Tactile stimulation and hemispheric asymmetries modulate auditory perception and neural responses in primary auditory cortex.

Although multisensory integration has been an important area of recent research, most studies focused on audiovisual integration. Importantly, however, the combination of audition and touch can guide our behavior as effectively which we studied here using psychophysics and functional magnetic resonance imaging (fMRI). We tested whether task-irrelevant tactile stimuli would enhance auditory detection, and whether hemispheric asymmetries would modulate these audiotactile benefits using lateralized sounds. Spatially aligned task-irrelevant tactile stimuli could occur either synchronously or asynchronously with the sounds. Auditory detection was enhanced by non-informative synchronous and asynchronous tactile stimuli, if presented on the left side. Elevated fMRI-signals to left-sided synchronous bimodal stimulation were found in primary auditory cortex (A1). Adjacent regions (planum temporale, PT) expressed enhanced BOLD-responses for synchronous and asynchronous left-sided bimodal conditions. Additional connectivity analyses seeded in right-hemispheric A1 and PT for both bimodal conditions showed enhanced connectivity with right-hemispheric thalamic, somatosensory and multisensory areas that scaled with subjects' performance. Our results indicate that functional asymmetries interact with audiotactile interplay which can be observed for left-lateralized stimulation in the right hemisphere. There, audiotactile interplay recruits a functional network of unisensory cortices, and the strength of these functional network connections is directly related to subjects' perceptual sensitivity.

A mechanistic, model-based approach to safety assessment in clinical development.

Assessing the safety of pharmacotherapies is a primary goal of clinical trials in drug development. The low frequency of relevant side effects, however, often poses a significant challenge for risk assessment. Methodologies allowing robust extrapolation of safety statistics based on preclinical data and information from clinical trials with limited numbers of patients are hence needed to further improve safety and efficacy in the drug development process. Here, we present a generic systems pharmacology approach integrating prior physiological and pharmacological knowledge, preclinical data, and clinical trial results, which allows predicting adverse event rates related to drug exposure. Possible fields of application involve high-risk populations, novel drug candidates, and different dosing scenarios. As an example, the approach is applied to simvastatin and pravastatin and the prediction of myopathy rates in a population with a genotype leading to a significantly increased myopathy risk.CPT: Pharmacometrics & Systems Pharmacology (2012) 1, e13; doi:10.1038/psp.2012.14; advance online publication 7 November 2012.

Increased proteasome subunit protein expression and proteasome activity in colon cancer relate to an enhanced activation of nuclear factor E2-related factor 2 (Nrf2).

An elevated proteasome activity contributes to tumorigenesis, particularly by providing cancer cells with antiapoptotic protection and efficient clearance from irregular proteins. Still, the underlying mechanisms are poorly known. In this study, we report that in colon cancer patients, higher proteasome activity was detected in tumoral tissue compared with surrounding normal tissue, and also that increased levels of proteasomal subunit proteins, such as S5a/PSMD4 and alpha-5/PSMA5, could be detected. Colon tumors showed higher nuclear levels of nuclear factor E2-related factor 2 (Nrf2), a transcription factor supposed to be involved in the control of proteasomal subunit protein expression. The induction or overexpression of Nrf2 led to stronger S5a and alpha-5 expression in the human colon cancer cell lines, Colo320 and Lovo, as well as in NCM460 colonocytes along with higher proteasome activity. The small interfering RNA (siRNA)-mediated Nrf2 knockdown decreased S5a and alpha-5 expression and reduced proteasome activity. Additionally, Nrf2-dependent S5a and alpha-5 expression conferred protection from tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis, an effect preceded by an increased nuclear factor (NF)-kappaB activation and higher expression of antiapoptotic NF-kappaB target genes. These findings point to an important role of Nrf2 in the gain of proteasome activity, thereby contributing to colorectal carcinogenesis. Nrf2 may therefore serve as a potential target in anticancer therapy.

Click train encoding in primary and non-primary auditory cortex of anesthetized macaque monkeys.

We studied encoding of temporally modulated sounds in 28 multiunits in the primary auditory cortical field (AI) and in 35 multiunits in the secondary auditory cortical field (caudomedial auditory cortical field, CM) by presenting periodic click trains with click rates between 1 and 300 Hz lasting for 2-4 s. We found that all multiunits increased or decreased their firing rate during the steady state portion of the click train and that all except two multiunits synchronized their firing to individual clicks in the train. Rate increases and synchronized responses were most prevalent and strongest at low click rates, as expressed by best modulation frequency, limiting frequency, percentage of responsive multiunits, and average rate response and vector strength. Synchronized responses occurred up to 100 Hz; rate response occurred up to 300 Hz. Both auditory fields responded similarly to low click rates but differed at click rates above approximately 12 Hz at which more multiunits in AI than in CM exhibited synchronized responses and increased rate responses and more multiunits in CM exhibited decreased rate responses. These findings suggest that the auditory cortex of macaque monkeys encodes temporally modulated sounds similar to the auditory cortex of other mammals. Together with other observations presented in this and other reports, our findings also suggest that AI and CM have largely overlapping sensitivities for acoustic stimulus features but encode these features differently.

Contribution of self-motion perception to acoustic target localization.

CONCLUSION: The findings of this study suggest that acoustic spatial perception during head movement is achieved by the vestibular system, which is responsible for the correct dynamic of acoustic target pursuit. OBJECTIVE: The ability to localize sounds in space during whole-body rotation relies on the auditory localization system, which recognizes the position of sound in a head-related frame, and on the sensory systems, namely the vestibular system, which perceive head and body movement. The aim of this study was to analyse the contribution of head motion cues to the spatial representation of acoustic targets in humans. MATERIAL AND METHODS: Healthy subjects standing on a rotating platform in the dark were asked to pursue with a laser pointer an acoustic target which was horizontally rotated while the body was kept stationary or maintained stationary while the whole body was rotated. The contribution of head motion to the spatial acoustic representation could be inferred by comparing the gains and phases of the pursuit in the two experimental conditions when the frequency was varied. RESULTS: During acoustic target rotation there was a reduction in the gain and an increase in the phase lag, while during whole-body rotations the gain tended to increase and the phase remained constant. The different contributions of the vestibular and acoustic systems were confirmed by analysing the acoustic pursuit during asymmetric body rotation. In this particular condition, in which self-motion perception gradually diminished, an increasing delay in target pursuit was observed.

Sequence sensitivity of neurons in cat primary auditory cortex.

Properties of sequence-sensitive neurons in primary auditory cortex of cats were explored in detail. Stimuli were sequences of two tones, in which the frequency and intensity of the first tone and the temporal separation between the first and second, or probe, tone were parametrically varied. After presentation of the first tone, the responses of 32 single units and 48 multiunits to the probe tone were found to be enhanced up to 140-5270% (median 340%) above the response obtained in the single-tone condition. Probe tone enhancement was induced from a considerable number of sequence conditions and depended on the frequency and intensity of the first tone and on the temporal separation between the onsets of the first and the probe tone. On average, the maximally enhanced response occurred when the first tone was 1 octave below or above the probe tone and its intensity was 14 dB louder than the probe tone. The most effective temporal separation of the tones for an enhancement effect was approximately 100 ms. The range of enhancing tones was largely outside the excitatory tuning curve of a neuron. Results extend previous findings of properties of sequence-sensitive neurons in the auditory cortex of echolocating bats and non-echolocating mammals, and suggest that sequence-sensitive neurons are quite common and involved in the cortical representation of spectrotemporal patterns of acoustic signals.

Correlations between neural discharges are related to receptive field properties in cat primary auditory cortex.

The functional role of correlated neural activity in auditory cortex for the processing of sounds was explored by investigating whether and how cross-correlation parameters are related to receptive field similarities of neurons. Multi-unit activity was recorded simultaneously from several sites of isofrequency domains in primary auditory cortex. At each site various receptive field properties were determined. From the discharges of pairs of clusters, normalized cross-correlation histograms (CCH) were calculated for extended periods of spontaneous activity and for periods with noise-burst stimulation. In both conditions, most CCHs exhibited a symmetrical positivity near the origin of the CCH, a few to several tens of milliseconds wide. Cross-correlation histograms were characterized with two parameters: the correlation strength, which was estimated from the peak correlation, and the correlation width, i.e. the time period of correlated firing, which was measured as the width of the positivity at half height. It was found that correlation strength increased and correlation width narrowed with increasing similarity of the receptive fields of two clusters. These relationships were observed both in the acoustically-driven and spontaneous conditions. Specifically, correlation strength was most strongly associated with similarity in binaural interaction and in temporal response properties such as response onset, response offset and the temporal pattern of the response. Correlation width was predominantly associated with similarity in characteristic frequency, bandwidth and intensity threshold. Results suggest that correlated activity, reflecting potential mechanisms involved in the neural computation in auditory cortex, provides a means to evaluate the properties of the functional organization of auditory cortex. Systematic relationships were found between correlation properties and the receptive field-based organization of cortical processing, suggesting that similar general mechanisms are utilized in many parts of the sensory cortex. In particular, the magnitude and/or the time period of synchronized firing of neurons is increased if the receptive field properties of the involved neurons are similar.

Processing of sound sequences in macaque auditory cortex: response enhancement.

It is well established that the tone-evoked response of neurons in auditory cortex can be attenuated if another tone is presented several hundred milliseconds before. The present study explores in detail a complementary phenomenon in which the tone-evoked response is enhanced by a preceding tone. Action potentials from multiunit groups and single units were recorded from primary and caudomedial auditory cortical fields in lightly anesthetized macaque monkeys. Stimuli were two suprathreshold tones of 100-ms duration, presented in succession. The frequency of the first tone and the stimulus onset asynchrony (SOA) between the two tones were varied systematically, whereas the second tone was fixed. Compared with presenting the second tone in isolation, the response to the second tone was enhanced significantly when it was preceded by the first tone. This was observed in 87 of 130 multiunit groups and in 29 of 69 single units with no obvious difference between different auditory fields. Response enhancement occurred for a wide range of SOA (110-329 ms) and for a wide range of frequencies of the first tone. Most of the first tones that enhanced the response to the second tone evoked responses themselves. The stimulus, which on average produced maximal enhancement, was a pair with a SOA of 120 ms and with a frequency separation of about one octave. The frequency/SOA combinations that induced response enhancement were mostly different from the ones that induced response attenuation. Results suggest that response enhancement, in addition to response attenuation, provides a basic neural mechanism involved in the cortical processing of the temporal structure of sounds.

Neuronal mechanisms of auditory backward recognition masking in macaque auditory cortex.

The sensation of a single sound event can be altered by subsequent sounds. This study searched for neural mechanisms of such retroactive effects in macaque auditory cortex by comparing neural responses to single tones with responses to two consecutive tones. Retroactive influences were found to affect late parts of the response to a tone, which comprised 53/134 of the recordings of action potentials and 88/131 of the recordings of field potentials performed in primary, caudal, and medial auditory fields. If before or during the occurrence of the late response to the first tone a second tone was presented the late response was suppressed. Suppression of late cortical responses parallels perceptual phenomena like backward recognition masking, suggesting that suppression of late responses provides a neural correlate of auditory backward effects.

Time course of forward masking tuning curves in cat primary auditory cortex.

Nonsimultaneous two-tone interactions were studied in the primary auditory cortex of anesthetized cats. Poststimulatory effects of pure tone bursts (masker) on the evoked activity of a fixed tone burst (probe) were investigated. The temporal interval from masker onset to probe onset (stimulus onset asynchrony), masker frequency, and intensity were parametrically varied. For all of the 53 single units and 58 multiple-unit clusters, the neural activity of the probe signal was either inhibited, facilitated, and/or delayed by a limited set of masker stimuli. The stimulus range from which forward inhibition of the probe was induced typically was centered at and had approximately the size of the neuron's excitatory receptive field. This "masking tuning curve" was usually V shaped, i.e., the frequency range of inhibiting masker stimuli increased with the masker intensity. Forward inhibition was induced at the shortest stimulus onset asynchrony between masker and probe. With longer stimulus onset asynchronies, the frequency range of inhibiting maskers gradually became smaller. Recovery from forward inhibition occurred first at the lower- and higher-frequency borders of the masking tuning curve and lasted the longest for frequencies close to the neuron's characteristic frequency. The maximal duration of forward inhibition was measured as the longest period over which reduction of probe responses was observed. It was in the range of 53-430 ms, with an average of 143 +/- 71 (SD) ms. Amount, duration and type of forward inhibition were weakly but significantly correlated with "static" neural receptive field properties like characteristic frequency, bandwidth, and latency. For the majority of neurons, the minimal inhibitory masker intensity increased when the stimulus onset asynchrony became longer. In most cases the highest masker intensities induced the longest forward inhibition. A significant number of neurons, however, exhibited longest periods of inhibition after maskers of intermediate intensity. The results show that the ability of cortical cells to respond with an excitatory activity depends on the temporal stimulus context. Neurons can follow higher repetition rates of stimulus sequences when successive stimuli differ in their spectral content. The differential sensitivity to temporal sound sequences within the receptive field of cortical cells as well as across different cells could contribute to the neural processing of temporally structured stimuli like speech and animal vocalizations.

Temporal processing in cat primary auditory cortex.

In this short review, we discuss several aspects of how temporal coding is reflected in the response of primary auditory cortical neurons. We attempt to establish a link between several different temporal response properties including onset latency, response strength to repetitive stimuli, and the recovery of a response from suppression by a preceding signal. The results suggest a relationship between temporal effects that are expressed at quite different time scales. The results are discussed in relation to spatial representational properties and to coding in other sensory cortices.

Stimulus-dependent modulations of correlated high-frequency oscillations in cat visual cortex.

The hypothesis that correlated neural activity is involved in the cortical representation of visual stimuli was examined by recording multi-unit activity and local field potentials from neurons with non-overlapping receptive fields in areas 17 and 18. Using coherence functions, correlations of oscillatory patterns (35-100 Hz) of neural signals were investigated under three stimulus conditions: (i) a whole field grating or a long bar moving across both receptive fields; (ii) masking the region between both receptive fields while stimulating the remaining visual field; and (iii) two separate stimuli simultaneously moving in opposite directions. Coherences of oscillations were found to be significantly higher in the first stimulus condition than in the other two conditions. Since different visual stimuli were reflected in the coherence of neural activity, we concluded that correlated neural activity is a potential candidate for coding of sensory information.

Different rules of spatial summation from beyond the receptive field for spike rates and oscillation amplitudes in cat visual cortex.

We measured spike rates in parallel with visually induced oscillations of multi-unit activity (MUA) and local field potentials (LFP) from cortical areas 17 and 18 of anesthetized cats. Variations in the three response types were systematically correlated with stimulus size and placement. Oscillation amplitudes of both MUA and LFP were on average low with stimuli covering just the receptive field and they increased progressively with larger stimuli, whereas average spike rates rather decreased monotonically with stimulus sizes beyond the receptive field (area 18) or reached a plateau with stimuli in the far surround (area 17). Thus, spike rates and oscillation amplitudes follow different rules of spatial summation. Since the spatial spread of the synchronized components of oscillations roughly matches the horizontal divergence zone of the pyramidal cells' axonal collaterals in area 17 and 18, the interconnected system of neighbouring columns seems to constitute a functional unit, within which the oscillations could exert their functional role.

Synchronous high-frequency oscillations in cat area 18.

The present study extends knowledge of the basic properties of correlated oscillatory activity patterns in the visual cortex of anaesthetized cats. Recordings with multiple electrodes were performed in area 18 and the correlations of multi-unit activity in the frequency range 35-80 Hz were determined using the coherence function. Statistical analysis revealed that the multi-unit correlations depended on the cortical distance between the recording sites, the orientation selectivity of the neurons and their cortical layer. On average, correlations dropped to chance level within several millimetres and were higher in lower than in upper cortical layers. Similar results were found by analysing the correlations of oscillatory patterns in local field potentials recorded from the same electrodes. Correlations of neurons with similar orientation preferences were higher than those of neurons with different orientation preferences. Comparison to a matched sample from area 17 showed that the correlations in areas 18 and 17 depended on similar properties of the neurons. The dependences of correlated oscillations resembled the known pattern and specificity of intra-areal fibre connections, suggesting that the correlations were intracortically established. Since correlations were specifically and not randomly related to the response properties of cortical neurons and were prominent in a visual area other than area 17, the findings suggest that correlated oscillatory activity provides a potential neural code supporting sensory information processing.

Coherent oscillations: a mechanism of feature linking in the visual cortex? Multiple electrode and correlation analyses in the cat.

Primary visual coding can be characterized by the receptive field (RF) properties of single neurons. Subject of this paper is our search for a global, second coding step beyond the RF-concept that links related features in a visual scene. In recent models of visual coding, oscillatory activities have been proposed to constitute such linking signals. We tested the neurophysiological relevance of this hypothesis for the visual system. Single and multiple spikes as well as local field potentials were recorded simultaneously from several locations in the primary visual cortex (A17 and A18) using 7 or 19 individually advanceable fiber-microelectrodes (250 or 330 microns apart). Stimulus-evoked (SE)-resonances of 35-85 Hz were found in these three types of signals throughout the visual cortex when the primary coding channels were activated by their specific stimuli. Stimulus position, orientation, movement direction and velocity, ocularity and stationary flicker caused specific SE-resonances. Coherent SE-resonances were found at distant cortical positions when at least one of the primary coding properties was similar. Coherence was found 1) within a vertical cortex column, 2) between neighbouring hypercolumns, and 3) between two different cortical areas. We assume that the coherence of SE-resonances is mediated by recurrent excitatory intra- and inter-areal connections via phase locking between assemblies that represent the linking features of the actual visual scene. Visually related activities are, thus, transiently labelled by a temporal code that signalizes their momentary association.