Defining the Boundaries of Patient Perception in Spinal Cord Stimulation Programming.

OBJECTIVES: Recent developments in spinal cord stimulation (SCS) programming have initiated new modalities of imperceptible stimulation. However, the boundaries of sensory perception are not well defined. The BEnchtop NEuromodulation Following endIng of Trial study aimed to create a map of perceptual threshold responses across a broad range of SCS parameters and programming to inform subperception therapy design. MATERIALS AND METHODS: This multicenter study was conducted at seven US sites. A total of 43 patients with low back and/or leg pain who completed a percutaneous commercial SCS trial were enrolled. Test stimulation was delivered through trial leads for approximately 90 minutes before removal. SCS parameters, including amplitude, frequency, pulse width (PW), electrode configuration, cycling, and multifrequency stimulation were varied during testing. Paresthesia threshold (PT), comfort level (CL), perceptual coverage area, and paresthesia quality (through patient selection of keywords) were collected. Differences were evaluated with analysis of variance followed by post hoc multiple comparisons using t-tests with Bonferroni correction. RESULTS: PT was primarily determined by PW and was insensitive to frequency for constant frequency stimulation (range: 20 Hz-10 kHz; F(1284) = 69.58, p < 0.0001). For all tests, CL was approximately 25% higher than PT. The dominant variable that influenced paresthesia quality was frequency. Sensations described as comfortable and tingling were most common for frequencies between 60 Hz and 2.4 kHz; unpleasant sensations were generally more common outside this range. Increasing distance between active electrodes from 7 mm to 14 mm, or cycling the SCS waveform at 1 Hz, decreased PT (p < 0.0001). Finally, PT for a low-frequency stimulus (ie, 60 Hz) was unaffected by mixing with a sub-PT high-frequency stimulus. CONCLUSIONS: In contrast to previous work investigating narrower ranges, PW primarily influenced PT, independently of frequency. Paresthesia quality was primarily influenced by pulse frequency. These findings advance our understanding of SCS therapy and may be used to improve future novel neuromodulation paradigms.

Task Engagement Improves Neural Discriminability in the Auditory Midbrain of the Marmoset Monkey.

While task-dependent changes have been demonstrated in auditory cortex for a number of behavioral paradigms and mammalian species, less is known about how behavioral state can influence neural coding in the midbrain areas that provide auditory information to cortex. We measured single-unit activity in the inferior colliculus (IC) of common marmosets of both sexes while they performed a tone-in-noise detection task and during passive presentation of identical task stimuli. In contrast to our previous study in the ferret IC, task engagement had little effect on sound-evoked activity in central (lemniscal) IC of the marmoset. However, activity was significantly modulated in noncentral fields, where responses were selectively enhanced for the target tone relative to the distractor noise. This led to an increase in neural discriminability between target and distractors. The results confirm that task engagement can modulate sound coding in the auditory midbrain, and support a hypothesis that subcortical pathways can mediate highly trained auditory behaviors.SIGNIFICANCE STATEMENT While the cerebral cortex is widely viewed as playing an essential role in the learning and performance of complex auditory behaviors, relatively little attention has been paid to the role of brainstem and midbrain areas that process sound information before it reaches cortex. This study demonstrates that the auditory midbrain is also modulated during behavior. These modulations amplify task-relevant sensory information, a process that is traditionally attributed to cortex.

Rapid Task-Related Plasticity of Spectrotemporal Receptive Fields in the Auditory Midbrain.

Previous research has demonstrated that auditory cortical neurons can modify their receptive fields when animals engage in auditory detection tasks. We tested for this form of task-related plasticity in the inferior colliculus (IC) of ferrets trained to detect a pure tone target in a sequence of noise distractors that did not overlap in time. During behavior, responses were suppressed at the target tone frequency in approximately half of IC neurons relative to the passive state. This suppression often resulted from a combination of a local tuning change and a global change in overall excitability. Local and global suppression were stronger when the target frequency was aligned to neuronal best frequency. Local suppression in the IC was indistinguishable from that described previously in auditory cortex, while global suppression was unique to the IC. The results demonstrate that engaging in an auditory task can change selectivity for task-relevant features in the midbrain, an area where these effects have not been reported previously. Significance statement: Previous studies have demonstrated that the receptive fields of cortical neurons are modified when animals engage in auditory behaviors, a process that is hypothesized to provide the basis for segregating sound sources in an auditory scene. This study demonstrates for the first time that receptive fields of neurons in the midbrain inferior colliculus are also modified during behavior. The magnitude of the tuning changes is similar to previous reports in cortex. These results support a hierarchical model of behaviorally driven sound segregation that begins in the subcortical auditory network.

Alignment of sound localization cues in the nucleus of the brachium of the inferior colliculus.

Accurate sound localization is based on three acoustic cues (interaural time and intensity difference and spectral cues from directional filtering by the pinna). In natural listening conditions, every spatial position of a sound source provides a unique combination of these three cues in "natural alignment." Although neurons in the central nucleus (ICC) of the inferior colliculus (IC) are sensitive to multiple cues, they do not favor their natural spatial alignment. We tested for sensitivity to cue alignment in the nucleus of the brachium of the IC (BIN) in unanesthetized marmoset monkeys. The BIN receives its predominant auditory input from ICC and projects to the topographic auditory space map in the superior colliculus. Sound localization cues measured in each monkey were used to synthesize broadband stimuli with aligned and misaligned cues; spike responses to these stimuli were recorded in the BIN. We computed mutual information (MI) between the set of spike rates and the stimuli containing either aligned or misaligned cues. The results can be summarized as follows: 1) BIN neurons encode more information about auditory space when cues are aligned compared with misaligned. 2) Significantly more units prefer aligned cues in the BIN than in ICC. 3) An additive model based on summing the responses to stimuli with the localization cues varying individually accurately predicts the alignment preference with all cues varying. Overall, the results suggest that the BIN is the first site in the ascending mammalian auditory system that is tuned to natural combinations of sound localization cues.

Linear processing of interaural level difference underlies spatial tuning in the nucleus of the brachium of the inferior colliculus.

The spatial location of sounds is an important aspect of auditory perception, but the ways in which space is represented are not fully understood. No space map has been found within the primary auditory pathway. However, a space map has been found in the nucleus of the brachium of the inferior colliculus (BIN), which provides a major auditory projection to the superior colliculus. We measured the spectral processing underlying auditory spatial tuning in the BIN of unanesthetized marmoset monkeys. Because neurons in the BIN respond poorly to tones and are broadly tuned, we used a broadband stimulus with random spectral shapes (RSSs) from which both spatial receptive fields and frequency sensitivity can be derived. Responses to virtual space (VS) stimuli, based on the animal's own ear acoustics, were compared with the predictions of a weight-function model of responses to the RSS stimuli. First-order (linear) weight functions had broad spectral tuning (approximately three octaves) and were excitatory in the contralateral ear, inhibitory in the ipsilateral ear, and biased toward high frequencies. Responses to interaural time differences and spectral cues were relatively weak. In cross-validation tests, the first-order RSS model accurately predicted the measured VS tuning curves in the majority of neurons, but was inaccurate in 25% of neurons. In some cases, second-order weighting functions led to significant improvements. Finally, we found a significant correlation between the degree of binaural weight asymmetry and the best azimuth. Overall, the results suggest that linear processing of interaural level difference underlies spatial tuning in the BIN.

Cutting-edge science and coffee: Auditory System Gordon Research Conference and Seminar 2012 report.

At the third Gordon Research Conference and Gordon Research Seminar on the Auditory System (2012), investigators from all career stages reported on emerging research in a broad range of sub-fields. A distinguishing feature of these conferences is their attention to junior investigators, and their experience is the focus of this conference report.

Acoustic basis of directional acuity in laboratory mice.

The acoustic basis of auditory spatial acuity was investigated in CBA/129 mice by relating patterns of behavioral errors to directional features of the head-related transfer function (HRTF). Behavioral performance was assessed by training the mice to lick a water spout during sound presentations from a "safe" location and to suppress the response during presentations from "warning" locations. Minimum audible angles (MAAs) were determined by delivering the safe and warning sounds from different locations in the inter-aural horizontal and median vertical planes. HRTFs were measured at the same locations by implanting a miniature microphone and recording the gain of sound energy near the ear drum relative to free field. Mice produced an average MAA of 31° when sound sources were located in the horizontal plane. Acoustic measures indicated that binaural inter-aural level differences (ILDs) and monaural spectral features of the HRTF change systematically with horizontal location and therefore may have contributed to the accuracy of behavioral performance. Subsequent manipulations of the auditory stimuli and the directional properties of the ear produced errors that suggest the mice primarily relied on ILD cues when discriminating changes in azimuth. The MAA increased beyond 80° when the importance of ILD cues was minimized by testing in the median vertical plane. Although acoustic measures demonstrated a less robust effect of vertical location on spectral features of the HRTF, this poor performance provides further evidence for the insensitivity to spectral cues that was noted during behavioral testing in the horizontal plane.

Information conveyed by inferior colliculus neurons about stimuli with aligned and misaligned sound localization cues.

Previous studies have demonstrated that single neurons in the central nucleus of the inferior colliculus (ICC) are sensitive to multiple sound localization cues. We investigated the hypothesis that ICC neurons are specialized to encode multiple sound localization cues that are aligned in space (as would naturally occur from a single broadband sound source). Sound localization cues including interaural time differences (ITDs), interaural level differences (ILDs), and spectral shapes (SSs) were measured in a marmoset monkey. Virtual space methods were used to generate stimuli with aligned and misaligned combinations of cues while recording in the ICC of the same monkey. Mutual information (MI) between spike rates and stimuli for aligned versus misaligned cues were compared. Neurons with best frequencies (BFs) less than ∼11 kHz mostly encoded information about a single sound localization cue, ITD or ILD depending on frequency, consistent with the dominance of ear acoustics by either ITD or ILD at those frequencies. Most neurons with BFs >11 kHz encoded information about multiple sound localization cues, usually ILD and SS, and were sensitive to their alignment. In some neurons MI between stimuli and spike responses was greater for aligned cues, while in others it was greater for misaligned cues. If SS cues were shifted to lower frequencies in the virtual space stimuli, a similar result was found for neurons with BFs <11 kHz, showing that the cue interaction reflects the spectra of the stimuli and not a specialization for representing SS cues. In general the results show that ICC neurons are sensitive to multiple localization cues if they are simultaneously present in the frequency response area of the neuron. However, the representation is diffuse in that there is not a specialization in the ICC for encoding aligned sound localization cues.

Tonotopic tuning in a sound localization circuit.

Nucleus laminaris (NL) neurons encode interaural time difference (ITD), the cue used to localize low-frequency sounds. A physiologically based model of NL input suggests that ITD information is contained in narrow frequency bands around harmonics of the sound frequency. This suggested a theory, which predicts that, for each tone frequency, there is an optimal time course for synaptic inputs to NL that will elicit the largest modulation of NL firing rate as a function of ITD. The theory also suggested that neurons in different tonotopic regions of NL require specialized tuning to take advantage of the input gradient. Tonotopic tuning in NL was investigated in brain slices by separating the nucleus into three regions based on its anatomical tonotopic map. Patch-clamp recordings in each region were used to measure both the synaptic and the intrinsic electrical properties. The data revealed a tonotopic gradient of synaptic time course that closely matched the theoretical predictions. We also found postsynaptic band-pass filtering. Analysis of the combined synaptic and postsynaptic filters revealed a frequency-dependent gradient of gain for the transformation of tone amplitude to NL firing rate modulation. Models constructed from the experimental data for each tonotopic region demonstrate that the tonotopic tuning measured in NL can improve ITD encoding across sound frequencies.

Sound localization cues in the marmoset monkey.

The most important acoustic cues available to the brain for sound localization are produced by the interaction of sound with the animal's head and external ears. As a first step in understanding the relation between these cues and their neural representation in a vocal new-world primate, we measured head-related transfer functions (HRTFs) across frequency for a wide range of sound locations in three anesthetized marmoset monkeys. The HRTF magnitude spectrum has a broad resonance peak at 6-12 kHz that coincides with the frequency range of the major call types of this species. A prominent first spectral notch (FN) in the HRTF magnitude above this resonance was observed at most source locations. The center frequency of the FN increased monotonically from approximately 12 to 26 kHz with increases in elevation in the lateral field. In the frontal field FN frequency changed in a less orderly fashion with source position. From the HRTFs we derived interaural time (ITDs) and level differences (ILDs). ITDs and ILDs (below 12 kHz) varied as a function of azimuth between +/-250 micros and +/-20dB, respectively. A reflexive orienting behavioral paradigm was used to confirm that marmosets can orient to sound sources.

Diversity of gain modulation by noise in neocortical neurons: regulation by the slow afterhyperpolarization conductance.

Neuronal firing is known to depend on the variance of synaptic input as well as the mean input current. Several studies suggest that input variance, or "noise," has a divisive effect, reducing the slope or gain of the firing frequency-current (f-I) relationship. We measured the effects of current noise on f-I relationships in pyramidal neurons and fast-spiking (FS) interneurons in slices of rat sensorimotor cortex. In most pyramidal neurons, noise had a multiplicative effect on the steady-state f-I relationship, increasing gain. In contrast, noise reduced gain in FS interneurons. Gain enhancement in pyramidal neurons increased with stimulus duration and was correlated with the amplitude of the slow afterhyperpolarization (sAHP), a major mechanism of spike-frequency adaptation. The 5-HT2 receptor agonist alpha-methyl-5-HT reduced the sAHP and eliminated gain increases, whereas augmenting the sAHP conductance by spike-triggered dynamic-current clamp enhanced the gain increase. These results indicate that the effects of noise differ fundamentally between classes of neocortical neurons, depending on specific biophysical properties including the sAHP conductance. Thus, noise from background synaptic input may enhance network excitability by increasing gain in pyramidal neurons with large sAHPs and reducing gain in inhibitory FS interneurons.

Two-dimensional time coding in the auditory brainstem.

Avian nucleus magnocellularis (NM) spikes provide a temporal code representing sound arrival times to downstream neurons that compute sound source location. NM cells act as high-pass filters by responding only to discrete synaptic events while ignoring temporally summed EPSPs. This high degree of input selectivity insures that each output spike from NM unambiguously represents inputs that contain precise temporal information. However, we lack a quantitative description of the computation performed by NM cells. A powerful model for predicting output firing rate given an arbitrary current input is given by a linear/nonlinear cascade: the stimulus is compared with a known relevant feature by linear filtering, and based on that comparison, a nonlinear function predicts the firing response. Spike-triggered covariance analysis allows us to determine a generalization of this model in which firing depends on more than one spike-triggering feature or stimulus dimension. We found two current features relevant for NM spike generation; the most important simply smooths the current on short time scales, whereas the second confers sensitivity to rapid changes. A model based on these two features captured more mutual information between current and spikes than a model based on a single feature. We used this analysis to characterize the changes in the computation brought about by pharmacological manipulation of the biophysical properties of the neurons. Blockage of low-threshold voltage-gated potassium channels selectively eliminated the requirement for the second stimulus feature, generalizing our understanding of input selectivity by NM cells. This study demonstrates the power of covariance analysis for investigating single neuron computation.