Binaural Interactions in Primary Auditory Cortex of the Awake Macaque

D.H. Reser1, Y.I. Fishman1, J.C. Arezzo1,2 and M. Steinschneider1,2

1 Departments of Neuroscience and , 2 Neurology, Albert Einstein College of Medicine, Bronx, NY 10461, USA


    Abstract
 Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Notes
 References
 
The functional organization of primary auditory cortex in non-primates is generally modeled as a tonotopic gradient with an orthogonal representation of independently mapped binaural interaction columns along the isofrequency contours. Little information is available regarding the validity of this model in the primate brain, despite the importance of binaural cues for sound localization and auditory scene analysis. Binaural and monaural responses of A1 to pure tone stimulation were studied using auditory evoked potentials, current source density and multiunit activity. Key findings include: (i) differential distribution of binaural responses with respect to best frequency, such that 74% of the sites exhibiting binaural summation had best frequencies below 2000 Hz; (ii) the pattern of binaural responses was variable with respect to cortical depth, with binaural summation often observed in the supragranular laminae of sites showing binaural suppression in thalamorecipient laminae; and (iii) dissociation of binaural responses between the initial and sustained action potential firing of neuronal ensembles in A1. These data support earlier findings regarding the temporal and spatial complexity of responses in A1 in the awake state, and are inconsistent with a simple orthogonal arrangement of binaural interaction columns and best frequency in A1 of the awake primate.


    Introduction
 Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Notes
 References
 
Topographical representation of frequency and the spatial distribution of binaural interactions are major organizational features of mammalian primary auditory cortex (A1) (Rose and Woolsey, 1949Go; Merzenich and Brugge, 1973Go; Merzenich et al., 1975Go; Morel et al., 1993Go). These systems appear to be independent, in that the representation of binaural activity is roughly orthogonal to the gradient of isofrequency contours on the cortical surface (Schreiner, 1998Go). This arrangement produces alternating bands of binaural summation and suppression along the isofrequency contours of A1. Although tonotopic organization of A1 has been reported for multiple mammalian species (Merzenich and Brugge, 1973Go; Imig and Brugge, 1978Go; Imig and Reale, 1980Go; Kelly and Sally, 1988Go; Morel et al., 1993Go; Kelly and Judge, 1994Go), the distribution of binaural interactions in A1 has been studied extensively only in non-primate species [cat (Abeles and Goldstein, 1970Go; Imig and Adrian, 1977Go; Imig and Brugge, 1978Go; Middlebrooks et al., 1980Go; Imig and Reale, 1981Go; Middlebrooks and Zook, 1983Go); ferret (Kelly and Judge, 1994Go); chinchilla (Benson and Teas, 1976Go); rat (Kelly and Sally, 1988Go)].

Functional information about binaural interactions in primate A1 is sparse. Brugge and Merzenich (Brugge and Merzenich, 1973Go) examined the responses of cortical neurons in macaques driven by interaural differences in time and intensity, and Ahissar and colleagues (Ahissar et al., 1992Go) studied the temporal properties of single units in macaque A1 in response to moving stimuli, but neither group commented specifically on the organization of responses to simultaneous bilateral stimulation. The anatomical similarity in auditory cortical organization between macaques and humans makes the monkey an attractive model for comparison of animal and human binaural organization (Galaburda and Sanides, 1980Go). However, the paucity of information about the organization of binaural interactions in the primate limits our ability to extrapolate from results obtained in the cat to human binaural interactions.

An additional confound of previous physiologic studies of binaural organization in A1 arises from the common use of anesthetized preparations. It is now clear that sustained excitatory and inhibitory components of auditory cortical responses are modified by barbiturate anesthesia (Karmos et al., 1993Go; Zurita et al., 1994Go). Further, it is reasonable to expect that the pattern of binaural interactions, and the timing of excitatory and inhibitory activity driven by monaural and binaural stimulation might vary with depth, as the distribution of thalamocortical and cortico-cortical inputs changes across cortical laminae. A more complete examination of the pattern of binaural processing in A1 in unanesthetized subjects is therefore warranted.

The present study examined the pattern of binaural processing in A1 of the unanesthetized monkey using simultaneous multichannel recordings of auditory evoked potentials (AEP), multiple unit activity (MUA) and the derived one-dimensional current source density (CSD). These procedures have been used previously to examine the temporal sequence and laminar distribution of cortical activation in response to complex auditory stimuli in A1 (Steinschneider et al., 1994Go), as well as organizational features of visual and somatosensory cortices (Arezzo et al., 1986Go; Vaughan et al., 1992Go; Schroeder et al., 1995Go). This study was intended to: (i) determine whether neuronal ensembles in primate A1 exhibit a pattern of binaural interactions similar to that reported for single units in the cat; (ii) characterize the distribution of binaural responses in A1 of the awake monkey with respect to tonotopic and laminar organizations; and (iii) describe the temporal pattern of neuronal ensemble responses to binaural stimulation. Portions of this work have been reported in abstract form (Reser et al., 1994Go).


    Materials and Methods
 Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Notes
 References
 
Five adult male macaques weighing between 3.0 and 5.0 kg were studied. They were housed in our AAALAC accredited facility under the supervision of staff veterinarians. Surgical and recording procedures were performed in accordance with NIH and IACUC guidelines.

Each subject was surgically implanted with guide tube matrices using procedures described in detail elsewhere (Steinschneider et al., 1994Go). Briefly, under sodium pentobarbital anesthesia ~2.0 cm2 of bone overlying the dorsolateral convexity of each hemisphere was removed. Epidural matrices composed of 20 Ga. stainless steel guide tubes were positioned above and anterior to A1, angled 30° off vertical to approximate the anterior–posterior tilt of the superior temporal plane. The matrices were embedded in a dental acrylic pedestal secured to the skull with inverted machine screws. Plastic headbars incorporated into the pedestal allowed painless head restraint during recording.

Stimuli were composed of tone bursts ranging in frequency from 0.2 to 12 kHz, generated and delivered using Soundesigner IITM and ProToolsTM software (Digidesign Equipment, Menlo Park, CA) on a Macintosh Quadra 950 computer. Each tone was 175 ms long, with 10 ms linear ‘on’ and ‘off’ ramps, and was delivered through external headphones (Sony model MDR7020) separated from the ears by 3.5-inch-long sections of plastic tubing (1 inch diameter). All tones were presented at 60 dB SPL, as measured by an ‘A’ weighted sound pressure meter (Bruel & Kjaer Instruments model 2236) placed at the opening of the plastic tubes, in the approximate position and angle of the external auditory meatus. Frequency-dependent variations in the output intensity of the headphones were corrected using a 15-band graphic equalizer (Rane Instruments model GE60). The inter-stimulus interval was 658 ms.

All recordings were conducted in an electrically shielded, sound attenuated chamber. At the start of each recording session, the animal was comfortably restrained in a custom fitted chair and its head was painlessly fixed to a frame-mounted headbar. The animal was maintained in an awake state throughout the recording by frequent reinforcement with preferred foods, but was not performing any behavioral task during the session. The awake state of the animal was further monitored by continuous examination of the intracortical EEG for slow wave activity associated with drowsiness.

Neural signals were recorded with a linear electrode array consisting of 14 fixed recording contacts with 150 µm intercontact spacing, for a total array length of ~2.0 mm (Barna et al., 1981Go). This configuration was usually sufficient to sample from all A1 laminae simultaneously. The impedance of each channel was between 0.1 and 0.5 M{Omega} at 1 kHz, and was confirmed prior to each electrode penetration. The multicontact electrode was mounted on a microdrive attached to the head frame at an angle parallel to the guide tubes, and the electrode was advanced through the guide tubes and positioned in auditory cortex. Responses to 80 dB SPL clicks were used to place the recording array across the major polarity inversion of the AEP. This usually placed the largest MUA in the middle channels of the electrode array, corresponding to lower lamina 3 and lamina 4 (Steinschneider et al., 1992Go).

Electrodes were impedance matched using a unity gain headstage preamplifier, and neural signals were bandpass filtered (3 Hz–3 kHz, –6 dB/octave) and amplified 5000 times. The resulting signals were digitized (3.4 kHz A/D rate) and averaged using a commercially available software package (Neuroscan Instruments, Herndon, VA). Each averaged response of 300 ms duration was computed from 75 stimulus presentations and included a pre-stimulus epoch of 25 ms.

To generate the MUA waveform, the output of the amplifiers was high pass filtered above 500 Hz (–24 dB/octave), full-wave rectified, amplified an additional eight times, digitized and averaged. Several steps were taken to ensure that spectral aliasing due to undersampling of the MUA signal did not compromise the MUA waveform. Analog filtering removed very high frequency components prior to digitization. Furthermore, empirical studies have shown that the spectral energy above 1000 Hz in the cortical MUA is minimal (Schroeder et al., 1998Go). Finally, MUA digitized at a rate of 3400 Hz yielded an MUA envelope essentially identical to the same signals digitized at 6000 Hz (twice the upper cutoff frequency of the amplifiers) (<5% difference in amplitude). Taken together, this indicates that spectral aliasing did not seriously contaminate the averaged waveforms at the A/D rates used in this study.

MUA represents changes in the synchronous action potential firing rate of a local neuronal population. The MUA signal is the weighted sum of the envelope of the extracellular action potentials from cells within a sphere around the recording contact (Legatt et al., 1980Go; Arezzo et al., 1986Go). At the electrode impedance of the present study, the radius of this sphere was 75–100 µm (Schroeder et al., 1990Go). MUA above the pre- stimulus baseline reflects increased net firing of the local cell population, while below baseline MUA indicates decreased action potential activity. Using comparable techniques, Nelken and colleagues have shown that the MUA is similar to the responses of local neuronal clusters in A1 (Nelken et al., 1994Go). Although MUA simultaneously recorded from multiple cortical laminae allows rapid sampling of synchronized activity in neural ensembles in A1, the technique does have important limitations. These include the inability to determine cell types contributing to the population response, the potential for masking the response patterns of single neurons, and the weighting of the averaged signal toward larger neurons and cells close to the recording electrodes.

One-dimensional CSD was derived from the second spatial derivative of the field potential using the three-point formula described by Freeman and Nicholson (Freeman and Nicholson, 1975Go). CSD is an index of the net transmembrane current at each electrode in the array, and indicates whether the electrode is near local extracellular current sources or sinks. Current sinks reflect regions of net inward current, and are usually generated by net excitatory synaptic activity or passive return from hyperpolarizing currents. Conversely, sources indicate net hyperpolarizing current or circuit completing currents from regions of net depolarization. Interpretation of the CSD is aided by examination of concurrently recorded MUA, which helps distinguish between active CSD components and passive currents effecting circuit closure. Sinks accompanied by temporally overlapping increases in action potential firing, as measured by MUA, are likely to be the result of net excitatory synaptic activity, as opposed to passive, circuit-completing current. Conversely, CSD sources that are coincident with reduced action potential firing can be interpreted as regions of local hyperpolarization. More complete discussions of the relative strengths of coordinated MUA and CSD interpretation are available (Vaughan et al., 1992Go; Tenke et al., 1993Go; Schroeder et al., 1995Go, 1998Go).

After positioning the electrode array within the auditory cortex, the spectral sensitivity of the local neuronal population was determined. Tones were presented in pseudo-random order to the contralateral ear. The best frequency (BF) was defined as the tone that evoked the largest area under the summed MUA waveform from all channels within the initial 40 ms. This interval was selected because it is the approximate duration of the initial cortical response to a unitary (click) stimulus (Steinschneider et al., 1992Go).

The responsiveness of each site to binaural, monaural ipsilateral and monaural contralateral stimulation was evaluated with tones corresponding to the on-line estimate of BF. Responses were classified according to the types defined previously (Imig and Adrian, 1977Go). Four classes were identified: binaural summation (EE), contralateral monaural dominance (EI), ipsilateral monaural dominance (IE) and no interaction (EO). Classification was based on the area under the summed MUA curve from three adjacent electrode channels spanning lower lamina 3 and lamina 4 from 0–40 ms, and at least 10% difference in response amplitude between conditions was required for classification of binaural interactions. Sites exhibiting <10% amplitude difference were assigned to the EO category. The MUA signal is dominated by activity in channels in layers 3 and 4 during the initial 40 ms period. The relationship between neural activity in the initial 40 ms and the longer duration components of the cortical response was also examined, as described in the Results section.

The wide range of response amplitudes across cortical regions precluded direct comparison of responses between electrode penetrations. Therefore, distribution-free measures (Siegel, 1956Go) were used for all comparisons within and between electrode penetrations. Specific tests applied to each data set are identified in the appropriate section of the Results.

At the end of recording, each animal was deeply anesthetized with sodium pentobarbital and transcardially perfused with saline solution and 10% neutral buffered formalin. The brain was removed and processed for histological examination. Frontal sections of 80 µm thickness were cut on a freezing microtome and stained for Nissl substance or acetyl cholinesterase (AChe) according to published methods (Bakst and Amaral, 1984Go). A1 was located using published criteria (Pandya and Sanides, 1973Go; Morel et al., 1993Go), and 42/51 electrode tracks were identified by serial reconstruction of histological sections. Electrode tracks which deviated from perpendicular by >15° were excluded from this report. A1 was characterized by a high-to-low, caudomedial-to-anterolateral BF gradient and dense staining for Nissl and AChe. A1 was distinguished from the rostral field by reversals in the tonotopic gradient along the guide tube matrix (Morel et al., 1993Go; Hackett et al., 1998Go).


    Results
 Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Notes
 References
 
Results are based on 51 electrode penetrations into A1. BFs of cortical sites ranged from 0.2 to 12 kHz. Two penetrations into postero-medial A1 had BFs higher than 12 kHz, however, for statistical purposes, these regions were assigned a numerical BF of 12 kHz, since that was the highest frequency available in our stimulus set. As outlined in the Methods, the initial MUA was used to classify each electrode penetration. Thirty-seven percent (19/51) of the A1 sites examined were characterized as EE, 39% (20/51) as EI, 22% (11/51) as EO and 2% (1/51) as IE.

Frequency Dependence of Binaural Interaction Types in Monkey A1

Binaural interactions were differentially distributed with respect to BF in A1. The median BF across all electrode penetrations was 1900 Hz. EE responses were observed ~3 times more often in regions of lower BF (below median) than regions of higher BF. In contrast, EI interactions were more common in cortical sites of higher BF. These differences were statistically significant ({chi}2 = 8.9, df = 2, P < 0.02; {chi}2 for multiple independent observations, Ho: equal distribution of EE/EI/EO responses with respect to median BF). The frequency of occurrence of each response class for both low and high frequency regions is depicted graphically in Figure 1Go. Over 78% of EE penetrations (15/19) were encountered in regions with BF lower than the median, while 65% of EI penetrations (13/20) were found in regions with BF > 1900 Hz. In regions of very high BF (>9 kHz), no penetrations of the EE type were observed (0/8). Sites with no observed binaural interaction (EO) were approximately evenly distributed in regions of high and low BF, while ipsilateral dominance (IE) was observed too infrequently to identify any pattern with respect to BF.



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Figure 1.  Frequency of occurrence of each class of binaural interaction relative to BF. Median BF for all sites studied was 1900 Hz. For display purposes, two electrode penetrations with BFs of 1900 Hz were included in the low BF category.

 
Laminar Distribution of Action Potential Firing and Transmembrane Current in A1

At each site studied, BF tones elicited a characteristic pattern of cortical activation. The initial response consisted of a brief, short latency current sink that was centered in the thalamorecipient laminae (lamina 4 and lower lamina 3). This sink was followed by a second sink, maximal in the superficial laminae, which lasted ~20–40 ms. Associated current sources, representing circuit completing currents, surround the thalamorecipient and supragranular sinks. This pattern is consistent with previous CSD analyses of A1 (Muller-Preuss and Mitzdorf, 1984Go; Steinschneider et al., 1992Go, 1994Go). The early sink is presumed to reflect monosynaptic activation of the thalamorecipient laminae, while the supragranular sink is driven by polysynaptic activity. Binaural stimulation differentially affected these current sinks and thus altered the laminar pattern of intracortical current flow.

EI Interaction

Figure 2Go depicts the MUA and CSD from a representative EI penetration with a BF of 12 kHz. Contralateral stimulation produced an initial burst of excitatory MUA centered in lower lamina 3/lamina 4 (dark arrowhead, upper traces) spatially and temporally coincident with the earliest intracortical current sink (dark arrowhead, lower traces; filled circles indicate corresponding MUA and CSD channels). Current sinks are marked by downward deflections in the waveform and are filled in black, while gray filled upward deflections denote current sources. The peaks of the initial MUA and CSD waveforms (first drop line) occurred ~13 ms after stimulus presentation. They reflect pre- and the earliest postsynaptic activity in the thalamorecipient laminae. A second, broader burst of excitatory MUA was evident in the thalamorecipient laminae and supragranular cortical layers (second drop line). This activity was associated with the large current sink maximal in supragranular laminae, ~500 µm above the initial sink.



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Figure 2.  MUA and CSD from a representative EI electrode penetration of 12 kHz BF. Approximate cortical laminae are shown at the extreme left, with filled circles denoting corresponding MUA and CSD channels. Solid arrows in the contralateral condition indicate MUA and CSD components in the thalamorecipient zone (lamina 4 and lower lamina 3). The open arrow in the binaural condition indicates supragranular CSD. Note the relative increase in sustained supragranular activity in the binaural condition, despite the larger responses in the thalamorecipient zone evoked by contralateral stimulation. Little or no thalamorecipient CSD or MUA was observed in the ipsilateral condition in this penetration. Drop lines indicate relative timing of MUA and CSD events (14 ms separation). The arrowheads over each timeline indicate the beginning and the end of the stimulus tone. To highlight differences in the spatial and temporal pattern of activation in A1 across conditions, MUA and CSD in this and later figures are restricted to the channels in which salient activity was recorded. Graphical cues within figures indicate equivalent depths along the electrode array.

 
In EI columns, MUA in the thalamorecipient laminae was larger, by definition, for monaural contralateral stimulation than for binaural stimulation (see left and middle columns in Fig. 2Go). The associated CSD patterns reflected the MUA differences between conditions, with the larger thalamorecipient current sinks in response to contralateral stimulation. In contrast, current flow in supragranular laminae associated with the second burst of excitatory MUA (Fig. 2Go, open arrow) could be equal in magnitude to or larger with binaural stimulation, even when thalamorecipient activity was sharply reduced relative to the contralateral response. This pattern is especially evident in the CSD pattern from the EI site depicted in Figure 3Go (BF = 5 kHz), where the thalamorecipient sink evoked by binaural stimulation was 70–80% of the equivalent contralateral sink amplitude. In contrast, the binaural supragranular sink was ~125% of the contralateral response.



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Figure 3.  CSD from an EI site in a different animal from the site shown in Figure 2Go, showing a similar pattern of thalamocortical and supragranular current evoked by each stimulus condition. The solid arrow indicates the thalamorecipient current, which was largest in response to contralateral stimulation. In contrast, binaural stimulation evoked the largest depolarization in the supragranular laminae. Note also the relatively large supragranular current sink in the ipsilateral condition (open arrow), with very little activity evident in the thalamorecipient laminae. BF = 5 kHz.

 
Monaural ipsilateral stimulation often produced little or no post-synaptic responses in the thalamorecipient laminae of an EI column, even at sites that responded vigorously to binaural stimulation (Fig. 2Go). In cases where ipsilateral activity was evident in an EI column (e.g. Fig. 3Go), post-synaptic activity was generally concentrated in the supragranular laminae (Fig. 3Go, open arrowhead, right column).

In EI penetrations, the magnitude of the supragranular current sink evoked by contralateral stimulation was strongly correlated with the size of the sink in the thalamorecipient zone, somewhat less so in the binaural condition and not at all in the ipsilateral condition. Comparison of the relationship between these CSD components provides an index of the degree to which post- synaptic activity in the supragranular tissue is associated with activation of the thalamorecipient laminae. This relation was quantified using the Spearman rank correlation of the two current sinks across electrode penetrations. The results of this analysis for all of the EI sites are graphically depicted in Figure 4AGo. The correlation between thalamocortical and supragranular activity in the contralateral condition is consistent with a substantial contribution from a direct thalamocortical projection to the supragranular sink (Rs = 0.64, P < 0.005), while the weak association of the supragranular sink with the thalamocortical activity in the ipsilateral condition (Rs = –0.17, n.s.) is consistent with an origin of supragranular activity outside of the cortical column in question. The degree of association between the supragranular and thalamocortical sinks in the binaural condition was intermediate between the monaural conditions in EI penetrations (Rs = 0.39, n.s.).



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Figure 4.  Regression lines indicating the correlation between thalamorecipient and supragranular current sink magnitude for each stimulus condition in EI (A) and EE (B) electrode penetrations. Plots reflect all EI and EE sites for which circumscribed thalamocortical and supragranular current sinks could be identified (n = 19 EI, 14 EE). R-values indicate Spearman rank order correlation coefficients for each stimulus condition.

 
The onset of the supragranular current sink driven by monaural ipsilateral stimulation was delayed relative to the equivalent contralateral supragranular sink (Fig. 5Go). The mean delay across all EI columns was 10 ms, with a range of 2–23 ms. Figure 5Go shows the main supragranular current sink from the contralateral and ipsilateral responses of the recording site shown in Figure 3Go. The contralateral current sink is shown in black, overlaid with the ipsilateral sink shown in gray. The contralateral sink consisted of two main components: a large early peak (a), followed by a slower peak (b), which appears as a deflection in the rebound phase of the early peak. In comparison, peak (a) is not visible in the ipsilateral response, which has a shallow onset slope, and is dominated by the slower peak (b). The separation of onsets between these two components may be underestimated in Figure 5Go, as the onset of the earlier peak is truncated by the preceding current source in the contralateral condition. This source predominantly reflects passive current return from the active depolarization of the deeper (thalamorecipient) laminae. The absence of this source in the ipsilateral condition is consistent with the relative absence of excitatory activity in the thalamorecipient zone.



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Figure 5.  Enlarged ipsilateral and contralateral supragranular current sinks from the electrode penetration depicted in Figure 3Go, illustrating the composite nature of the supragranular depolarization. Contralateral stimulation resulted in an early depolarization beginning ~20 ms after stimulus onset (a) and peaking at ~32 ms, followed by a second deflection (b) peaking at 43 ms. The early activation was not evident in the ipsilateral condition, which produced only the slower component (b), with an onset latency of ~25 ms. The actual difference in latency of the two components may be underestimated in this instance, as the contralateral current sink is superimposed on an earlier source. This source likely reflects current return from the initial depolarization of the subjacent laminae (see text for details).

 
Clear early and late components in the supragranular current sink were observed in 22/45 penetrations (in four penetrations, supragranular sinks were spread across several CSD channels, so a well-circumscribed primary supragranular current sink could not be identified). Resolution of the supragranular current sink into two peaks was significantly more common in EI penetrations (15/22, 68%; {chi}2 = 9.36, df = 2, P < 0.01; Ho: equal probability of component separation among response classes) than the other response classes (2/22 EE, 9%; 6/22 EO, 27 %; 1/22 IE, 5%). The persistence of the later component in the ipsilateral condition with little or no thalamocortical postsynaptic activation suggests that the second peak reflects activity of projections that are not intrinsic to the local cortical column.

EE Interaction

The sequence and laminar pattern of intracortical activity in EE areas were fundamentally similar to those described for EI columns, with an initial current sink in the thalamorecipient laminae, followed by a later sink in the supragranular laminae. Figure 6Go depicts MUA and CSD from an EE penetration with a BF of ~1400 Hz. The initial excitatory MUA burst was maximal in the thalamorecipient laminae, peaked ~15 ms after stimulus onset and was largest in response to binaural stimuli. In this case, ipsilateral stimulation evoked a robust pattern of thalamocortical MUA.



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Figure 6.  MUA and CSD from a representative EE electrode penetration of 1400 Hz BF. The estimated laminar positions and identification of corresponding MUA and CSD channels are as in Figure 2Go. Binaural stimulation evoked large amplitude MUA (solid arrowhead) extending across the entire active region sampled by the electrode array. Ipsilateral stimulation evoked a relatively large amplitude thalamorecipient MUA in this penetration, in contrast to the EI sites shown in Figures 2 and 3GoGo. The thalamorecipient CSD also reflects the binaural summation response of this site, with the largest initial current sink in response to binaural stimulation (open arrow), as compared with the contralateral condition (solid arrow).

 
In contrast to EI sites, supragranular activity in EE regions was not closely associated with the magnitude of activation in thalamorecipient laminae. For both contralateral monaural and binaural stimulation, Spearman analysis revealed a weaker association between thalamorecipient and supragranular CSD components in EE sites relative to EI penetrations (see Fig. 4BGo). The largest correlation coefficient was obtained for the contralateral stimulation; however, the association between supragranular and thalamocortical postsynaptic activity was not significant, even for this condition. In general, the magnitude of ipsilateral responses in either the thalamorecipient or supragranular laminae could not be predicted from the pattern of binaural interactions of the region being studied.

IE Interaction

Ipsilaterally dominant sites were rare and comprised only 2% of the penetrations in A1. Because of limited data, it is not possible to generalize IE characteristics. However, in the one case studied, ipsilateral dominance extended across multiple laminae including both thalamorecipient and supragranular depths. Two major AEP generators, centered on the thalamorecipient and supragranular laminae, were identified in the response profile of the IE site. This pattern is similar to that observed with the EE and EI types of binaural interaction.

Binaural Interactions Varied Across Cortical Laminae

Binaural interactions in cortical columns may not be adequately characterized based solely on responses confined to a single lamina. Although the electrode penetrations in this study were classified based on the initial MUA component, the field potentials and resulting CSD exhibited a complex laminar pattern of activity. In approximately one-third of the sites studied, the initial CSD current sink and earliest MUA were largest in the contralateral condition, but the second burst of MUA and the associated supragranular sink were largest in response to binaural stimulation (16/51 penetrations, 31%). Figure 7Go shows a representative penetration (2750 Hz BF) demonstrating this dissociation. The most noticeable feature of this site was the difference in the depth and timing of the maximal MUA and CSD driven by each stimulus condition. Contralateral stimulation evoked an initial current sink and MUA burst in the thalamorecipient zone, followed by depolarization of the supragranular laminae. Binaural stimulation elicited an initial thalamorecipient zone burst of MUA that was smaller than that evoked by contralateral stimulation. However, the initial burst was followed by a second burst of MUA that was maximal in amplitude in supragranular laminae and larger than any of the MUA peaks elicited by contralateral stimulation (open arrow ;— ;middle traces). The CSD profile is consistent with the pattern of MUA, with a maximal early sink in thalamorecipient laminae associated with contralateral stimulation and a maximal later sink in supragranular laminae driven by binaural stimulation (drop lines). In this penetration, binaural stimulation evoked a supragranular current sink that was approximately twice the amplitude of that driven by monaural contralateral or ipsilateral stimulation. In comparison, contralateral stimulation evoked an earlier thalamo- recipient current that was ~4-fold greater than that associated with binaural stimulation (solid arrow, left column). In the thalamorecipient laminae, this site is clearly contralateral dominant; however, the largest field potential change occurs in the supragranular laminae in response to binaural stimulation, illustrating the dependence of the binaural classification on the depth of cortical tissue examined. Variability in the laminar distribution of evoked activity was most prominent in the field potential and resulting CSD, with a more consistent spread of evoked MUA across channels. The initial MUA component is largely restricted to a few electrode channels, allowing us to use the summed MUA as a basis for classifying binaural interactions, while the timing and distribution of field potentials represent additional information about the postsynaptic contribution to the MUA response. This highlights the advantage of simultaneously recording both types of information.



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Figure 7.  MUA and CSD from an electrode penetration of 2750 Hz BF illustrating the dissociation of binaural interactions between thalamorecipient and supragranular laminae. The initial response reveals contralateral monaural dominance in both MUA and CSD from the thalamorecipient laminae (left column, solid arrows), with binaural responses predominating in the superficial laminae (middle column, open arrows). Drop lines highlight the temporal relationship between the large MUA response to binaural stimulation and the supragranular current sink, while the contralateral MUA response is largest at the time of the initial thalamocortical depolarization.

 
Time Dependence of Binaural Interactions

The phasic and tonic portions of the pure tone response in A1 often have very different binaural characteristics. This was examined using the area under the summed MUA waveform from all active channels as an index of the relationship between initial and sustained action potential firing. Summing activity across channels enhances temporal features of the cortical response at the expense of laminar specificity. A mismatch between the summation characteristics of the ‘on’ (0–40 ms) and sustained (40–175 ms) action potential firing rate was observed in 24/51 penetrations (47%), which led to differential classification of initial and sustained binaural responses. Approximately 60% of the observed mismatches went from EO or EI in the early response to EE or IE in the later activity.

Figure 8Go illustrates summed MUA responses from three electrode penetrations into A1, covering the range of frequencies tested in this study. In each penetration, the activity occurring from 0 to 40 ms after stimulus onset was markedly different with respect to binaural interaction characteristics than the activity during the 40–175 ms period. These relationships are quantified for each penetration in the histograms at the bottom of Figure 8Go.



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Figure 8.  Temporal dissociation of binaural interactions, as indicated by summed MUA responses across all channels for three separate electrode penetrations (top half of the figure). In each case, the sustained MUA recorded between 40 and 175 ms shows different binaural interactions from the initial activity recorded from 0 to 40 ms. The display gain was changed between penetrations in order to emphasize the relative differences between stimulus conditions within penetrations. Histograms in the bottom half of the figure illustrate the relative magnitude of initial and sustained MUA for each penetration. Note that the direction of the change in dominance was variable across penetrations.

 

    Discussion
 Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Notes
 References
 
Studies in the cat have repeatedly demonstrated that neurons exhibiting binaural summation are segregated from those responding primarily to monaural stimulation (Abeles and Goldstein, 1970Go; Imig and Adrian, 1977Go; Middlebrooks et al., 1980Go; Imig and Reale, 1981Go; Middlebrooks and Pettigrew, 1981Go; Clarey et al., 1994Go). This segregation is both radial from the pial surface, forming columns of neurons that show binaural preference (Abeles and Goldstein, 1970Go; Middlebrooks et al., 1980Go), and correlated with the topography of A1, such that alternating bands of summation and suppression responses are grouped roughly orthogonally to the tonotopic map (Imig and Adrian, 1977Go; Middlebrooks et al., 1980Go). A similar pattern has been reported in the ferret (Kelly and Judge, 1994Go). Phillips and Irvine (1979, 1983) questioned the extent of homogeneous binaural responses in the radial dimension of the cortex, and suggested that the uniform columnar organization of binaural interactions described by other investigators could be partially explained by the relatively narrow band of tissue sampled in those studies (e.g. units in laminae 3 and 4).

Our data are consistent with segregation of binaural interactions in thalamorecipient laminae of A1 of the awake monkey. However, the concept of homogeneous binaural interaction columns extending throughout the radial dimension of A1 in the awake macaque is not supported by our results. We observed considerable variability of binaural interactions along the depth of cortical tissue, consistent with the findings of Phillips and Irvine (Phillips and Irvine, 1983Go). Specifically, binaural responses in superficial laminae often differed from responses in thalamorecipient laminae. This disparity was most prominent in the pattern of transmembrane current measured across depths. Differential effects of binaural stimulation on components of the CSD illustrate the utility of recording field potential changes concurrently with changes in action potential activity. Classification of binaural interactions on the basis of activity in the thalamorecipient laminae may be inadequate for the accurate description of the behavior of a given neuronal population.

Binaural Summation is Differentially Distributed with Respect to BF in Monkey A1

A principal observation of this investigation was the differential localization of binaural interactions with respect to the tono- topic gradient of A1. Previous studies of binaural organization in the cat have deliberately concentrated on regions of relatively high BF (Imig and Adrian, 1977Go; Middlebrooks et al., 1980Go), where alternating bands of binaural activity were most sharply defined (Middlebrooks and Zook, 1983Go). Low frequency regions were excluded in order to avoid neurons sensitive to ITDs (Middlebrooks et al., 1980Go). Interestingly, studies in the cat all reported finding numerous EE regions in the higher frequency portion of the tonotopic representation in A1. In our sample, EE penetrations were encountered much more frequently in areas of relatively low BF (< median BF ;of ;1900 Hz), and no EE regions were observed in the highest quartile of the frequency range tested (~9–12 kHz). The spatiotemporal model of A1 organization proposed by Schreiner (Schreiner, 1998Go) contains functionally independent overlapping representations of BF and binaural interactions. Further study will be required to determine whether this species difference represents an evolutionary difference in the functional organization of A1 for binaural information between cats and primates.

Cat studies have suggested that EI regions correspond to patches of dense thalamic input, while callosal input preferentially targets EE regions (Imig and Brugge, 1978Go; Middlebrooks et al., 1980Go) [but see also (Matsubara and Phillips, 1988Go; Wallace et al. 1991Go)]. Patchy termination of thalamic afferents has been described in the monkey (Pandya and Rosene, 1993Go; Hashikawa et al., 1995Go), but has not been correlated with binaural interactions. Our data predict that if callosal patches do correspond to EE regions in the monkey, these patches should be clustered in the low frequency regions of the tonotopic gradient. Brugge and Merzenich reported that neurons in A1 of the awake monkey with characteristic frequencies below 2700 Hz were far more likely to exhibit sensitivity to interaural time differences (ITD) than higher frequency units (Brugge and Merzenich, 1973Go). Our data are consistent with the hypothesis that EE interactions may contribute to ITD sensitivity in the macaque.

Binaural Interactions Are Variable with Respect to Major Generators of Cortical Activity Along the Depth of A1

The spatial and temporal pattern of CSD sources and sinks evoked by binaural and ipsilateral stimulation were similar to the basic A1 profile previously described in cats (Konig et al., 1972Go) and monkeys (Muller-Preuss and Mitzdorf, 1984Go; Steinschneider et al., 1992Go). Steinschneider and colleagues (Steinschneider et al., 1992Go) proposed a general neural circuit composed of a monosynaptic thalamocortical input into lamina 4 stellate cells followed rapidly by depolarization of the basal dendritic arbors of lamina 3 pyramidal neurons as the major generator of the initial current sink. The later, superficial current sink was attributed to polysynaptic input into the apical dendritic arbors of lamina 3 pyramidal neurons.

The current sinks composing the initial response were differentially affected by changes in the stimulus location. The supragranular current sink likely includes cortico-cortical projections from distant cortical sites, as well as from local cell populations, while the thalamorecipient sink is composed largely of feed-forward projections originating in the medial geniculate body. This is evident in the strong correlation between the magnitude of the thalamocortical current sink and the supragranular sink in EI regions, and the absence of the early component in the ipsilateral response, which exhibited very little transmembrane current in the thalamorecipient laminae. The slower component of the supragranular compound sink may reflect feedback projections, as indicated by the longer onset latency and rise time of this component relative to the thalamo- recipient sink. Anatomical data support the notion of feedback projection into the supragranular laminae of A1 (Rouiller et al., 1991Go; Pandya and Rosene, 1993Go). The persistence of the later component in the ipsilateral condition in the absence of significant thalamocortical activity is consistent with synaptic activity originating outside of the main thalamocortical projection into A1.

Differences in binaural interactions between the superficial and thalamorecipient laminae could be explained by deviations in the angle of electrode penetration, such that the recording array straddled multiple functional regions of cortex. However, placement of the electrode array in such a fashion would be expected to produce increases in the superficial channels in response to monaural stimulation in approximately half of the observed cases. When there was a difference, responses in the superficial channels were almost always larger in response to binaural stimulation. This is inconsistent with random placement across functional boundaries. Furthermore, little change in BF was observed along the depth of cortex. This stability suggests that the observed responses were the product of functionally similar cell populations. Additional studies in awake subjects are necessary to confirm this finding.

Binaural Interactions are Temporally Variable in A1: Implications for Modeling of Stimulus Location

Ahissar and colleagues suggested that stimulus movement could be encoded by means of shifting patterns of local ‘effective connectivity,’ as expressed by correlated changes in firing patterns between neurons (Ahissar et al., 1992Go). They showed that the sustained activity of cortical neurons was more sensitive to movement of sound sources than the ‘on’ response. Moreover, they reported that ‘effectively connected’ neurons could respond to movement with sustained firing when the ‘on’ response was absent, suggesting that the ‘on’ and sustained components were functionally independent. The observed dissociation between the ‘on’ and sustained components of the A1 response to pure tones may be related to this model of movement encoding. Dissociation of the ‘on’ and sustained responses of single units in cat auditory cortex have also been described with respect to azimuth sensitivity for a stationary target (Eggermont and Mossup, 1998Go), and in response to simultaneous binaural stimulation (Brugge et al., 1969Go; Phillips and Irvine, 1979Go, 1983Go).

Possible Effects of Anesthesia

The apparent conflicts between the evidence presented here and the columnar model of binaural interactions in A1 may be related to the use of barbiturate anesthesia in earlier studies. Barbiturates suppress the later components of subcortical (Webster and Aitken, 1971Go; Aitken and Prain, 1974Go; Zurita et al., 1994Go) and cortical (Brugge et al., 1969Go; Makela et al., 1990Go; Karmos et al., 1993Go; Zurita et al., 1994Go; Juckel et al., 1996Go) evoked responses. In our study, activity in the superficial cortical laminae tended to occur later and have a more sustained character than the activity in the thalamorecipient laminae. Anesthesia may have masked sustained activation of the superficial laminae in previous studies, resulting in homogeneous binaural interaction profiles along the depth of recorded tissue.

The results of this investigation suggest several courses for future investigations. Combined tract tracing and physiological studies will be required to determine the exact pattern of binaural interactions in cortico-cortical projections which impinge upon A1 in the primate. Investigations in the primate that combine identification of local binaural response properties with variation of the direction and movement of stimuli will give a clearer picture of the processing of ‘real world’ stimuli.


    Notes
 Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Notes
 References
 
The authors thank Dr Charles Schroeder for assistance with surgical preparation and for helpful discussions; Shirley Seto, Susana Chan, J.P. Noonan and Mona Litwak for expert technical assistance; Linda O'Donnell for secretarial support; and Drs Ingela Danielsson and T.R. Van De Water for helpful comments. We are grateful to Dr Steve Walkley and May Huang, who provided equipment and assistance with histological preparations. This work was performed in partial fulfilment of the requirements of the Department of Neuroscience and the Sue Golding Graduate Division of the Albert Einstein College of Medicine for the Doctor of Philosophy degree (D.H.R.). Supported in part by DC000657 and the Institute for the Study of Music and Neurologic Function of Beth Abraham Hospital.

Address correspondence to Mitchell Steinschneider, MD, PhD, Room 322, Kennedy Bldg, 1410 Pelham Parkway South, Bronx, NY 10461, USA. Email: steinsch{at}aecom.yu.edu.


    References
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 Introduction
 Materials and Methods
 Results
 Discussion
 Notes
 References
 
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