Activity-induced gene expression in the human brain.

Activity-induced gene expression underlies synaptic plasticity and brain function. Here, using molecular sequencing techniques, we define activity-dependent transcriptomic and epigenomic changes at the tissue and single-cell level in the human brain following direct electrical stimulation of the anterior temporal lobe in patients undergoing neurosurgery. Genes related to transcriptional regulation and microglia-specific cytokine activity displayed the greatest induction pattern, revealing a precise molecular signature of neuronal activation in the human brain.

Immediate neural impact and incomplete compensation after semantic hub disconnection.

The human brain extracts meaning using an extensive neural system for semantic knowledge. Whether broadly distributed systems depend on or can compensate after losing a highly interconnected hub is controversial. We report intracranial recordings from two patients during a speech prediction task, obtained minutes before and after neurosurgical treatment requiring disconnection of the left anterior temporal lobe (ATL), a candidate semantic knowledge hub. Informed by modern diaschisis and predictive coding frameworks, we tested hypotheses ranging from solely neural network disruption to complete compensation by the indirectly affected language-related and speech-processing sites. Immediately after ATL disconnection, we observed neurophysiological alterations in the recorded frontal and auditory sites, providing direct evidence for the importance of the ATL as a semantic hub. We also obtained evidence for rapid, albeit incomplete, attempts at neural network compensation, with neural impact largely in the forms stipulated by the predictive coding framework, in specificity, and the modern diaschisis framework, more generally. The overall results validate these frameworks and reveal an immediate impact and capability of the human brain to adjust after losing a brain hub.

Common fronto-temporal effective connectivity in humans and monkeys.

Human brain pathways supporting language and declarative memory are thought to have differentiated substantially during evolution. However, cross-species comparisons are missing on site-specific effective connectivity between regions important for cognition. We harnessed functional imaging to visualize the effects of direct electrical brain stimulation in macaque monkeys and human neurosurgery patients. We discovered comparable effective connectivity between caudal auditory cortex and both ventro-lateral prefrontal cortex (VLPFC, including area 44) and parahippocampal cortex in both species. Human-specific differences were clearest in the form of stronger hemispheric lateralization effects. In humans, electrical tractography revealed remarkably rapid evoked potentials in VLPFC following auditory cortex stimulation and speech sounds drove VLPFC, consistent with prior evidence in monkeys of direct auditory cortex projections to homologous vocalization-responsive regions. The results identify a common effective connectivity signature in human and nonhuman primates, which from auditory cortex appears equally direct to VLPFC and indirect to the hippocampus. VIDEO ABSTRACT.

Similar but separate systems underlie perceptual bistability in vision and audition.

The dynamics of perceptual bistability, the phenomenon in which perception switches between different interpretations of an unchanging stimulus, are characterised by very similar properties across a wide range of qualitatively different paradigms. This suggests that perceptual switching may be triggered by some common source. However, it is also possible that perceptual switching may arise from a distributed system, whose components vary according to the specifics of the perceptual experiences involved. Here we used a visual and an auditory task to determine whether individuals show cross-modal commonalities in perceptual switching. We found that individual perceptual switching rates were significantly correlated across modalities. We then asked whether perceptual switching arises from some central (modality-) task-independent process or from a more distributed task-specific system. We found that a log-normal distribution best explained the distribution of perceptual phases in both modalities, suggestive of a combined set of independent processes causing perceptual switching. Modality- and/or task-dependent differences in these distributions, and lack of correlation with the modality-independent central factors tested (ego-resiliency, creativity, and executive function), also point towards perceptual switching arising from a distributed system of similar but independent processes.

Promoting the perception of two and three concurrent sound objects: An event-related potential study.

The auditory environment typically comprises several simultaneously active sound sources. In contrast to the perceptual segregation of two concurrent sounds, the perception of three simultaneous sound objects has not yet been studied systematically. We conducted two experiments in which participants were presented with complex sounds containing sound segregation cues (mistuning, onset asynchrony, differences in frequency or amplitude modulation or in sound location), which were set up to promote the perceptual organization of the tonal elements into one, two, or three concurrent sounds. In Experiment 1, listeners indicated whether they heard one, two, or three concurrent sounds. In Experiment 2, participants watched a silent subtitled movie while EEG was recorded to extract the object-related negativity (ORN) component of the event-related potential. Listeners predominantly reported hearing two sounds when the segregation promoting manipulations were applied to the same tonal element. When two different tonal elements received manipulations promoting them to be heard as separate auditory objects, participants reported hearing two and three concurrent sounds objects with equal probability. The ORN was elicited in most conditions; sounds that included the amplitude- or the frequency-modulation cue generated the smallest ORN amplitudes. Manipulating two different tonal elements yielded numerically and often significantly smaller ORNs than the sum of the ORNs elicited when the same cues were applied on a single tonal element. These results suggest that ORN reflects the presence of multiple concurrent sounds, but not their number. The ORN results are compatible with the horse-race principle of combining different cues of concurrent sound segregation.

EEG signatures accompanying auditory figure-ground segregation.

In everyday acoustic scenes, figure-ground segregation typically requires one to group together sound elements over both time and frequency. Electroencephalogram was recorded while listeners detected repeating tonal complexes composed of a random set of pure tones within stimuli consisting of randomly varying tonal elements. The repeating pattern was perceived as a figure over the randomly changing background. It was found that detection performance improved both as the number of pure tones making up each repeated complex (figure coherence) increased, and as the number of repeated complexes (duration) increased - i.e., detection was easier when either the spectral or temporal structure of the figure was enhanced. Figure detection was accompanied by the elicitation of the object related negativity (ORN) and the P400 event-related potentials (ERPs), which have been previously shown to be evoked by the presence of two concurrent sounds. Both ERP components had generators within and outside of auditory cortex. The amplitudes of the ORN and the P400 increased with both figure coherence and figure duration. However, only the P400 amplitude correlated with detection performance. These results suggest that 1) the ORN and P400 reflect processes involved in detecting the emergence of a new auditory object in the presence of other concurrent auditory objects; 2) the ORN corresponds to the likelihood of the presence of two or more concurrent sound objects, whereas the P400 reflects the perceptual recognition of the presence of multiple auditory objects and/or preparation for reporting the detection of a target object.

Theta oscillations accompanying concurrent auditory stream segregation.

The ability to isolate a single sound source among concurrent sources is crucial for veridical auditory perception. The present study investigated the event-related oscillations evoked by complex tones, which could be perceived as a single sound and tonal complexes with cues promoting the perception of two concurrent sounds by inharmonicity, onset asynchrony, and/or perceived source location difference of the components tones. In separate task conditions, participants performed a visual change detection task (visual control), watched a silent movie (passive listening) or reported for each tone whether they perceived one or two concurrent sounds (active listening). In two time windows, the amplitude of theta oscillation was modulated by the presence vs. absence of the cues: 60-350ms/6-8Hz (early) and 350-450ms/4-8Hz (late). The early response appeared both in the passive and the active listening conditions; it did not closely match the task performance; and it had a fronto-central scalp distribution. The late response was only elicited in the active listening condition; it closely matched the task performance; and it had a centro-parietal scalp distribution. The neural processes reflected by these responses are probably involved in the processing of concurrent sound segregation cues, in sound categorization, and response preparation and monitoring. The current results are compatible with the notion that theta oscillations mediate some of the processes involved in concurrent sound segregation.

Effects of multiple congruent cues on concurrent sound segregation during passive and active listening: an event-related potential (ERP) study.

In two experiments, we assessed the effects of combining different cues of concurrent sound segregation on the object-related negativity (ORN) and the P400 event-related potential components. Participants were presented with sequences of complex tones, half of which contained some manipulation: one or two harmonic partials were mistuned, delayed, or presented from a different location than the rest. In separate conditions, one, two, or three of these manipulations were combined. Participants watched a silent movie (passive listening) or reported after each tone whether they perceived one or two concurrent sounds (active listening). ORN was found in almost all conditions except for location difference alone during passive listening. Combining several cues or manipulating more than one partial consistently led to sub-additive effects on the ORN amplitude. These results support the view that ORN reflects a combined, feature-unspecific assessment of the auditory system regarding the contribution of two sources to the incoming sound.

Stable individual characteristics in the perception of multiple embedded patterns in multistable auditory stimuli.

The ability of the auditory system to parse complex scenes into component objects in order to extract information from the environment is very robust, yet the processing principles underlying this ability are still not well understood. This study was designed to investigate the proposal that the auditory system constructs multiple interpretations of the acoustic scene in parallel, based on the finding that when listening to a long repetitive sequence listeners report switching between different perceptual organizations. Using the "ABA-" auditory streaming paradigm we trained listeners until they could reliably recognize all possible embedded patterns of length four which could in principle be extracted from the sequence, and in a series of test sessions investigated their spontaneous reports of those patterns. With the training allowing them to identify and mark a wider variety of possible patterns, participants spontaneously reported many more patterns than the ones traditionally assumed (Integrated vs. Segregated). Despite receiving consistent training and despite the apparent randomness of perceptual switching, we found individual switching patterns were idiosyncratic; i.e., the perceptual switching patterns of each participant were more similar to their own switching patterns in different sessions than to those of other participants. These individual differences were found to be preserved even between test sessions held a year after the initial experiment. Our results support the idea that the auditory system attempts to extract an exhaustive set of embedded patterns which can be used to generate expectations of future events and which by competing for dominance give rise to (changing) perceptual awareness, with the characteristics of pattern discovery and perceptual competition having a strong idiosyncratic component. Perceptual multistability thus provides a means for characterizing both general mechanisms and individual differences in human perception.

Chemopreventive properties of trans-resveratrol against the cytotoxicity of chloroacetanilide herbicides in vitro.

The beneficial effect of trans-resveratrol (RESV) on health is well documented. Our aim was to study the putative preventive effect of RESV on the cytotoxicity of frequently used herbicides (alachlor, acetochlor). Estrogen receptor positive (ER+) MCF-7 human mammary carcinoma, HepG2 (ER+) human hepatocellular carcinoma and VERO estrogen receptor negative (ER-) non-transformed monkey fibroblast cell lines were treated with alachlor and acetochlor (2-500 microg/ml) as toxic agents, and RESV (10 microM) as preventive agent. The MTT dye reduction assay was performed to test cytotoxicity, and flow cytometry to test cell proliferation and apoptosis. RESV is not cytotoxic in the concentration range of 1-100 microM on neither cell lines examined after 24 h, but cytotoxic on Vero and MCF-7 cells at 100 microM after 48h, and on all three cell lines after 72 h. On both ER+ cell lines a stimulation of viability occurs in the low concentration range (0.5-12.5 microM) as detected by the MTT assay. Cell cycle analysis of the culture shows a significant increase of S-phase cells at low concentrations of RESV (10-50 microM) and a decrease in the 100-200 microM concentration range. The ratio of apoptotic cells significantly increases after the administration of 50 microM RESV, depending on the incubation time. The cytotoxicity of 20-65 microg/ml alachlor and 10-65 microg/ml acetochlor was significantly decreased by the addition of 10 microM RESV in Vero ER- cells whereas no significant change was detected on ER+ cell lines MCF-7 and HepG2. These results show that RESV protects non-transformed ER- cells, but has no such effect on ER+ tumor cells.

Effect of simultaneous administration of Avemar and cytostatic drugs on viability of cell cultures, growth of experimental tumors, and survival tumor-bearing mice.

Avemar (Biromedicina Co., Budapest, Hungary), a wheat germ preparation with immunomodulant and antimetastatic activity, was applied simultaneously with cytostatic drugs of different modes of action, in vitro and in vivo, in order to find out whether this simultaneous administration exerts an antagonistic or a synergistic effect on the viability of cell cultures, tumor growth, and survival of animals, inoculated with a transplantable mouse tumor (3LL-HH). In vitro, Avemar did not influence the effect on the viability of MCF-7, HepG2, or Vero cells, exerted by Dacarbazine, 5-fluorouracyl, or Adriblastina. In vivo, Avemar, combined with Endoxan, Navelbine, and doxorubicin, did not prevent the tumor growth inhibitory effect of the cytostatic drugs. The combination of Avemar with the cytostatic drugs did not increase the toxicity of the cytostatic compounds, and did not exert any toxic effect. Avemar may be administered together with cytostatic drugs, without the risk of increasing toxicity or decreasing antiproliferative activity.

The efficacy of tamoxifen in estrogen receptor-positive breast cancer cells is enhanced by a medical nutriment.

Avemar, a fermented wheat germ extract, has been applied in the supplementary therapy of human cancers. Because tamoxifen is commonly used in the therapy of ER+ breast cancer, in this study the combined effect of tamoxifen and Avemar treatment was investigated on MCF-7 breast cancer cells, in order to detect a possible agonistic or antagonistic action. Cytotoxicity was measured by MTT assay, the percentage of mitoses and apoptotic cells was determined morphologically, apoptosis and S-phase was measured by flow cytometry, and estrogen-receptor activity was determined by semiquantitative measurement of the estrogen-responsive pS2 gene mRNA production. Tamoxifen (1 nM) alone had no effect on the percentage of the apoptotic cell fraction and significantly reduced the percentage of the S-phase, compared to untreated cells. Avemar (625 microg/mL) significantly increased apoptosis after 48 hours of treatment. Tamoxifen together with Avemar significantly increased apoptosis already 24 hours after starting treatment but had only a slight (not significant) effect on mitosis and S-phase. Estrogen-receptor activity of MCF-7 cells was enhanced by Avemar, decreased by tamoxifen, and was further decreased by combined tamoxifen and Avemar treatment. As apoptosis increased when Avemar was added to tamoxifen treatment, the use of supplementary therapy with Avemar in the case of ER+ breast tumors may enhance the therapeutic effects of tamoxifen.