A two-stage group-sequential design for delayed treatment responses with the possibility of trial restart.

Common statistical theory applicable to confirmatory phase III trial designs usually assumes that patients are enrolled simultaneously and there is no time gap between enrollment and outcome observation. However, in practice, patients are enrolled successively and there is a lag between the enrollment of a patient and the measurement of the primary outcome. For single-stage designs, the difference between theory and practice only impacts on the trial duration but not on the statistical analysis and its interpretation. For designs with interim analyses, however, the number of patients already enrolled into the trial and the number of patients with available outcome measurements differ, which can cause issues regarding the statistical analyses of the data. The main issue is that current methodologies either imply that at the time of the interim analysis there are so-called pipeline patients whose data are not used to make a statistical decision (like stopping early for efficacy) or the enrollment into the trial needs to be at least paused for interim analysis to avoid pipeline patients. There are methods for delayed responses available that introduced error-spending stopping boundaries for the enrollment of patients followed by critical values to reject the null hypothesis in case the stopping boundaries have been crossed beforehand. Here, we will discuss other solutions, considering different boundary determination algorithms using conditional power and introducing a design allowing for recruitment restart while keeping the type I error rate controlled.

Delayed complete remission of hemifacial spasms following microvascular decompression and the implications for optimal time of revision surgery.

BACKGROUND: Microvascular decompression (MVD) is an effective method for directly treating hemifacial spasms (HFS). The timing for the consideration of failed MVD and reoperation has been paradoxical. OBJECTIVE: This study aimed to investigate the delayed complete remission of HFS in terms of prevalence rate, duration between surgery and delayed complete remission, and predictive factors. METHODS: A hundred patients with HFS who underwent MVD from 2012-2021 were enrolled in the study. All HFS occurred as a result of compression of the facial nerve by adjacent blood vessels. Clinical information, intraoperative findings, and surgical outcomes were incorporated for data analysis. RESULTS: In the first week after MVD, 67 of 100 patients achieved complete remission of HFS, while the remaining 33 had incomplete remission. In long-term follow-up, 26 individuals gradually developed delayed complete remission with a median duration of 9.1 months. Finally, 86 of 100 patients achieved complete long-term remission. Recurrent HFS and incomplete remission were found in 7 and 7 patients, respectively. Factors associated with postoperative complete remission in the first week were a severe degree of facial nerve compression (p = 0.047, OR 2.75, 95% CI 1.01-7.40), with long-term complete remission was left-sided HFS (p = 0.012, OR 5.73, 95% CI 1.47-22.36), and with the appearance of delayed complete remission was the prolonged duration of HFS at least 3 years before MVD (p = 0.046, OR 3.75, 95% CI 1.03-13.76). Transient facial paresis was found in 11% of the patients. Of them, facial nerve function recovered completely in all cases. CONCLUSIONS: A delayed complete remission of HFS could be expected in long-term follow-up after MVD and is probably related to a longer duration of HFS before surgery. Unnecessary reoperation should be avoided in the early years following the first surgery.

Clinical outcomes and predictors of delayed echocardiographic response to cardiac resynchronization therapy.

INTRODUCTION: The clinical outcomes and mechanisms of delayed responses to cardiac resynchronization therapy (CRT) remain unclear. We aimed to investigate the differences in outcomes and gain insight into the mechanisms of early and delayed responses to CRT. METHODS: This retrospective study included 110 patients who underwent CRT implantation. Positive response to CRT was defined as ≥15% reduction of left ventricular (LV) end-systolic volume on echocardiography at 1 year (early phase) and 3 years (delayed phase) after implantation. The latest mechanical activation site (LMAS) of the LV was identified using two-dimensional speckle-tracking radial strain analysis. RESULTS: Seventy-eight (71%) patients exhibited an early response 1 year after CRT implantation. Of 32 non-responders in the early phase, 12 (38%) demonstrated a delayed response, and 20 (62%) were classified as non-responders after 3 years. During the follow-up time of 10.3 ± 0.5 years, the delayed and early responders had a similar prognosis of mortality and heart failure (HF) hospitalization. In contrast, non-responders had a worse prognosis. Multivariate analysis revealed that a longer duration (months) between initial HF hospitalization and CRT (odds ratio [OR]: 1.126; 95% confidence interval [CI]: 1.036-1.222; p = .005), non-exact concordance of LV lead location with LMAS (OR: 32.744; 95% CI: 1.101-973.518; p = .044), and pre-QRS duration (OR: 0.901; 95% CI: 0.827-0.981; p = .016) were independent predictors of delayed response to CRT compared with early response. CONCLUSION: The prognoses were similar regardless of the response time after CRT. A longer history of HF, suboptimal LV lead position, and shorter pre-QRS duration were related to delayed response than early response.

Contribution of default mode network to game and delayed-response task performance: Power and connectivity analyses of theta oscillation in the monkey.

Neuroimaging studies have demonstrated the presence of a default mode network (DMN) which shows greater activity during rest, and an executive network (EN) which is activated during cognitive tasks. DMN and EN are thought to have competing functions. However, recent studies reported that the two networks show coactivation during some cognitive tasks. To clarify how DMN works and how DMN interacts with EN for cognitive control, we recorded EEG activities in the medial prefrontal (anterior DMN: aDMN), posterior cingulate/precuneus (posterior DMN: pDMN), and lateral prefrontal (EN) areas in the monkey. As cognitive tasks, we employed a monkey-monkey competitive video game (GAME) and a delayed-response (DR) task. We focused on theta oscillation because of its importance in cognitive control. We also examined theta band connectivity among the three network areas using the Granger causality analysis. DMN and EN were found to work cooperatively in both tasks. In all the three network areas, we found GAME-task-related, but no DR-task-related, increase in theta power from the resting level, maybe because of the higher cognitive demand associated with the GAME task performance. The information flow conveyed by the theta oscillation was directed more to aDMN than from aDMN for both tasks. The GAME-task-related increase in theta power in aDMN is supposed to be supported by more information flow conveyed by the theta oscillation from EN and pDMN.

Behavioral measurements of motor readiness in mice.

Motor planning facilitates rapid and precise execution of volitional movements. Although motor planning has been classically studied in humans and monkeys, the mouse has become an increasingly popular model system to study neural mechanisms of motor planning. It remains yet untested whether mice and primates share common behavioral features of motor planning. We combined videography and a delayed response task paradigm in an autonomous behavioral system to measure motor planning in non-body-restrained mice. Motor planning resulted in both reaction time (RT) savings and increased movement accuracy, replicating classic effects in primates. We found that motor planning was reflected in task-relevant body features. Both the specific actions prepared and the degree of motor readiness could be read out online during motor planning. The online readout further revealed behavioral evidence of simultaneous preparation for multiple actions under uncertain conditions. These results validate the mouse as a model to study motor planning, demonstrate body feature movements as a powerful real-time readout of motor readiness, and offer behavioral evidence that motor planning can be a parallel process that permits rapid selection of multiple prepared actions.

Time of onset and factors associated with delayed response post intradetrusor injection of onabotulinumtoxin a in patients with neurogenic and idiopathic overactive bladder syndrome.

Objective: The objective of this study was to determine risk factors for delayed response in patients with neurogenic and idiopathic overactive bladder (OAB) after intradetrusor onabotulinumtoxin A injection. Subjects and Methods: This is a retrospective study that included 87 patients who underwent onabotulinumtoxin A intradetrusor injection from October 2011 to November 2019. Patients were followed up at 2, 4, and 12 weeks post intervention in the outpatient clinic and over the phone. The data of patients with early response were compared with those with late response using univariate and multivariate analyses. Results: The study included 87 patients. The mean age was 41 ± 15.3 standard deviation, and 69% of the participants were female. Fifty-one percent were diagnosed with neurogenic OAB. A median response time to onabotulinumtoxin A injection of 7 days was demonstrated, and patients who responded during the first 7 days post procedure were considered early responders. Independent predictors for late response include diabetes (Relative risk: 3.89, P = 0.018, and 95% confidence interval [CI]: 1.26-11.98), >1 BTX-A session (Relative risk: 4, P = 0.011, and 95% CI: 1.38-11.6), and wet OAB (RR: 9.94, P = 0.002, and 95% CI: 2.31-42.17). Conclusions: The median time of onset post intradetrusor injection of onabotulinumtoxin A was found to be 7 days. Diabetes mellitus, wet OAB, and <1 Botox sessions were independent risk factors for late onset of response.

A Model for Reinfections and the Transition of Epidemics.

Reinfections of infected individuals during a viral epidemic contribute to the continuation of the infection for longer periods of time. In an epidemic, contagion starts with an infection wave, initially growing exponentially fast until it reaches a maximum number of infections, following which it wanes towards an equilibrium state of zero infections, assuming that no new variants have emerged. If reinfections are allowed, multiple such infection waves might occur, and the asymptotic equilibrium state is one in which infection rates are not negligible. This paper analyzes such situations by expanding the traditional SIR model to include two new dimensionless parameters, ε and θ, characterizing, respectively, the kinetics of reinfection and a delay time, after which reinfection commences. We find that depending on these parameter values, three different asymptotic regimes develop. For relatively small θ, two of the regimes are asymptotically stable steady states, approached either monotonically, at larger ε (corresponding to a stable node), or as waves of exponentially decaying amplitude and constant frequency, at smaller ε (corresponding to a spiral). For θ values larger than a critical, the asymptotic state is a periodic pattern of constant frequency. However, when ε is sufficiently small, the asymptotic state is a wave. We delineate these regimes and analyze the dependence of the corresponding population fractions (susceptible, infected and recovered) on the two parameters ε and θ and on the reproduction number R0. The results provide insights into the evolution of contagion when reinfection and the waning of immunity are taken into consideration. A related byproduct is the finding that the conventional SIR model is singular at large times, hence the specific quantitative estimate for herd immunity it predicts will likely not materialize.

Effects of DPTQ, a novel positive allosteric modulator of the dopamine D1 receptor, on spontaneous eye blink rate and spatial working memory in the nonhuman primate.

RATIONALE: Dopamine (DA) signaling through the D1 receptor has been shown to be integral to multiple aspects of cognition, including the core process of working memory. The discovery of positive allosteric modulators (PAMs) of the D1 receptor has enabled treatment modalities that may have alternative benefits to orthosteric D1 agonists arising from a synergism of action with functional D1 receptor signaling. OBJECTIVES: To investigate this potential, we have studied the effects of the novel D1 PAM DPTQ on a spatial delayed response working memory task in the rhesus monkey. Initial studies indicated that DPTQ binds to primate D1R with high affinity and selectivity and elevates spontaneous eye blink rate in rhesus monkeys in a dose-dependent manner consistent with plasma ligand exposures and central D1activation. RESULTS: Based on those results, DPTQ was tested at 2.5 mg/kg IM in the working memory task. No acute effect was observed 1 h after dosing, but performance was impaired 48 h later. Remarkably, this deficit was immediately followed by a significant enhancement in cognition over the next 3 days. In a second experiment in which DPTQ was administered on days 1 and 5, the early impairment was smaller and did not reach statistical significance, but statistically significant enhancement of performance was observed over the following week. Lower doses of 0.1 and 1.0 mg/kg were also capable of producing this protracted enhancement without inducing any transient impairment. CONCLUSIONS: DPTQ exemplifies a class of D1PAMs that may be capable of providing long-term improvements in working memory.

Partial SAA patients benefit from delayed response of IST.

Introduction: Severe aplastic anemia(SAA)is a severe disease characterized by immune-mediated bone marrow failure and pancytopenia. Immunosuppressive therapy (ATG plus CsA, IST) is the standard treatment for patients who are not suitable for allogeneic hematopoietic stem cell transplantation (allo-HSCT). Some patients have a delayed response after 6 months of ATG, and unnecessary to be given secondary ATG or allo-HSCT. We attempted to distinguish patients who may get potential delayed response from those who were really not responsive to IST. Methods: We collected data from 45 SAA patients who were assessed no-response to IST at 6 months after rATG and failed to receive secondary ATG or allo-HSCT. Results: CsA plus eltrombopag (EPAG) group has an extra 75% response rate while CsA maintenance group has an extra 44% response rate at 12 months. ATG was applied within 30 days after diagnosis, ATG dosage was suffificient (ATG/lymphocyte ≥2), and absolute reticulocyte count (ARC) was ≥30×109 /L at 6 months, indicated patients could get delayed response and benefifit from CsA maintenance. Addition of EPAG could give an even better response. Otherwise, secondary ATG or allo-HSCT treatment were recommended to be given immediately. Clinical Trial Registration: https://www.chictr.org.cn/searchproj.aspx, identifier ChiCTR2300067615.

[Numerical Response Analysis of PM2.5-O3 Compound Pollution in Beijing].

The multi-scale variation trend of PM2.5-O3 compound pollution events was analyzed based on air quality data, meteorological data, and COVID-19 data in Beijing from 2015 to 2020. For the threshold of compound pollution, a compound pollution index was proposed, and the numerical response trend was evaluated based on the generalized additive model. A distributed lag nonlinear model was introduced to analyze the risk response relationship between compound pollution and influencing factors. The results showed that the events of PM2.5-O3 compound pollution in Beijing decreased annually. At the same time, due to the influence of pollutant emissions and meteorological conditions, there were obvious seasonal effects, week effects, holiday effects, and epidemic effects. The composite pollution index had no correlation with rainfall but had a linear positive correlation with O3 and air temperature and a nonlinear correlation with other explanatory variables. Air pollutants and meteorological conditions had obvious lag effects on the composite pollution index, and the lag effects were mainly concentrated in 1-3 d. PM2.5, PM10, O3, SO2, and air temperature in high-value areas significantly increased the risk of compound pollution. The CO (1-6 mg·m-3), NO2 (38-118 µg·m-3), and relative humidity (54%-87%) in the median section would also increase the risk of compound pollution, as would low wind speed. The compound pollution events showed a trend of multi-day continuous pollution in the numerical response. Compared with PM2.5 and PM10, compound pollution events were more dependent on O3, and the compound pollution rate in high-value areas was 30.7%-47.5%. CO and relative humidity had little effect on compound pollution events. The air temperature had the greatest impact, and 84.7% of the composite pollution incidents occurred at 20-30℃.

Separating Inhibitory and Excitatory Responses of Epileptic Brain to Single-Pulse Electrical Stimulation.

To enable an accurate recognition of neuronal excitability in an epileptic brain for modeling or localization of epileptic zone, here the brain response to single-pulse electrical stimulation (SPES) has been decomposed into its constituent components using adaptive singular spectrum analysis (SSA). Given the response at neuronal level, these components are expected to be the inhibitory and excitatory components. The prime objective is to thoroughly investigate the nature of delayed responses (elicited between 100[Formula: see text]ms-1 s after SPES) for localization of the epileptic zone. SSA is a powerful subspace signal analysis method for separation of single channel signals into their constituent uncorrelated components. The consistency in the results for both early and delayed brain responses verifies the usability of the approach.

Delay-related activity in marmoset prefrontal cortex.

Persistent delay-period activity in prefrontal cortex (PFC) has long been regarded as a neural signature of working memory (WM). Electrophysiological investigations in macaque PFC have provided much insight into WM mechanisms; however, a barrier to understanding is the fact that a portion of PFC lies buried within the principal sulcus in this species and is inaccessible for laminar electrophysiology or optical imaging. The relatively lissencephalic cortex of the New World common marmoset (Callithrix jacchus) circumvents such limitations. It remains unknown, however, whether marmoset PFC neurons exhibit persistent activity. Here, we addressed this gap by conducting wireless electrophysiological recordings in PFC of marmosets performing a delayed-match-to-location task on a home cage-based touchscreen system. As in macaques, marmoset PFC neurons exhibited sample-, delay-, and response-related activity that was directionally tuned and linked to correct task performance. Models constructed from population activity consistently and accurately predicted stimulus location throughout the delay period, supporting a framework of delay activity in which mnemonic representations are relatively stable in time. Taken together, our findings support the existence of common neural mechanisms underlying WM performance in PFC of macaques and marmosets and thus validate the marmoset as a suitable model animal for investigating the microcircuitry underlying WM.

Bayesian adaptive model selection design for optimal biological dose finding in phase I/II clinical trials.

Identification of the optimal dose presents a major challenge in drug development with molecularly targeted agents, immunotherapy, as well as chimeric antigen receptor T-cell treatments. By casting dose finding as a Bayesian model selection problem, we propose an adaptive design by simultaneously incorporating the toxicity and efficacy outcomes to select the optimal biological dose (OBD) in phase I/II clinical trials. Without imposing any parametric assumption or shape constraint on the underlying dose-response curves, we specify curve-free models for both the toxicity and efficacy endpoints to determine the OBD. By integrating the observed data across all dose levels, the proposed design is coherent in dose assignment and thus greatly enhances efficiency and accuracy in pinning down the right dose. Not only does our design possess a completely new yet flexible dose-finding framework, but it also has satisfactory and robust performance as demonstrated by extensive simulation studies. In addition, we show that our design enjoys desirable coherence properties, while most of existing phase I/II designs do not. We further extend the design to accommodate late-onset outcomes which are common in immunotherapy. The proposed design is exemplified with a phase I/II clinical trial in chronic lymphocytic leukemia.

Paludismo importado no falciparum: aspectos de interés para el tratamiento de los pacientes / Imported non-falciparum malaria: aspects of interest for patient therapeutic management

Introducción: El paludismo es una enfermedad febril aguda potencialmente mortal causada por parásitos transmitidos por el mosquito Anopheles. El paludismo no falciparum (PNF), producido por otras especies de Plasmodium, está menos documentado en la literatura internacional, a pesar de su prevalencia. Objetivos: Describir aspectos clínicos y epidemiológicos de interés para el tratamiento en pacientes ingresados con diagnóstico de PNF importado, y determinar la relación existente entre la respuesta al tratamiento y otras variables. Métodos: Se realizó un estudio transversal analítico de 89 pacientes adultos con PNF importado, ingresados en el Departamento de Medicina del Instituto de Medicina Tropical Pedro Kourí, entre enero de 1997 a diciembre de 2017. Se determinó la pauta de profilaxis y tratamiento según los criterios de las guías publicadas y los fármacos disponibles en Cuba, y la definición de paludismo complicado según la OMS en 2003. Hubo respuesta demorada al tratamiento, cuando el paciente demoraba más de 7 días en negativizar la gota gruesa. Resultados: Predominaron los pacientes del sexo masculino, y una media de edad de 37,2 años. El 55,1 por ciento de los pacientes provenía de la región de las Américas y en el 85,4 por ciento se aisló Plasmodium vivax. La respuesta al tratamiento fue excelente con los esquemas combinados utilizados a base de cloroquina. Fue significativa la relación existente entre la demorada respuesta al tratamiento con la gravedad del cuadro clínico y el estado no inmune de los pacientes. Conclusiones: El PNF es una importante causa de paludismo importado en pacientes provenientes de áreas endémicas, fundamentalmente de América. Se distingue por parasitemias bajas, un cuadro clínico caracterizado por fiebre, escalofríos, cefaleas y evolución hacia cuadros no complicados. La cloroquina fue el medicamento de elección, aunque la repuesta demorada al tratamiento no justifica su suspensión o variación(AU)

Introduction: Malaria is a potentially fatal acute febrile illness caused by parasites transmitted by the Anopheles mosquito. Non-falciparum malaria (NFM), caused by other Plasmodium species, is less documented in the international literature, despite its prevalence. Objectives: To describe clinical and epidemiological aspects of interest for the treatment of patients hospitalized with a diagnosis of imported NFM, and to determine the relationship between response to treatment and other variables. Methods: It was conducted an analytical cross-sectional study of 89 adult patients with imported NFM, admitted to the Department of Medicine of the Institute of Tropical Medicine Pedro Kourí, between January 1997 to December 2017. The prophylaxis and treatment guideline was determined according to the published guidelines and drugs available in Cuba, and the definition of severe malaria by WHO in 2003. There was delayed response to treatment when the patient took more than 7 days to become negative for thick blood smear. Results: Patients were predominantly male, with a mean age of 37.2 years. Plasmodium vivax was isolated in 85.4 percent of the patients and 55.1 percent were from the Americas region. The response to treatment was excellent with the chloroquine-based combination regimens used. The relationship between the delayed response to treatment and the severity of the clinical picture and the non-immune status of the patients was significant. Conclusions: NFM is an important cause of imported malaria in patients from endemic areas, mainly from the Americas. It is characterized by low parasitemia, clinical manifestations of fever, chills, headache and evolution towards uncomplicated symptoms. Chloroquine was the drug of choice, although the delayed response to treatment does not justify its suspension or variation(AU)

Extending the two-stage single arm phase II clinical trial design to the delayed response scenario.

Two-stage single arm designs are widely used in phase II clinical trials with binary endpoints. The trial may be stopped early due to insufficient positive responses in the first stage. There may be some enrolled subjects who have yet to respond by the end of the first stage, and their data are ignored if the first stage results in rejection of the trial. It is possible that the result after the first stage is rejection by a slim margin, while the results of pipeline subjects are quite positive. In this case, combining the data from the two sources may provide a valuable opportunity to rescue a promising treatment that was mistakenly rejected. We propose a novel double-check design to take advantage of the pipeline subjects' data to establish a rescue criterion based on two-stage design. When the rescue criterion is met, the decision to reject the trial at the end of the first stage can be reversed, allowing the trial to continue. A derivation based on a binomial distribution shows that the double-check strategy can strictly preserve the type I error rate. Further examination shows that the strategy can provide a slight increase in overall power and a substantial increase in conditional power when the proportion of positive response at the end of the first stage is at the margin. The extra rescue opportunity's cost is pretty low, only a slight increasing in the expected sample size.

Robust group sequential designs for trials with survival endpoints and delayed response.

Randomized clinical trials in oncology typically utilize time-to-event endpoints such as progression-free survival or overall survival as their primary efficacy endpoints, and the most commonly used statistical test to analyze these endpoints is the log-rank test. The power of the log-rank test depends on the behavior of the hazard ratio of the treatment arm to the control arm. Under the assumption of proportional hazards, the log-rank test is asymptotically fully efficient. However, this proportionality assumption does not hold true if there is a delayed treatment effect. Cancer immunology has evolved over time and several cancer vaccines are available in the market for treating existing cancers. This includes sipuleucel-T for metastatic hormone-refractory prostate cancer, nivolumab for metastatic melanoma, and pembrolizumab for advanced nonsmall-cell lung cancer. As cancer vaccines require some time to elicit an immune response, a delayed treatment effect is observed, resulting in a violation of the proportional hazards assumption. Thus, the traditional log-rank test may not be optimal for testing immuno-oncology drugs in randomized clinical trials. Moreover, the new immuno-oncology compounds have been shown to be very effective in prolonging overall survival. Therefore, it is desirable to implement a group sequential design with the possibility of early stopping for overwhelming efficacy. In this paper, we investigate the max-combo test, which utilizes the maximum of two weighted log-rank statistics, as a robust alternative to the log-rank test. The new test is implemented for two-stage designs with possible early stopping at the interim analysis time point. Two classes of weights are investigated for the max-combo test: the Fleming and Harrington (1981) Gρ,γ$G^{\rho , \gamma }$ weights and the Magirr and Burman (2019) modest (τ∗)$ (\tau ^{*})$  weights.

Intermittent theta burst stimulation can improve the spatially-delayed responses of working memory / 中华物理医学与康复杂志

Objective:To observe any effect of intermittent theta burst stimulation (iTBS) on the spatially-delayed responses of working memory using cynomolgus macaques.Methods:The working memory of six male cynomolgus macaques (8-9 years old) was trained using a spatially-delayed response task. They were then randomly divided into an iTBS group and a control group, each of 3. The iTBS group was given iTBS at an intensity of 35% of the maximum output, with 2 seconds of stimulation followed by 8 seconds of rest with trains of 50Hz bursts repeated at a frequency of 5Hz over a period of 192 seconds once daily for 5 days, while the control group was given sham iTBS. Before and after the 5 days, the body weight and working memory of each animal were evaluated. The total number of effective feeding episodes, and of effective feeding episodes with short and long delay periods were recorded.Results:There was no significant change in the average body weight of either group before and after the modeling and iTBS intervention. After the intervention the number of total effective feeding cases and those with a short delay period were both significantly higher in the iTBS group than in the control group. However, no significant inter-group differences in the effective feeding cases with a long delay period were observed.Conclusions:iTBS is effective in improving the spatially-delayed responses of working memory, at least in cynomolgus macaques.

Identification of a Brain Network Underlying the Execution of Freely Chosen Movements.

Action selection refers to the decision regarding which action to perform in order to reach a desired goal, that is, the "what" component of intention. Whether the action is freely chosen or externally instructed involves different brain networks during the selection phase, but it is assumed that the way an action is selected should not influence the subsequent execution phase of the same movement. Here, we aim to test this hypothesis by investigating whether the modality of movement selection influences the brain networks involved during the execution phase of the movement. Twenty healthy volunteers performed a delayed response task in an event-related functional magnetic resonance imaging design to compare freely chosen and instructed unimanual or bimanual movements during the execution phase. Using activation analyses, we found that the pre-supplementary motor area (preSMA) and the parietal and cerebellar areas were more activated during the execution phase of freely chosen as compared to instructed movements. Connectivity analysis showed an increase of information flow between the right posterior parietal cortex and the cerebellum for freely chosen compared to instructed movements. We suggest that the parieto-cerebellar network is particularly engaged during freely chosen movement to monitor the congruence between the intentional content of our actions and their outcome.

Rapid suppression and sustained activation of distinct cortical regions for a delayed sensory-triggered motor response.

The neuronal mechanisms generating a delayed motor response initiated by a sensory cue remain elusive. Here, we tracked the precise sequence of cortical activity in mice transforming a brief whisker stimulus into delayed licking using wide-field calcium imaging, multiregion high-density electrophysiology, and time-resolved optogenetic manipulation. Rapid activity evoked by whisker deflection acquired two prominent features for task performance: (1) an enhanced excitation of secondary whisker motor cortex, suggesting its important role connecting whisker sensory processing to lick motor planning; and (2) a transient reduction of activity in orofacial sensorimotor cortex, which contributed to suppressing premature licking. Subsequent widespread cortical activity during the delay period largely correlated with anticipatory movements, but when these were accounted for, a focal sustained activity remained in frontal cortex, which was causally essential for licking in the response period. Our results demonstrate key cortical nodes for motor plan generation and timely execution in delayed goal-directed licking.