Mapping the 40-Hz auditory steady-state response using current density reconstructions
Introduction
The aSSR is an oscillation of the electrical potential on the scalp that follows the envelope of periodic stimuli such as amplitude modulated (AM) tones or click trains. First reported as a 40-Hz aSSR in 1981 by Galambos et al. (1981), SSRs have been found at other modulation rates (Rickards and Clark, 1984), and in other sensory systems (Snyder, 1992, Tallon-Baudry et al., 1997). While higher modulation frequencies are less dependent on subject state, the 40-Hz aSSR is typically larger and can be used as a rapid, objective hearing screening test in adults (Aoyagi et al., 1993).
The proposed models of aSSR generation can be divided into focal models, with activity dominated by either cortical or subcortical sites, and distributed models, involving resonance between thalamic and cortical structures. There is conflicting evidence as to which of these models best describes the origin of the aSSR.
The focal cortical hypothesis is supported by source-localization studies in humans (Gutschalk et al., 1999, Pantev et al., 1996) using magnetoencephalography (MEG). Pantev et al. (1996) used MEG to record the 40-Hz aSSR over the contralateral scalp with a 37-channel magnetometer and modeled the generator as a single moving dipole in the superior temporal gyrus. The position of this dipole oscillated from medial to lateral and back to medial as the aSSR varied sinusoidally at the modulation frequency. They also confirmed the results of Romani et al. (1982), who found that the aSSR is tonotopically arranged in the cortex when modeled by a single moving dipole, with high carrier frequencies located medial to low frequencies. Gutschalk et al. (1999) used a 122-channel whole-head magnetometer to localize the generators of a deconvolved aSSR near 40 Hz. They modeled the sources as two pairs of symmetric fixed dipoles, one pair in the superior temporal gyrus on each side. Changes in the 40 Hz aSSR with alertness (Dobie and Wilson, 1998), attention (Tiitinen et al., 1993), and anesthesia (Gilron et al., 1998, Plourde, 1993) also suggest a predominantly cortical generation site. The cortical hypothesis is supported by the morphologic similarity between the 40-Hz aSSR electrical waveform recorded from the surface of cat cortex (Makela et al., 1990), and the scalp potential recorded from humans. In the rat, the phase of this response reversed as the electrode advanced through the outer layer of the cortex, providing strong evidence that the aSSR is generated in the cortex (Franowicz and Barth, 1995).
Rickards and Clark (1984) found large phase shifts between the aSSR at low (25–70 Hz) and high (75–200 Hz) modulation rates. This phase shift, which represents a change in response latency, was interpreted as a change in the response generator. Moreover, John and Picton (2000) found latencies of 10 ms for the aSSR evoked by stimuli with modulation frequencies of 150–190 Hz. This is consistent with a generator at the same level as wave V of the auditory brainstem response (ABR), supporting the subcortical hypothesis at high modulation rates.
Lesion studies have also suggested subcortical generation sites for the aSSR, even at 40 Hz. Investigators have found that aspiration of the feline auditory cortex did not change the 40-Hz aSSR (Kiren et al., 1994). They also found that ipsilateral inferior colliculus lesions reduced the amplitude of the aSSR and contralateral inferior colliculus lesions abolished it. Others have found decreases in amplitude and increases in latency of the 40-Hz aSSR when patients with thalamic lesions were compared to controls (Spydell et al., 1985). However, only one of the five patients with temporal lobe lesions had amplitudes or latencies outside the control range. They concluded that the aSSR was generated subcortically.
A recent case report (Santarelli and Conti, 1999) suggests that while subcortical sites may be necessary for generating the aSSR, they may not be sufficient. They recorded a robust middle latency response (MLR), but no aSSR, in a patient in which both auditory cortices were intact, but multiple ischemic lesions were found in the white matter connecting cortex to thalamus. As the MLR is thought to reflect activity in both primary and non-primary thalamo-cortical pathways (Kraus and McGee, 1995), the presence of the MLR suggests that ascending auditory pathways are intact. The absence of the aSSR in this patient suggests that a thalamo-cortical network in addition to the pathway responsible for the MLR is required to generate the aSSR. Assuming that the sources of the aSSR at 40 Hz were broadly distributed from temporal cortex to thalamus, Ribary et al. (1991) found MEG source-localization data supporting a thalamo-cortical network generating the aSSR.
The results of other studies have suggested that the aSSR may influence activity in even more widely distributed regions of the brain. Patel and Balaban (2000) studied changes in the phase of the 40-Hz aSSR across carrier frequency. They found significant coherence between frontal and occipital sources when the carrier frequency changed in melodic fashion. This suggests that the 40-Hz aSSR may have additional components generated by frontal and occipital sources. Frontal sources are not without precedence in the auditory evoked potential literature. For example, Picton et al. (1999) found mN100 sources in the temporal lobes, as well as frontal regions using focal and distributed source models.
The lack of consensus concerning the generators of the aSSR prompted us to conduct additional studies to help define the origins of the aSSR. Using positron emission tomography, we compared the brain regions activated by a continuous, 85 dB SPL 1 kHz tones versus the same tone modulated at 40 Hz at 100% modulation depth (Reyes et al., 2004). Using the same subjects and same stimuli, we now report on the electrophysiological source-localization results using 64 electrode scalp recordings. To identify the electrophysiological generators of the aSSR, we employed current density reconstruction methods (LORETA and MinNorm) because they make no assumptions about the number of sources. These analyses will include source-localization in isolation as well as weighted source-localization incorporating the PET results from these same subjects.
Section snippets
Subjects
Nine young-adult subjects (five female, four male, mean age 26, standard deviation 4) participated in this study. They all gave their informed written consent to participate and all protocols were reviewed and approved by the Radioactive Drug Research Committee, the Radiation Safety Committee and the Institutional Review Board of the Veteran’s Administration Western New York Healthcare System as required by the Declaration of Helsinki. Each subject’s hearing was evaluated using pure tone
Topography
Fig. 1(a) shows the grand mean waveform (at Cz) following CAR. Note that in the 100-ms time window, there are four cycles of the 40-Hz response (i.e., four repetitions of the 25-ms period of the 40-Hz response). The isopotential map (Fig. 1(b)) clearly shows a change in polarity across the scalp with a broad negativity antero-centrally and a broad positivity postero-laterally. This figure also demonstrates how the polarity in these regions reverses over the course of one cycle of the 40-Hz aSSR
Discussion
The goal of this study was to map the structures and sequence of activation underlying the 40-Hz aSSR. To identify the structures, we assumed that PET was the gold standard in identifying the location of brain activity evoked by acoustic stimulation and incorporated data from a PET study using the same subjects and stimuli (Reyes et al., 2004). To study the sequence of activation, we took advantage of the temporal resolution of EPs, which is several orders of magnitude better than functional
Summary
LORETA analysis independent of the PET results identified peaks in current density in right temporal lobe, right brainstem/cerebellum, right parietal lobe, left cerebellum/temporal lobe, and right frontal lobe. Using the PET results to inform LORETA did not substantively change the cortical sources, but eliminated the subcortical source, and added two right frontal sources. Both LORETA analyses revealed considerable phase dispersion across identified sources. MinNorm analysis incorporating PET
Acknowledgments
This work was completed as part of the doctoral dissertation of the first author. This work was supported by NIH (DC3306 and DC04835), as well as the James H. Cummings Foundation, Buffalo, NY.
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