Yonatan I. Fishman

Click train encoding in primary auditory cortex of the awake monkey: Evidence for two mechanisms subserving pitch perception

Multiunit activity (MUA) and current source density (CSD) patterns evoked by click trains are examined in primary auditory cortex (A1) of three awake monkeys. Temporal and spectral features of click trains are differentially encoded in A1. Encoding of temporal features occurs at rates of 100-200 Hz through phase-locked activity in the MUA and CSD, is independent of pulse polarity pattern, and occurs in high best frequency (BF) regions of A1. The upper limit of ensemble-wide phase-locking is about 400 Hz in the input to A1, as manifested in the cortical middle laminae CSD and MUA of thalamocortical fibers. In contrast, encoding of spectral features occurs in low BF regions, and resolves both the f0 and harmonics of the stimuli through local maxima of activity determined by the tonotopic organization of the recording sites. High-pass filtered click trains decrease spectral encoding in low BF regions without modifying phase-locked responses in high BF regions. These physiological responses parallel features of human pitch perception for click trains, and support the existence of two distinct physiological mechanisms involved in pitch perception: the first using resolved harmonic components and the second utilizing unresolved harmonics that is based on encoding stimulus waveform periodicity.

Searching for the Mismatch Negativity in Primary Auditory Cortex of the Awake Monkey: Deviance Detection or Stimulus Specific Adaptation?

The mismatch negativity (MMN) is a preattentive component of the auditory event-related potential that is elicited by a change in a repetitive acoustic pattern. While MMN has been extensively used in human electrophysiological studies of auditory processing, the neural mechanisms and brain regions underlying its generation remain unclear. We investigate possible homologs of the MMN in macaque primary auditory cortex (A1) using a frequency oddball paradigm in which rare “deviant” tones are randomly interspersed among frequent “standard” tones. Standards and deviants had frequencies equal to the best frequency (BF) of the recorded neural population or to a frequency that evoked a response half the amplitude of the BF response. Early and later field potentials, current source density components, multiunit activity, and induced high-gamma band responses were larger when elicited by deviants than by standards of the same frequency. Laminar analysis indicated that differences between deviant and standard responses were more prominent in later activity, thus suggesting cortical amplification of initial responses driven by thalamocortical inputs. However, unlike the human MMN, larger deviant responses were characterized by the enhancement of “obligatory” responses rather than the introduction of new components. Furthermore, a control condition wherein deviants were interspersed among many tones of variable frequency replicated the larger responses to deviants under the oddball condition. Results suggest that differential responses under the oddball condition in macaque A1 reflect stimulus-specific adaptation rather than deviance detection per se. We conclude that neural mechanisms of deviance detection likely reside in cortical areas outside of A1.

Representation of the voice onset time (VOT) speech parameter in population responses within primary auditory cortex of the awake monkey.

Voice onset time (VOT) signifies the interval between consonant onset and the start of rhythmic vocal-cord vibrations. Differential perception of consonants such as /d/ and /t/ is categorical in American English, with the boundary generally lying at a VOT of 20-40 ms. This study tests whether previously identified response patterns that differentially reflect VOT are maintained in large-scale population activity within primary auditory cortex (A1) of the awake monkey. Multiunit activity and current source density patterns evoked by the syllables /da/ and /ta/ with variable VOTs are examined. Neural representation is determined by the tonotopic organization. Differential response patterns are restricted to lower best-frequency regions. Response peaks time-locked to both consonant and voicing onsets are observed for syllables with a 40- and 60-ms VOT, whereas syllables with a 0- and 20-ms VOT evoke a single response time-locked only to consonant onset. Duration of aspiration noise is represented in higher best-frequency regions. Representation of VOT and aspiration noise in discrete tonotopic areas of A1 suggest that integration of these phonetic cues occurs in secondary areas of auditory cortex. Findings are consistent with the evolving concept that complex stimuli are encoded by synchronized activity in large-scale neuronal ensembles.

Pitch vs. spectral encoding of harmonic complex tones in primary auditory cortex of the awake monkey.

Neuromagnetic studies in humans and single-unit studies in monkeys have provided conflicting views regarding the role of primary auditory cortex (A1) in pitch encoding. While the former support a topographic organization based on the pitch of complex tones, single-unit studies support the classical tonotopic organization of A1 defined by the spectral composition of the stimulus. It is unclear whether the incongruity of these findings is due to limitations of noninvasive recordings or whether the discrepancy genuinely reflects pitch representation based on population encoding. To bridge these experimental approaches, we examined neuronal ensemble responses in A1 of the awake monkey using auditory evoked potential (AEP), multiple-unit activity (MUA) and current source density (CSD) techniques. Macaque monkeys can perceive the missing fundamental of harmonic complex tones and therefore serve as suitable animal models for studying neural encoding of pitch. Pure tones and harmonic complex tones missing the fundamental frequency (f0) were presented at 60 dB SPL to the ear contralateral to the hemisphere from which recordings were obtained. Laminar response profiles in A1 reflected the spectral content rather than the pitch (missing f0) of the compound stimuli. These findings are consistent with single-unit data and indicate that the cochleotopic organization is preserved at the level of A1. Thus, it appears that pitch encoding of multi-component sounds is more complex than suggested by noninvasive studies, which are based on the assumption of a single dipole generator within the superior temporal gyrus. These results support a pattern recognition mechanism of pitch encoding based on a topographic representation of stimulus spectral composition at the level of A1.

Complex tone processing in primary auditory cortex of the awake monkey. I. Neural ensemble correlates of roughness

Previous physiological studies [e.g., Bieser and Muller-Preuss, Exp. Brain Res. 108, 273-284 (1996); Schulze and Langner, J. Comp. Physiol. A 181, 651-663 (1997); Steinschneider et al., J. Acoust. Soc. Am. 104, 2935-2955 (1998)] have suggested that neural activity in primary auditory cortex (A1) phase-locked to the waveform envelope of complex sounds with low (<300 Hz) periodicities may represent a neural correlate of roughness perception. However, a correspondence between these temporal response patterns and human psychophysical boundaries of roughness has not yet been demonstrated. The present study examined whether the degree of synchronized phase-locked activity of neuronal ensembles in A1 of the awake monkey evoked by complex tones parallels human psychoacoustic data defining the existence region and frequency dependence of roughness. Stimuli consisted of three consecutive harmonics of fundamental frequencies (f(0)s) ranging from 25 to 4000 Hz. The center frequency of the complex tones was fixed at the best frequency (BF) of the cortical sites, which ranged from 0.3 to 10 kHz. Neural ensemble activity in the thalamorecipient zone (lower lamina III) and supragranular cortical laminae (upper lamina III and lamina II) was measured using multiunit activity and current source density techniques and the degree of phase-locking to the f0 was quantified by spectral analysis. In the thalamorecipient zone, the stimulus f0 at which phase-locking was maximal increased with BF and reached an upper limit between 75 and 150 Hz for BFs greater than about 3 kHz. Estimates of limiting phase-locking rates also increased with BF and approximated psychoacoustic values for the disappearance of roughness. These physiological relationships parallel human perceptual data and therefore support the relevance of phase-locked activity of neuronal ensembles in A1 for the physiological representation of roughness.

Complex tone processing in primary auditory cortex of the awake monkey. II. Pitch versus critical band representation

Noninvasive neurophysiological studies in humans support the existence of an orthogonal spatial representation of pure tone frequency and complex tone pitch in auditory cortex [Langner et al., J. Comp. Physiol. A 181, 665-676 (1997)]. However, since this topographic organization is based on neuromagnetic responses evoked by wideband harmonic complexes (HCs) of variable fundamental frequency (f0), and thus interharmonic frequency separation (deltaF), critical band filtering effects due to differential resolvability of harmonics may have contributed to shaping these responses. To test this hypothesis, the present study examined responses evoked by three-component HCs of variable f0 in primary auditory cortex (A1) of the awake monkey. The center frequency of the HCs was fixed at the best frequency (BF) of the cortical site. Auditory evoked potential (AEP), multiunit activity, and current source density techniques were used to evaluate A1 responses as a function of f0 (=deltaF). Generally, amplitudes of nearly all response components increased with f0, such that maximal responses were evoked by HCs comprised of low-order resolved harmonics. Statistically significant increases in response amplitude typically occurred at deltaFs between 10% and 20% of center frequency, suggestive of critical bandlike behavior. Complex tone response amplitudes also reflected nonlinear summation in that they could not be predicted by the pure tone frequency sensitivity curves of the cortical sites. A mechanism accounting for the observed results is proposed which involves mutual lateral inhibitory interactions between responses evoked by stimulus components lying within the same critical band. As intracortical AEP components likely to be propagated to the scalp were also strongly modulated by deltaF, these findings indicate that noninvasive recordings of responses to complex sounds may require a consideration of critical band effects in their interpretation.

The Mechanisms and Meaning of the Mismatch Negativity

The mismatch negativity (MMN) is a pre-attentive auditory event-related potential (ERP) component that is elicited by a change in a repetitive acoustic pattern. It is obtained by subtracting responses evoked by frequent ‘standard’ sounds from responses evoked by infrequent ‘deviant’ sounds that differ from the standards along some acoustic dimension, e.g., frequency, intensity, or duration, or abstract feature. The MMN has been attributed to neural generators within the temporal and frontal lobes. The mechanisms and meaning of the MMN continue to be debated. Two dominant explanations for the MMN have been proposed. According to the “neural adaptation” hypothesis, repeated presentation of the standards results in adapted (i.e., attenuated) responses of feature-selective neurons in auditory cortex. Rare deviant sounds activate neurons that are less adapted than those stimulated by the frequent standard sounds, and thus elicit a larger ‘obligatory’ response, which yields the MMN following the subtraction procedure. In contrast, according to the “sensory memory” hypothesis, the MMN is a ‘novel’ (non-obligatory) ERP component that reflects a deviation between properties of an incoming sound and those of a neural ‘memory trace’ established by the preceding standard sounds. Here, we provide a selective review of studies which are relevant to the controversy between proponents of these two interpretations of the MMN. We also present preliminary neurophysiological data from monkey auditory cortex with potential implications for the debate. We conclude that the mechanisms and meaning of the MMN are still unresolved and offer remarks on how to make progress on these important issues.Abstract The mismatch negativity (MMN) is a pre-attentive auditory event-related potential (ERP) component that is elicited by a change in a repetitive acoustic pattern. It is obtained by subtracting responses evoked by frequent ‘standard’ sounds from responses evoked by infrequent ‘deviant’ sounds that differ from the standards along some acoustic dimension, e.g., frequency, intensity, or duration, or abstract feature. The MMN has been attributed to neural generators within the temporal and frontal lobes. The mechanisms and meaning of the MMN continue to be debated. Two dominant explanations for the MMN have been proposed. According to the “neural adaptation” hypothesis, repeated presentation of the standards results in adapted (i.e., attenuated) responses of feature-selective neurons in auditory cortex. Rare deviant sounds activate neurons that are less adapted than those stimulated by the frequent standard sounds, and thus elicit a larger ‘obligatory’ response, which yields the MMN following the subtraction procedure. In contrast, according to the “sensory memory” hypothesis, the MMN is a ‘novel’ (non-obligatory) ERP component that reflects a deviation between properties of an incoming sound and those of a neural ‘memory trace’ established by the preceding standard sounds. Here, we provide a selective review of studies which are relevant to the controversy between proponents of these two interpretations of the MMN. We also present preliminary neurophysiological data from monkey auditory cortex with potential implications for the debate. We conclude that the mechanisms and meaning of the MMN are still unresolved and offer remarks on how to make progress on these important issues.

Efficacy and ototoxicity of different cyclodextrins in Niemann–Pick C disease

Niemann–Pick type C (NPC) disease is a fatal, neurodegenerative, lysosomal storage disorder characterized by intracellular accumulation of unesterified cholesterol (UC) and other lipids. While its mechanism of action remains unresolved, administration of 2‐hydroxypropyl‐β‐cyclodextrin (HPβCD) has provided the greatest disease amelioration in animal models but is ototoxic. We evaluated other cyclodextrins (CDs) for treatment outcome and chemical interaction with disease‐relevant substrates that could pertain to mechanism.

Neural representation of harmonic complex tones in primary auditory cortex of the awake monkey

Many natural sounds are periodic and consist of frequencies (harmonics) that are integer multiples of a common fundamental frequency (F0). Such harmonic complex tones (HCTs) evoke a pitch corresponding to their F0, which plays a key role in the perception of speech and music. “Pitch-selective” neurons have been identified in non-primary auditory cortex of marmoset monkeys. Noninvasive studies point to a putative “pitch center” located in a homologous cortical region in humans. It remains unclear whether there is sufficient spectral and temporal information available at the level of primary auditory cortex (A1) to enable reliable pitch extraction in non-primary auditory cortex. Here we evaluated multiunit responses to HCTs in A1 of awake macaques using a stimulus design employed in auditory nerve studies of pitch encoding. The F0 of the HCTs was varied in small increments, such that harmonics of the HCTs fell either on the peak or on the sides of the neuronal pure tone tuning functions. Resultant response-amplitude-versus-harmonic-number functions (“rate-place profiles”) displayed a periodic pattern reflecting the neuronal representation of individual HCT harmonics. Consistent with psychoacoustic findings in humans, lower harmonics were better resolved in rate-place profiles than higher harmonics. Lower F0s were also temporally represented by neuronal phase-locking to the periodic waveform of the HCTs. Findings indicate that population responses in A1 contain sufficient spectral and temporal information for extracting the pitch of HCTs by neurons in downstream cortical areas that receive their input from A1.

Neural Representation of Concurrent Harmonic Sounds in Monkey Primary Auditory Cortex: Implications for Models of Auditory Scene Analysis

The ability to attend to a particular sound in a noisy environment is an essential aspect of hearing. To accomplish this feat, the auditory system must segregate sounds that overlap in frequency and time. Many natural sounds, such as human voices, consist of harmonics of a common fundamental frequency (F0). Such harmonic complex tones (HCTs) evoke a pitch corresponding to their F0. A difference in pitch between simultaneous HCTs provides a powerful cue for their segregation. The neural mechanisms underlying concurrent sound segregation based on pitch differences are poorly understood. Here, we examined neural responses in monkey primary auditory cortex (A1) to two concurrent HCTs that differed in F0 such that they are heard as two separate “auditory objects” with distinct pitches. We found that A1 can resolve, via a rate-place code, the lower harmonics of both HCTs, a prerequisite for deriving their pitches and for their perceptual segregation. Onset asynchrony between the HCTs enhanced the neural representation of their harmonics, paralleling their improved perceptual segregation in humans. Pitches of the concurrent HCTs could also be temporally represented by neuronal phase-locking at their respective F0s. Furthermore, a model of A1 responses using harmonic templates could qualitatively reproduce psychophysical data on concurrent sound segregation in humans. Finally, we identified a possible intracortical homolog of the “object-related negativity” recorded noninvasively in humans, which correlates with the perceptual segregation of concurrent sounds. Findings indicate that A1 contains sufficient spectral and temporal information for segregating concurrent sounds based on differences in pitch.