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Cyclic and sleep-like spontaneous alternations of brain state under urethane anaesthesia.

Clement EA, Richard A, Thwaites M, Ailon J, Peters S, Dickson CT - PLoS ONE (2008)

Bottom Line: Individual states and their transitions resembled the REM/nREM cycle of natural sleep in their EEG components, evolution, and time frame ( approximately 11 minute period).Other physiological variables such as muscular tone, respiration rate, and cardiac frequency also covaried with forebrain state in a manner identical to sleep.Our results suggest that urethane promotes a condition of behavioural unconsciousness that closely mimics the full spectrum of natural sleep.

View Article: PubMed Central - PubMed

Affiliation: Centre for Neuroscience, University of Alberta, Edmonton, Alberta, Canada.

ABSTRACT

Background: Although the induction of behavioural unconsciousness during sleep and general anaesthesia has been shown to involve overlapping brain mechanisms, sleep involves cyclic fluctuations between different brain states known as active (paradoxical or rapid eye movement: REM) and quiet (slow-wave or non-REM: nREM) stages whereas commonly used general anaesthetics induce a unitary slow-wave brain state.

Methodology/principal findings: Long-duration, multi-site forebrain field recordings were performed in urethane-anaesthetized rats. A spontaneous and rhythmic alternation of brain state between activated and deactivated electroencephalographic (EEG) patterns was observed. Individual states and their transitions resembled the REM/nREM cycle of natural sleep in their EEG components, evolution, and time frame ( approximately 11 minute period). Other physiological variables such as muscular tone, respiration rate, and cardiac frequency also covaried with forebrain state in a manner identical to sleep. The brain mechanisms of state alternations under urethane also closely overlapped those of natural sleep in their sensitivity to cholinergic pharmacological agents and dependence upon activity in the basal forebrain nuclei that are the major source of forebrain acetylcholine. Lastly, stimulation of brainstem regions thought to pace state alternations in sleep transiently disrupted state alternations under urethane.

Conclusions/significance: Our results suggest that urethane promotes a condition of behavioural unconsciousness that closely mimics the full spectrum of natural sleep. The use of urethane anaesthesia as a model system will facilitate mechanistic studies into sleep-like brain states and their alternations. In addition, it could also be exploited as a tool for the discovery of new molecular targets that are designed to promote sleep without compromising state alternations.

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Related in: MedlinePlus

Urethane anaesthetized animals displayed spontaneous and cyclic alternations of brain state.A) Spectra and raw EEG traces of different spontaneous states under urethane. During the activated state, the nCTX showed low voltage fast activity and the HPC showed prominent theta at ∼4 Hz. During the transition state, there was an increase in overall power with a shift to lower frequencies at both sites; raw EEG traces showed irregular and moderately high amplitude activity. During the deactivated state, there was an even more prominent shift to low (∼1 Hz) frequencies with a further increase in overall power and raw EEG traces displaying prominent rhythmic high amplitude slow activity. B) Continuous EEG traces of a spontaneous transition from activated to deactivated patterns. Positions from where the expanded traces in A were taken are shown. The transition between activated and deactivated patterns was marked by a gradual increase in the amplitude of the signals whereas the transition between deactivated and activated patterns was more abrupt. C), Continuous EEG traces over an even longer time scale demonstrated a regular and cyclic alternation of state as observed by the fluctuations in amplitude. The position from where traces in B were taken are shown. D) A spectrographic representation of the neocortical trace shown in C. The most prominent fluctuation of power was centered at a frequency of circa 1 Hz. E) Plot of power at 1 Hz from the spectrograph in D. The power values showed a cyclic fluctuation in amplitude continuing over the entire time of recording with an average period of ∼9 minutes. F) Autocorrelation of power values from the experiment shown in (E) that showed a prominent rhythmic fluctuation at a similar period (9 min). G) Scatter plot of alternation period across time. The period length for the experiment illustrated remained stable as shown by the linear fit with a slope value not significantly different from zero (p = 0.46). H) The left panel shows regression lines for cycle periods across time for all experiments having 6 or more cycles. Different experiments are represented by different colored lines and demonstrate a general lack of variation within, but some variation across, animals. Thirty eight of the forty one animals displayed here showed no significant regression at a p level of 0.05. The right panel is a scatter plot of the average periods for each experiment (equivalent colors to the right panel) and the overall average (10.3±0.4 min) across all experiments.
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pone-0002004-g001: Urethane anaesthetized animals displayed spontaneous and cyclic alternations of brain state.A) Spectra and raw EEG traces of different spontaneous states under urethane. During the activated state, the nCTX showed low voltage fast activity and the HPC showed prominent theta at ∼4 Hz. During the transition state, there was an increase in overall power with a shift to lower frequencies at both sites; raw EEG traces showed irregular and moderately high amplitude activity. During the deactivated state, there was an even more prominent shift to low (∼1 Hz) frequencies with a further increase in overall power and raw EEG traces displaying prominent rhythmic high amplitude slow activity. B) Continuous EEG traces of a spontaneous transition from activated to deactivated patterns. Positions from where the expanded traces in A were taken are shown. The transition between activated and deactivated patterns was marked by a gradual increase in the amplitude of the signals whereas the transition between deactivated and activated patterns was more abrupt. C), Continuous EEG traces over an even longer time scale demonstrated a regular and cyclic alternation of state as observed by the fluctuations in amplitude. The position from where traces in B were taken are shown. D) A spectrographic representation of the neocortical trace shown in C. The most prominent fluctuation of power was centered at a frequency of circa 1 Hz. E) Plot of power at 1 Hz from the spectrograph in D. The power values showed a cyclic fluctuation in amplitude continuing over the entire time of recording with an average period of ∼9 minutes. F) Autocorrelation of power values from the experiment shown in (E) that showed a prominent rhythmic fluctuation at a similar period (9 min). G) Scatter plot of alternation period across time. The period length for the experiment illustrated remained stable as shown by the linear fit with a slope value not significantly different from zero (p = 0.46). H) The left panel shows regression lines for cycle periods across time for all experiments having 6 or more cycles. Different experiments are represented by different colored lines and demonstrate a general lack of variation within, but some variation across, animals. Thirty eight of the forty one animals displayed here showed no significant regression at a p level of 0.05. The right panel is a scatter plot of the average periods for each experiment (equivalent colors to the right panel) and the overall average (10.3±0.4 min) across all experiments.

Mentions: In long term (>45 minute) field (EEG) recordings made from neocortical and hippocampal sites in urethane-anaesthetized rats, a spontaneous and highly regular alternation of electrographic state between activated and deactivated patterns was noted. Activated EEG patterns consisted of low amplitude fast activity at neocortical sites concomitant with theta (rhythmic 3–5 Hz) activity at hippocampal sites while deactivated EEG patterns were characterized by large-amplitude slow oscillatory (∼1 Hz) activity at both neocortical and hippocampal sites (Figure 1A). As previously reported [10], the spontaneous evolution between these states was stereotyped and involved a gradual transition from the activated to the deactivated state (5.23±0.60 minutes, range: 2.75 to 8.58, n = 10) and then a rapid (52±4 s, range: 34 to 78, n = 10) shift back into the activated state (Figure 1B). This cycle repeated itself in a stable and consistent rhythmic fashion as demonstrated by observation of the amplitude fluctuations of long-duration plots of raw EEG traces (Figure 1C) and spectrographic plots computed on the same EEG traces (Figure 1D). Within spectrograms, the highest power fluctuations were centered at a frequency of 1 Hz (especially in the neocortex) so the period and rhythmicity of the alternations were systematically characterized by extracting this frequency band across time (Figure 1E). The precise time points of alternations between states were denoted by calculating a threshold value (corresponding to the saddle of the bimodal distribution of the power at 1 Hz across time) that separated activated from deactivated patterns (values below the threshold were considered to be activated while those above were considered to be deactivated). Autocorrelations of the de-trended power at 1 Hz were highly rhythmic (Figure 1F) and successive periods maintained a consistent duration across time (Figure 1G). This consistency was observed in the vast majority of experiments (38 of 41 see Fig 1H) by showing that least-squares linear fitting of the period durations across time did not result in significant slope values (p>0.05). All of these results were consistent with a systematic and stable cyclic process.


Cyclic and sleep-like spontaneous alternations of brain state under urethane anaesthesia.

Clement EA, Richard A, Thwaites M, Ailon J, Peters S, Dickson CT - PLoS ONE (2008)

Urethane anaesthetized animals displayed spontaneous and cyclic alternations of brain state.A) Spectra and raw EEG traces of different spontaneous states under urethane. During the activated state, the nCTX showed low voltage fast activity and the HPC showed prominent theta at ∼4 Hz. During the transition state, there was an increase in overall power with a shift to lower frequencies at both sites; raw EEG traces showed irregular and moderately high amplitude activity. During the deactivated state, there was an even more prominent shift to low (∼1 Hz) frequencies with a further increase in overall power and raw EEG traces displaying prominent rhythmic high amplitude slow activity. B) Continuous EEG traces of a spontaneous transition from activated to deactivated patterns. Positions from where the expanded traces in A were taken are shown. The transition between activated and deactivated patterns was marked by a gradual increase in the amplitude of the signals whereas the transition between deactivated and activated patterns was more abrupt. C), Continuous EEG traces over an even longer time scale demonstrated a regular and cyclic alternation of state as observed by the fluctuations in amplitude. The position from where traces in B were taken are shown. D) A spectrographic representation of the neocortical trace shown in C. The most prominent fluctuation of power was centered at a frequency of circa 1 Hz. E) Plot of power at 1 Hz from the spectrograph in D. The power values showed a cyclic fluctuation in amplitude continuing over the entire time of recording with an average period of ∼9 minutes. F) Autocorrelation of power values from the experiment shown in (E) that showed a prominent rhythmic fluctuation at a similar period (9 min). G) Scatter plot of alternation period across time. The period length for the experiment illustrated remained stable as shown by the linear fit with a slope value not significantly different from zero (p = 0.46). H) The left panel shows regression lines for cycle periods across time for all experiments having 6 or more cycles. Different experiments are represented by different colored lines and demonstrate a general lack of variation within, but some variation across, animals. Thirty eight of the forty one animals displayed here showed no significant regression at a p level of 0.05. The right panel is a scatter plot of the average periods for each experiment (equivalent colors to the right panel) and the overall average (10.3±0.4 min) across all experiments.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2289875&req=5

pone-0002004-g001: Urethane anaesthetized animals displayed spontaneous and cyclic alternations of brain state.A) Spectra and raw EEG traces of different spontaneous states under urethane. During the activated state, the nCTX showed low voltage fast activity and the HPC showed prominent theta at ∼4 Hz. During the transition state, there was an increase in overall power with a shift to lower frequencies at both sites; raw EEG traces showed irregular and moderately high amplitude activity. During the deactivated state, there was an even more prominent shift to low (∼1 Hz) frequencies with a further increase in overall power and raw EEG traces displaying prominent rhythmic high amplitude slow activity. B) Continuous EEG traces of a spontaneous transition from activated to deactivated patterns. Positions from where the expanded traces in A were taken are shown. The transition between activated and deactivated patterns was marked by a gradual increase in the amplitude of the signals whereas the transition between deactivated and activated patterns was more abrupt. C), Continuous EEG traces over an even longer time scale demonstrated a regular and cyclic alternation of state as observed by the fluctuations in amplitude. The position from where traces in B were taken are shown. D) A spectrographic representation of the neocortical trace shown in C. The most prominent fluctuation of power was centered at a frequency of circa 1 Hz. E) Plot of power at 1 Hz from the spectrograph in D. The power values showed a cyclic fluctuation in amplitude continuing over the entire time of recording with an average period of ∼9 minutes. F) Autocorrelation of power values from the experiment shown in (E) that showed a prominent rhythmic fluctuation at a similar period (9 min). G) Scatter plot of alternation period across time. The period length for the experiment illustrated remained stable as shown by the linear fit with a slope value not significantly different from zero (p = 0.46). H) The left panel shows regression lines for cycle periods across time for all experiments having 6 or more cycles. Different experiments are represented by different colored lines and demonstrate a general lack of variation within, but some variation across, animals. Thirty eight of the forty one animals displayed here showed no significant regression at a p level of 0.05. The right panel is a scatter plot of the average periods for each experiment (equivalent colors to the right panel) and the overall average (10.3±0.4 min) across all experiments.
Mentions: In long term (>45 minute) field (EEG) recordings made from neocortical and hippocampal sites in urethane-anaesthetized rats, a spontaneous and highly regular alternation of electrographic state between activated and deactivated patterns was noted. Activated EEG patterns consisted of low amplitude fast activity at neocortical sites concomitant with theta (rhythmic 3–5 Hz) activity at hippocampal sites while deactivated EEG patterns were characterized by large-amplitude slow oscillatory (∼1 Hz) activity at both neocortical and hippocampal sites (Figure 1A). As previously reported [10], the spontaneous evolution between these states was stereotyped and involved a gradual transition from the activated to the deactivated state (5.23±0.60 minutes, range: 2.75 to 8.58, n = 10) and then a rapid (52±4 s, range: 34 to 78, n = 10) shift back into the activated state (Figure 1B). This cycle repeated itself in a stable and consistent rhythmic fashion as demonstrated by observation of the amplitude fluctuations of long-duration plots of raw EEG traces (Figure 1C) and spectrographic plots computed on the same EEG traces (Figure 1D). Within spectrograms, the highest power fluctuations were centered at a frequency of 1 Hz (especially in the neocortex) so the period and rhythmicity of the alternations were systematically characterized by extracting this frequency band across time (Figure 1E). The precise time points of alternations between states were denoted by calculating a threshold value (corresponding to the saddle of the bimodal distribution of the power at 1 Hz across time) that separated activated from deactivated patterns (values below the threshold were considered to be activated while those above were considered to be deactivated). Autocorrelations of the de-trended power at 1 Hz were highly rhythmic (Figure 1F) and successive periods maintained a consistent duration across time (Figure 1G). This consistency was observed in the vast majority of experiments (38 of 41 see Fig 1H) by showing that least-squares linear fitting of the period durations across time did not result in significant slope values (p>0.05). All of these results were consistent with a systematic and stable cyclic process.

Bottom Line: Individual states and their transitions resembled the REM/nREM cycle of natural sleep in their EEG components, evolution, and time frame ( approximately 11 minute period).Other physiological variables such as muscular tone, respiration rate, and cardiac frequency also covaried with forebrain state in a manner identical to sleep.Our results suggest that urethane promotes a condition of behavioural unconsciousness that closely mimics the full spectrum of natural sleep.

View Article: PubMed Central - PubMed

Affiliation: Centre for Neuroscience, University of Alberta, Edmonton, Alberta, Canada.

ABSTRACT

Background: Although the induction of behavioural unconsciousness during sleep and general anaesthesia has been shown to involve overlapping brain mechanisms, sleep involves cyclic fluctuations between different brain states known as active (paradoxical or rapid eye movement: REM) and quiet (slow-wave or non-REM: nREM) stages whereas commonly used general anaesthetics induce a unitary slow-wave brain state.

Methodology/principal findings: Long-duration, multi-site forebrain field recordings were performed in urethane-anaesthetized rats. A spontaneous and rhythmic alternation of brain state between activated and deactivated electroencephalographic (EEG) patterns was observed. Individual states and their transitions resembled the REM/nREM cycle of natural sleep in their EEG components, evolution, and time frame ( approximately 11 minute period). Other physiological variables such as muscular tone, respiration rate, and cardiac frequency also covaried with forebrain state in a manner identical to sleep. The brain mechanisms of state alternations under urethane also closely overlapped those of natural sleep in their sensitivity to cholinergic pharmacological agents and dependence upon activity in the basal forebrain nuclei that are the major source of forebrain acetylcholine. Lastly, stimulation of brainstem regions thought to pace state alternations in sleep transiently disrupted state alternations under urethane.

Conclusions/significance: Our results suggest that urethane promotes a condition of behavioural unconsciousness that closely mimics the full spectrum of natural sleep. The use of urethane anaesthesia as a model system will facilitate mechanistic studies into sleep-like brain states and their alternations. In addition, it could also be exploited as a tool for the discovery of new molecular targets that are designed to promote sleep without compromising state alternations.

Show MeSH
Related in: MedlinePlus