Closed-loop recruitment of striatal parvalbumin interneurons prevents the onset of compulsive behaviors

2022 ◽  
Author(s):  
Sirenia Lizbeth Mondragon-Gonzalez ◽  
Christiane Schreiweis ◽  
Eric BURGUIERE
Keyword(s):  
Closed Loop ◽  
Time Window ◽  
Critical Time ◽  
Repetitive Behaviors ◽  
Cellular Mechanisms ◽  
Potential Implication ◽  
Delta Band ◽  
Parvalbumin Interneurons ◽  
Compulsive Behaviors ◽  
Band Signal

A prominent electrophysiological feature of compulsive behaviours is striatal hyperactivity; but its underlying dysfunctional cellular mechanisms still need to be characterized. Within the striatum, parvalbumin-positive interneurons (PVI) exert a powerful feedforward inhibition essential for the regulation of striatal activity. To investigate the potential implication of striatal PVI in aberrant repetitive behaviors, we used the Sapap3 mutant mice which exhibit compulsive-like behaviours characterized by excessive self-grooming. When striatal PVI in the centromedial striatum of Sapap3 mice were we optogenetically activated, we first showed that the number of compulsive-like events were greatly reduced. To investigate further the critical time-window when striatal PVI needed to be recruited for the behavioural regulation of compulsive-like grooming, we then designed a novel closed-loop stimulation pipeline. We identified a transient 1-4 Hz oscillations in the orbitofrontal cortex that temporally predicted grooming onsets. Exploiting this delta band signal as a biomarker, we were able to provide on-demand stimulation of striatal PVI shortly before predicted grooming events. This targeted closed-loop optogenetics approach greatly reduced grooming events and demonstrated that the recruitment of striatal PVI regulated the initiations of compulsive-like behaviours.

Translational approach to study flexibility as an endophenotype of obsessive compulsive disorders

2014 ◽  
Vol 29 (S3) ◽  
pp. 546-546
Author(s):  
N. Benzina ◽  
S.L. Mondragon ◽  
N. Ouarti ◽  
L. Mallet ◽  
E. Burguiere
Keyword(s):  
Reversal Learning ◽  
Behavioral Flexibility ◽  
Repetitive Behaviors ◽  
Reward Contingency ◽  
Neural Basis ◽  
Obsessive Compulsive ◽  
Compulsive Behaviors ◽  
Translational Approach ◽  
Obsessive Compulsive Disorders ◽  
Compulsive Disorders

Behavioral flexibility is the ability of a subject to change its behavior according to contextual cues. In humans, Obsessive Compulsive Disorders (OCD) is characterized by repetitive behavior, performed through rigid rituals. This phenomenological observation has led to explore the idea that OCD patients may have diminished behavioral flexibility. To address this question we developed innovative translational approaches across multiple species, including human patients suffering from obsessive-compulsive disorders, and rodent genetic models of OCD to provide original data in the perspective of enlightening the neurocognitive bases of compulsive behaviors. Behavioral flexibility may be challenged in experimental tasks such as reversal learning paradigms. In these tasks, the subject has to respond to either of two different visual stimuli but only one stimulus is positively rewarded while the other is not. After this first association has been learned, reward contingency are inverted, so that the previously neutral stimulus is now rewarded, while the previously rewarded stimulus is not. Performance in reversal learning is indexed by the number of perseverative errors committed when participants maintain their response towards previously reinforced stimulus in spite of negative reward. Unsurprisingly, this behavioral task has been adapted to mice using various response modalities (T-maze, lever press, nose-poke). Using animal models of compulsive behaviors give much more possibilities to study the deficient functions and their underlying neural basis that could lead to pathological repetitive behaviors. Here we present new behavioral set-ups that we developed in parallel in human (i.e. healthy subjects and OCD patients) and mice (i.e. controls and SAPAP3-KO mice) to study the role of the behavioral flexibility as a possible endophenotype of OCD. We observed that the subjects suffering of compulsive behaviors showed perseverative maladaptive behaviors in these tasks. By comparing the results of a similar task-design in humans and mouse models we will discuss the pertinence of such translational approach to further study the neurocognitive basis of compulsive behaviors.

scholarly journals Time-Varying Associations Between an Exposure History and a Subsequent Health Outcome: A landmark Approach to Identify Critical Windows.

2021 ◽  
Author(s):  
Maude Wagner ◽  
Francine Grodstein ◽  
Karen Leffondre ◽  
Cécilia Samieri ◽  
Cécile Proust-Lima
Keyword(s):  
Risk Factors ◽  
Health Outcome ◽  
Measurement Errors ◽  
Mixed Model ◽  
Time Window ◽  
Time Windows ◽  
Critical Time ◽  
Cumulative Exposure ◽  
Exposure Measurement ◽  
Exposure History

Abstract Background: Long-term behavioral and health risk factors constitute a primary focus of research on the etiology of chronic diseases. Yet, identifying critical time-windows during which risk factors have the strongest impact on disease risk is challenging. To assess the trajectory of association of an exposure history with an outcome, the weighted cumulative exposure index (WCIE) has been proposed, with weights reflecting the relative importance of exposures at different times. However, WCIE is restricted to a complete observed error-free exposure whereas exposures are often measured with intermittent missingness and error. Moreover, it rarely explores exposure history that is very distant from the outcome as usually sought in life-course epidemiology.Methods: We extend the WCIE methodology to (i) exposures that are intermittently measured with error, and (ii) contexts where the exposure time-window precedes the outcome time-window using a landmark approach. First, the individual exposure history up to the landmark time is estimated using a mixed model that handles missing data and error in exposure measurement, and the predicted complete error-free exposure history is derived. Then the WCIE methodology is applied to assess the trajectory of association between the predicted exposure history and the health outcome collected after the landmark time. In our context, the health outcome is a longitudinal marker analyzed using a mixed model.Results: A simulation study first demonstrates the correct inference obtained with this approach. Then, applied to the Nurses’ Health Study (19,415 women) to investigate the association between body mass index history (collected from midlife) and subsequent cognitive decline (evaluated after age 70), the method identified two major critical windows of association: long before the first cognitive evaluation (roughly 24 to 12 years), higher levels of BMI were associated with poorer cognition. In contrast, adjusted for the whole history, higher levels of BMI became associated with better cognition in the last years prior to the first cognitive interview, thus reflecting reverse causation (changes in exposure due to underlying disease).Conclusions: This approach, easy to implement, provides a flexible tool for studying complex dynamic relationships and identifying critical time windows while accounting for exposure measurement errors.

scholarly journals Clinical Evaluation of Herbal Medicine (ICH-012) in Treating Acute Cerebral Haemorrhage: Safety and Efficacy from 6- to 72-Hour Time Window (CRRICHTrial-II)

2018 ◽  
Vol 2018 ◽  
pp. 1-7 ◽  
Author(s):  
Qixin Zhang ◽  
Liling Zeng ◽  
Xiuyan Chen ◽  
Yuexiang Zhou ◽  
Baoying Gong ◽  
...  
Keyword(s):  
Herbal Medicine ◽  
Ct Scan ◽  
Time Window ◽  
Rapid Change ◽  
Herbal Medicines ◽  
Critical Time ◽  
Cerebral Haemorrhage ◽  
High Morbidity ◽  
Safety And Efficacy ◽  
Link Type

Background. Hypertensive intracerebral haemorrhage (HICH), which is characterized by rapid change, high morbidity, and mortality, is extremely dangerous. Both medical and surgical treatments lack definitive evidence and remain controversial. A prospective RCT that we have conducted has shown that the usage of the herbal medicine ICH-012 within 6 h of the event may increase the risk of haematoma enlargement and gastrointestinal bleeding. However, the volume of haematoma remains stable after 6 h. Thus, we will increase the time window to the period from 6 to 72 h after onset to evaluate the safety and efficacy of ICH-012 treating ICH (ClinicalTrial.gov ID: NCT03354026). Methods/Design. The CRRICHTrial-II study, a prospective, double-blinded, controlled, multicentre RCT, includes three groups: A, B, and C. Group A patients were treated with 8 herbal medicines (with 2 herbal medicines of Hirudo and Tabanus as well as 6 other combined herbal medicines of Group B) and Group C were placebo. Patients should meet all the inclusion criteria: age between 18 and 80 and diagnosis of HICH by brain CT scan between 6 and 72 h from the onset. The CT scan will be taken at four critical time points: baseline, between 6 and 72h, 24h after onset, and between 10 and 14 days after onset. The drug intervention lasts 10 days, and there is a follow-up visit taken after 90 days. The haematoma enlargement after 24 h onset as demonstrated by CT is the primary outcome. Discussion. A large amount of data from high-quality RCTs is needed for the extensive clinical application of herbal medicine. The CRRICHTrial-II will evaluate the safety and effectiveness of ICH-012 in a safer time window between 6 and 72 h and investigate the possible mechanisms of action and direction of herbal medicine in the haematoma growth after HICH. Trial registration at ClinicalTrial.gov, ID: NCT03354026, is registered on 23rd Nov. 2017.

Right-time vs real-time pro-active construction safety and health system architecture

2016 ◽  
Vol 16 (3) ◽  
pp. 253-280 ◽  
Author(s):  
Jochen Teizer
Keyword(s):  
Supply Chain ◽  
Real Time ◽  
Occupational Safety ◽  
Time Window ◽  
Data Gathering ◽  
Critical Time ◽  
Construction Safety ◽  
Content Type ◽  
Safety And Health ◽  
High Concern

Purpose The purpose of this paper is to investigate the critical time window for pro-active construction accident prevention and response. Large to small organisations throughout the entire construction supply chain continue to be challenged to adequately prevent accidents. Construction worker injuries and fatalities represent significant waste of resources. Although the five C’s (culture, competency, communication, controls and contractors) have been focusing on compliance, good practices and best-in-class strategies, even industry leaders have only marginal improvements in recorded safety statistics for many years. Design/methodology/approach Right-time vs real-time construction safety and health identifies three major focus areas to aid in the development of a strategic, as opposed to tactical, response. Occupational safety and health by design, real-time safety and health monitoring and alerts and education, training and feedback leveraging state-of-the-art technology provide meaningful predictive, quantitative and qualitative measures to identify, correlate and eliminate hazards before workers get injured or incidents cause collateral damage. Findings The current state and development of existing innovative initiatives in the occupational construction safety and health domain are identified. A framework for right-time vs real-time construction safety and health presents the specific focus on automated safety and health data gathering, analysis and reporting to achieve better safety performance. The developed roadmap for right-time vs real-time safety and health is finally tested in selected application scenarios of high concern in the construction industry. Originality/value A strategic roadmap to eliminate hazards and accidents through right-time vs real-time automation is presented that has practical as well as social implications on conducting a rigorous safety culture and climate in a construction business and its entire supply chain.

scholarly journals Critical Time-Window for NO–cGMP-Dependent Long-Term Memory Formation after One-Trial Appetitive Conditioning

2002 ◽  
Vol 22 (4) ◽  
pp. 1414-1425 ◽  
Author(s):  
Ildikó Kemenes ◽  
György Kemenes ◽  
Richard J. Andrew ◽  
Paul R. Benjamin ◽  
Michael O'Shea
Keyword(s):  
Time Window ◽  
Critical Time ◽  
Memory Formation ◽  
Long Term Memory ◽  
Appetitive Conditioning ◽  
Term Memory

Blindness short after treatment of acute primary angle closure in China

2020 ◽  
pp. bjophthalmol-2020-316259
Author(s):  
Shuning Li ◽  
Guangxian Tang ◽  
Su Jie Fan ◽  
Gang Zhai ◽  
Jianhua Lv ◽  
...  
Keyword(s):  
Risk Factors ◽  
Time Window ◽  
Case Series ◽  
Critical Time ◽  
Education Level ◽  
Angle Closure ◽  
Retrospective Case ◽  
Acute Primary Angle Closure ◽  
Factors Associated ◽  
Primary Angle Closure

AimsTo study the risk factors associated with blindness after treatment of acute primary angle closure (APAC), and to identify the critical time window to decrease rate of blindness.MethodsIn this multicentre retrospective case series, 1030 consecutive subjects (1164 eyes) with APAC in China were recruited. The rates of blindness were analysed up to 3 months after treatment of APAC. A logistic regression was used to identify the risk factors associated with blindness, including age, gender, distance to hospital, rural or urban settings, treatment method, education level, time from symptom to treatment (TST, hours) and presenting intraocular pressure (IOP). The critical time window associated with a blindness rate of ≤1% was calculated based on a cubic function by fitting TST to the rate of blindness at each time point.ResultsThe rate of blindness after APAC was 12.54% after treatment. In multivariate regression, education level, TST and presenting IOP were risk factors for blindness (p=0.022, 0.004 and 0.001, respectively). The critical time window associated with a blindness rate of ≤1% was 4.6 hours.Conclusions and relevanceEducation level, TST and presenting IOP were risk factors for blindness after APAC. Timely medical treatment is key in reducing blindness after APAC.

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