Longer Interstimulus Intervals Research Articles

Oscillatory support for rapid frequency change processing in infants

Rapid auditory processing and auditory change detection abilities are crucial aspects of speech and language development, particularly in the first year of life. Animal models and adult studies suggest that oscillatory synchrony, and in particular low-frequency oscillations play key roles in this process. We hypothesize that infant perception of rapid pitch and timing changes is mediated, at least in part, by oscillatory mechanisms. Using event-related potentials (ERPs), source localization and time-frequency analysis of event-related oscillations (EROs), we examined the neural substrates of rapid auditory processing in 4-month-olds. During a standard oddball paradigm, infants listened to tone pairs with invariant standard (STD, 800–800Hz) and variant deviant (DEV, 800–1200Hz) pitch. STD and DEV tone pairs were first presented in a block with a short inter-stimulus interval (ISI) (Rapid Rate: 70ms ISI), followed by a block of stimuli with a longer ISI (Control Rate: 300ms ISI). Results showed greater ERP peak amplitude in response to the DEV tone in both conditions and later and larger peaks during Rapid Rate presentation, compared to the Control condition. Sources of neural activity, localized to right and left auditory regions, showed larger and faster activation in the right hemisphere for both rate conditions. Time-frequency analysis of the source activity revealed clusters of theta band enhancement to the DEV tone in right auditory cortex for both conditions. Left auditory activity was enhanced only during Rapid Rate presentation. These data suggest that local low-frequency oscillatory synchrony underlies rapid processing and can robustly index auditory perception in young infants. Furthermore, left hemisphere recruitment during rapid frequency change discrimination suggests a difference in the spectral and temporal resolution of right and left hemispheres at a very young age.

Context heterogeneity has a sustained impact on attention deployment: Behavioral and electrophysiological evidence

In visual search, similar nearby stimuli can be grouped and thus enhance processing of an embedded target. The aim of the present study was to examine the time course of attention deployment after a brief presentation of stimulus arrays of different heterogeneity. Targets in less heterogeneous, grouped contexts yielded higher accuracy and larger N2pc amplitudes than targets in more heterogeneous, random contexts, indicating more efficient selection in the former. Subsequently presented probes yielded shorter reaction times and a larger posterior positivity when presented at the target location. This advantage was more pronounced after grouped compared to random contexts at the shorter compared to the longer interstimulus interval. The results show that less heterogeneous contexts that allow for grouping not only enhance processing of stimuli within that context, but have a sustained effect on visual attention.

Early ERP Signature of Hearing Impairment in Visual Rhyme Judgment

Postlingually acquired hearing impairment (HI) is associated with changes in the representation of sound in semantic long-term memory. An indication of this is the lower performance on visual rhyme judgment tasks in conditions where phonological and orthographic cues mismatch, requiring high reliance on phonological representations. In this study, event-related potentials (ERPs) were used for the first time to investigate the neural correlates of phonological processing in visual rhyme judgments in participants with acquired HI and normal hearing (NH). Rhyme task word pairs rhymed or not and had matching or mismatching orthography. In addition, the inter-stimulus interval (ISI) was manipulated to be either long (800 ms) or short (50 ms). Long ISIs allow for engagement of explicit, top-down processes, while short ISIs limit the involvement of such mechanisms. We hypothesized lower behavioral performance and N400 and N2 deviations in HI in the mismatching rhyme judgment conditions, particularly in short ISI. However, the results showed a different pattern. As expected, behavioral performance in the mismatch conditions was lower in HI than in NH in short ISI, but ERPs did not differ across groups. In contrast, HI performed on a par with NH in long ISI. Further, HI, but not NH, showed an amplified N2-like response in the non-rhyming, orthographically mismatching condition in long ISI. This was also the rhyme condition in which participants in both groups benefited the most from the possibility to engage top-down processes afforded with the longer ISI. Taken together, these results indicate an early ERP signature of HI in this challenging phonological task, likely reflecting use of a compensatory strategy. This strategy is suggested to involve increased reliance on explicit mechanisms such as articulatory recoding and grapheme-to-phoneme conversion.

The influence of prior experience and expected timing on vibrotactile discrimination

Vibrotactile discrimination tasks involve perceptual judgements on stimulus pairs separated by a brief interstimulus interval (ISI). Despite their apparent simplicity, decision making during these tasks is biased by prior experience in a manner that is not well understood. A striking example is when participants perform well on trials where the first stimulus is closer to the mean of the stimulus-set than the second stimulus, and perform comparatively poorly when the first stimulus is further from the stimulus mean. This “time-order effect” suggests that participants implicitly encode the mean of the stimulus-set and use this internal standard to bias decisions on any given trial. For relatively short ISIs, the magnitude of the time-order effect typically increases with the distance of the first stimulus from the global mean. Working from the premise that the time-order effect reflects the loss of precision in working memory representations, we predicted that the influence of the time-order effect, and this superimposed “distance” effect, would monotonically increase for trials with longer ISIs. However, by varying the ISI across four intervals (300, 600, 1200, and 2400 ms) we instead found a complex, non-linear dependence of the time-order effect on both the ISI and the distance, with the time-order effect being paradoxically stronger at short ISIs. We also found that this relationship depended strongly on participants' prior experience of the ISI (from previous task titration). The time-order effect not only depends on participants' expectations concerning the distribution of stimuli, but also on the expected timing of the trials.

The Effect of Prenatal Methamphetamine Exposure on Attention as Assessed by Continuous Performance Tests

To assess for the increased risk of attention-deficit hyperactivity disorder (ADHD) in young children with prenatal methamphetamine exposure from the multicenter, longitudinal Infant Development, Environment, and Lifestyle (IDEAL) study. The IDEAL study enrolled 412 mother-infant pairs at 4 sites (Tulsa, OK; Des Moines, IA; Los Angeles, CA; and Honolulu, HI). Methamphetamine-exposed subjects (n = 204) were identified by self-report and/or gas chromatography/mass spectrometry confirmation of amphetamine and metabolites in infant meconium. Matched subjects (n = 208) denied methamphetamine use and had a negative meconium screen. This analysis included a subsample of 301 subjects who were administered the Conners' Kiddie Continuous Performance Test (K-CPT) at 5.5 years of age (153 exposed and 148 comparison). Hierarchical linear models adjusted for covariates tested exposure effects on K-CPT measures. Using the same covariates, logistic regression was used to determine the effect of exposure on the incidence of a positive ADHD confidence index score, defined as greater than 50%. There were no differences between the groups in omission or commission errors or reaction time for correct trials. However, methamphetamine exposure was associated with subtle differences in other outcomes predictive of ADHD, including increased slope of reaction time across blocks (p < .001), increased variability in reaction time with longer interstimulus intervals (p < .01), and increased likelihood of greater than 50% on the ADHD confidence index (odds ratio, 3.1; 95% confidence interval, 1.2-7.8; p = .02). Prenatal methamphetamine exposure was associated with subtle differences in K-CPT scores at 5.5 years of age. Even at this relatively young age, these children exhibit indicators of risk for ADHD and warrant monitoring.

Is it a face of a woman or a man? Visual mismatch negativity is sensitive to gender category

The present study investigated whether gender information for human faces was represented by the predictive mechanism indexed by the visual mismatch negativity (vMMN) event-related brain potential (ERP). While participants performed a continuous size-change-detection task, random sequences of cropped faces were presented in the background, in an oddball setting: either various female faces were presented infrequently among various male faces, or vice versa. In Experiment 1 the inter-stimulus-interval (ISI) was 400 ms, while in Experiment 2 the ISI was 2250 ms. The ISI difference had only a small effect on the P1 component, however the subsequent negativity (N1/N170) was larger and more widely distributed at longer ISI, showing different aspects of stimulus processing. As deviant-minus-standard ERP difference, a parieto-occipital negativity (vMMN) emerged in the 200–500 ms latency range (~350 ms peak latency in both experiments). We argue that regularity of gender on the photographs is automatically registered, and the violation of the gender category is reflected by the vMMN. In conclusion the results can be interpreted as evidence for the automatic activity of a predictive brain mechanism, in case of an ecologically valid category.

Temporal properties of shape processing by event-related MEG adaptation

Object recognition is a fundamental mechanism of visual processing and requires the extraction of shape information. Early visual areas have been linked to the analysis of local image features, while higher visual areas of the ventral visual pathway rather mediate the perception and recognition of global shapes. Investigations of the spatiotemporal characteristics of shape analysis in the human visual cortex by rapid event-related fMRI adaptation in combination with a region of interest analysis suggested a transient manner of contour integration and shape processing in early visual areas compared to sustained processing in higher visual areas. fMRI adaptation (or repetition suppression) paradigms offer the possibility to enhance the restricted spatial resolution of conventional fMRI by focusing on decreased responses for repeated stimulus presentation. However, improving our understanding of complex neuronal mechanisms in the human brain requires the investigation not only at high spatial but also temporal resolution. A limitation of fMRI adaptation can be found in its poor temporal resolution which EEG- and MEG-techniques can overcome, though at a lower spatial resolution. The present study aimed to investigate temporal characteristics of shape processing in the human brain by adapting the principles of fMRI adaption in a MEG study. In parallel to an earlier fMRI study, the two stimuli of a trial were presented at varied interstimulus intervals. Additional analyses by means of a dipole analysis and co-registration of MEG and fMRI data were conducted. Adaptation was observed for the short as well as the longer interstimulus interval. Interestingly, the latency of the adaptation effects varied with the interstimulus interval. The findings support a late onset of adaption that possibly underlies global discrimination processes and recognition in higher areas of the ventral visual pathway. Further, the present results indicate a useful extension of adaptation paradigms and 'region of interest'-analyses from fMRI to MEG at a high temporal resolution.

Recovery From Forward Masking in Elderly Cochlear Implant Users

To compare temporal aspects of peripheral neural responses and central auditory perception between groups of younger adult and elderly cochlear implant users. Cohort study. Academic hospital and cochlear implant center. Adult cochlear implant users aged 28 to 57 years in the younger group (n = 5) and 61 to 89 years (n = 9) in the elderly group. All subjects used Advanced Bionics devices. Diagnostic. Time constants of neural (i.e., electrically evoked compound action potentials [ECAPs]) and perceptual recovery from forward masking. Interstimulus intervals (ISIs) were varied in both experiments. ECAP recovery rates were equivalent between groups, and no correlation was found between ECAP recovery and age. No correlations were found between ECAP recovery and speech perception. Psychophysical recovery was significantly slower in the elderly compared with the younger subjects (p < 0.0005), with a significant effect of age (R2 = 0.70, p < 0.0005). At the longest ISI (240 ms), elderly subjects experienced a mean maximum threshold shift of 35.2% (relative to 1 ms ISI) versus 14.8% for younger subjects. There was a significant positive relationship between psychophysical recovery and consonant-nucleus-consonant word scores (R2 = 0.62, p < 0.001), although no relationship was found with Hearing in Noise Test sentences. These findings suggest that difficulties observed in speech perception by elderly CI users may be due to age-related changes in the central rather than peripheral auditory system. With further study, these results may provide information to allow clinicians to assess patients' temporal processing abilities and facilitate setting program parameters that will maximize their auditory perceptual experience with a cochlear implant.

Intracellular Na+ concentration influences short‐term plasticity of glutamate transporter‐mediated currents in neocortical astrocytes

Fast synaptic transmission requires a rapid clearance of the released neurotransmitter from the extracellular space. Glial glutamate transporters (excitatory amino acid transporters, EAATs) strongly contribute to glutamate removal. In this work, we investigated the paired-pulse plasticity of synaptically activated, glutamate transporter-mediated currents (STCs) in cortical layer 2/3 astrocytes. STCs were elicited by local electrical stimulation in layer 4 in the presence of ionotropic glutamate (AMPA and NMDA), GABAA, and GABAB receptor antagonists. In experiments with low [Na(+)]i (5 mM) intrapipette solution, STCs elicited by paired-pulse stimulation demonstrated paired-pulse facilitation (PPF) at short (<250 ms) interstimulus intervals (ISIs) and paired-pulse depression at longer ISIs. In experiments with close to physiological, high [Na(+)]i (20 mM) intrapipette solution, PPF of STCs at short ISIs was significantly reduced. In addition, the STC kinetics was slowed in the presence of high [Na(+)]i. Exogenous GABA increased astrocytic [Na(+)]i, reduced the mean STC amplitude, decreased PPF at short ISIs, and slowed STC kinetics. All GABA-induced changes were blocked by NO-711 and SNAP-5114, GABA transporter (GATs) antagonists. In experiments with the low intrapipette solution, GAT blockade under control conditions decreased PPF at short ISIs both at room and at near physiological temperatures. Dialysis of single astrocyte with low [Na(+)]i solution increased the amplitude and reduced PPR of evoked field potentials recorded in the vicinity of the astrocyte. We conclude that (1) endogenous GABA via GATs may influence EAAT functioning and (2) astrocytic [Na(+)]i modulates the short-term plasticity of STCs and in turn the efficacy of glutamate removal.

Enhanced propriospinal excitation from hand muscles to wrist flexors during reach-to-grasp in humans

In humans, propriospinal neurons located at midcervical levels receive peripheral and corticospinal inputs and probably participate in the control of grip tasks, but their role in reaching movements, as observed in cats and primates, is still an open question. The effect of ulnar nerve stimulation on flexor carpi radialis (FCR) motor evoked potential (MEP) was tested during reaching tasks and tonic wrist flexion. Significant MEP facilitation was observed at the end of reach during reach-to-grasp but not during grasp, reach-to-point, or tonic contractions. MEP facilitation occurred at a longer interstimulus interval than expected for convergence of corticospinal and afferent volleys at motoneuron level and was not paralleled by a change in the H-reflex. These findings suggest convergence of the two volleys at propriospinal level. Ulnar-induced MEP facilitation was observed when conditioning stimuli were at 0.75 motor response threshold (MT), but not 1 MT. This favors an increased excitability of propriospinal neurons rather than depression of their feedback inhibition, as has been observed during tonic power grip tasks. It is suggested that the ulnar-induced facilitation of FCR MEP during reach may be due to descending activation of propriospinal neurons, assisting the early recruitment of large motoneurons for rapid movement. Because the feedback inhibitory control is still open, this excitation can be truncated by cutaneous inputs from the palmar side of the hand during grasp, thus assisting movement termination. It is concluded that the feedforward activation of propriospinal neurons and their feedback control may be involved in the internal model, motor planning, and online adjustments for reach-to-grasp movements in humans.

Temporal binding during apparent movement of the human body

Alternating between static images of human bodies with an appropriate interstimulus interval (ISI) produces apparent biological motion. Here we investigate links between apparent biological motion and time perception. We presented two pictures of the initial and final positions of a human movement separated by six different ISIs. The shortest movement path between two positions was always biomechanically impossible. Participants performed two tasks: In an explicit task, participants judged whether they saw the longer, feasible movement path between the two postures, or the shorter, biomechanically impossible path. In an implicit task, participants judged the duration of a white square surrounding the picture sequence. At longer ISIs participants were more likely to see a longer, feasible movement path (explicit task) and underestimated the duration of body picture pairs, compared to trials displaying degraded body pictures (implicit task). We argue that perceiving apparent biological motion involves temporal binding of two static pictures into a continuous movement. Such temporal binding may be mediated by a top-down mechanism that produces a percept of biological motion in the absence of any retinal motion.

Auditory repetition enhancement at short interstimulus intervals for frequency-modulated tones

Frequency-modulated (FM) sweeps are important components of most natural sounds. To examine the processing of these stimuli we applied a two-tone paradigm. Repeated stimulus presentation usually leads to reduced neuronal responses. However, in a former study repetition enhancements which have been observed when FM tones were separated by short interstimulus intervals (ISIs) of ≤ 200 ms. To further investigate this repetition effect in response to FM tones, we recorded magnetoencephalogram (MEG) in humans during the presentation of consecutive FM sweep pairs separated by ISIs between 100 and 600 ms. We presented FM sweep pairs in six experimental conditions: a) two upward FM tones, b) two downward FM tones, c) an upward followed by a downward FM tone and d) a downward followed by an upward FM tone. Sequences of single upward and single downward FM tones served as control conditions. N1m amplitude was enhanced for repeated compared with different FM-direction tone pairs. This effect was found for the shortest ISI of 100 ms and disappeared at longer ISIs. Furthermore, mean peak latencies in response to the second tone were prolonged in same-direction pairs at the shortest ISI of 100 ms. At ISIs ≥ 300 ms slight enhancement effects occurred between 180 and 400 ms after the second stimulus. This is in accordance with a previous MEG study from our laboratory which demonstrated an enhancement effect for sustained fields at latencies of 150–350 ms after the second stimulus for same compared to different FM tone pairs separated by an ISI of 200 ms.

Exploring the pathophysiology of Mal de Debarquement

Mal de debarquement syndrome (MdDS) is a disorder of perceived motion most often occurring following a cruise. We report findings from a patient with MdDS who underwent a transcranial magnetic stimulation protocol to quantify cortical excitability. These data were compared to those from 40 controls. The patient with MdDS exhibited high levels of intracortical facilitation. These findings will provide insight on the pathophysiology of MdDS, and will help guide future work on this rare condition. Mal de debarquement syndrome (MdDS) occurs when habituation to passive background movement becomes resistant to readaptation to stable conditions and results in a phantom perception of self-motion. MdDS typically disappears quickly after return to stable ground; however, in rare instances the symptoms may persist for months to years (persistent MdDS). While the etiology of persistent MdDS is poorly understood, it does not appear to originate from vestibular dysfunction as vestibular tests are normal and the symptoms do not respond to vestibular therapy [2]. Rather, MdDS appears to be a disorder of neuroplasticity and sensory rearrangement [2]. To our knowledge, there have been no studies examining the neurophysiologic characteristics of the disorder. In this case study we report findings from a patient with persistent MdDS who underwent an extensive transcranial magnetic stimulation (TMS) protocol to quantify motor cortical excitability. Specifically, we quantified the duration of the corticospinal silent period using single-pulse TMS. The silent period is observed when a subject performs a slight contraction and a single TMS stimulus is applied to the motor cortex (Fig. 1a). Additionally, we quantified intracortical facilitation (ICF) and short-interval intracortical inhibition (SICI) using paired-pulse TMS. Paired-pulse TMS combines a conditioning stimulus (CP) with a test stimulus (TP) at different interstimulus intervals, and the relative change in motor evoked potential (MEP) size is expressed relative to an unconditioned test pulse. At a short interstimulus interval of 3 ms, the CP inhibits the MEP in comparison to the TP only (SICI), whereas at a longer interstimulus intervals of 15 ms it facilitates the MEP (ICF) (Fig. 1b). The patient was a 63-year-old female (160.2 cm, 77.3 kg) who complained of sensations of unsteadiness and a feeling of the floor moving under her feet after disembarking from a 7-day cruise *3.5 years ago (3/2007). She reported having to regularly reach out to steady herself against stationary objects, and that MdDS had greatly impacted her quality of life (subjective scoring of six out of ten on a visual analog scale for the impact of MdDS on her quality of life). Several other hallmark features of MdDS were present including mild cognitive slowing and transient improvement in symptoms with re-exposure to passive movement [2]. Physical examination was unremarkable. Diagnostic testing including sural sensory and peroneal motor conduction studies, needle EMG, and MRI of the brain were all normal. Additionally, the patient had unremarkable findings on Dix-Hallpike testing and the caloric reflex test. The patient did not have migraine or other primary headache as defined by the International B. C. Clark (&) Department of Biomedical Sciences, Ohio Musculoskeletal and Neurological Institute (OMNI), Ohio University, 211 Irvine Hall, Athens, OH 45701, USA e-mail: clarkb2@ohio.edu

A motor cortex excitability and gait analysis on Parkinsonian patients

Transcranial magnetic stimulation (TMS) parameters were recorded in a lower limb muscle and correlated with the gait parameters of 25 patients with Parkinson's disease (PD) with and without dopamine substitution treatment (DST) and 10 control subjects. Single and paired-pulse TMS were recorded in the tibialis anterior muscle (TA). Gait analysis was performed using a 3D motion analysis system. Parkinsonian patients (PP) did not differ from the control subjects (CS) in terms of relaxed motor threshold, active motor threshold (AMT), cortical silent period (CSP), motor-evoked potential (MEP) amplitude and area, or paired-pulse TMS with short interstimulus intervals (ISI). At longer ISIs, paired-pulse TMS showed that the amplitudes of the conditioned MEPs were lower in untreated PP than in CS. DST partially compensated for this difference. Gait analysis showed that the gait of PP undergoing no treatment was slower and the stride length shorter than normal. Both of these parameters improved under DST, however. Analysis of data obtained on all the subjects combined showed that both of the latter parameters were correlated with the paired-pulse MEP amplitude and area at longer ISIs. In PP, the cortical areas responsible for the lower limb movements seem to undergo intracortical facilitation (ICF) impairments, whereas the intracortical inhibition process is normal. The ICF level was found to be associated to the stride length and the velocity. The fact that only these two gait parameters were found to be dopa responsive indicates that dopaminergic treatment may improve gait disorders by restoring the ICF.

Stimulus Novelty, and Not Neural Refractoriness, Explains the Repetition Suppression of Laser-Evoked Potentials

Brief radiant laser pulses selectively activate skin nociceptors and elicit transient brain responses (laser-evoked potentials [LEPs]). When LEPs are elicited by pairs of stimuli (S1-S2) delivered at different interstimulus intervals (ISIs), the S2-LEP is strongly reduced at short ISIs (250 ms) and progressively recovers at longer ISIs (2,000 ms). This finding has been interpreted in terms of order of arrival of nociceptive volleys and refractoriness of neural generators of LEPs. However, an alternative explanation is the modulation of another experimental factor: the novelty of the eliciting stimulus. To test this alternative hypothesis, we recorded LEPs elicited by pairs of nociceptive stimuli delivered at four ISIs (250, 500, 1,000, 2,000 ms), using two different conditions. In the constant condition, the ISI was identical across the trials of each block, whereas in the variable condition, the ISI was varied randomly across trials and single-stimulus trials were intermixed with paired trials. Therefore the time of occurrence of S2 was both less novel and more predictable in the constant than in the variable condition. In the constant condition, we observed a significant ISI-dependent suppression of the biphasic negative-positive wave (N2-P2) complex of the S2-LEP. In contrast, in the variable condition, the S2-LEP was completely unaffected by stimulus repetition. The pain ratings elicited by S2 were not different in the two conditions. These results indicate that the repetition-suppression of the S2-LEP is not due to refractoriness in nociceptive afferent pathways, but to a modulation of novelty and/or temporal predictability of the eliciting stimulus. This provides further support to the notion that stimulus saliency constitutes a crucial determinant of LEP magnitude and that a significant fraction of the brain activity time-locked to a brief and transient sensory stimulus is not directly related to the quality and the intensity of the corresponding sensation, but to bottom-up attentional processes.

Hearing requires otoferlin-dependent efficient replenishment of synaptic vesicles in hair cells

Inner hair cell ribbon synapses indefatigably transmit acoustic information. The proteins mediating their fast vesicle replenishment (hundreds of vesicles per s) are unknown. We found that an aspartate to glycine substitution in the C(2)F domain of the synaptic vesicle protein otoferlin impaired hearing by reducing vesicle replenishment in the pachanga mouse model of human deafness DFNB9. In vitro estimates of vesicle docking, the readily releasable vesicle pool (RRP), Ca(2+) signaling and vesicle fusion were normal. Moreover, we observed postsynaptic excitatory currents of variable size and spike generation. However, mutant active zones replenished vesicles at lower rates than wild-type ones and sound-evoked spiking in auditory neurons was sparse and only partially improved during longer interstimulus intervals. We conclude that replenishment does not match the release of vesicles at mutant active zones in vivo and a sufficient standing RRP therefore cannot be maintained. We propose that otoferlin is involved in replenishing synaptic vesicles.

Acute high-frequency rTMS of the left dorsolateral prefrontal cortex and attentional control in healthy young men

Previous studies have shown that high-frequency repetitive transcranial magnetic stimulation (rTMS) over the dorsolateral prefrontal cortex induces neuromodulation in prefrontal and striatal regions. We hypothesized that high-frequency rTMS over the dorsolateral prefrontal cortex would influence attentional control, which has been associated with neural activity in the same region. Seventeen healthy young men volunteered to participate in a sham-controlled rTMS study. Participants received both rTMS and sham stimulation on separate days and the Conners' continuous performance test was used to assess response inhibition and attentional vigilance. Results indicated that participants showed fewer commission errors during trials after rTMS as compared with sham stimulation, at longer interstimulus intervals (ISIs), which suggests that high-frequency rTMS may have the potential to improve response inhibition. This finding contributes to the understanding of the relationship between the dorsolateral prefrontal cortex and attentional control and suggests possible therapeutic applications for high-frequency rTMS.

Psychophysical Evaluation of a Sanshool Derivative (Alkylamide) and the Elucidation of Mechanisms Subserving Tingle

Previous studies investigated the neural and molecular underpinnings of the tingle sensation evoked by sanshool and other natural or synthetic alkylamides. Currently, we sought to characterize the psychophysical properties associated with administration of these compounds. Like other chemesthetic stimuli, the synthetic tingle analog isobutylalkylamide (IBA) evoked a sensation that was temporally dynamic. Repeated IBA application at short (30 sec) interstimulus intervals (ISI) resulted in a tingle sensation that increased across trials. Application at longer ISIs (∼30 min) resulted in a sensation of decreased intensity consistent with self-desensitization. Prior treatment with the TRPV1 or TRPA1 agonists, capsaicin and mustard oil did not cross-desensitize the tingle sensation evoked by IBA suggesting that neither TRPV1 nor TRPA1 participate in the transduction mechanism sub-serving tingle. When evaluated over 30-min time period, lingual IBA evoked a sensation that was described initially as tingling and pungent but after approximately 15 min, as a cooling sensation. Further, we found that the sensation evoked by lingual IBA was potentiated by simultaneous application of cold (0°C) and cool (21°C) thermal stimuli but was unaffected by warm (33°C) and hot (41°C) temperatures. Finally, to test the hypothesis that the tingling sensation is subserved by the activation of mechanosensitve fibers, we evaluated lingual tactile thresholds in the presence and absence of lingual IBA. The presence of IBA significantly raised lingual tactile thresholds, whereas capsaicin did not, identifying a role for mechanosensitive fibers in conveying the tingle sensation evoked by sanshool-like compounds. Collectively, these results show that lingual alkylamide evokes a complex sensation that is temporally dynamic and consistent with in vitro and in vivo experiments suggesting these compounds activate mechanosensitve neurons via blockade of KCNK two-pore potassium channels to induce the novel tingling sensation.

Interaction between nitric oxide synthase inhibitor induced oscillations and the activation flow coupling response

The role of nitric oxide (NO) in the activation-flow coupling (AFC) response to periodic electrical forepaw stimulation was investigated using signal averaged laser Doppler (LD) flowmetry. LD measures of calculated cerebral blood flow (CBF) were obtained both prior and after intra-peritoneal administration of the non-selective nitric oxide synthase (NOS) inhibitor, N G-nitro- l-arginine ( l-NNA) (40 mg/kg). Characteristic baseline low frequency vasomotion oscillations (0.17 Hz) were observed after l-NNA administration. These LD CBF oscillations were synchronous within but not between hemispheres. l-NNA reduced the magnitude of the AFC response ( p < 0.05) for longer stimuli (1 min) with longer inter-stimulus intervals (2 min). In contrast, the magnitude of the AFC response for short duration stimuli (4 s) with short inter-stimulus intervals (20 s) was augmented ( p < 0.05) after l-NNA. An interaction occurred between l-NNA induced vasomotion oscillations and the AFC response with the greatest increase occurring at the stimulus harmonic closest to the oscillatory frequency. Nitric oxide may therefore modulate the effects of other vasodilators involved in vasomotion oscillations and the AFC response.

A method for removing cochlear implant artifact

When cortical auditory evoked potentials (CAEPs) are recorded in individuals with a cochlear implant (CI), electrical artifact can make the CAEP difficult or impossible to measure. Since increasing the interstimulus interval (ISI) increases the amplitude of physiological responses without changing the artifact, subtracting CAEPs recorded with a short ISI from those recorded with a longer ISI should show the physiological response without any artifact. In the first experiment, N1–P2 responses were recorded using a speech syllable and tone, paired with ISIs that changed randomly between 0.5 and 4 s. In the second experiment, the same stimuli, at ISIs of either 500 or 3000 ms, were presented in blocks that were homogeneous or random with respect to the ISI or stimulus. In the third experiment, N1–P2 responses were recorded using pulse trains with 500 and 3000 ms ISIs in 4 CI listeners. The results demonstrated: (1) N1–P2 response amplitudes generally increased with increasing ISI. (2) Difference waveforms were largest for the homogeneous and random-stimulus blocks than for the random-ISI block. (3) The subtraction technique almost completely eliminated the electrical artifact in individuals with cochlear implants. Therefore, the subtraction technique is a feasible method of removing from the N1–P2 response the electrical artifact generated by the cochlear implant.