Research ReportEthanol reduces the phase locking of neural activity in human and rodent brain
Highlights
►Phase variability of auditory event-related oscillations (EROs) was measured in humans and rats. ►Phase locking of EROs was higher for the rare (target) tone than the frequent (non-target) tone in both species. ►Ethanol produced significant reductions in phase locking in both rats and humans. ►Increases in phase locking in the beta frequencies correlated significantly with overall ratings of intoxication. ►Reductions in phase locking in the alpha frequencies correlated with blood ethanol concentrations.
Introduction
The neurobehavioral effects of ethanol range from mild euphoria, anxiolysis and disinhibition to impaired coordination, ataxia, decreased mentation, slurred speech, nausea and vomiting, and finally to respiratory failure, coma and death, depending on the dose imbibed (Schuckit, 1995). The presumed neuromolecular basis for these behavioral effects includes actions on lipids, at high doses, and more direct molecular targets such as enzymes, neurotransmitter receptors, and ion channels at doses that typically produce intoxication in humans (Harris et al., 2008, Vengeliene et al., 2008). While much progress has been made on identifying molecular targets for ethanol, less insight has been gained into how ethanol's actions at the molecular level may translate to its behavioral and intoxicating effects. The global behavioral effects of ethanol most likely require the integration of a number of functional neuronal areas distributed over the brain that are in constant interaction with each other. It has been suggested that such large scale integration and communication within the brain could be mediated by groups of neurons that oscillate within a specific frequency range and enter into precise phase-locking, or synchrony, over a limited period of time (Hipp et al., 2011, Lachaux et al., 1999, Sauseng and Klimesch, 2008). Measures of neuronal phase synchrony of event-related neurophysiological events may therefore be a sensitive way to measure the effects of ethanol on local and global neural networks.
Event-related potentials (ERPs) are a series of negative and positive voltage deflections that are time locked typically to either sensory or cognitive events. They consist of several components that are averaged from the ongoing EEG that generally occur between 50 and 1000 ms. It has been suggested that the stimuli that evoke ERP components, like the P300, influence oscillatory changes within the dynamics of ongoing EEG rhythms (Basar-Eroglu and Basar, 1991, Demiralp et al., 2001a, Demiralp et al., 2001b, Karakas et al., 2000a, Karakas et al., 2000b, Schurmann et al., 1995, Schurmann et al., 2001, Yordanova and Kolev, 1996). This synchronization or enhancement of ongoing EEG oscillations by a time locked cognitive and/or sensory process is termed an event-related oscillation (ERO) (Basar et al., 2000, Begleiter and Porjesz, 2006, Roach and Mathalon, 2008). EROs are thought to arise by a “phase re-ordering” of the background EEG in several frequency bands (Basar, 1980, Makeig et al., 2002). EROs are typically estimated by a decomposition of the EEG signal into phase and magnitude information for a range of frequencies and then changes in those frequencies are characterized with respect to their energy and phase relationships over a millisecond time scale with respect to task events.
Event-related oscillations over the spectral range of the EEG (1–50 Hz) have been suggested to underlie a number of different cognitive processes. For instance, event-related alpha oscillations have been attributed to attentional resources, semantic memory, and stimulus processing (Basar et al., 1997, Klimesch et al., 1994, Klimesch et al., 1997a, Klimesch et al., 1997b), whereas, beta and gamma oscillations have been associated with sensory integrative processes (Basar et al., 2001a, Basar et al., 2001b, Schurmann et al., 1997). Oscillations in the delta and theta frequency ranges have been associated with signal detection, decision-making, conscious awareness, recognition memory and episodic retrieval (Basar et al., 1999c, Basar et al., 2001c, Basar et al., 2001d, Doppelmayr et al., 1998, Gevins et al., 1998, Klimesch et al., 1994, Klimesch et al., 2001, Schurmann et al., 2001). It has been suggested that high frequency oscillations (above 30 Hz) reflect synchronization of neuronal ensembles that are interacting over short distances in response to primarily sensory processes (Bressler and Freeman, 1980, Ohl et al., 2003), whereas, lower frequency oscillations (1–4 Hz) are generated by synchronization of ensembles interacting at longer distances during higher cognitive processing (Kopell et al., 2000, Lubar, 1997).
Cognitive and behavioral processes most likely involve the coordination of a large number of neurons into assemblies that are in communication within individual brain areas as well as across different subsystems (Damasio, 1990, Neuenschwander et al., 1996, Sejnowski, 1986, Singer, 1990, Singer, 1993). Recent studies suggest that this may be indexed by stimulus-dependent neuronal synchronization (phase locking) of EROs. Phase locking of EROs can be measured in both humans (Roach and Mathalon, 2008, Sauseng and Klimesch, 2008) and more recently in rodent models (Criado and Ehlers, 2009, Criado and Ehlers, 2010a, Criado and Ehlers, 2010b, Ehlers and Criado, 2009), allowing for translational studies to be conducted.
We have argued that ethanol may produce its effects on micro as well as macro electrophysiology by introducing an increased level of noise or randomness in neuronal processing. Several studies provide data that are descriptively supportive of this idea. For instance, Aston-Jones et al. (1982) demonstrated that low doses of ethanol, although having no effect on the mean spontaneous discharge of rat locus coeruleus neurons, significantly increased the variability in the latency at which those neurons fired in response to sensory stimuli. At the level of the EEG, we have previously demonstrated that consumed ethanol produces increased randomness as indexed by a decrease in the nonlinear structure of EEG oscillations (Ehlers, 1992, Ehlers et al., 1998b). The present study was conducted to further explore that hypothesis by measuring the effects of ethanol on ERO phase synchrony (phase locking) in both humans and animals. We predicted that an ethanol-induced increase in the randomness of neuromolecular interactions would result in a reduction of synchrony or phase locking both within a neuronal population and between neuronal populations. To assess this hypothesis, we explored three main questions: (1) Do phase locking measures of EROs differentiate infrequent from frequent tones in rats and humans? (2) Do phase locking measures of EROs differentiate placebo from ethanol in both humans and rats? and (3) Do these measures correlate with a person's subjective report of intoxication and/or blood ethanol concentration?
Section snippets
Phase locking in response to frequent and infrequent tones in rats and humans
Thirty-eight (38) human participants completed the ethanol/placebo challenge study and had valid electrophysiological data available for the current analyses. These individuals had a mean ± SE age of 20.53 ± 0.34 yrs, and 11.89 ± 1.09 yrs of education. They drank an average of 4.5 ± 0.56 days per month, and consumed an average of 5.18 ± 0.58 drinks per occasion. Forty-six rats completed the protocol, had data available for analyses, and had verified electrode locations.
To address the first major research
Discussion
Macroelectrophysiological recordings reflect the activity of large-scale neuronal assemblies; exactly how these neural assemblies organize to generate behavior is largely unknown. However, a body of knowledge is beginning to emerge that suggests that the phase locking of frequency specific, neuro-oscillatory activity within and between neural assemblies may underlie the processes whereby the brain organizes and communicates information (Basar et al., 1999a, Basar et al., 1999b, Roach and
Human participants
Males between the ages of 18 and 25 years were recruited using a combination of venue-based method and a respondent-driven procedure that has been described elsewhere (Ehlers et al., 1998a). Following telephone screening with research staff to complete a questionnaire (Schuckit, 1984, Schuckit and Gold, 1988) that was used to select individuals who met eligibility for the study; all subjects signed informed consent, and the study was approved by The Scripps Research Institute Internal Review
Funding
This study was supported in part by the National Institutes of Health (NIH), National Institute on Alcoholism and Alcohol Abuse grants, AA006059, AA019969 and AA010201 awarded to CLE.
Acknowledgments
The authors thank Evie Phillips for her assistance in data collection, and to Shirley Sanchez for assistance in editing the manuscript.
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