Low-Intensity Ultrasound Causes Direct Excitation of Auditory Cortical Neurons.

Cochlear implantation is the first-line treatment for severe and profound hearing loss in children and adults. However, deaf patients with cochlear malformations or with cochlear nerve deficiencies are ineligible for cochlear implants. Meanwhile, the limited spatial selectivity and high risk of invasive craniotomy restrict the wide application of auditory brainstem implants. A noninvasive alternative strategy for safe and effective neuronal stimulation is urgently needed to address this issue. Because of its advantage in neural modulation over electrical stimulation, low-intensity ultrasound (US) is considered a safe modality for eliciting neural activity in the central auditory system. Although the neural modulation ability of low-intensity US has been demonstrated in the human primary somatosensory cortex and primary visual cortex, whether low-intensity US can directly activate auditory cortical neurons is still a topic of debate. To clarify the direct effects on auditory neurons, in the present study, we employed low-intensity US to stimulate auditory cortical neurons in vitro. Our data show that both low-frequency (0.8 MHz) and high-frequency (>27 MHz) US stimulation can elicit the inward current and action potentials in cultured neurons. c-Fos staining results indicate that low-intensity US is efficient for stimulating most neurons. Our study suggests that low-intensity US can excite auditory cortical neurons directly, implying that US-induced neural modulation can be a potential approach for activating the auditory cortex of deaf patients.

Auditory cortical activity elicited by infrared laser irradiation from the outer ear in Mongolian gerbils.

Infrared neural stimulation has been studied for its potential to replace an electrical stimulation of a cochlear implant. No studies, however, revealed how the technic reliably evoke auditory cortical activities. This research investigated the effects of cochlear laser stimulation from the outer ear on auditory cortex using brain imaging of activity-dependent changes in mitochondrial flavoprotein fluorescence signal. An optic fiber was inserted into the gerbil's ear canal to stimulate the lateral side of the cochlea with an infrared laser. Laser stimulation was found to activate the identified primary auditory cortex. In addition, the temporal profile of the laser-evoked responses was comparable to that of the auditory responses. Our results indicate that infrared laser irradiation from the outer ear has the capacity to evoke, and possibly manipulate, the neural activities of the auditory cortex and may substitute for the present cochlear implants in future.

The effects of acute and chronic exposure to 900 MHz radiofrequency radiation on auditory brainstem response in adult rats.

The aim of this study was to determine the effects of short and long-term RFR exposure on ABR by evaluating lipid peroxidation and antioxidant status in adult rats. Sixty male albino Wistar rats were randomly divided into four groups. S1:1 week sham, S10:10 weeks sham, E1:1 week RFR, E10:10 weeks RFR. Experimental group rats were exposed to RFR 2 h/day, 5 days/week during the test period. Sham rats were kept in the same conditions without RFR. After the experiment, ABRs were recorded from the mastoids of rats using tone burst acoustic stimuli. Biochemical investigations in rat brain and ultrastructural analysis in temporal cortex were performed. ABR wave I latency prolonged in E1-group and shortened in E10-group compared to their shams. TBARS level increased in E1-group, decreased in E10-group, on the contrary, SOD and CAT activities and GSH level decreased in E1-group, increased in E10-group compared to their sham groups. Edema was present in the neuron and astrocyte cytoplasms and astrocyte end-feet in both E1 and E10 groups. Our results suggest that 900 MHz RFR may have negative effects on the auditory system in acute exposure and no adverse effects in chronic exposure without weekends.

Selective enhancement of low-gamma activity by tACS improves phonemic processing and reading accuracy in dyslexia.

The phonological deficit in dyslexia is associated with altered low-gamma oscillatory function in left auditory cortex, but a causal relationship between oscillatory function and phonemic processing has never been established. After confirming a deficit at 30 Hz with electroencephalography (EEG), we applied 20 minutes of transcranial alternating current stimulation (tACS) to transiently restore this activity in adults with dyslexia. The intervention significantly improved phonological processing and reading accuracy as measured immediately after tACS. The effect occurred selectively for a 30-Hz stimulation in the dyslexia group. Importantly, we observed that the focal intervention over the left auditory cortex also decreased 30-Hz activity in the right superior temporal cortex, resulting in reinstating a left dominance for the oscillatory response. These findings establish a causal role of neural oscillations in phonological processing and offer solid neurophysiological grounds for a potential correction of low-gamma anomalies and for alleviating the phonological deficit in dyslexia.

A Single Exposure to GSM-1800 MHz Signals in the Course of an Acute Neuroinflammatory Reaction can Alter Neuronal Responses and Microglial Morphology in the Rat Primary Auditory Cortex.

During mobile phone conversations, the temporal lobe neural networks involved in processing auditory information are exposed to electromagnetic fields (EMF) such as pulse-modulated GSM-1800 MHz radiofrequencies that convey wireless communications. The effects of these EMF on the brain affected by a pathological condition remain little investigated. In this study, rats injected with lipopolysaccharide (LPS) to induce neuroinflammation were exposed "head-only" to GSM-1800 MHz signals for two hours at a specific absorption rate (SAR) that reached an average value of 1.55 W/kg in the auditory cortex (ACx). Immunodetection of Iba1, a microglial marker, and electrophysiological recordings in the ACx three to six hours after global system for communication (GSM) exposure, or sham-exposure, showed that exposure to GSM-1800 MHz resulted in a growth of microglial processes and a reduction in spontaneous firing rate. More importantly, there was a significant reduction in evoked responses to artificial and natural stimuli and an increase in response duration. The response latency and the bandwidth of the frequency tuning were unchanged, but the GSM exposure led to a higher proportion of cortical sites exhibiting abnormally high acoustic thresholds. These modifications were not observed in rats exposed to GSM-1800 MHz without pretreatment with LPS. Together our data provide evidence that in neuroinflammatory conditions, acute exposure to GSM-1800 MHz can significantly affect microglia and neuronal activity underling auditory perception.

Ultrasound Produces Extensive Brain Activation via a Cochlear Pathway.

Ultrasound (US) can noninvasively activate intact brain circuits, making it a promising neuromodulation technique. However, little is known about the underlying mechanism. Here, we apply transcranial US and perform brain mapping studies in guinea pigs using extracellular electrophysiology. We find that US elicits extensive activation across cortical and subcortical brain regions. However, transection of the auditory nerves or removal of cochlear fluids eliminates the US-induced activity, revealing an indirect auditory mechanism for US neural activation. Our findings indicate that US activates the ascending auditory system through a cochlear pathway, which can activate other non-auditory regions through cross-modal projections. This cochlear pathway mechanism challenges the idea that US can directly activate neurons in the intact brain, suggesting that future US stimulation studies will need to control for this effect to reach reliable conclusions.

Ultrasonic Neuromodulation Causes Widespread Cortical Activation via an Indirect Auditory Mechanism.

Ultrasound has received widespread attention as an emerging technology for targeted, non-invasive neuromodulation based on its ability to evoke electrophysiological and motor responses in animals. However, little is known about the spatiotemporal pattern of ultrasound-induced brain activity that could drive these responses. Here, we address this question by combining focused ultrasound with wide-field optical imaging of calcium signals in transgenic mice. Surprisingly, we find cortical activity patterns consistent with indirect activation of auditory pathways rather than direct neuromodulation at the ultrasound focus. Ultrasound-induced activity is similar to that evoked by audible sound. Furthermore, both ultrasound and audible sound elicit motor responses consistent with a startle reflex, with both responses reduced by chemical deafening. These findings reveal an indirect auditory mechanism for ultrasound-induced cortical activity and movement requiring careful consideration in future development of ultrasonic neuromodulation as a tool in neuroscience research.

Egocentric and allocentric representations in auditory cortex.

A key function of the brain is to provide a stable representation of an object's location in the world. In hearing, sound azimuth and elevation are encoded by neurons throughout the auditory system, and auditory cortex is necessary for sound localization. However, the coordinate frame in which neurons represent sound space remains undefined: classical spatial receptive fields in head-fixed subjects can be explained either by sensitivity to sound source location relative to the head (egocentric) or relative to the world (allocentric encoding). This coordinate frame ambiguity can be resolved by studying freely moving subjects; here we recorded spatial receptive fields in the auditory cortex of freely moving ferrets. We found that most spatially tuned neurons represented sound source location relative to the head across changes in head position and direction. In addition, we also recorded a small number of neurons in which sound location was represented in a world-centered coordinate frame. We used measurements of spatial tuning across changes in head position and direction to explore the influence of sound source distance and speed of head movement on auditory cortical activity and spatial tuning. Modulation depth of spatial tuning increased with distance for egocentric but not allocentric units, whereas, for both populations, modulation was stronger at faster movement speeds. Our findings suggest that early auditory cortex primarily represents sound source location relative to ourselves but that a minority of cells can represent sound location in the world independent of our own position.

Ncm, a Photolabile Group for Preparation of Caged Molecules: Synthesis and Biological Application.

Ncm, 6-nitrocoumarin-7-ylmethyl, is a photolabile protective group useful for making "caged" molecules. Ncm marries the reliable photochemistry of 2-nitrobenzyl systems with the excellent stability and spectroscopic properties of the coumarin chromophore. From simple, commercially available starting materials, preparation of Ncm and its caged derivatives is both quick and easy. Photorelease of Ncm-caged molecules occurs on the microsecond time scale, with quantum efficiencies of 0.05-0.08. We report the synthesis and physical properties of Ncm and its caged derivatives. The utility of Ncm-caged glutamate for neuronal photostimulation is demonstrated in cultured hippocampal neurons and in brain slice preparations.

Expression of c-Fos in rat auditory and limbic systems following 22-kHz calls.

In the present study, adult Long-Evans rats were exposed either to natural conspecific aversive 22-kHz vocalizations or to artificial call-like stimuli with comparable frequency-temporal features, followed by c-Fos immunohistochemistry. The natural 22-kHz vocalizations was either played from a recording or produced by a foot-shocked animal located nearby (live vocalizations). In comparison with controls (non-exposed animals), c-Fos immunoreactivity was significantly increased in the inferior colliculus (IC), auditory cortex (AC), periaqueductal grey (PAG), basolateral amygdala (BA), and hippocampus (Hip) of rats exposed to either live or recorded 22-kHz natural vocalizations. Exposure to live natural vocalizations of the foot-shocked animal resulted in a similar pattern of c-Fos activity, as did exposure to the playback of the natural vocalizations. In contrast to this, foot-shocked rats (emitting the 22-kHz vocalizations) had the c-Fos positivity increased markedly in the PAG and only slightly in the AC. The expression of c-Fos also increased in the IC, AC, and in the PAG in animals exposed to the artificial call-like stimuli, when compared to controls; however, the increase was much less pronounced. In this case, c-Fos expression was not increased in the hippocampus or basolateral amygdala. Interestingly, almost no c-Fos expression was found in the medial nucleus of the geniculate body in any of the experimental groups. These findings suggest that differences exist between the processing of important natural conspecific vocalizations and artificial call-like stimuli with similar frequency-temporal features, and moreover they suggest the specific role of individual brain structures in the processing of such calls.

Bidirectional Regulation of Innate and Learned Behaviors That Rely on Frequency Discrimination by Cortical Inhibitory Neurons.

The ability to discriminate tones of different frequencies is fundamentally important for everyday hearing. While neurons in the primary auditory cortex (AC) respond differentially to tones of different frequencies, whether and how AC regulates auditory behaviors that rely on frequency discrimination remains poorly understood. Here, we find that the level of activity of inhibitory neurons in AC controls frequency specificity in innate and learned auditory behaviors that rely on frequency discrimination. Photoactivation of parvalbumin-positive interneurons (PVs) improved the ability of the mouse to detect a shift in tone frequency, whereas photosuppression of PVs impaired the performance. Furthermore, photosuppression of PVs during discriminative auditory fear conditioning increased generalization of conditioned response across tone frequencies, whereas PV photoactivation preserved normal specificity of learning. The observed changes in behavioral performance were correlated with bidirectional changes in the magnitude of tone-evoked responses, consistent with predictions of a model of a coupled excitatory-inhibitory cortical network. Direct photoactivation of excitatory neurons, which did not change tone-evoked response magnitude, did not affect behavioral performance in either task. Our results identify a new function for inhibition in the auditory cortex, demonstrating that it can improve or impair acuity of innate and learned auditory behaviors that rely on frequency discrimination.

Memory formation and retrieval of neuronal silencing in the auditory cortex.

Sensory stimuli not only activate specific populations of cortical neurons but can also silence other populations. However, it remains unclear whether neuronal silencing per se leads to memory formation and behavioral expression. Here we show that mice can report optogenetic inactivation of auditory neuron ensembles by exhibiting fear responses or seeking a reward. Mice receiving pairings of footshock and silencing of a neuronal ensemble exhibited a fear response selectively to the subsequent silencing of the same ensemble. The valence of the neuronal silencing was preserved for at least 30 d and was susceptible to extinction training. When we silenced an ensemble in one side of auditory cortex for conditioning, silencing of an ensemble in another side induced no fear response. We also found that mice can find a reward based on the presence or absence of the silencing. Neuronal silencing was stored as working memory. Taken together, we propose that neuronal silencing without explicit activation in the cerebral cortex is enough to elicit a cognitive behavior.

Repetitive transcranial magnetic stimulation improve tinnitus in normal hearing patients: a double-blind controlled, clinical and neuroimaging outcome study.

BACKGROUND AND PURPOSE: Tinnitus is a frequent disorder which is very difficult to treat and there is compelling evidence that tinnitus is associated with functional alterations in the central nervous system. Targeted modulation of tinnitus-related cortical activity has been proposed as a promising new treatment approach. We aimed to investigate both immediate and long-term effects of low frequency (1 Hz) repetitive transcranial magnetic stimulation (rTMS) in patients with tinnitus and normal hearing. METHODS: Using a parallel design, 20 patients were randomized to receive either active or placebo stimulation over the left temporoparietal cortex for five consecutive days. Treatment results were assessed by using the Tinnitus Handicap Inventory. Ethyl cysteinate dimmer-single photon emission computed tomography (SPECT) imaging was performed before and 14 days after rTMS. RESULTS: After active rTMS there was significant improvement of the tinnitus score as compared to sham rTMS for up to 6 months after stimulation. SPECT measurements demonstrated a reduction of metabolic activity in the inferior left temporal lobe after active rTMS. CONCLUSION: These results support the potential of rTMS as a new therapeutic tool for the treatment of chronic tinnitus, by demonstrating a significant reduction of tinnitus complaints over a period of at least 6 months and significant reduction of neural activity in the inferior temporal cortex, despite the stimulation applied on the superior temporal cortex.

Corticofugal modulation of initial sound processing in the brain.

The brain selectively extracts the most relevant information in top-down processing manner. Does the corticofugal system, a "back projection system," constitute the neural basis of such top-down selection? Here, we show how focal activation of the auditory cortex with 500 nA electrical pulses influences the auditory information processing in the cochlear nucleus (CN) that receives almost unprocessed information directly from the ear. We found that cortical activation increased the response magnitudes and shortened response latencies of physiologically matched CN neurons, whereas decreased response magnitudes and lengthened response latencies of unmatched CN neurons. In addition, cortical activation shifted the frequency tunings of unmatched CN neurons toward those of the activated cortical neurons. Our data suggest that cortical activation selectively enhances the neural processing of particular auditory information and attenuates others at the first processing level in the brain based on sound frequencies encoded in the auditory cortex. The auditory cortex apparently implements a long-range feedback mechanism to select or filter incoming signals from the ear.

Effects of the task of categorizing FM direction on auditory evoked magnetic fields in the human auditory cortex.

We examined effects of the task of categorizing linear frequency-modulated (FM) sweeps into rising and falling on auditory evoked magnetic fields (AEFs) from the human auditory cortex, recorded by means of whole-head magnetoencephalography. AEFs in this task condition were compared with those in a passive condition where subjects had been asked to just passively listen to the same stimulus material. We found that the M100-peak latency was significantly shorter for the task condition than for the passive condition in the left but not in the right hemisphere. Furthermore, the M100-peak latency was significantly shorter in the right than in the left hemisphere for the passive and the task conditions. In contrast, the M100-peak amplitude did not differ significantly between conditions, nor between hemispheres. We also analyzed the activation strength derived from the integral of the absolute magnetic field over constant time windows between stimulus onset and 260 ms. We isolated an early, narrow time range between about 60 ms and 80 ms that showed larger values in the task condition, most prominently in the right hemisphere. These results add to other imaging and lesion studies which suggest a specific role of the right auditory cortex in identifying FM sweep direction and thus in categorizing FM sweeps into rising and falling.

Neural interactions within and beyond the critical band elicited by two simultaneously presented narrow band noises: a magnetoencephalographic study.

Neural activities elicited in the auditory system are systematically organized according to the frequency characteristics of corresponding sound inputs. This systematic frequency alignment, called 'tonotopy,' plays an important role in auditory perception. By means of magnetoencephalography (MEG) we investigated here interactions between neural groups activated by two simultaneously presented narrow-band noises (NBNs) within the human cortical tonotopic map. Auditory evoked fields indicated that the neural interactions activated by these NBNs depended on the frequency difference between them: the amplitude of the N1m-response systematically increased with increasing frequency difference between the NBNs until the critical bandwidth was reached. In contrast, the N1m decreased with frequency difference exceeding the critical bandwidth. The different N1m-response patterns within and beyond the critical band seem to result from the combination of inhibitory and excitatory neural processes in the auditory pathway and may contribute to the perception of complex sound patterns like speech and music.

Neuromagnetic responses to chords are modified by preceding musical scale.

Previous psychological studies have shown that musical chords primed by Western musical scale in a tonal and modal schema are perceived in a hierarchy of stability. We investigated such priming effects on auditory magnetic responses to tonic-major and submediant-minor chords preceded by major scales and tonic-minor and submediant-major chords preceded by minor scales. Musically trained subjects participated in the experiment. During MEG recordings, subjects judged perceptual stability of the chords. The tonic chords were judged to be stable, whereas the submediant chords were judged to be unstable. Dipole moments of N1m response originating in the auditory cortex were larger in the left hemisphere for the submediant chords than for the tonic chords preceded by the major but not minor scales. No difference in the N1m or P2m moment was found for the chords presented without preceding scales. These results suggest priming effects of the tonal schema, interacting with contextual modality, on neural activity of the auditory cortex as well as perceptual stability of the chords. It is inferred that modulation of the auditory cortical activity is associated with attention induced by tonal instability and modality shift, which characterize the submediant chords.

Modulation of the receptive fields of midbrain neurons elicited by thalamic electrical stimulation through corticofugal feedback.

The ascending and descending projections of the central auditory system form multiple tonotopic loops. This study specifically examines the tonotopic pathway from the auditory thalamus to the auditory cortex and then to the auditory midbrain in mice. We observed the changes of receptive fields in the central nucleus of the inferior colliculus of the midbrain evoked by focal electrical stimulation of the ventral division of the medial geniculate body of the thalamus. The receptive field of an auditory neuron was characterized by five parameters: the best frequency, minimum threshold, bandwidth, size of receptive field, and average spike number. We found that focal thalamic stimulation changed the parametric values characterizing the recorded collicular receptive fields toward those characterizing the stimulated thalamic receptive fields. Cortical inactivation with muscimol prevented the development of the collicular plasticity induced by focal thalamic stimulation. Our data suggest that the intact colliculo-thalamo-cortico-collicular loops are important for the coordination of sound-guided plasticity in the central auditory system.

Corticofugal modulation of multi-parametric auditory selectivity in the midbrain of the big brown bat.

Corticofugal modulation of sub-cortical auditory selectivity has been shown previously in mammals for frequency, amplitude, time, and direction domains in separate studies. As such, these studies do not show if multi-parametric corticofugal modulation can be mediated through the same sub-cortical neuron. Here we specifically studied corticofugal modulation of best frequency (BF), best amplitude (BA), and best azimuth (BAZ) at the same neuron in the inferior colliculus of the big brown bat, Eptesicus fuscus, using focal electrical stimulation in the auditory cortex. Among 53 corticofugally inhibited collicular neurons examined, cortical electrical stimulation produced a shift of all three measurements (i.e., BF, BA, and BAZ) toward the value of stimulated cortical neuron in 13 (24.5%) neurons, two measurements (i.e., BF and BAZ or BA and BAZ) in 19 (36%) neurons, and one measurement in 16 (30%) neurons. Cortical electrical stimulation did not shift any of these measurements in the remaining five (9.5%) neurons. Corticofugally induced collicular BF shift was symmetrical, whereas the shift in collicular BA or BAZ was asymmetrical. The amount of shift in each measurement was significantly correlated with each measurement difference between recorded collicular and stimulated cortical neurons. However, shifts of three measurements were not correlated with each other. Furthermore, average measurement difference between collicular and cortical neurons was larger for collicular neurons with measurement shifts than for those without shifts. These data indicate that multi-parametric corticofugal modulation can be mediated through the same subcortical neuron based on the difference in auditory selectivity between subcortical and cortical neurons.

Early experience impairs perceptual discrimination.

Sensory experience can reorganize cortical sensory representations in an epoch of early development. During this period, cortical sensory neurons may shift their response selectivity and become tuned to more frequently occurring stimuli. Although this enlarged cortical representation is believed to underlie improved sensory processing of the experienced stimuli, its precise perceptual consequences are still unknown. We show that rearing rats in a single-frequency tonal environment results in enlarged cortical representations of the frequencies near that of the experienced tone, but the animals are impaired in perceptual discrimination of the over-represented frequencies. By contrast, discrimination of the neighboring under-represented frequencies is substantially improved. Computational analysis indicated that the altered perceptual ability could be fully accounted for by the sound exposure-induced reorganization of cortical primary auditory representations. These results indicate that early experience shapes sensory perception. The same plasticity processes may be important in optimizing phonemic representations in humans.