Quantitative susceptibility mapping reveals alterations of dentate nuclei in common types of degenerative cerebellar ataxias.

The cerebellar nuclei are a brain region with high iron content. Surprisingly, little is known about iron content in the cerebellar nuclei and its possible contribution to pathology in cerebellar ataxias, with the only exception of Friedreich's ataxia. In the present exploratory cross-sectional study, quantitative susceptibility mapping was used to investigate volume, iron concentration and total iron content of the dentate nuclei in common types of hereditary and non-hereditary degenerative ataxias. Seventy-nine patients with spinocerebellar ataxias of types 1, 2, 3 and 6; 15 patients with Friedreich's ataxia; 18 patients with multiple system atrophy, cerebellar type and 111 healthy controls were also included. All underwent 3 T MRI and clinical assessments. For each specific ataxia subtype, voxel-based and volumes-of-interest-based group analyses were performed in comparison with a corresponding age- and sex-matched control group, both for volume, magnetic susceptiblity (indicating iron concentration) and susceptibility mass (indicating total iron content) of the dentate nuclei. Spinocerebellar ataxia of type 1 and multiple system atrophy, cerebellar type patients showed higher susceptibilities in large parts of the dentate nucleus but unaltered susceptibility masses compared with controls. Friedreich's ataxia patients and, only on a trend level, spinocerebellar ataxia of type 2 patients showed higher susceptibilities in more circumscribed parts of the dentate. In contrast, spinocerebellar ataxia of type 6 patients revealed lower susceptibilities and susceptibility masses compared with controls throughout the dentate nucleus. Spinocerebellar ataxia of type 3 patients showed no significant changes in susceptibility and susceptibility mass. Lower volume of the dentate nuclei was found to varying degrees in all ataxia types. It was most pronounced in spinocerebellar ataxia of type 6 patients and least prominent in spinocerebellar ataxia of type 3 patients. The findings show that alterations in susceptibility revealed by quantitative susceptibility mapping are common in the dentate nuclei in different types of cerebellar ataxias. The most striking changes in susceptibility were found in spinocerebellar ataxia of type 1, multiple system atrophy, cerebellar type and spinocerebellar ataxia of type 6. Because iron content is known to be high in glial cells but not in neurons of the cerebellar nuclei, the higher susceptibility in spinocerebellar ataxia of type 1 and multiple system atrophy, cerebellar type may be explained by a reduction of neurons (increase in iron concentration) and/or an increase in iron-rich glial cells, e.g. microgliosis. Hypomyelination also leads to higher susceptibility and could also contribute. The lower susceptibility in SCA6 suggests a loss of iron-rich glial cells. Quantitative susceptibility maps warrant future studies of iron content and iron-rich cells in ataxias to gain a more comprehensive understanding of the pathogenesis of these diseases.

Motor training-related brain reorganization in patients with cerebellar degeneration.

Cerebellar degeneration progressively impairs motor function. Recent research showed that cerebellar patients can improve motor performance with practice, but the optimal feedback type (visual, proprioceptive, verbal) for such learning and the underlying neuroplastic changes are unknown. Here, patients with cerebellar degeneration (N = 40) and age- and sex-matched healthy controls (N = 40) practiced single-joint, goal-directed forearm movements for 5 days. Cerebellar patients improved performance during visuomotor practice, but a training focusing on either proprioceptive feedback, or explicit verbal feedback and instruction did not show additional benefits. Voxel-based morphometry revealed that after training gray matter volume (GMV) was increased prominently in the visual association cortices of controls, whereas cerebellar patients exhibited GMV increase predominantly in premotor cortex. The premotor cortex as a recipient of cerebellar efferents appears to be an important hub in compensatory remodeling following damage of the cerebro-cerebellar motor system.

Neurostructural changes and declining sensorimotor function due to cerebellar cortical degeneration.

Neurodegeneration of the cerebellum progresses over years and primarily affects cerebellar cortex. It leads to a progressive loss of control and coordination of gait, posture, speech, fine motor, and oculomotor function. Yet, little is known how the cerebro-cerebellar network compensates for the loss in cerebellar cortical neurons. To address this knowledge gap, we examined 30 people with cerebellar cortical degeneration and a group of 30 healthy controls. We assessed visuomotor performance during a forearm-pointing task to 10°, 25°, and 50° targets. In addition, using MRI imaging, we determined neurodegenerative-induced changes in gray matter volume (GMV) in the cerebro-cerebellar network and correlated them to markers of motor performance. The main results are as follows: first, the relative joint position error (RJPE) during pointing was significantly greater in the ataxia group for all targets confirming the expected motor control deficit. Second, in the ataxia group, GMV was significantly reduced in cerebellar cortex but increased in the deep cerebellar nuclei. Motor error (RJPE) correlated negatively with decreased cerebellar GMV but positively with increased GMV in supplementary motor area (SMA) and premotor cortex. GMV of the deep cerebellar nuclei did not correlate significantly with markers of motor performance. We discuss whether the GMV changes in the cerebellar output nuclei and the extracerebellar efferent targets in secondary motor cortex can be understood as a central compensatory response to the neurodegeneration of the cerebellar cortex.NEW & NOTEWORTHY Neurodegeneration of the cerebellum progresses over years and primarily affects cerebellar cortex. It leads to a progressive loss of control and coordination of movement. We here show that the neurodegenerative process not only leads to cells loss in cerebellar cortex but also induces neurostructural changes in the form of increased gray matter in the efferent targets of the cerebellar cortex, namely, the cerebellar output nuclei, the SMA, and premotor cortex.

A pilot study: Auditory steady-state responses (ASSR) can be measured in human fetuses using fetal magnetoencephalography (fMEG).

BACKGROUND: Auditory steady-state responses (ASSRs) are ongoing evoked brain responses to continuous auditory stimuli that play a role for auditory processing of complex sounds and speech perception. Transient auditory event-related responses (AERRs) have previously been recorded using fetal magnetoencephalography (fMEG) but involve different neurological pathways. Previous studies in children and adults demonstrated that the cortical components of the ASSR are significantly affected by state of consciousness and by maturational changes in neonates and young infants. To our knowledge, this is the first study to investigate ASSRs in human fetuses. METHODS: 47 fMEG sessions were conducted with 24 healthy pregnant women in three gestational age groups (30-32 weeks, 33-35 weeks and 36-39 weeks). The stimulation consisted of amplitude-modulated (AM) tones with a duration of one second, a carrier frequency (CF) of 500 Hz and a modulation frequency (MF) of 27 Hz or 42 Hz. Both tones were presented in a random order with equal probability adding up to 80-100 repetitions per tone. The ASSR across trials was quantified by assessing phase synchrony in the cortical signals at the stimulation frequency. RESULTS AND CONCLUSION: Ten out of 47 recordings were excluded due to technical problems or maternal movements. Analysis of the included 37 fetal recordings revealed a statistically significant response for the phase coherence between trials for the MF of 27 Hz but not for 42 Hz. An exploratory subgroup analysis moreover suggested an advantage in detectability for fetal behavioral state 2F (active asleep) compared to 1F (quiet asleep) detected using fetal heart rate. In conclusion, this pilot study is the first description of a method to detect human ASSRs in fetuses. The findings warrant further investigations of the developing fetal brain.

Heart rate variability parameters and fetal movement complement fetal behavioral states detection via magnetography to monitor neurovegetative development.

Fetal behavioral states are defined by fetal movement and heart rate variability (HRV). At 32 weeks of gestational age (GA) the distinction of four fetal behavioral states represented by combinations of quiet or active sleep or awakeness is possible. Prior to 32 weeks, only periods of fetal activity and quiesence can be distinguished. The increasing synchronization of fetal movement and HRV reflects the development of the autonomic nervous system (ANS) control. Fetal magnetocardiography (fMCG) detects fetal heart activity at high temporal resolution, enabling the calculation of HRV parameters. This study combined the criteria of fetal movement with the HRV analysis to complete the criteria for fetal state detection. HRV parameters were calculated including the standard deviation of the normal-to-normal R-R interval (SDNN), the mean square of successive differences of the R-R intervals (RMSSD, SDNN/RMSSD ratio, and permutation entropy (PE) to gain information about the developing influence of the ANS within each fetal state. In this study, 55 magnetocardiograms from healthy fetuses of 24-41 weeks' GA were recorded for up to 45 min using a fetal biomagnetometer. Fetal states were classified based on HRV and movement detection. HRV parameters were calculated for each state. Before GA 32 weeks, 58.4% quiescence and 41.6% activity cycles were observed. Later, 24% quiet sleep state (1F), 65.4% active sleep state (2F), and 10.6% active awake state (4F) were observed. SDNN increased over gestation. Changes of HRV parameters between the fetal behavioral states, especially between 1F and 4F, were statistically significant. Increasing fetal activity was confirmed by a decrease in PE complexity measures. The fHRV parameters support the differentiation between states and indicate the development of autonomous nervous control of heart rate function.

Magnetoencephalographic signatures of numerosity discrimination in fetuses and neonates.

Numerosity discrimination has been demonstrated in newborns, but not in fetuses. Fetal magnetoencephalography allows non-invasive investigation of neural responses in neonates and fetuses. During an oddball paradigm with auditory sequences differing in numerosity, evoked responses were recorded and mismatch responses were quantified as an indicator for auditory discrimination. Thirty pregnant women with healthy fetuses (last trimester) and 30 healthy term neonates participated. Fourteen adults were included as a control group. Based on measurements eligible for analysis, all adults, all neonates, and 74% of fetuses showed numerical mismatch responses. Numerosity discrimination appears to exist in the last trimester of pregnancy.

Perceptual organization of auditory streaming-task relies on neural entrainment of the stimulus-presentation rate: MEG evidence.

BACKGROUND: Humans are able to extract regularities from complex auditory scenes in order to form perceptually meaningful elements. It has been shown previously that this process depends critically on both the temporal integration of the sensory input over time and the degree of frequency separation between concurrent sound sources. Our goal was to examine the relationship between these two aspects by means of magnetoencephalography (MEG). To achieve this aim, we combined time-frequency analysis on a sensor space level with source analysis. Our paradigm consisted of asymmetric ABA-tone triplets wherein the B-tones were presented temporally closer to the first A-tones, providing different tempi within the same sequence. Participants attended to the slowest B-rhythm whilst the frequency separation between tones was manipulated (0-, 2-, 4- and 10-semitones). RESULTS: The results revealed that the asymmetric ABA-triplets spontaneously elicited periodic-sustained responses corresponding to the temporal distribution of the A-B and B-A tone intervals in all conditions. Moreover, when attending to the B-tones, the neural representations of the A- and B-streams were both detectable in the scenarios which allow perceptual streaming (2-, 4- and 10-semitones). Alongside this, the steady-state responses tuned to the presentation of the B-tones enhanced significantly with increase of the frequency separation between tones. However, the strength of the B-tones related steady-state responses dominated the strength of the A-tones responses in the 10-semitones condition. Conversely, the representation of the A-tones dominated the B-tones in the cases of 2- and 4-semitones conditions, in which a greater effort was required for completing the task. Additionally, the P1 evoked fields' component following the B-tones increased in magnitude with the increase of inter-tonal frequency difference. CONCLUSIONS: The enhancement of the evoked fields in the source space, along with the B-tones related activity of the time-frequency results, likely reflect the selective enhancement of the attended B-stream. The results also suggested a dissimilar efficiency of the temporal integration of separate streams depending on the degree of frequency separation between the sounds. Overall, the present findings suggest that the neural effects of auditory streaming could be directly captured in the time-frequency spectrum at the sensor-space level.

Sensitivity to Auditory Spectral Width in the Fetus and Infant - An fMEG Study.

Auditory change detection is crucial for the development of the auditory system and a prerequisite for language development. In neonates, stimuli with broad spectral width like white noise (WN) elicit the highest response compared to pure tone and combined tone stimuli. In the current study we addressed for the first time the question how fetuses react to "WN" stimulation. Twenty-five fetuses (M age = 34.59 weeks GA, SD ± 2.35) and 28 healthy neonates and infants (M age = 37.18 days, SD ± 15.52) were tested with the first paradigm, wherein 500 Hz tones, 750 Hz tones, and WN segments were randomly presented and auditory evoked responses (AERs) were measured using fetal magnetoencephalography (fMEG). In the second paradigm, 12 fetuses (M age = 25.7 weeks GA, SD ± 2.4) and 6 healthy neonates (M age = 23 days and SD ± 6.2) were presented with two auditory oddball conditions: condition 1 consisted of attenuated WN as standard and 500 Hz tones and WN as deviants. In condition 2, standard 500 Hz tones were intermixed with WN and attenuated WN. AERs to volume change and change in spectral width were evaluated. In both paradigms, significantly higher AER amplitudes to WN than to pure tones replicated prior findings in neonates and infants. In fetuses, no significant differences were found between the auditory evoked response amplitudes of WN segments and pure tones (both paradigms). A trend toward significance was reached when comparing the auditory evoked response amplitudes elicited by attenuated WN with those elicited by WN (loudness change, second paradigm). As expected, we observed high sensibility to spectral width in newborns and infants. However, in the group of fetuses, no sensibility to spectral width was observed. This negative finding may be caused by different attenuation levels of the maternal tissue for different frequency components.

Modulations of neural activity in auditory streaming caused by spectral and temporal alternation in subsequent stimuli: a magnetoencephalographic study.

BACKGROUND: The aim of the present study was to identify a specific neuronal correlate underlying the pre-attentive auditory stream segregation of subsequent sound patterns alternating in spectral or temporal cues. Fifteen participants with normal hearing were presented with series' of two consecutive ABA auditory tone-triplet sequences, the initial triplets being the Adaptation sequence and the subsequent triplets being the Test sequence. In the first experiment, the frequency separation (delta-f) between A and B tones in the sequences was varied by 2, 4 and 10 semitones. In the second experiment, a constant delta-f of 6 semitones was maintained but the Inter-Stimulus Intervals (ISIs) between A and B tones were varied. Auditory evoked magnetic fields (AEFs) were recorded using magnetoencephalography (MEG). Participants watched a muted video of their choice and ignored the auditory stimuli. In a subsequent behavioral study both MEG experiments were replicated to provide information about the participants' perceptual state. RESULTS: MEG measurements showed a significant increase in the amplitude of the B-tone related P1 component of the AEFs as delta-f increased. This effect was seen predominantly in the left hemisphere. A significant increase in the amplitude of the N1 component was only obtained for a Test sequence delta-f of 10 semitones with a prior Adaptation sequence of 2 semitones. This effect was more pronounced in the right hemisphere. The additional behavioral data indicated an increased probability of two-stream perception for delta-f = 4 and delta-f = 10 semitones with a preceding Adaptation sequence of 2 semitones. However, neither the neural activity nor the perception of the successive streaming sequences were modulated when the ISIs were alternated. CONCLUSIONS: Our MEG experiment demonstrated differences in the behavior of P1 and N1 components during the automatic segregation of sounds when induced by an initial Adaptation sequence. The P1 component appeared enhanced in all Test-conditions and thus demonstrates the preceding context effect, whereas N1 was specifically modulated only by large delta-f Test sequences induced by a preceding small delta-f Adaptation sequence. These results suggest that P1 and N1 components represent at least partially-different systems that underlie the neural representation of auditory streaming.

Fetal Magnetoencephalography - Achievements and Challenges in the Study of Prenatal and Early Postnatal Brain Responses: A Review.

Fetal magnetoencephalography (fMEG) is the only non-invasive method for investigating evoked brain responses and spontaneous brain activity generated by the fetus in utero. Fetal auditory as well as visual evoked fields have been successfully recorded in basic stimulus-response studies. Moreover, paradigms investigating precursors for cognitive development, such as habituation and mismatch response have been applied successfully with fMEG. These and other studies have shown that the prenatal stage of life could be an important indicator for later cognitive development. This review addresses the achievements of fMEG and constructively discusses its challenges. It concludes with proposals for future studies as well as with designated new applications. Fetal MEG is a promising, and to date it is the only non-invasive approach for the prenatal assessment of precursors for cognitive development. Future fMEG studies might even enable the diagnosis of developmental delays. Furthermore, fMEG could be critical for the implementation and evaluation of fetal intervention programs in at-risk populations.

Early development of brain responses to rapidly presented auditory stimulation: a magnetoencephalographic study.

BACKGROUND: The processing of rapidly presented stimuli has been shown to be a precursor for the perception of speech in infants, long before they learn to speak. However, the onset and early development of rapid temporal processing (RTP) skills is not yet well understood. The main goal of this study was to assess the development of RTP skills during the prenatal and early postnatal stages of life. METHODOLOGY: Tone pairs were presented in two difficulties (long and short) and event-related magnetic fields were recorded using MEG. Pregnant women (22) (gestational ages between 29 and 38 weeks') participated in the fetal study and 15 returned for a neonatal follow-up study between 2 and 38 days after delivery or 38 and 44 weeks gestational age (GA). RESULTS: In the postnatal follow-up study, a trend towards two peaks with increasing chronological and gestational age was observed in the longer tone pair. However, no such trend was evident in neonatal responses to the short tone pairs or in fetal recordings. CONCLUSIONS: Neonates showed a gradual trend to successful processing of the longer tone pair with increasing age. By 22 days of chronological age, the infants processed this tone pair successfully, as indicated by two-peak waveforms. Therefore, the first 3 weeks of life could be critical for the development of RTP. SIGNIFICANCE: This study is a first approach towards the assessment of early RTP development. The results provide promising indications for future studies, which might lead to an early detection of deficits in speech perception and therefore prevent further language impairments.

Modulation of auditory evoked responses to spectral and temporal changes by behavioral discrimination training.

BACKGROUND: Due to auditory experience, musicians have better auditory expertise than non-musicians. An increased neocortical activity during auditory oddball stimulation was observed in different studies for musicians and for non-musicians after discrimination training. This suggests a modification of synaptic strength among simultaneously active neurons due to the training. We used amplitude-modulated tones (AM) presented in an oddball sequence and manipulated their carrier or modulation frequencies. We investigated non-musicians in order to see if behavioral discrimination training could modify the neocortical activity generated by change detection of AM tone attributes (carrier or modulation frequency). Cortical evoked responses like N1 and mismatch negativity (MMN) triggered by sound changes were recorded by a whole head magnetoencephalographic system (MEG). We investigated (i) how the auditory cortex reacts to pitch difference (in carrier frequency) and changes in temporal features (modulation frequency) of AM tones and (ii) how discrimination training modulates the neuronal activity reflecting the transient auditory responses generated in the auditory cortex. RESULTS: The results showed that, additionally to an improvement of the behavioral discrimination performance, discrimination training of carrier frequency changes significantly modulates the MMN and N1 response amplitudes after the training. This process was accompanied by an attention switch to the deviant stimulus after the training procedure identified by the occurrence of a P3a component. In contrast, the training in discrimination of modulation frequency was not sufficient to improve the behavioral discrimination performance and to alternate the cortical response (MMN) to the modulation frequency change. The N1 amplitude, however, showed significant increase after and one week after the training. Similar to the training in carrier frequency discrimination, a long lasting involuntary attention to the deviant stimulus was observed. CONCLUSION: We found that discrimination training differentially modulates the cortical responses to pitch changes and to envelope fluctuation changes of AM tones. This suggests that discrimination between AM tones requires additional neuronal mechanisms compared to discrimination process between pure tones. After the training, the subjects demonstrated an involuntary attention switch to the deviant stimulus (represented by the P3a-component in the MEG) even though attention was not prerequisite.

Hemispheric asymmetry of auditory evoked fields elicited by spectral versus temporal stimulus change.

The investigation of functional hemispheric asymmetries regarding auditory processing in the human brain still remains a challenge. Classical lesion and recent neuroimaging studies indicated that speech is dominantly processed in the left hemisphere, whereas music is dominantly processed in the right. However, recent studies demonstrated that the functional hemispheric asymmetries were not limited to the processing of highly cognitive sound signals like speech and music but rather originated from the basic neural processing of elementary sound features, that is, spectral and temporal acoustic features. Here, in contrast to previous studies, we used carefully composed tones and pulse trains as stimuli, balanced the overall physical sound input between spectral and temporal change conditions, and demonstrated the time course of neural activity evoked by spectral versus temporal sound input change by means of magnetoencephalography (MEG). These original findings support the hypothesis that spectral change is dominantly processed in the right hemisphere, whereas temporal change is dominantly processed in the left.

Cortical steady-state responses to central and peripheral auditory beats.

Different types of generation mechanisms of 40-Hz auditory steady-state response (ASSR) were investigated using diotic and dichotic stimulation with 500- and 540-Hz pure tones of 1.0-s duration and 2.0-s stimulus onset asynchrony. When the sum of both tones was presented to both ears simultaneously, they interacted at cochlear level and resulted in perception of a 40-Hz beat termed "peripheral beat." Dichotic presentation of the 500-Hz tone to one ear and the 540-Hz tone to the other one resulted in beat perception as the effect of central interaction, most likely in the superior olivary nuclei and was termed "central beat." ASSR and transient N1m responses were found in the averaged 151-channel whole-head magnetoencephalographic recordings under both stimulus conditions and were modeled with single spatiotemporal equivalent current dipoles in both hemispheres. The ASSR sources in both conditions were more anterior, more inferior, and more medial compared with N1m sources. Right hemispheric lateralization of the magnetic field strength was found for the ASSR in both stimulus conditions. Although the central and peripheral beat interacted at different levels of the auditory system, the initial responses were projected along the afferent auditory pathway and activated common cortical sources.

Serial magnetoencephalographic study of fetal and newborn auditory discriminative evoked responses.

The mismatch negativity (MMN) response elicited to auditory stimuli is an indicator for cognitive function of sound discrimination in humans. MMN was successfully recorded in previous studies in newborns and fetuses (33-40 weeks of gestation) with magnetoencephalography (MEG). The aim of our study was to perform systematic serial MMN recordings on fetuses starting at 28 weeks of gestation with a follow up recording within 2 weeks after birth. The recording of weak magnetic fields from the fetal brain were performed with the 151 channel MEG system called SARA (SQUID Array for Reproductive Assessment). Two tone bursts were presented in a sequence of a standard complex tone of 500 Hz intermixed with a deviant complex tone of 750 Hz in 12% of the stimuli, inter-stimulus interval 800+/-100 ms. Eighteen pregnant women between 28th and 39th gestational weeks participated in the study. Measurements were performed every two weeks and once after delivery. The averaged evoked responses to standard and deviant tones were obtained and subtraction between them was calculated. A successful detection of response to the frequency change was found in 66% of the fetal data and 89% of the neonatal data. Responses to the standard tone were detected in 56% of all records. In the 28-39 week gestational age group, the discriminative brain responses to tone frequency change could be detected as early as 28 weeks. Although not statistically significant, a decrease in latency was observed with increase in gestational age. The ability of the fetus to detect changes in sounds is a prerequisite to normal development for cognitive function; related to language learning and clinical aspects of auditory disorders.

Sound frequency change detection in fetuses and newborns, a magnetoencephalographic study.

The mismatch negativity (MMN) response to auditory stimuli has been successfully recorded in newborns thus demonstrating the discriminative cognitive ability. The aim of our study was to determine whether and when such an MMN response could be detected in the human fetus. The recordings of weak magnetic fields from the fetal brain were performed with the 151 channel MEG system called SARA (SQUID Array for Reproductive Assessment). Two tone bursts were presented in a sequence of a standard complex tone of 500 Hz intermixed with a deviant complex tone of 750 Hz in 12% of the stimuli. Sound intensity delivered over the maternal abdomen was 110 dB. The interstimulus interval (ISI) varied between 500 ms and 1100 ms. Fetal response, corresponding to sound frequency change detection, was calculated from the records where responses to standard and deviant tones were observed. A successful response was found in 60% of 25 fetal recordings. The MMN response with an average latency of 321 ms was observed in 48% of the fetal data. In 12% of the fetal data, a late component, referred to as the late discriminative negativity (LDN) response, was detected with an average latency of 458 ms. The same paradigm was applied in 5 newborns after birth. The capability for sound discrimination is a prerequisite for normal speech development. The investigation of sound discrimination and related cortical activity of the fetus can help to identify and determine the nature of deficits caused by central processes in the auditory system at very early stages.

Frequency specificity of 40-Hz auditory steady-state responses.

Auditory steady-state responses (ASSR) to amplitude modulated (AM) tones with carrier frequencies between 250 and 4000 Hz and modulation frequencies near 40 Hz were recorded using a 37-channel neuro-magnetometer placed above the auditory cortex contralateral to the stimulated right ear. The ASSR sources were likely in the primary auditory cortex, located more anteriorly and more medially than the N1m sources. The ASSR amplitude decreased with increasing carrier frequency, the amplitude at 250 Hz being three times larger than at 4000 Hz. The amplitude of the ASSR to a test sound decreased in the presence of an interfering second AM sound. This suppression of the ASSR to the test stimulus was greater when the carrier frequency of the interfering stimulus was higher than that of the test tone and was greater when the test stimulus had a lower carrier frequency. Similar frequency specificity was observed when the interfering sound was a non-modulated pure tone. These results differ from those found for the ASSR elicited by modulation frequencies above 80 Hz or for the transient brainstem and middle-latency responses and suggest substantial interactions between phase-locked activities at the level of the primary auditory cortex.

Auditory cortical response patterns to multiple rhythms of AM sound.

OBJECTIVE: Multiple amplitude modulation (AM) of a tone results in a time series with a complex structure of envelope fluctuations. In this study the cortical responses elicited by such an auditory stimulus were investigated. It was hypothesized that the auditory cortex responds simultaneously with different patterns of activity corresponding to the different rhythm of periodical stimulus fluctuations. The relations of these response patterns to either steady-state responses (SSR) in the 40 Hz range or the transient slow auditory evoked responses were investigated. DESIGN: Auditory evoked magnetic fields were recorded from the left temporal cortex of nine healthy humans in response to 250 Hz tones that were amplitude modulated with the sum of two sinusoids of 38 and 40 Hz. The stimulus was presented continuously to the subject's right ear at the intensity of 70 dB sensation level. In addition, the responses to 250 Hz tone-burst stimuli with duration of 20, 50, 100, and 200 msec, respectively, were recorded. The tone-bursts were presented at an inter-stimulus interval (ISI) of 0.5 sec, which was equivalent to the slowest rhythm of the multiple-AM stimulus. Magnetic source analysis was applied to all elicited waveforms. RESULTS: From all subjects SSR at 38 and 40 Hz were clearly recognizable and were superimposed by a periodical response pattern corresponding to 2 Hz stimulus envelope fluctuations. A positive peak with latency of 70 msec was the mostly pronounced response to tone-burst stimulation at the ISI of 0.5 sec and resembles the low-frequency response pattern to the AM stimulus. The N1-P2 complex showed an almost complete suppression at 0.5 sec ISI. In contrast, it was the most prominent evoked response activity when using a longer ISI of 3 sec. Source locations in overlapping areas were estimated for the SSR in the 40 Hz range, the prominent peak of low-frequency response to the AM stimulus, and the P1 peak at tone-burst stimulation, respectively. These were separated from the N1 source location by about 0.5 cm in anterior and 0.5 cm in medial direction. CONCLUSION: As a result of multiple AM the stimulus signal envelope fluctuates with frequencies of 2 Hz and around 40 Hz. The auditory cortex responds to this stimulus with different response patterns. Both modulation signals at 38 and 40 Hz were almost linearly represented as steady-state responses. The evoked response patterns to stimulus fluctuations at low-frequency rhythm resemble the slow cortical auditory evoked responses. The 2 Hz stimulus rhythm is perceived as loudness fluctuation, and 40 Hz modulation is perceived as a rough sound. It is assumed that the different cortical representations correspond to both types of perception of the complex AM sound.