Research paperTonal frequency affects amplitude but not topography of rhesus monkey cranial EEG components
Introduction
Altered auditory evoked potentials (AEP) recorded with scalp electro-encephalography (EEG) are key markers of altered neural processing in several neuro-psychiatric diseases, including schizophrenia (SZ). The most promising candidate bio-marker of impaired auditory processing in SZ is the attenuation of auditory mismatch negativity (Javitt et al., 1993, Javitt et al., 2008, Näätänen et al., 1978) (MMN), a fronto-central negative deflection that is observed when a regular sequence of sounds is interrupted by a rare and/or unexpected sound (Näätänen et al., 1978). The identification of a presumed homolog of human MMN in the rhesus monkey established this species as one of the most important animal model systems for altered auditory function in SZ (Fishman, 2014, Gil-da-Costa et al., 2013, Javitt et al., 2000, Javitt et al., 1992, Javitt et al., 1996, Javitt et al., 1995). A number of studies using either active or passive frequency-based oddball paradigms to study MMN or the related P3 have provided a very detailed understanding of how differences in tonal frequency are represented in rhesus monkey AEPs (Arthur and Starr, 1984, Fishman, 2014, Gil-da-Costa et al., 2013). However, to date there is no study that has systematically quantified how absolute tonal frequency itself is represented. This is particularly surprising given the range of interesting tonal frequency-based phenomena that can be observed in the human. In particular, tonal frequency can change both the amplitude (Antinoro and Skinner, 1968, Antinoro et al., 1969, Picton et al., 1978, Stelmack et al., 1977) and the topography (i.e. the spatial distribution of potentials on the scalp) of auditory evoked EEG components (Bertrand et al., 1991, Verkindt et al., 1995, Woods et al., 1993, Woods et al., 1991). A better understanding of how tonal frequency affects auditory evoked EEG responses in the rhesus monkey will establish a more solid foundation on which to build the interpretation of frequency MMN in this species. Hence, the goal of the current study was to determine if AEPs in the rhesus monkey show a similar dependence on tonal frequency as in humans.
In order to enable an optimal inter-species comparison, it is necessary to use the same measure of neural activity in both species. For example, while EEG is a global estimate of brain-wide processing that is dominated by slow postsynaptic potentials in large groups of synchronized pyramidal cells (Luck and Kappenman, 2012), intracranial recordings that are commonly used in the rhesus monkey measure electrical activity in the immediate vicinity of the electrode tip; there is therefore little to no direct overlap between the signals recorded by the two methods (Nelken and Ulanovsky, 2007). Thus, the presence or absence of an effect of tonal frequency on intracranial neural activity recorded from one small region of auditory cortex would have limited relevance to the question of whether the same effects will be observed in EEG, which would have direct translational relevance to humans.
Several studies have shown that EEG in the rhesus monkey can be recorded directly from the scalp (Attaheri et al., 2015, Gil-da-Costa et al., 2013, Gindrat et al., 2014, Honing et al., 2012, Itoh et al., 2015). Scalp recordings have the advantage of being homologous to human EEG. However, scalp EEG in the rhesus monkey faces certain technical challenges. (1) It requires daily setup, as EEG scalp electrodes need to be positioned anew for each recording session. This introduces a potential source of variability as electrode position and/or impedance may vary between days. (2) In contrast to humans, rhesus monkeys have thicker temporalis muscles that cover much of the lateral aspect of their skulls. This can lead to stronger signal attenuation and/or muscle artifacts (Woodman, 2013). (3) Finally, while scalp EEG is ideally suited to be complemented by fMRI (Gil-da-Costa et al., 2013), it is less suitable for combination with invasive methods that could relate the observed EEG signals to intracranial processes.
As an alternative to scalp EEG, a number of researchers have recorded EEG from electrodes embedded in, but not penetrating through, the skull (Godlove et al., 2011, Purcell et al., 2013, Sander et al., 2010, Woodman et al., 2007). EEG recorded from the skull (cranial EEG) does not suffer from the technical challenges of scalp EEG: (1) Skull electrodes are implanted permanently so that setup time is negligible and day-to-day variability is minimal. (2) Skull electrodes can be covered by a layer of acrylic to reduce the volume conduction of artifacts from the temporalis muscles. (3) Hardware necessary for more invasive techniques can be embedded in the same head-cap that encloses the cranial EEG electrodes. This method has therefore received growing interest in the fields of visual and cognitive neuroscience (Godlove et al., 2011, Purcell et al., 2013, Sander et al., 2010, Woodman et al., 2007). Its potential as a translational platform was showcased by a series of studies that used rhesus monkey cranial EEG as a bridge method to relate the N2b, an EEG component recorded from the human scalp, to intracranial neural activity in the monkey frontal eye-field (Purcell et al., 2013, Woodman, 2013, Woodman et al., 2007). In the auditory domain cranial EEG has received less attention. For example, while the topography of auditory components in the rhesus monkey has been described in great detail using epidural ECoG recordings (Arezzo et al., 1975), no study has systematically described these components using cranial EEG. Hence, it is not known how rhesus monkey cranial EEG components compare to scalp EEG in the human (Näätänen and Picton, 1987, Picton et al., 1974, Woods et al., 1993) as well as the monkey (Gil-da-Costa et al., 2013, Itoh et al., 2015) on the one hand, and monkey ECoG on the other (Arezzo et al., 1975, Legatt et al., 1986). The recording of AEPs with cranial EEG will be particularly informative because it can build on detailed descriptions of intracranial auditory components using both ECoG and Current Source Density (CSD) (Arezzo et al., 1975, Fishman, 2014, Javitt et al., 1996, Javitt et al., 1994, Legatt et al., 1986).
The current study will compare two basic properties of rhesus monkey cranial EEG to well-established findings from human scalp EEG. In particular, the study will focus on two findings related to tonal frequency: (a) the dependence of N1 amplitude on tonal frequency (Antinoro et al., 1969, Antinoro and Skinner, 1968, Picton et al., 1978, Stelmack et al., 1977); and (b) changes of component topography with tonal frequency (Woods et al., 1993). This study will test if both of these effects can be detected in rhesus monkey cranial EEG, to strengthen the translational potential of the rhesus monkey for the study of auditory function in general, and auditory deficits in SZ in particular. In order to provide a solid foundation for these two main questions, the paper also provides a detailed phenomenological description of timing and topography of auditory EEG components that can be recorded from the rhesus monkey skull. This will ultimately help to further establish cranial EEG as a translational platform for future studies of auditory function that combine intracranial recordings and microinjection with cranial EEG and behavior. Furthermore, the study aims to relate auditory evoked potentials recorded from the skull to potentials previously recorded from rhesus monkey epidural ECoG electrodes (Arezzo et al., 1975).
Section snippets
Identification and description of extracranial auditory EEG components
Electrical activity was recorded from arrays of up to 32 cranial EEG electrodes implanted in four rhesus macaques (Fig. 1) while the animals passively listened to sequences of brief 80 dB SPL loud tones (Fig. 2). Fig. 3 provides an example of the auditory evoked EEG responses in the rhesus monkey following the presentation of pure tones with a tonal frequency between 500 and 4000 Hz and a 5 ms onset taper. For the representative example animal in Fig. 3, the first 50 ms after tone-onset was
Discussion
The current study identified and described 8 AEPs recorded with up to 32 cranial electrodes from the skulls of 4 awake rhesus macaques. The identified potentials share many similarities both with intracranially recorded epidural potentials in the rhesus monkey as well as EEG potentials recorded from the scalp in both humans (Näätänen and Picton, 1987, Picton et al., 1974, Woods et al., 1993) and macaques (Attaheri et al., 2015, Gil-da-Costa et al., 2013, Honing et al., 2012, Itoh et al., 2015).
Subjects
Experiments were performed on 4 adult male macaque monkeys (monkeys R, W, J and S). The treatment of the monkeys was in accordance with the guidelines set by the U.S. Department of Health and Human Services (National Institutes of Health) for the care and use of laboratory animals. All methods were approved by the Institutional Animal Care and Use Committee at the University of Pittsburgh. One animal (animal R, 10.5 kg, 12 years) had previously performed simple cognitive tasks in a different
Conflicts of interest
None of the authors have potential conflicts of interest to be disclosed.
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