Activation of Human Cerebral and Cerebellar Cortex by Auditory Stimulation at 40 Hz

Abstract

We used functional brain imaging with positron emission tomography (PET)-H 2 15 O to study a remarkable neurophysiological finding in the normal brain. Auditory stimulation at various frequencies in the gamma range elicits a steady-state scalp electroencephalographic (EEG) response that peaks in amplitude at 40 Hz, with smaller amplitudes at lower and higher stimulation frequencies. We confirmed this finding in 28 healthy subjects, each studied with monaural trains of stimuli at 12 different stimulation rates (12, 20, 30, 32, 35, 37.5, 40, 42.5, 45, 47.5, 50, and 60 Hz). There is disagreement as to whether the peak in the amplitude of the EEG response at 40 Hz corresponds simply to a superimposition of middle latency auditory evoked potentials, neuronal synchronization, or increased cortical synaptic activity at this stimulation frequency. To clarify this issue, we measured regional cerebral blood flow (rCBF) with PET-H 2 15 O in nine normal subjects at rest and during auditory stimulation at four different frequencies (12, 32, 40, and 47 Hz) and analyzed the results with statistical parametric mapping. The behavior of the rCBF response was similar to the steadystate EEG response, reaching a peak at 40 Hz. This finding suggests that the steady-state amplitude peak is related to increased cortical synaptic activity. Additionally, we found that, compared with other stimulation frequencies, 40 Hz selectively activated the auditory region of the pontocerebellum, a brain structure with important roles in cortical inhibition and timing. Key words: steady-state auditory evoked potentials; gamma oscillatory activity; regional cerebral blood flow; positron emission tomography; cerebellum; auditory cortexIn humans, auditory stimulation at different gamma frequencies elicits an electroencephalographic (EEG) steady-state response (SSR) that cycles at the stimulation frequency and has the greatest amplitude when the stimulus is given at 40 Hz (Galambos et al., 1981). Lower or higher frequencies produce a response of smaller amplitude. These oscillatory responses seem to be generated at the level of the auditory cortex, although modulated by thalamocortical systems (Makela and Hari, 1987;Steriade et al., 1991). The significance and origin of the steady-state potentials continue to be debated (Basar et al., 1987;Santarelli et al., 1995;Gutschalk et al., 1999). It is unclear whether the power increment of the steady-state auditory response at 40 Hz results merely from the temporal coherence (phase summation) of "middle latency" evoked responses, phase synchronization of a pool of cortical neurons, or a true increase in cortical synaptic activity at 40 Hz. Synaptic activity causes an increment in regional cerebral blood flow (rCBF). To test the hypothesis that the enhanced response at 40 Hz reflects increased synaptic cortical activity, we measured rCBF with positron emission tomography (PET) in the auditory cortex and other brain regions during auditory stimulation at different frequencies. A rise in rCBF at 40 Hz stimulatio...

Cerebellum and auditory function: An ALE meta‐analysis of functional neuroimaging studies

“…Because imaging studies explicitly manipulating cognitive, emotion, or motor confounds were specifically excluded from this study, cerebellar activation also did not depend on variations in these conditions. Although the relatively few neuroimaging studies intended specifically to examine cerebellar auditory responses have designed their tasks to focus on one or another hypothesized specific function [e.g., timing: Ackermann et al, 2001;Pastor et al, 2002;speech processing: Mathiak et al, 2002;, our data suggest that the revealed cerebellar activations are more likely related to the general processing of auditory stimuli. This is the kind of result that can be revealed most clearly by a meta-analysis of multiple published studies.…”

“…Despite having been confirmed repeatedly across different animal species [Aitikin and Boyd, 1975;Huang and Liu, 1990;Sun et al, 1983;Wolfe and Kos, 1975;Xi et al, 1994], we know of no positron emission tomography (PET) or functional magnetic resonance imaging (fMRI) studies that have tested specifically for a purely sensory role for the cerebellum in auditory processing. Instead, most studies have focused on higherlevel aspects of auditory processing, such as the timing and duration of sounds for speech perception [Mathiak et al, 2002[Mathiak et al, , 2004, processing of stimuli presentation rate [Ackermann et al, 2001;Pastor et al, 2002], or perceptual timing in general [Jueptner et al, 1995;Mangels et al, 1998;Nichelli et al, 1996]. Again, our hypothesis posits that cerebellar involvement in audition is more fundamental, operating at the level of the basic mechanisms of active auditory sensory data acquisition.…”

“…Moreover, its maximum showed the fourth highest ALE value after the three temporal peaks. The ALE meta-analysis indicated a good level of concordance for the location of cerebellar foci across studies, even though these studies differed greatly in tasks, contrasts, and stimuli, ranging from passive listening to pure tones [Lockwood et al, 1999;Sevostianov et al, 2002] or clicks [Ackermann et al, 2001;Ortuñ o et al, 2002;Pastor et al, 2002] to various types of active auditory discrimination [Belin et al, 1998[Belin et al, , 2002Poeppel et al, 2004] and masking tasks [van Dijk and Backes, 2003]. Because imaging studies explicitly manipulating cognitive, emotion, or motor confounds were specifically excluded from this study, cerebellar activation also did not depend on variations in these conditions.…”

Natural Frequencies of Human Corticothalamic Circuits

“…In this case, visual flashes, or auditory tones, are presented at different rates, and the stimulation frequency that results in the largest EEG or magnetoencephalography output, the resonance frequency, is detected. This standardized approach yielded consistent results and demonstrated the existence of clear-cut resonance frequencies in specific parts of the human corticothalamic system, ϳ10 Hz (Narici and Romani, 1989;Regan, 1989;Silberstein, 1995;Rager and Singer, 1998;Herrmann, 2001) in visual cortex and ϳ40 Hz in auditory cortex (Galambos et al, 1981;Pastor et al, 2002). However, steady-state responses, as other responses evoked by the stimulation of peripheral receptors, can only probe a limited set of primary sensory cortices.…”

40 Hz Auditory Steady-State Response Is a Pharmacodynamic Biomarker for Cortical NMDA Receptors

“…Such entrainment of auditory cortical neurons can be recorded by noninvasive methods such as electroencephalography (EEG) and is termed auditory steady-state response (ASSR). In humans, the scalp-recorded ASSR is maximal when auditory stimuli are delivered at ∼ 40 Hz (Galambos et al, 1981;Pastor et al, 2002) and appears to reflect resonance frequency of the underlying neural circuits (Llinas, 1988;Llinas et al, 1991;Rosanova et al, 2009). A key part of the circuitry responsible for entrainment to exogenous stimuli appears to involve parvalbumin-positive (PV+), GABAergic basket interneurons and the pyramidal cells of the upper layers of the sensory cortex (Cardin et al, 2009;Carlen et al, 2012;Sohal et al, 2009).…”