Circadian Rhythm

oncology, circadian rhythm, cancer

Circadian rhythm is being studied in conjunction with oncology studies due to its links to cancer development and cancer treatment effectiveness and side effects. 

Circadian Rhythm and Cancer Link

Circadian rhythm is an endogenous clock that is present in nearly all organisms and is governed by the 24- hour light/dark cycle. This rhythm regulates biological functions from sleep patterns to cellular activities such as metabolism and cell division. The central clock is located within the brain’s suprachiasmatic nucleus (SCN) and environmental cues stimulate the SCN to communicate information to peripheral clocks, located in organs and cells. Research has shown links between sleep disturbances, such as shift work and jet lag, and the development of certain types of cancers.

 

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Table 1CR Cancer treatments

Cleveland Clinic Journal of Medicine. (2017, September 25). Sleep disturbances in cancer patients: Underrecognized and undertreated. Retrieved October 05, 2018, from https://www.mdedge.com/ccjm/article/95907/sleep-medicine/sleep- disturbances-cancer-patients-underrecognized-and/page/0/1




Sleep Disturbances and Cancer Treatment
Sleep disturbances are a common side effect reported by those who receive cancer therapies during and after treatment (see table 1). Patients with newly diagnosed cancer, or patients recently treated, report sleep disturbances at twice the rate of the general population.Insomnia and other sleep disturbances can lead to an increased risk of many serious medical conditions, including stroke, seizures, diabetes, heart disease, depression, and anxiety. In addition, patients not receiving adequate sleep while taking anticancer drugs see a decrease in immune response and treatment effectiveness, as well as an increased risk for infection. 

Researchers are finding that targeting particular circadian timings to coincide with cancer treatments is a powerful tool in fighting cancer. This is due to circadian rhythm not only applying to the 24 hour sleep/wake period, but it also existing at the cellular level where many cancer-related processes take place, like apoptosis and cell proliferation. The relationship between the circadian rhythm of the metabolism and timing of dosing is also being assessed during preclinical studies due to the consequences metabolism has on the pharmacokinetics and pharmacodynamics of anticancer drugs. 

Measuring Circadian Rhythm in Animal Models
Researchers are using animal models from mouse to non-human primate to evaluate sleep disturbances throughout cancer progression and treatment. Sleep can be measured by physical activity correlated to resting periods. Identifying sleep duration is often used when studying circadian rhythm. Another way to measure sleep is by EEG that measures the electrical signals in the brain. In this way, the different stages during sleep can be identified. Sleep is determined by physiological changes in EEG together with the EMG (electromyogram – muscle movement) and EOG (electrooculogram - eye movement). Other variables including temperature, blood pressure and neuroendocrine function can be added to gain additional information about the circadian process.  

The EEG recordings are classified into five frequency bands:

  • Delta (0.5 to 4 Hz)
  • Theta (4 to 8 Hz)
  • Alpha (8 to 11.5 Hz)
  • Beta1 (11.5 to 15 Hz) and Beta2 (15 to 35 Hz)
  • Gamma (30-100+ Hz)




DSI Circadian Rhythm Technology

DSI telemetry is completely implantable and designed for acquiring physiologic data from conscious, freely moving laboratory animals, reducing animal stress and ensuring the most reliable data. Our circadian rhythm technology offers researchers the ability to monitor real-time EEG, EMG and EOG to study sleep in preclinical models, including mice, rats, rabbits, dogs, pigs, non-human primates, and other species.  



Circadian Rhythm Telemetry Implants for Mouse (Miniature) and Small Animal Models
       
PhystioTel implants are designed for use in mice (including transgenic), hamsters, rats, guinea pigs, rabbits, and species of similar size.


HD X02

HDS02



Circadian Rhythm Telemetry Implants for Large Animal Models
Designed for use in canines, non-human primates, swine, sheep, and species of similar size. Our large animal PhysioTel digital implants give researchers the power of acquiring and analyzing physiologic data from animals in a group housed setting. 


L03

L04



Hardwired Monitoring Systems for Small Animals

DSI’s hardwired solutions provide a minimally invasive method to offer continuous measurement (EEG, EMG, EOG, etc.) during central nervous system studies with small animals.  Hardwired solutions allow the use of a tether to monitor up to 12 EEG/EMG channels.    

A setup would include use of electrodes, wires, and commutators. EEG and/or EMG signals from this tethered approach are brought into DSI’s Ponemah software platform by the use of digital signal conditioners/amplifiers.

Learn more about Signal Conditioners and accessory PODS from DSI.



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The Power of Ponemah Software
Data collection and analysis for preclinical studies

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Easy Experiment Management
  • Save time with intuitive user interface and automated subject setup 
  • Simplify data management with automated file handling
  • Review previous days’ results during acquisition to observe mid-experiment data
  • Visualize sampling configuration and protocols with tabbed sampling layout
  • Use scheduled sampling function to collect periodic data from more subjects at user-defined intervals

Robust Connectivity with 3rd Party Solutions
  • Acquire high quality video recordings in Ponemah's integrated solution with Noldus Media Recorder and synchronize with physiologic signals for better interpretation of your data
  • Import and analyze CNS data - EEG and EMG data with video recordings - in NeuroScore Data Analysis Software 
  • Allow 3rd party applications to view Ponemah derived parameter data with Remote Connection
Flexible Data Analysis
  • Analyze data using time-based averages or on a beat-by-beat basis
  • Immediate results with real-time parameter calculations and trend graph generation
  • Complete control of data analysis with adjustable settings to analyze signals from various species and unique morphologies
  • Automatic export of calculated data to MS Excel® to view and analyze results across multiple days of acquisition

Smart, Powerful Tools
  • Refine data analysis post-acquisition to change how parameters are measured or eliminate signal noise from results
  • Use multiple graph and reporting presentations to view, sort and sync calculated parameters
  • Select data sections to view and report using Data Reduction and Data Parser rules.
  • Receive automated email or text alerts for subject- and system-level conditions

ScheduledSampling

Flexible Licensing Options
  • 3, 6, and 12 month subscription or full purchase options
  • Available for acquisition and post-analysis systems, plus analysis modules
  • Ideal for trials and short-term studies


CNS Data Analysis Software
The Power to Process More Data in Less Time

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NeuroScore™ is DSI’s Central Nervous System (CNS) analysis software used to analyze neurophysiology data collected in Dataquest A.R.T.Ponemah, EDF/EDF+ and other file formats. NeuroScore increases CNS analysis throughput by delivering summarized results with unsurpassed speed. Designed to efficiently analyze large, continuous data sets common to sleep and seizure studies, this modular platform provides the power and consistency required for CNS research applications. NeuroScore is a versatile, streamlined solution that combines easy-to-use tools, efficient data processing, and accurate data analysis to reduce time to results.

NeuroScore’s modular design allows it to be tailored to a specific research application. The core software is the foundation of the analysis platform and contains the majority of the program features and functions. Choose from the optional modules to enhance the core software (see below). 

Request your free 30 day trial of NeuroScore software today!


Batch Processing Module

This module increases data throughput by automating analysis processes on multiple recording at once. Build and execute custom workflows for ultimate versatility to:

  • Automatically Score multiple recordings
  • Export signal or parameter data
  • Generate and export reports
  • Perform all three within a single workflow
Once complete, the recording can be opened to view and augment automated scorings performed during the Batch workflow.
Seizure Detection
The spike train detector is designed primarily for seizure detection from EEG waveforms. The detector scans the waveform for repeating spike activity using amplitude-based criteria. Events are visually displayed within the waveform allowing for manual editing and confirmation. Several parameters including the spike train duration and number of spikes can be displayed per event or summarized over longer time intervals.
Automated Rodent Sleep Scoring

This module automatically assigns a vigilance stage to each epoch based on EEG, EMG, and activity data. Stages scored include Paradoxical Sleep, Slow Wave Sleep (with option to distinguish between SWS-1 and SWS-2), Wake, and Active Wake. The frequency content of the EEG and presence of muscle activity and movement are used as the basis of the scoring criteria. Automated scoring takes a few minutes or less for each 24 hour data set, and can dramatically reduce analysis time and variability in comparison to manual scoring. 



Automated Large Animal Sleep Scoring

This module automatically assigns a vigilance stage to each epoch within a large animal dataset. The algorithm is based upon the American Academy of Sleep Medicine standards for human sleep scoring and relies on EEG, EMG, EOG, and activity data from each subject. Stages assigned include REM, Non-REM (N1, N2, N3), Wake, and Active Wake. Automated scoring takes a few minutes or less for each 24 hour data set, and can dramatically reduce analysis time and variability in comparison to manual scoring. 


Video Synchronization

This module imports video data acquired with either Dataquest A.R.T. or Ponemah and synchronizes it with the physiologic waveforms, allowing playback in real-time or fast speed. View the subjects’ behavior to validate or further classify detected events or scored vigilance stages. Incorporating video data can improve the confidence level of your results. 




Ponemah Full System Package


System Set Up

Receivers and Transceivers
Telemetry implants broadcast telemetry data via radio frequency signals to the receiver or transceiver located under or near the cage. Multiple options exist and selection depends on study design. 

Communication Manager
The MX2 for small animals or the CLC for large animals manage communication between your chosen implant and Ponemah software. Fully calibrated telemetry data acquisition, optimized to maintain data integrity throughout the system. 

Ambient Pressure Reference
(only used when collecting a pressure signal)

The APT-2 is a special type of barometer that measure atmospheric pressure during dynamic corrections via a digital signal to the computer. It is required when measuring pressure via pressure transmitters in order to compensate for the absolute (relative to a vacuum) measurements taken by the transmitters. 

Network Hardware
DSI recommends using a dedicated network to permit the hardware to communicate to the computer. A router is used to assign IP addresses and a switch with PoE (Power over Ethernet) is used to power the hardware and allow multiple connections to the network. 



Circadian Rhythm and Sleep References Citing DSI Technology

Authier, S., et al. "Video-electroencephalography in conscious non human primate using radiotelemetry and computerized analysis: refinement of a safety pharmacology model." 
Journal of Pharmacological and Toxicological Methods, 60.1 (2009): 88-93.

Brager, Allison J., et al. “Sleep Loss and the Inflammatory Response in Mice Under Chronic Environmental Circadian Disruption.” PLoS ONE, vol. 8, no. 5, 2013, doi:10.1371/journal.pone.0063752.

Crofts, H. S., et al. "Investigation of the sleep electrocorticogram of the common marmoset (Callithrix jacchus) using radiotelemetry." Clinical Neurophysiology, 112.12 (2001): 2265-2273.

Bastlund, Jesper F., et al. "Spontaneous epileptic rats show changes in sleep architecture and hypothalamic pathology." Epilepsia 46.6 (2005): 934-938.

Borniger, J. C., Ii, W. H., S., Emmer, K. M., Zhang, N., Zalenski, A. A., . . . Devries, A. C. (2018). A Role for Hypocretin/Orexin in Metabolic and Sleep Abnormalities in a Mouse Model of Non- metastatic Breast Cancer. Cell Metabolism, 28(1). doi:10.1016/j. cmet.2018.04.021

Borniger, J. C., Gaudier-Diaz, M. M., Zhang, N., Nelson, R. J., & Devries, A. C. (2015). Cytotoxic chemotherapy increases sleep and sleep fragmentation in non-tumor-bearing mice. Brain, Behavior, and Immunity, 47, 218-227. doi:10.1016/j.bbi.2014.11.00

Datta, Subimal, and Robert Ross MacLean. "Neurobiological mechanisms for the regulation of mammalian sleep–wake behavior: reinterpretation of historical evidence and inclusion of contemporary cellular and molecular evidence." Neuroscience & Biobehavioral Reviews,31.5 (2007): 775-824.

Hadjimarkou MM, Benham R, Schwarz JM, Holder MK, Mong JA.  Estradiol suppresses rapid eye movement sleep and activation of sleep-active neurons in the ventrolateral preoptic area.  European Journal of Neuroscience 2008; 27: 1780-1792.

Horner RL Brooks D Kozer LF Leung E Hamrahi H Render-Teixeira CL/ Makin H Kimoff RJ Phillipson EA Sleep architecture in a canine model of obstructive sleep apnea Journal of Sleep and Sleep Disorders Research 1998; 21: 791-934

Ivarsson M, Paterson LM, Hutson PH.  Antidepressants and REM sleep in Wistar-Kyoto and Sprague-Dawley rats.  European Journal of Pharmacology 2005; 522: 63-71.

Mavanji, Vijayakumar, et al. "Elevated sleep quality and orexin receptor mRNA in obesity-resistant rats." International Journal of Obesity 34.11 (2010): 1576-1588.

Morairty SR, Hedley L, Flores J,  Martin R, Kilduff TS.  Selective 5HT2A and 5HT6 Receptor Antagonists Promote Sleep in Rats. SLEEP 2008; 31: 34-44. 

Morrow JD and Opp MR. Sleep-wake behavior and responses of interleukin-6-deficient mice to sleep deprivation. Brain, Behavior and Immunity 2005; 19 1: 28-39.

Olviadoti MD, Opp MR.  Effects of I.C.V. administration of interleukin-1 on sleep and body temperature of interleukin-6-deficient mice.  Neuroscience 2008; 153: 338-348.

Tang X, Sanford LD.  Telemetric Recording of Sleep and Home Cage Activity in Mice.  SLEEP 2002; 25: 677-685.

Wisor JP, Schmidt MA, Clegern WC. Cerebral microglia mediate sleep/wake and neuroinflammatory effects of methamphetamine. Brain, Behavior, and Immunity, 25 (2011) 767–776.




References

Fiorentino, L., & Ancoli-Israel, S. (2007). Sleep Dysfunction in Patients with Cancer. Current Treatment Options in Neurology9(5), 337–346.