of life. The clinical trial was registered prospectively in the clinical trial registry of the Istituto Nazionale dei Tumori of Milan as INT54/16.

Warm-Up Improves Balance Control Differently in the Dominant and Non-Dominant Leg in Young Sportsmen According to Their Experience in Asymmetric or Symmetric Sports.

The aim of this study was to investigate the acute effects of a warm-up on balance control and inter-limb balance asymmetries by analyzing the influence of the nature of the sport practiced by participants. Twelve sportspeople were recruited. They had to stand on a force plate for 30 s in a one-leg stance on their dominant (used to perform skilled movements) and non-dominant leg (used to support the body) before and 2, 5, 10, 15 and 20 min after a 10 min warm-up exercise performed at moderate intensity on a cycle ergometer. The center of foot pressure displacements was recorded. Statistical analysis was performed by considering one group of all participants and with two subgroups according to the symmetrical or asymmetrical nature of the sport they practiced. The warm-up exercise improved acute balance control only on the dominant leg after a 20 min rest without significantly reducing inter-limb balance asymmetries. This effect was more characteristic of participants with experience in asymmetric sports. These results confirm previous findings of the greater sensitivity of the dominant leg to the physiological state and reveal that between-leg differences in balance control appear mainly in subjects with experience in asymmetric sports in a specific physiological condition (post-warm-up state).

Biomechanical analysis of the "running" vs. "conventional" diagonal stride uphill techniques as performed by elite cross-country skiers.

PURPOSE: This study aimed to compare biomechanical aspects of a novel "running" diagonal stride (DSRUN) with "conventional" diagonal stride (DSCONV) skiing techniques performed at high speed. METHODS: Ten elite Italian male junior cross-country skiers skied on a treadmill at 10 km/h and at a 10° incline utilizing both variants of the diagonal stride technique. The 3-dimensional kinematics of the body, poles, and roller skis; the force exerted through the poles and foot plantar surfaces; and the angular motion of the leg joints were determined. RESULTS: Compared to DSCONV, DSRUN demonstrated shorter cycle times (1.05 ± 0.05 s vs. 0.75 ± 0.03 s (mean ± SD), p < 0.001) due to a shorter rolling phase (0.40 ± 0.04 s vs. 0.09 ± 0.04 s, p < 0.001); greater force applied perpendicularly to the roller skis when they had stopped rolling forward (413 ± 190 N vs. 890 ± 170 N, p < 0.001), with peak force being attained earlier; prolonged knee extension, with a greater range of motion during the roller ski-stop phase (28° ± 4° vs. 16° ± 3°, p = 0.00014); and more pronounced hip and knee flexion during most of the forward leg swing. The mechanical work performed against friction during rolling was significantly less with DSRUN than with DSCONV (0.04 ± 0.01 J/m/kg vs. 0.10 ± 0.02 J/m/kg, p < 0.001). CONCLUSION: Our findings demonstrate that DSRUN is characterize by more rapid propulsion, earlier leg extension, and a greater range of motion of knee joint extension than DSCONV. Further investigations, preferably on snow, should reveal whether DSRUN results in higher acceleration and/or higher peak speed.

Phenotypic Composition of Commercial Anti-CD19 CAR T Cells Affects In Vivo Expansion and Disease Response in Patients with Large B-cell Lymphoma.

PURPOSE: In clinical trials, the expansion and persistence of chimeric antigen receptor (CAR) T cells correlate with therapeutic efficacy. However, properties of CAR T cells that enable their in vivo proliferation have still to be consistently defined and the role of CAR T bag content has never been investigated in a real-life setting. EXPERIMENTAL DESIGN: Residual cells obtained after washing 61 anti-CD19 CAR T product bags were analyzed to identify tisagenlecleucel/Tisa-cel and axicabtagene ciloleucel/Axi-cel phenotypic features associated with postinfusion CAR T-cell in vivo expansion and with response and survival. RESULTS: While Tisa-cel was characterized by a significant enrichment in CAR+CD4+ T cells with central memory (P < 0.005) and effector (P < 0.005) phenotypes and lower rates of CAR+CD8+ with effector memory (P < 0.005) and naïve-like (P < 0.05) phenotypes as compared with Axi-cel, the two products displayed similar expansion kinetics. In vivo CAR T-cell expansion was influenced by the presence of CAR T with a CD8+ T central memory signature (P < 0.005) in both Tisa-cel and Axi-cel infusion products and was positively associated with response and progression-free survival (P < 0.05). CONCLUSIONS: Our data indicate that despite the great heterogeneity of Tisa-cel and Axi-cel products, the differentiation status of the infused cells mediates CAR T-cell in vivo proliferation that is necessary for antitumor response.

Associative memory storage and retrieval: involvement of theta oscillations in hippocampal information processing.

Theta oscillations are thought to play a critical role in neuronal information processing, especially in the hippocampal region, where their presence is particularly salient. A detailed description of theta dynamics in this region has revealed not only a consortium of layer-specific theta dipoles, but also within-layer differences in the expression of theta. This complex and articulated arrangement of current flows is reflected in the way neuronal firing is modulated in time. Several models have proposed that these different theta modulators flexibly coordinate hippocampal regions, to support associative memory formation and retrieval. Here, we summarily review different approaches related to this issue and we describe a mechanism, based on experimental and simulation results, for memory retrieval in CA3 involving theta modulation.