Cortical map plasticity as a function of vagus nerve stimulation rate.

BACKGROUND: Repeatedly pairing a brief train of vagus nerve stimulation (VNS) with an external event can reorganize the sensory or motor cortex. A 30 Hz train of sixteen VNS pulses paired with a tone significantly increases the number of neurons in primary auditory cortex (A1) that respond to tones near the paired tone frequency. The effective range of VNS pulse rates for driving cortical map plasticity has not been defined. OBJECTIVE/HYPOTHESIS: This project investigated the effects of VNS rate on cortical plasticity. We expected that VNS pulse rate would affect the degree of plasticity caused by VNS-tone pairing. METHODS: Rats received sixteen pulses of VNS delivered at a low (7.5 Hz), moderate (30 Hz), or high (120 Hz) rate paired with 9 kHz tones 300 times per day over a 20 day period. RESULTS: More A1 neurons responded to the paired tone frequency in rats from the moderate rate VNS group compared to naïve controls. The response strength was also increased in these rats. In contrast, rats that received high or low rate VNS failed to exhibit a significant increase in the number of neurons tuned to sounds near 9 kHz. CONCLUSION: Our results demonstrate that the degree of cortical plasticity caused by VNS-tone pairing is an inverted-U function of VNS pulse rate. The apparent high temporal precision of VNS-tone pairing helps identify optimal VNS parameters to achieve the beneficial effects from restoration of sensory or motor function.

Effects of vagus nerve stimulation on extinction of conditioned fear and post-traumatic stress disorder symptoms in rats.

Exposure-based therapies help patients with post-traumatic stress disorder (PTSD) to extinguish conditioned fear of trauma reminders. However, controlled laboratory studies indicate that PTSD patients do not extinguish conditioned fear as well as healthy controls, and exposure therapy has high failure and dropout rates. The present study examined whether vagus nerve stimulation (VNS) augments extinction of conditioned fear and attenuates PTSD-like symptoms in an animal model of PTSD. To model PTSD, rats were subjected to a single prolonged stress (SPS) protocol, which consisted of restraint, forced swim, loss of consciousness, and 1 week of social isolation. Like PTSD patients, rats subjected to SPS show impaired extinction of conditioned fear. The SPS procedure was followed, 1 week later, by auditory fear conditioning (AFC) and extinction. VNS or sham stimulation was administered during half of the extinction days, and was paired with presentations of the conditioned stimulus. One week after completion of extinction training, rats were given a battery of behavioral tests to assess anxiety, arousal and avoidance. Results indicated that rats given SPS 1 week prior to AFC (PTSD model) failed to extinguish the freezing response after eleven consecutive days of extinction. Administration of VNS reversed the extinction impairment and attenuated reinstatement of the conditioned fear response. Delivery of VNS during extinction also eliminated the PTSD-like symptoms, such as anxiety, hyperarousal and social avoidance for more than 1 week after VNS treatment. These results provide evidence that extinction paired with VNS treatment can lead to remission of fear and improvements in PTSD-like symptoms. Taken together, these findings suggest that VNS may be an effective adjunct to exposure therapy for the treatment of PTSD.

Cortical Map Plasticity as a Function of Vagus Nerve Stimulation Intensity.

BACKGROUND: Pairing sensory or motor events with vagus nerve stimulation (VNS) can reorganize sensory or motor cortex. Repeatedly pairing a tone with a brief period of VNS increases the proportion of primary auditory cortex (A1) responding to the frequency of the paired tone. However, the relationship between VNS intensity and cortical map plasticity is not known. OBJECTIVE/HYPOTHESIS: The primary goal of this study was to determine the range of VNS intensities that can be used to direct cortical map plasticity. METHODS: The rats were exposed to a 9 kHz tone paired with VNS at intensities of 0.4, 0.8, 1.2, or 1.6 mA. RESULTS: In rats that received moderate (0.4-0.8 mA) intensity VNS, 75% more cortical neurons were tuned to frequencies near the paired tone frequency. A two-fold effective range is broader than expected based on previous VNS studies. Rats that received high (1.2-1.6 mA) intensity VNS had significantly fewer neurons tuned to the same frequency range compared to the moderate intensity group. CONCLUSION: This result is consistent with previous results documenting that VNS is memory enhancing as a non-monotonic relationship of VNS intensity.

Degraded auditory processing in a rat model of autism limits the speech representation in non-primary auditory cortex.

Although individuals with autism are known to have significant communication problems, the cellular mechanisms responsible for impaired communication are poorly understood. Valproic acid (VPA) is an anticonvulsant that is a known risk factor for autism in prenatally exposed children. Prenatal VPA exposure in rats causes numerous neural and behavioral abnormalities that mimic autism. We predicted that VPA exposure may lead to auditory processing impairments which may contribute to the deficits in communication observed in individuals with autism. In this study, we document auditory cortex responses in rats prenatally exposed to VPA. We recorded local field potentials and multiunit responses to speech sounds in primary auditory cortex, anterior auditory field, ventral auditory field. and posterior auditory field in VPA exposed and control rats. Prenatal VPA exposure severely degrades the precise spatiotemporal patterns evoked by speech sounds in secondary, but not primary auditory cortex. This result parallels findings in humans and suggests that secondary auditory fields may be more sensitive to environmental disturbances and may provide insight into possible mechanisms related to auditory deficits in individuals with autism.

Knockdown of the dyslexia-associated gene Kiaa0319 impairs temporal responses to speech stimuli in rat primary auditory cortex.

One in 15 school age children have dyslexia, which is characterized by phoneme-processing problems and difficulty learning to read. Dyslexia is associated with mutations in the gene KIAA0319. It is not known whether reduced expression of KIAA0319 can degrade the brain's ability to process phonemes. In the current study, we used RNA interference (RNAi) to reduce expression of Kiaa0319 (the rat homolog of the human gene KIAA0319) and evaluate the effect in a rat model of phoneme discrimination. Speech discrimination thresholds in normal rats are nearly identical to human thresholds. We recorded multiunit neural responses to isolated speech sounds in primary auditory cortex (A1) of rats that received in utero RNAi of Kiaa0319. Reduced expression of Kiaa0319 increased the trial-by-trial variability of speech responses and reduced the neural discrimination ability of speech sounds. Intracellular recordings from affected neurons revealed that reduced expression of Kiaa0319 increased neural excitability and input resistance. These results provide the first evidence that decreased expression of the dyslexia-associated gene Kiaa0319 can alter cortical responses and impair phoneme processing in auditory cortex.

Detection and identification of speech sounds using cortical activity patterns.

We have developed a classifier capable of locating and identifying speech sounds using activity from rat auditory cortex with an accuracy equivalent to behavioral performance and without the need to specify the onset time of the speech sounds. This classifier can identify speech sounds from a large speech set within 40 ms of stimulus presentation. To compare the temporal limits of the classifier to behavior, we developed a novel task that requires rats to identify individual consonant sounds from a stream of distracter consonants. The classifier successfully predicted the ability of rats to accurately identify speech sounds for syllable presentation rates up to 10 syllables per second (up to 17.9 ± 1.5 bits/s), which is comparable to human performance. Our results demonstrate that the spatiotemporal patterns generated in primary auditory cortex can be used to quickly and accurately identify consonant sounds from a continuous speech stream without prior knowledge of the stimulus onset times. Improved understanding of the neural mechanisms that support robust speech processing in difficult listening conditions could improve the identification and treatment of a variety of speech-processing disorders.

Vagus nerve stimulation during rehabilitative training improves forelimb strength following ischemic stroke.

Upper limb impairment is a common debilitating consequence of ischemic stroke. Physical rehabilitation after stroke enhances neuroplasticity and improves limb function, but does not typically restore normal movement. We have recently developed a novel method that uses vagus nerve stimulation (VNS) paired with forelimb movements to drive specific, long-lasting map plasticity in rat primary motor cortex. Here we report that VNS paired with rehabilitative training can enhance recovery of forelimb force generation following infarction of primary motor cortex in rats. Quantitative measures of forelimb function returned to pre-lesion levels when VNS was delivered during rehab training. Intensive rehab training without VNS failed to restore function back to pre-lesion levels. Animals that received VNS during rehab improved twice as much as rats that received the same rehabilitation without VNS. VNS delivered during physical rehabilitation represents a novel method that may provide long-lasting benefits towards stroke recovery.

Increasing diversity of neural responses to speech sounds across the central auditory pathway.

Neurons at higher stations of each sensory system are responsive to feature combinations not present at lower levels. As a result, the activity of these neurons becomes less redundant than lower levels. We recorded responses to speech sounds from the inferior colliculus and the primary auditory cortex neurons of rats, and tested the hypothesis that primary auditory cortex neurons are more sensitive to combinations of multiple acoustic parameters compared to inferior colliculus neurons. We independently eliminated periodicity information, spectral information and temporal information in each consonant and vowel sound using a noise vocoder. This technique made it possible to test several key hypotheses about speech sound processing. Our results demonstrate that inferior colliculus responses are spatially arranged and primarily determined by the spectral energy and the fundamental frequency of speech, whereas primary auditory cortex neurons generate widely distributed responses to multiple acoustic parameters, and are not strongly influenced by the fundamental frequency of speech. We found no evidence that inferior colliculus or primary auditory cortex was specialized for speech features such as voice onset time or formants. The greater diversity of responses in primary auditory cortex compared to inferior colliculus may help explain how the auditory system can identify a wide range of speech sounds across a wide range of conditions without relying on any single acoustic cue.

Cortical speech-evoked response patterns in multiple auditory fields are correlated with behavioral discrimination ability.

Different speech sounds evoke unique patterns of activity in primary auditory cortex (A1). Behavioral discrimination by rats is well correlated with the distinctness of the A1 patterns evoked by individual consonants, but only when precise spike timing is preserved. In this study we recorded the speech-evoked responses in the primary, anterior, ventral, and posterior auditory fields of the rat and evaluated whether activity in these fields is better correlated with speech discrimination ability when spike timing information is included or eliminated. Spike timing information improved consonant discrimination in all four of the auditory fields examined. Behavioral discrimination was significantly correlated with neural discrimination in all four auditory fields. The diversity of speech responses across recordings sites was greater in posterior and ventral auditory fields compared with A1 and anterior auditor fields. These results suggest that, while the various auditory fields of the rat process speech sounds differently, neural activity in each field could be used to distinguish between consonant sounds with accuracy that closely parallels behavioral discrimination. Earlier observations in the visual and somatosensory systems that cortical neurons do not rely on spike timing should be reevaluated with more complex natural stimuli to determine whether spike timing contributes to sensory encoding.

Inverted-U function relating cortical plasticity and task difficulty.

Many psychological and physiological studies with simple stimuli have suggested that perceptual learning specifically enhances the response of primary sensory cortex to task-relevant stimuli. The aim of this study was to determine whether auditory discrimination training on complex tasks enhances primary auditory cortex responses to a target sequence relative to non-target and novel sequences. We collected responses from more than 2000 sites in 31 rats trained on one of six discrimination tasks that differed primarily in the similarity of the target and distractor sequences. Unlike training with simple stimuli, long-term training with complex stimuli did not generate target-specific enhancement in any of the groups. Instead, cortical receptive field size decreased, latency decreased, and paired pulse depression decreased in rats trained on the tasks of intermediate difficulty, whereas tasks that were too easy or too difficult either did not alter or degraded cortical responses. These results suggest an inverted-U function relating neural plasticity and task difficulty.

Vagus nerve stimulation modulates cortical synchrony and excitability through the activation of muscarinic receptors.

Vagus nerve stimulation (VNS) is an FDA approved treatment for drug-resistant epilepsy and depression. Recently, we demonstrated the capacity for repeatedly pairing sensory input with brief pulses of VNS to induce input specific reorganization in rat auditory cortex. This was subsequently used to reverse the pathological neural and perceptual correlates of hearing loss induced tinnitus. Despite its therapeutic potential, VNS mechanisms of action remain speculative. In this study, we report the acute effects of VNS on intra-cortical synchrony, excitability, and sensory processing in anesthetized rat auditory cortex. VNS significantly increased and decorrelated spontaneous multi-unit activity, and suppressed entrainment to repetitive noise burst stimulation at 6-8 Hz but not after application of the muscarinic antagonist scopolamine. Collectively, these experiments demonstrate the capacity for VNS to acutely influence cortical synchrony and excitability and strengthen the hypothesis that acetylcholine and muscarinic receptors are involved in VNS mechanisms of action. These results are discussed with respect to their possible implications for sensory processing, neural plasticity, and epilepsy.

Experience dependent plasticity alters cortical synchronization.

Theories of temporal coding by cortical neurons are supported by observations that individual neurons can respond to sensory stimulation with millisecond precision and that activity in large populations is often highly correlated. Synchronization is highest between neurons with overlapping receptive fields and modulated by both sensory stimulation and behavioral state. It is not yet clear whether cortical synchronization is an epiphenomenon or a critical component of efficient information transmission. Experimental manipulations that generate receptive field plasticity can be used to test the relationship between synchronization and receptive fields. Here we demonstrate that increasing receptive field size in primary auditory cortex by repeatedly pairing a train of tones with nucleus basalis (NB) stimulation increases synchronization, and decreasing receptive field size by pairing different tone frequencies with NB stimulation decreases synchronization. These observations seem to support the conclusion that neural synchronization is simply an artifact caused by common inputs. However, pairing tone trains of different carrier frequencies with NB stimulation increases receptive field size without increasing synchronization, and environmental enrichment increases synchronization without increasing receptive field size. The observation that receptive fields and synchronization can be manipulated independently suggests that common inputs are only one of many factors shaping the strength and temporal precision of cortical synchronization and supports the hypothesis that precise neural synchronization contributes to sensory information processing.

Environmental enrichment selectively increases glutamatergic responses in layer II/III of the auditory cortex of the rat.

Prolonged exposure to environmental enrichment (EE) induces behavioral adaptation accompanied by detectable morphological and physiological changes. Auditory EE is associated with an increased auditory evoked potential (AEP) and increased auditory gating in the primary auditory cortex. We sought physiological correlates to such changes by comparing synaptic currents in control vs. EE-raised rats, in a primary auditory cortex (AI) slice preparation. Pharmacologically isolated glutamatergic or GABA(A)-receptor-mediated currents were measured using perforated patch whole-cell recordings. Glutamatergic AMPA receptor (AMPAR)-mediated excitatory postsynaptic currents (EPSCs) displayed a large amplitude increase (64+/-11% in EE vs. control) accompanied by a rise-time decrease (-29+/-6% in EE vs. control) and decrease in pair pulse ratio in layer II/III but not in layer V. Changes in glutamatergic signaling were not associated with changes in the ratio between N-methyl-D aspartate-receptor (NMDAR)-mediated vs. AMPAR-mediated components, in amplitude or pair pulse ratio of GABAergic transmission, or in passive neuronal properties. A realistic computational model was used for integrating in vivo and in vitro results, and for determining how EE synapses correct for phase error of the inputs. We found that EE not only increases the mean firing frequency of the responses, but also improves the robustness of auditory processing by decreasing the dependence of the output firing on the phase difference of the input signals. We conclude that behavioral and electrophysiological differences detected in vivo in rats exposed to an auditory EE are accompanied and possibly caused by selective changes in cortical excitatory transmission. Our data suggest that auditory EE selectively enhances excitatory glutamatergic synaptic transmission in layer II/III without greatly altering inhibitory GABAergic transmission.

Anesthesia suppresses nonsynchronous responses to repetitive broadband stimuli.

Although many aspects of sensory processing are qualitatively similar in awake and anesthetized subjects, important state-dependent differences are known to exist. To investigate the effects of anesthesia on temporal processing in rat auditory cortex, multi-unit neural responses to trains of broadband clicks were recorded prior to, 15 min following, and 5 h following the administration of a ketamine-based anesthetic. While responses to clicks in isolation were relatively stable between states, responses to subsequent clicks exhibited increases in latency, peak latency, response duration, and post-onset suppression under anesthesia. Ketamine anesthetic reduced the maximum rate at which multi-unit clusters entrained to repeated clicks. No multi-unit clusters entrained to stimulus presentation rates greater than 33 Hz under anesthesia, compared with 85% and 81% in the pre- and post-anesthetic condition, respectively. Anesthesia also induced oscillatory activity that was not present in awake subjects. Finally, ketamine anesthesia abolished all tonic excitatory and suppressive nonsynchronous responses to click trains. The results of this study suggest that ketamine-based anesthesia significantly alters neural coding of broadband click trains in auditory cortex.

Response to broadband repetitive stimuli in auditory cortex of the unanesthetized rat.

This study examines the ability of multi-unit clusters (MUCs) in layer IV/V of primary auditory cortex of the awake rat to respond to a series of broadband click trains. The data from 113 multi-unit clusters were analyzed for synchronous and nonsynchronized responses using several methods. Synchronous responses were measured using window analysis, circular statistics and spectral analysis. Nonsynchronous responses were measured during different time intervals during the click train (first 50 ms, 50-450 ms, and the entire click train). The results demonstrate that multi-unit clusters are capable of synchronizing to clicks at rates up to 166 Hz. The mean synchronization boundary (limiting rate) for the group was found to be 72 Hz. Mean peak response rate, mean response duration, and mean time-to-peak response decreased as the stimulus presentation rate (SPR) increased, resulting in a temporal sharpening of the population response. For fast SPRs (>50 Hz), 50% of MUCs exhibited nonsynchronous responses in which the firing rate increased with SPR, although this activity was most prevalent during the first 50 ms of the response. Sustained increases in firing rate with SPR were seen in 8% of the MUCs, while another 38% of MUCs exhibited sustained decreases during the click train.

Spectral features control temporal plasticity in auditory cortex.

Cortical responses are adjusted and optimized throughout life to meet changing behavioral demands and to compensate for peripheral damage. The cholinergic nucleus basalis (NB) gates cortical plasticity and focuses learning on behaviorally meaningful stimuli. By systematically varying the acoustic parameters of the sound paired with NB activation, we have previously shown that tone frequency and amplitude modulation rate alter the topography and selectivity of frequency tuning in primary auditory cortex. This result suggests that network-level rules operate in the cortex to guide reorganization based on specific features of the sensory input associated with NB activity. This report summarizes recent evidence that temporal response properties of cortical neurons are influenced by the spectral characteristics of sounds associated with cholinergic modulation. For example, repeated pairing of a spectrally complex (ripple) stimulus decreased the minimum response latency for the ripple, but lengthened the minimum latency for tones. Pairing a rapid train of tones with NB activation only increased the maximum following rate of cortical neurons when the carrier frequency of each train was randomly varied. These results suggest that spectral and temporal parameters of acoustic experiences interact to shape spectrotemporal selectivity in the cortex. Additional experiments with more complex stimuli are needed to clarify how the cortex learns natural sounds such as speech.

Sensory input directs spatial and temporal plasticity in primary auditory cortex.

The cortical representation of the sensory environment is continuously modified by experience. Changes in spatial (receptive field) and temporal response properties of cortical neurons underlie many forms of natural learning. The scale and direction of these changes appear to be determined by specific features of the behavioral tasks that evoke cortical plasticity. The neural mechanisms responsible for this differential plasticity remain unclear partly because important sensory and cognitive parameters differ among these tasks. In this report, we demonstrate that differential sensory experience directs differential plasticity using a single paradigm that eliminates the task-specific variables that have confounded direct comparison of previous studies. Electrical activation of the basal forebrain (BF) was used to gate cortical plasticity mechanisms. The auditory stimulus paired with BF stimulation was systematically varied to determine how several basic features of the sensory input direct plasticity in primary auditory cortex (A1) of adult rats. The distributed cortical response was reconstructed from a dense sampling of A1 neurons after 4 wk of BF-sound pairing. We have previously used this method to show that when a tone is paired with BF activation, the region of the cortical map responding to that tone frequency is specifically expanded. In this report, we demonstrate that receptive-field size is determined by features of the stimulus paired with BF activation. Specifically, receptive fields were narrowed or broadened as a systematic function of both carrier-frequency variability and the temporal modulation rate of paired acoustic stimuli. For example, the mean bandwidth of A1 neurons was increased (+60%) after pairing BF stimulation with a rapid train of tones and decreased (-25%) after pairing unmodulated tones of different frequencies. These effects are consistent with previous reports of receptive-field plasticity evoked by natural learning. The maximum cortical following rate and minimum response latency were also modified as a function of stimulus modulation rate and carrier-frequency variability. The cortical response to a rapid train of tones was nearly doubled if BF stimulation was paired with rapid trains of random carrier frequency, while no following rate plasticity was observed if a single carrier frequency was used. Finally, we observed significant increases in response strength and total area of functionally defined A1 following BF activation paired with certain classes of stimuli and not others. These results indicate that the degree and direction of cortical plasticity of temporal and receptive-field selectivity are specified by the structure and schedule of inputs that co-occur with basal forebrain activation and suggest that the rules of cortical plasticity do not operate on each elemental stimulus feature independently of others.

Distributed representation of spectral and temporal information in rat primary auditory cortex.

Modulations of amplitude and frequency are common features of natural sounds, and are prominent in behaviorally important communication sounds. The mammalian auditory cortex is known to contain representations of these important stimulus parameters. This study describes the distributed representations of tone frequency and modulation rate in the rat primary auditory cortex (A1). Detailed maps of auditory cortex responses to single tones and tone trains were constructed from recordings from 50-60 microelectrode penetrations introduced into each hemisphere. Recorded data demonstrated that the cortex uses a distributed coding strategy to represent both spectral and temporal information in the rat, as in other species. Just as spectral information is encoded in the firing patterns of neurons tuned to different frequencies, temporal information appears to be encoded using a set of filters covering a range of behaviorally important repetition rates. Although the average A1 repetition rate transfer function (RRTF) was low-pass with a sharp drop-off in evoked spikes per tone above 9 pulses per second (pps), individual RRTFs exhibited significant structure between 4 and 10 pps, including substantial facilitation or depression to tones presented at specific rates. No organized topography of these temporal filters could be determined.