Invited Review
Effects of pharmacological agents, sleep deprivation, hypoxia and transcranial magnetic stimulation on electroencephalographic rhythms in rodents: Towards translational challenge models for drug discovery in Alzheimer’s disease

https://doi.org/10.1016/j.clinph.2012.07.023Get rights and content

Abstract

Different kinds of challenge can alter spontaneous ongoing electroencephalographic (EEG) rhythms in animal models, thus providing paradigms to evaluate treatment effects in drug discovery. The effects of challenges represented by pharmacological agents, hypoxia, sleep deprivation and transcranial magnetic stimulation (TMS) on EEG rhythms are here reviewed to build a knowledge platform for innovative translational models for drug discovery in Alzheimer’s disease (AD). It has been reported that antagonists of cholinergic neurotransmission cause synchronisation of spontaneous ongoing EEG rhythms in terms of enhanced power of EEG low frequencies and decreased power of EEG high frequencies. Acetylcholinesterase inhibitors and serotonergic drugs may restore a normal pattern of EEG desynchronisation. Sleep deprivation and hypoxia challenges have also been reported to elicit abnormal synchronisation of spontaneous ongoing EEG rhythms in rodents. The feasibility and reproducibility of TMS have been demonstrated in rodents but information on a consistent modulation of EEG after TMS manipulation is very limited. Transgenic mice over-expressing human amyloid precursor protein complementary DNAs (cDNAs) harbouring the ‘Swedish’ mutation and PS-1 cDNAs harbouring the A264E mutation, which recapitulate some of the pathological features of AD, exhibit alterations of spontaneous ongoing EEG rhythms at several low and high frequencies. This does not appear, however, to be a consequence of beta-amyloid deposition in the brain. The present review provides a critical evaluation of changes of spontaneous ongoing EEG rhythms due to the experimental manipulations described above, in order to stimulate the promote more adherent models fitting dynamics in humans.

Highlights

► Analysis of electroencephalographic (EEG) rhythms in animal models of deficit and drug-induced EEG normalisation provides a useful approach to drug discovery. ► Effects on EEG rhythms of challenges represented by administration of pharmacological agents, hypoxia, sleep deprivation and transcranial magnetic stimulation provide a knowledge platform for preclinical investigation in Alzheimer’s disease. ► Expected changes of EEG rhythms due to experimental manipulations can promote preclinical innovative translational models fitting dynamics in humans.

Introduction

It is well known that Alzheimer’s disease (AD) is a progressive, neurodegenerative disease of the elderly, characterised by memory loss as well as additional cognitive and behavioural abnormalities. Early AD is associated with pathological changes in the basal forebrain cholinergic system, thalamocortical system, associative parietal–temporal areas and the complex of inter-related brain regions formed by the entorhinal cortex, hippocampus and amygdala (Daulatzai, 2010). Cholinergic neurotransmission protects neurons from amyloid beta (Abeta) production and its toxicity, which are enhanced by cholinergic depletion (Mohamed et al., 2011, Schliebs and Arendt, 2011). Symptomatic therapies target the cholinergic and glutamatergic systems, but no approved therapy is currently available to slow down or halt the neurodegenerative process.

A key objective of AD research is to develop and validate procedures for effective early proof-of-concept studies to evaluate novel symptomatic and disease-modifying agents in humans. The European Innovative Medicines Initiative project, PharmaCog, (IMI Undertaking on Neurodegenerative disorders, 2008) has adopted a strategy of parallel preclinical and human research for this purpose. In particular, procedures transiently interfering with cortical activity and cognitive processes in healthy volunteers and normal animals, that is, challenge models, are evaluated in this project. Such deficit models overcome the inherent difficulty of detecting significant improvements in cognitive performance in normal subjects. Pharmacological challenges include systemic administration of cholinergic or glutamatergic antagonists such as scopolamine and ketamine, hypoxia, sleep deprivation (SD) and transcranial magnetic stimulation (TMS). Validation of these models in drug discovery requires that potential symptomatic drugs normalise deficits or pathological alteration induced by challenge models in key neurophysiological mechanisms and cognitive processes.

In this article, the literature on animal models is reviewed in order to weigh the relative value of resting state or spontaneous ongoing electroencephalographic (EEG) patterns as putative ‘end’ points for an understanding of neurodegenerative processes. The aim is also to review drug effects in relevant animal models. The interest in these markers stems from the fact that recording of EEG activity is relatively inexpensive and able to probe the brain key features of oscillatory nature (Berger, 1929, Nunez, 2000, Michel et al., 2004, Rossini et al., 2007, Rossini, 2009, Babiloni et al., 2009a). Furthermore, spontaneous ongoing EEG rhythms in the resting state seem to reflect, at least at group level, preclinical and clinical stages of AD in humans (Babiloni et al., 2004, Babiloni et al., 2006a). From a translational point of view, spontaneous ongoing EEG rhythms show some similarities in humans and rodents. For example, alertness in humans and rodents is associated with enhanced power of low-voltage fast frequencies in EEG rhythms (i.e., beta rhythms spanning about 14–30 Hz), whereas non-rapid eye movement (REM) sleep and drowsiness are characterised by the enhanced power of high-voltage slow frequencies in EEG rhythms (i.e., delta and theta rhythms spanning about 1–7 Hz; Marshall and Born, 2002, Vyazovskiy et al., 2005). Anxiety has been shown to increase the power of low-voltage high frequencies in the resting-state EEG rhythms in both humans and rodents (Sviderskaia et al., 2001, Oathes et al., 2008). Finally, there is converging evidence that cholinergic and monoaminergic drugs have similar effects on spontaneous ongoing EEG rhythms in humans and rodents (Dimpfel et al., 1992, Jongsma et al., 1998, Jongsma et al., 2000, Coenen and Van Luijtelaar, 2003, Dimpfel, 2005). In the following sections, basic concepts about EEG techniques and markers are introduced.

Section snippets

Electroencephalographic techniques for translational research on AD

In humans, spontaneous ongoing scalp EEG rhythms reflect extracellular ion flow due to excitatory and inhibitory postsynaptic potentials in large populations of cortical pyramidal neurons (Nunez, 2000). There is a consensus that scalp EEG voltages mainly correspond to the local field potentials generated in superficial cortical layers, as local field potentials deriving from deeper cortical layers are attenuated by resistance of the head as a volume conductor. Specifically, the synaptic

Physiological generation of ongoing EEG rhythms

EEG activity characterised by slow-frequency oscillation and large-voltage amplitude can be observed in large slabs of neocortical tissue after an isolation procedure, suggesting that intrinsic cortical networks can sustain this type of slow, deactivated cortical oscillations (Timofeev et al., 2000). The presence of two distinct types of synchronised high-voltage, low-frequency rhythms has been suggested by the EEG recordings in cats and humans, namely one ensemble of slow-frequency rhythms in

Pharmacological modulation of ongoing EEG rhythms in animal models: the effects of cholinergic agonists and antagonists

Cholinergic therapies have been the mainstay of symptomatic therapeutic approaches in the treatment of AD for over 20 years. Acetylcholinesterase inhibitors sustain the availability of the natural transmitter by limiting its removal from the synapse. Alternatively, direct exogenous agonists or positive allosteric modulators of both nicotinic and muscarinic receptors still represent important therapeutic targets. For example, postsynaptic muscarinic M1 receptors are expressed in brain areas that

Pharmacological modulation of spontaneous ongoing EEG rhythms in animal models: interaction between cholinergic agents and other neuromodulatory agents

The interaction between cholinergic agents and other neuromodulatory (noradrenergic, dopaminergic, serotonergic and histaminergic) agents has contributed to the understanding of the physiology of spontaneous ongoing EEG rhythms and cortical arousal (Vertes, 1988, Jones and Cuello, 1989, Semba and Fibiger, 1989, Zaborszky, 1989). The available evidence suggests that these transmitters can indirectly modulate spontaneous ongoing cortical EEG rhythms by an action in the basal forebrain that

Effects of SD on EEG rhythms in animal models

Three sets of data are briefly discussed in this section: (1) the physiological model of the generation of EEG rhythms during sleep stages, (2) the main caveats of the experiments on SD in animal models and (3) the main effects of drug treatments on sleep.

A widely accepted model of sleep regulation postulates that sleep is under the control of two fundamental processes, the circadian and homeostatic processes (Daan et al., 1984). The circadian process governs the timing of virtually all 24 h

Effects of hypoxia on EEG rhythms recorded in animal models

Hypoxia is caused by a reduction in blood supply due to a variety of pathophysiological or traumatic insults to the brain. It is hypothesised to induce glucose hypometabolism in the hippocampus and other key brain areas subserving cognitive functions including memory. During sleep, repeated hypoxic events may affect respiratory cholinergic mechanism, respiratory regulation, upper airway patency and cerebral oxygenation (Peers et al., 2009, Scragg et al., 2005, Daulatzai, 2010). Diurnally,

Effects of TMS on EEG rhythms recorded in animal models

TMS enables the quantification of motor system excitability and transient ‘virtual’ functional lesions of cortical networks subserving cognitive functions including attention and episodic memory. Although this approach is routinely used in humans, its application to laboratory animal species is rare and little is known about the characteristics of animal TMS. Of note, TMS is non-invasive and produces predominantly interneuronal stimulation at low intensity, enabling its use in evaluating

Cortical spontaneous ongoing EEG rhythms in transgenic animal models of AD

Many laboratories have produced transgenic mice that recapitulate certain features of AD pathology, for example, mice which over-express the amyloid precursor protein (APP), which is associated with familial forms of AD (Howlett and Richardson, 2009). Histopathological assessment shows that APP transgenic mice demonstrate an accumulation of Abeta in plaques from an early age; these plaques are invariably surrounded by activated inflammatory cells such as astrocytes and microglia, as is common

Conclusions

We here reviewed the literature on spontaneous, ongoing, resting-state EEG rhythms as potential biomarkers for preclinical research in AD. Antagonists of cholinergic neurotransmission can synchronise spontaneous ongoing EEG rhythms in terms of enhanced power of EEG low frequencies and decreased power of EEG high frequencies. Acetylcholinesterase inhibitors and serotonergic drugs can restore a normal pattern of EEG desynchronisation. SD and hypoxia challenges also produce abnormal

Acknowledgements

The activity leading to the present review has received funding from the European Community’s Seventh Framework Programme (FP7/2007-2013) for the Innovative Medicine Initiative under Grant Agreement No. 115009 (Prediction of cognitive properties of new drug candidates for neurodegenerative diseases in early clinical development, PharmaCog). For further information on the PharmaCog project, please refer to http://www.alzheimer-europe.org. We thank the staff of University of Foggia for its help

References (182)

  • C. Babiloni et al.

    Fundamentals of electroencefalography, magnetoencefalography, and functional magnetic resonance imaging

    Int Rev Neurobiol

    (2009)
  • C. Babiloni et al.

    Directionality of EEG synchronization in Alzheimer’s disease subjects

    Neurobiol Aging

    (2009)
  • C. Babiloni et al.

    Hippocampal volume and cortical sources of EEG alpha rhythms in mild cognitive impairment and Alzheimer disease

    Neuroimage

    (2009)
  • C. Babiloni et al.

    Cortical sources of resting EEG rhythms in mild cognitive impairment and subjective memory complaint

    Neurobiol Aging

    (2010)
  • M.L. Bocca et al.

    Total sleep deprivation effect on disengagement of spatial attention as assessed by saccadic eye movements

    Clin Neurophysiol

    (2006)
  • G. Buzsáki et al.

    Electric activity in the neocortex of freely moving young and aged rats

    Neuroscience

    (1988)
  • G. Buzsáki et al.

    Temporal structure in spatially organized neuronal ensembles: a role for interneuron networks

    Curr Opin Neurobiol

    (1995)
  • F. Casamenti et al.

    Changes in cortical acetylcholine output induced by modulation of the nucleus basalis

    Brain Res Bull

    (1986)
  • A. Daurat et al.

    Detrimental influence of bright light exposure on alertness, performance, and mood in the early morning

    Neurophysiol Clin

    (1996)
  • T. Dierks et al.

    Dementia of the Alzheimer type: effects on the spontaneous EEG described by dipole sources

    Psychiatry Res

    (1993)
  • T. Dierks et al.

    Spatial pattern of cerebral glucose metabolism (PET) correlates with localization of intracerebral EEG-generators in Alzheimer’s disease

    Clin Neurophysiol

    (2000)
  • W. Dimpfel

    Pharmacological modulation of cholinergic brain activity and its reflection in special EEG frequency ranges from various brain areas in the freely moving rat (Tele-Stereo-EEG)

    Eur Neuropsychopharmacol

    (2005)
  • H.C. Dringenberg et al.

    Effect of tacrine on EEG slowing in the rat: enhancement by concurrent monoamine therapy

    Neurobiol Aging

    (2000)
  • H.C. Dringenberg et al.

    Electroencephalographic activation by tacrine, deprenyl, and quipazine: cholinergic vs. non-cholinergic contributions

    Eur J Pharmacol

    (2002)
  • H.C. Dringenberg et al.

    Electroencephalographic activation by fluoxetine in rats: role of 5-HT(1A) receptors and enhancement of concurrent acetylcholinesterase inhibitor treatment

    Neuropharmacology

    (2002)
  • U. Ebert et al.

    Altered seizure susceptibility after high-frequency transcranial magnetic stimulation in rats

    Neurosci Lett

    (1999)
  • B. Fimm et al.

    The effect of low arousal on visuo-spatial attention

    Neuropsychologia

    (2006)
  • A.A. Fingelkurts et al.

    The regularities of the discrete nature of multi-variability of EEG spectral patterns

    Int J Psychophysiol

    (2003)
  • A.A. Fingelkurts et al.

    New perspectives in pharmaco-electroencephalography

    Prog Neuropsychopharmacol Biol Psychiatry

    (2005)
  • W.H. Funderburk et al.

    The effect of atropine on cortical potentials

    Electroencephalogr Clin Neurophysiol

    (1951)
  • C. Geula et al.

    Cortical cholinergic fibers in aging and Alzheimer’s disease: a morphometric study

    Neuroscience

    (1989)
  • S. Grahnstedt et al.

    Platform sleep deprivation affects deep NREM in addition to REM sleep

    Behav Brain Res

    (1985)
  • Y. Harrison et al.

    One night of sleep loss impairs innovative thinking and flexible decision making

    Organ Behav Hum Decis Process

    (1999)
  • C. Huang et al.

    Discrimination of Alzheimer’s disease and mild cognitive impairment by equivalent EEG sources: a cross-sectional and longitudinal study

    Clin Neurophysiol

    (2000)
  • J.R. Ives et al.

    Electroencephalographic recording during transcranial magnetic stimulation in humans and animals

    Clin Neurophysiol

    (2006)
  • T. Ishida et al.

    Characteristic effects of anti-dementia drugs on rat sleep patterns

    J Pharmacol Sci

    (2009)
  • T. Ishida et al.

    Studies on wakefulness-promoting effect of memantine in rats

    Behav Brain Res

    (2010)
  • P. Jäkälä et al.

    Combined cholinergic and 5-HT2 receptor activation suppresses thalamocortical oscillations in aged rats

    Pharmacol Biochem Behav

    (1997)
  • B.E. Jones et al.

    Afferents to the basal forebrain cholinergic cell area from pontomesencephalic–catecholamine, serotonin, and acetylcholine–neurons

    Neuroscience

    (1989)
  • M.L. Jongsma et al.

    Time course of chronic diazepam effects on the auditory evoked potential of the rat

    Eur J Pharmacol

    (1998)
  • W.D. Killgore et al.

    Sleep deprivation reduces perceived emotional intelligence and constructive thinking skills

    Sleep Med

    (2008)
  • K. Kräuchi et al.

    The hypothermic effect of late evening melatonin does not block the phase delay induced by concurrent bright light in human subjects

    Neurosci Lett

    (1997)
  • M. Lancel et al.

    Effects of repeated sleep deprivation in the dark- or light-period on sleep in rats

    Physiol Behav

    (1989)
  • M.M. Lima et al.

    Blockage of dopaminergic D(2) receptors produces decrease of REM but not of slow wave sleep in rats after REM sleep deprivation

    Behav Brain Res

    (2008)
  • N.S. Akopian et al.

    Effect of acute hypoxia on the EEG and neuronal pulse activity of various brain structures in rats [in Russian]

    Fiziol Zh SSSR Im I M Sechenova

    (1982)
  • F. Aujard et al.

    Age-related effects on the biological clock and its behavioral output in a primate

    Chronobiol Int

    (2006)
  • R.S. Bitner et al.

    In vivo pharmacological characterization of a novel selective alpha7 neuronal nicotinic acetylcholine receptor agonist ABT-107: preclinical considerations in Alzheimer’s disease

    J Pharmacol Exp Ther

    (2010)
  • C. Babiloni et al.

    Apolipoprotein E and alpha brain rhythms in mild cognitive impairment: a multicentric electroencephalogram study

    Ann Neurol

    (2006)
  • C. Babiloni et al.

    White-matter lesions along the cholinergic tracts are related to cortical sources of EEG rhythms in amnesic mild cognitive impairment

    Hum Brain Mapp

    (2009)
  • F. Belardetti et al.

    Desynchronizing prosencephalic mechanisms in the acute “isolated brain” preparation

    Riv Neurol

    (1977)
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