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Rett syndrome (RTT) is a rare neurodevelopmental disorder that is usually caused by mutations of the MECP2 gene. Patients with RTT suffer from severe deficits in motor, perceptual and cognitive domains. Electroencephalogram (EEG) has provided useful information to clinicians and scientists, from the very first descriptions of RTT, and yet no reliable neurophysiological biomarkers related to the pathophysiology of the disorder or symptom severity have been identified to date. To identify consistently observed and potentially informative EEG characteristics of RTT pathophysiology, and ascertain areas most worthy of further systematic investigation, here we review the literature for EEG abnormalities reported in patients with RTT and in its disease models. While pointing to some promising potential EEG biomarkers of RTT, our review identify areas of need to realize the potential of EEG including (1) quantitative investigation of promising clinical-EEG observations in RTT, e.g., shift of mu rhythm frequency and EEG during sleep; (2) closer alignment of approaches between patients with RTT and its animal models to strengthen the translational significance of the work (e.g., EEG measurements and behavioral states); (3) establishment of large-scale consortium research, to provide adequate Ns to investigate age and genotype effects.

Independent Component Analysis (ICA) is a conventional approach to exclude non-brain signals such as eye-movements and muscle artifacts from electroencephalography (EEG). Due to other possible EEG contaminations, a rejection of independent components (ICs) is usually performed in semiautomatic mode and requires experts’ involvement. Noteworthy, as also revealed by our study, experts’ opinion about the nature of a component often disagrees highlighting the need to develop a robust and sustainable automatic system for EEG ICs classification. The current article presents a toolbox and crowdsourcing platform for Automatic Labeling of Independent Components in Electroencephalography (ALICE) available via linkhttp://alice.adase.org/. The ALICE toolbox aims to build a sustainable algorithm not only to remove artifacts but also to find specific patterns in EEG signals using ICA decomposition based on accumulated experts’ knowledge.The difference from previous toolboxes is that the ALICE project will accumulate different benchmarks based on crowdsourced visual labeling of ICs collected from publicly available and in-house EEG recordings. The choice of labeling is based on estimation of IC time-series, IC amplitude topography and spectral power distribution. The platform allows supervised ML model training and re-training on available data subsamples for better performance in specific tasks (i.e. movement artifact detection in healthy or autistic children). Also, current research implements the novel strategy for consentient labeling of ICs by several experts. The provided baseline model shows that it can be used not only for detection of noisy IC but also for automatic identifications of components related to the functional brain oscillations such as alpha and mu-rhythm.The ALICE project implies the creation and constant replenishment of the IC database, which will be used for continuous improvement of ML algorithms for automatic labeling and extraction of non-brain signals from EEG. The toolbox and current dataset are open-source and freely available to the researcher community.

SHANK3 encodes a scaffold protein involved in postsynaptic receptor density in glutamatergic synapses, including those in the parvalbumin (PV)+ inhibitory neurons—the key players in the generation of sensory gamma oscillations, such as 40-Hz auditory steady-state response (ASSR). However, 40-Hz ASSR was not studied in relation to SHANK3 functioning. Here, we present a 15-year-old girl (SH01) with previously unreported duplication of the first seven exons of the SHANK3 gene (22q13.33). SH01’s electroencephalogram (EEG) during 40-Hz click trains of 500 ms duration binaurally presented with inter-trial intervals of 500–800 ms were compared with those from typically developing children (n = 32). SH01 was diagnosed with mild mental retardation and learning disabilities (F70.88), dysgraphia, dyslexia, and smaller vocabulary than typically developing (TD) peers. Her clinical phenotype resembled the phenotype of previously described patients with 22q13.33 microduplications (≈30 reported so far). SH01 had mild autistic symptoms but below the threshold for ASD diagnosis and microcephaly. No seizures or MRI abnormalities were reported. While SH01 had relatively preserved auditory event-related potential (ERP) with slightly attenuated P1, her 40-Hz ASSR was totally absent significantly deviating from TD’s ASSR. The absence of 40-Hz ASSR in patients with microduplication, which affected the SHANK3 gene, indicates deficient temporal resolution of the auditory system, which might underlie language problems and represent a neurophysiological biomarker of SHANK3 abnormalities.

SHANK3 encodes scaffold protein involved in postsynaptic receptor density in glutamatergic synapses, including those in the parvalbumin (PV)+inhibitory neurons – the key players in generation of sensory gamma oscillations, such as 40-Hz auditory steady-state response(ASSR). Here we describe a clinical and neurophysiological phenotype of a 15-years old girl (SH01) with microduplication of 16389 bp in 22q13.33, affecting the SHANK3 gene in comparison to typically developing children (n=32). EEG were recorded during the binaurally presentation of 40-Hz clicks’ trains lasting for 500 ms with inter-trial intervals 500-800 ms. SH01 was diagnosed with mild mental retardation and learning disabilities(F70.88) and had problems with reading and writing, as well as smaller vocabulary than TD peers. Her clinical phenotype generally resembled the phenotype of previously described patients with 22q13.33 microduplication. SH01 had mild autistic symptoms but below the threshold for ASD diagnosis. No seizures or MRI abnormalities were reported. While SH01 had relatively preserved auditory event-related potential(ERP) with slightly attenuated P1, her 40-Hz ASSR was totally absent significantly deviating from TD’s ASSR. Absence of 40-Hz ASSR in patient with microduplication, affected SHANK3 gene, indicates deficient temporal resolution of the auditory system, that might underlie language problems, and represent neurophysiological biomarker of SHANK3 abnormalities.

Background: Deficits in perception and production of vocal pitch are often observed in people with autism spectrum disorder (ASD), but the neural basis of these abnormalities is unknown. In magnetoencephalogram (MEG), spectrally complex periodic sounds trigger two continuous neural responses – the auditory steady state response (ASSR) and the sustained field (SF). It has been shown that the SF in neurotypical individuals is associated with low-level analysis of pitch in the ‘pitch processing center’ of the Heschl’s gyrus. Therefore, this auditory response may reflect vocal pitch processing abnormalities in ASD. The SF, however, has never been studied in people with this disorder. Methods: We used MEG and individual brain models to investigate the ASSR and SF evoked by monaural 40 Hz click trains in boys with ASD (N=35) and neurotypical (NT) boys (N=35) aged 7-12-years.Results: In agreement with the previous research in adults, the cortical sources of the SF in children were located in the left and right Heschl’s gyri, anterolateral to those of the ASSR. In both groups, the SF and ASSR dominated in the right hemisphere and were higher in the hemisphere contralateral to the stimulated ear. The ASSR increased with age in both NT and ASD children and did not differ between the groups. The SF amplitude did not significantly change between the ages of 7 and 12 years. It was moderately attenuated in both hemispheres and was markedly delayed and displaced in the left hemisphere in boys with ASD. The SF delay in participants with ASD was present irrespective of their intelligence level and severity of autism symptoms.Limitations: We did not test the language abilities of our participants. Therefore, the link between SF and processing of vocal pitch in children with ASD remains speculative.Conclusion: Children with ASD demonstrate selective left-hemispheric abnormalities at the level of the core auditory cortex when processing spectrally complex periodic sound. The observed neural deficit may contribute to speech perception difficulties experienced by children with ASD, including their poor perception and production of linguistic prosody.

Background Deficits in perception and production of vocal pitch are often observed in people with autism spectrum disorder (ASD), but the neural basis of these deficits is unknown. In magnetoencephalogram (MEG), spectrally complex periodic sounds trigger two continuous neural responses—the auditory steady state response (ASSR) and the sustained field (SF). It has been shown that the SF in neurotypical individuals is associated with low-level analysis of pitch in the ‘pitch processing center’ of the Heschl’s gyrus. Therefore, alternations in this auditory response may reflect atypical processing of vocal pitch. The SF, however, has never been studied in people with ASD. Methods We used MEG and individual brain models to investigate the ASSR and SF evoked by monaural 40 Hz click trains in boys with ASD (N = 35) and neurotypical (NT) boys (N = 35) aged 7–12-years. Results In agreement with the previous research in adults, the cortical sources of the SF in children were located in the left and right Heschl’s gyri, anterolateral to those of the ASSR. In both groups, the SF and ASSR dominated in the right hemisphere and were higher in the hemisphere contralateral to the stimulated ear. The ASSR increased with age in both NT and ASD children and did not differ between the groups. The SF amplitude did not significantly change between the ages of 7 and 12 years. It was moderately attenuated in both hemispheres and was markedly delayed and displaced in the left hemisphere in boys with ASD. The SF delay in participants with ASD was present irrespective of their intelligence level and severity of autism symptoms. Limitations We did not test the language abilities of our participants. Therefore, the link between SF and processing of vocal pitch in children with ASD remains speculative. Conclusion Children with ASD demonstrate atypical processing of spectrally complex periodic sound at the level of the core auditory cortex of the left-hemisphere. The observed neural deficit may contribute to speech perception difficulties experienced by children with ASD, including their poor perception and production of linguistic prosody.

Due to severe motor impairments and the lack of expressive language abilities seen in most patients with Rett Syndrome (RTT), it has proven extremely difficult to obtain accurate measures of auditory processing capabilities in this population. Here, we examined early auditory cortical processing of pure tones and more complex phonemes in females with Rett Syndrome (RTT), by recording high-density auditory evoked potentials (AEP), which allow for objective evaluation of the timing and severity of processing deficits along the auditory processing hierarchy. We compared AEPs of 12 females with RTT to those of 21 typically developing (TD) peers aged 4–21 years, interrogating the first four major components of the AEP (P1: 60–90 ms; N1: 100–130 ms; P2: 135–165 ms; and N2: 245–275 ms). Atypicalities were evident in RTT at the initial stage of processing. Whereas the P1 showed increased amplitude to phonemic inputs relative to tones in TD participants, this modulation by stimulus complexity was absent in RTT. Interestingly, the subsequent N1 did not differ between groups, whereas the following P2 was hugely diminished in RTT, regardless of stimulus complexity. The N2 was similarly smaller in RTT and did not differ as a function of stimulus type. The P2 effect was remarkably robust in differentiating between groups with near perfect separation between the two groups despite the wide age range of our samples. Given this robustness, along with the observation that P2 amplitude was significantly associated with RTT symptom severity, the P2 has the potential to serve as a monitoring, treatment response, or even surrogate endpoint biomarker. Compellingly, the reduction of P2 in patients with RTT mimics findings in animal models of RTT, providing a translational bridge between pre-clinical and human research.

Due to severe motor impairments and the lack of expressive language abilities seen in most patients with Rett Syndrome (RTT), it has proven extremely difficult to obtain accurate measures of auditory processing capabilities in this population. Here, we examined early auditory cortical processing of pure tones and more complex phonemes females with confirmed mutation of the MECP2 gene. We recorded high-density auditory evoked potentials (AEP), which allow for objective evaluation of the timing and severity of processing deficits along the auditory processing hierarchy. We compared AEPs of 12 females with RTT to those of 21 typically developing (TD) peers aged 4-21 years, interrogating the first four major components of the AEP (P1: 60-90ms; N1: 100-130ms; P2: 135-165ms; N2: 245-275ms). Atypicalities were evident in RTT at the initial stage of processing. Whereas the initial P1 showed increased amplitude to phonemic inputs relative to tones in TD participants, this modulation by stimulus complexity was absent in RTT. Interestingly, the subsequent N1 did not differ between groups, whereas the following P2 was hugely diminished in RTT, regardless of stimulus complexity. The N2 was similarly smaller in RTT, and did not differ as a function of stimulus type. The P2 effect was remarkably robust in differentiating between groups with near perfect separation between the two groups despite the wide age range of our samples. Given this robustness, along with the observation that P2 amplitude was significantly associated with RTT symptom severity, the P2 has the potential to serve as a biomarker of treatment efficacy.Significance statementOur study points to dramatic reduction of the P2 component of the auditory evoked potential (AEP) as a potentially reliable biomarker of Rett Syndrome severity, with prospective applicability as an objective readout (neuromarker) of change in functional brain activity following therapeutic interventions administered in the context of clinical trials. Compellingly, the reduction of P2 amplitude in patients with RTT mimics findings in animal models of RTT, providing a translational bridge between pre-clinical and human research.

Rett syndrome (RTT), a rare neurodevelopmental disorder caused by mutations in the MECP2 gene, is typified by profound cognitive impairment and severe language impairment, rendering it very difficult to accurately measure auditory processing capabilities behaviorally in this population. Here we leverage the mismatch negativity (MMN) component of the event-related potential to measure the ability of RTT patients to decode and store occasional duration deviations in a stream of auditory stimuli. Sensory memory for duration, crucial for speech comprehension, has not been studied in RTT.High-density electroencephalography was successfully recorded in 18 females with RTT and 27 age-matched typically developing (TD) controls (aged 6–22 years). Data from seven RTT and three TD participants were excluded for excessive noise. Stimuli were 1 kHz tones with a standard duration of 100 ms and deviant duration of 180 ms. To assess the sustainability of sensory memory, stimulus presentation rate was varied with stimulus onset asynchronies (SOAs) of 450, 900, and 1800 ms. MMNs with maximum negativity over fronto-central scalp and a latency of 220–230 ms were clearly evident for each presentation rate in the TD group, but only for the shortest SOA in the RTT group. Repeated-measures ANOVA revealed a significant group by SOA interaction. MMN amplitude correlated with age in the TD group only. MMN amplitude was not correlated with the Rett Syndrome Severity Scale. This study indicates that while RTT patients can decode deviations in auditory duration, the span of this sensory memory system is severely foreshortened, with likely implications for speech decoding abilities.

Gamma oscillations facilitate information processing by shaping the excitatory input/output of neuronal populations. Recent studies in humans and nonhuman primates have shown that strong excitatory drive to the visual cortex leads to suppression of induced gamma oscillations, which may reflect inhibitory-based gain control of network excitation. The efficiency of the gain control measured through gamma oscillations may in turn affect sensory sensitivity in everyday life. To test this prediction, we assessed the link between self-reported sensitivity and changes in magneto-encephalographic gamma oscillations as a function of motion velocity of high-contrast visual gratings. The induced gamma oscillations increased in frequency and decreased in power with increasing stimulation intensity. As expected, weaker suppression of the gamma response correlated with sensory hypersensitivity. Robustness of this result was confirmed by its replication in the two samples: neurotypical subjects and people with autism, who had generally elevated sensory sensitivity. We conclude that intensity-related suppression of gamma response is a promising biomarker of homeostatic control of the excitation-inhibition balance in the visual cortex.

Gamma oscillations facilitate information processing by shaping the excitatory input/output of neuronal populations, and their suppression by strong excitatory drive may stem from inhibitory-based gain control of network excitation. Individual variations in the gamma suppression may therefore reflect efficiency of gain control and subjective sensitivity to everyday sensory events. To test this prediction, we assessed the link between self-reported sensory sensitivity and changes in magneto-encephalographic gamma oscillations as a function of motion velocity of high-contrast visual gratings. The induced gamma oscillations increased in frequency and decreased in power with increasing stimulation intensity. As expected, weaker suppression of the gamma response correlated with sensory hypersensitivity. Robustness of this result was confirmed by its replication in the two samples: neurotypical subjects and people with autism, who had generally higher sensory sensitivity. We conclude that intensity-related suppression of gamma response is a promising biomarker of homeostatic control of the excitation-inhibition balance in the visual cortex.

Gamma-band oscillations arise from the interplay between neural excitation (E) and inhibition (I) and may provide a non-invasive window into the state of cortical circuitry. A bell-shaped modulation of gamma response power by increasing the intensity of sensory input was observed in animals and is thought to reflect neural gain control. Here we sought to find a similar input-output relationship in humans with MEG via modulating the intensity of a visual stimulation by changing the velocity/temporal-frequency of visual motion.In the first experiment, adult participants observed static and moving gratings. The frequency of the MEG gamma response monotonically increased with motion velocity whereas power followed a bell-shape. In the second experiment, on a large group of children and adults, we found that despite drastic developmental changes in frequency and power of gamma oscillations, the relative suppression at high motion velocities was scaled to the same range of values across the life-span.In light of animal and modeling studies, the modulation of gamma power and frequency at high stimulation intensities characterizes the capacity of inhibitory neurons to counterbalance increasing excitation in visual networks. Gamma suppression may thus provide a non-invasive measure of inhibitory-based gain control in the healthy and diseased brain.

Background Inherited abnormalities of perception, recognition, and attention to faces have been implicated in the etiology of autism spectrum disorders (ASD) including abnormal components of event-related brain potentials (ERP) elicited by faces. Methods We examined familial aggregation of face processing ERP abnormalities previously implicated in ASD in 49 verbal individuals with ASD, 36 unaffected siblings (US), 18 unaffected fathers (UF), and 53 unrelated controls (UC). The ASD, US, and UC groups ranged in age from 12 to 21 years, the UF group ranged in age from 30 to 56 years. ERP responses to images of upright and inverted faces and houses were analyzed under disparate EEG reference schemes. Results Face-sensitive features of N170 and P1 were readily observed in all groups. Differences between ASD and control groups depended upon the EEG reference scheme. Notably, the superiority of face over object for N170 latency was attenuated in ASD subjects, but not their relatives; this occurred exclusively with the average reference. The difference in N170 amplitude between inverted and upright faces was reduced in both ASD and US groups relative to UC, but this effect was significant only with the vertex reference. Furthermore, similar group differences were observed for both inverted faces and inverted houses, suggesting a lack of face specificity for the attenuation of the N170 inversion effect in ASD. Conclusion The present findings refine understanding of face processing ERPs in ASD. These data provide only modest evidence for highly-selective ASD-sensitive ERP features, and underscore the sensitivity of these biomarkers to ERP reference scheme. These schemes have varied across published studies and must be accounted for in future studies of the relationship between these commonly acquired ERP characteristics, genotype, and ASD. Electronic supplementary material The online version of this article (10.1186/s13229-018-0220-x) contains supplementary material, which is available to authorized users.

Excitation/Inhibition (E/I) imbalance in neural networks is now considered among the core neural underpinnings of autism psychopathology. In motion perception at least two phenomena critically depend on E/I balance in visual cortex: spatial suppression (SS), and spatial facilitation (SF) corresponding to impoverished or improved motion perception with increasing stimuli size, respectively. While SS is dominant at high contrast, SF is evident for low contrast stimuli, due to the prevalence of inhibitory contextual modulations in the former, and excitatory ones in the latter case. Only one previous study (Foss-Feig et al., 2013) investigated SS and SF in Autism Spectrum Disorder (ASD). Our study aimed to replicate previous findings, and to explore the putative contribution of deficient inhibitory influences into an enhanced SF index in ASD—a cornerstone for interpretation proposed by Foss-Feig et al. (2013). The SS and SF were examined in 40 boys with ASD, broad spectrum of intellectual abilities (63 < IQ < 127) and 44 typically developing (TD) boys, aged 6–15 years. The stimuli of small (1°) and large (12°) radius were presented under high (100%) and low (1%) contrast conditions. Social Responsiveness Scale and Sensory Profile Questionnaire were used to assess the autism severity and sensory processing abnormalities. We found that the SS index was atypically reduced, while SF index abnormally enhanced in children with ASD. The presence of abnormally enhanced SF in children with ASD was the only consistent finding between our study and that of Foss-Feig et al. While the SS and SF indexes were strongly interrelated in TD participants, this correlation was absent in their peers with ASD. In addition, the SF index but not the SS index correlated with the severity of autism and the poor registration abilities. The pattern of results is partially consistent with the idea of hypofunctional inhibitory transmission in visual areas in ASD. Nonetheless, the absence of correlation between SF and SS indexes paired with a strong direct link between abnormally enhanced SF and autism symptoms in our ASD sample emphasizes the role of the enhanced excitatory influences by themselves in the observed abnormalities in low-level visual phenomena found in ASD.

People are very precise in the discrimination of a line orientation relative to the cardinal (vertical and horizontal) axes, while their orientation discrimination sensitivity along the oblique axes is less refined. This difference in discrimination sensitivity along cardinal and oblique axes is called the “oblique effect.” Given that the oblique effect is a basic feature of visual processing with an early developmental origin, its investigation in children with Autism Spectrum Disorder (ASD) may shed light on the nature of visual sensory abnormalities frequently reported in this population. We examined line orientation sensitivity along oblique and vertical axes in a sample of 26 boys with ASD (IQ > 68) and 38 typically developing (TD) boys aged 7–15 years, as well as in a subsample of carefully IQ-matched ASD and TD participants. Children were asked to detect the direction of tilt of a high-contrast black-and-white grating relative to vertical (90°) or oblique (45°) templates. The oblique effect was reduced in children with ASD as compared to TD participants, irrespective of their IQ. This reduction was due to poor orientation sensitivity along the vertical axis in ASD children, while their ability to discriminate line orientation along the oblique axis was unaffected. We speculate that this deficit in sensitivity to vertical orientation may reflect disrupted mechanisms of early experience-dependent learning that takes place during the critical period for orientation selectivity.

Studies of the effects of auditory rhythmic stimulation of different frequencies on psychophysiological and neurophysiological aspects of a number of cognitive processes are reported. These experiments showed that rhythmic stimulation at 0.75 Hz decreased motor reaction times in solving cognitive tasks as compared with rhythmic stimulation at 1.25 Hz and task solution without rhythmic stimulation. Subjective assessments of the durations of series also decreased. Slow rhythmic stimulation also led to decreases in the power of the alpha rhythm and increases in the amplitude of the P300 component in the right frontal, central, and parietal areas.

Changes in the functional status under the effect of intense mental exercise were studied in carriers of different variants of DAT1, DRD2, and COMT genes. The volunteers (n=140) performed 3-h monotonous mental work (information processing and logical problem solving). The degree of fatigue was evaluated before and after exercise by the HAM (Health status– Activity–Moods) and AMF (Acute Mental Fatigue) questionnaires. A signifi cant relationship between the DAT1, DRD2, and COMT gene polymorphism and changes in the mental sphere status were revealed. The effects of these polymorphisms were the most pronounced in girls. The results are discussed within the framework of hypothesis on the effects of changes in the phasic/tonic dopamine proportion on the studied functions.

The effect of the variants of the serotonin transporter gene (5-HTT) on aggressiveness was studied in male and female control subjects and athletes. Sports were found to generally decrease aggressiveness; this was true both for women doing nonaggressive sports and for men doing combat sports. The control group of men was characterized by higher indices of aggressiveness (physical and verbal aggression, negativism, and suspiciousness) than women were. Women, irrespective of age and whether they participated in sports, exhibited a relationship between 5-HTT gene variants and the displaced aggressiveness and negativism scales: the SS genotype was associated with a higher displaced aggressiveness and a low negativism. Men exhibited a different relationship. The general aggressiveness index was significantly higher in carriers of the LL genotype than in carriers of the SS genotype, whereas these subjects did not differ significantly in the parameters measured by individual scales. In men, the cerebral processes that are presumed to underlie aggressiveness were found to be related to 5-HTT gene variants. The HP component of the cerebral potential responsible for automatic detection of differences was increased and the P3a component responsible for involuntary attention and cognitive control. This suggests that carriers of the SS genotype use more cognitive resources to process information. This may be because the stimulus itself seems to be more “complex,” which results in the involvement of additional resources of the frontal cortex. It may also be assumed that carriers of the SS genotype tend to analyze the incoming information more deeply. This, more “serious” analysis of external information may underlie their refraining from impulsive behavior, which is often aggressive.

Four issues are discussed: the possible mechanism of subjective events, conscious versus unconscious brain functions, the rhythmic coding of mental operations and the possible brain basis of understanding. i. Several approaches have been developed to explain how subjective experience emerges from brain activity. One of them is the return of the nervous impulses to the sites of their primary projections, providing a synthesis of sensory information with memory and motivation [Ivanitsky, A.M., 1976. Brain Mechanisms of the Signal Evaluation. Medicina, Moscow 264 pp. (in Russian)]. Support for the existence of such a mechanism stems from studies upon the brain activity that subserves perception (visual and somato-sensory) and thought (verbal and imaginative). The cortical centres for information synthesis have been found. For perception, these are located in projection areas; for thinking — in frontal and temporal-parietal associative cortex. Closely related ideas were also developed by G. Edelman [Edelman, G.M., 1978. Group selection and phasic reentrant signaling: A theory of higher brain function. In: Eds. Edelman, G.M., Mountcastle, V.B. The Mindful Brain. Cortical Organization and the Group-selective Theory of Higher Brain Function. Cambridge, MA, MIT Press, pp 51–100.] in his re-entry theory of consciousness. Both theories emphasize the key role of memory and motivation in the origin of conscious function. ii. Conscious experience elucidates not all, but only salient brain functions. As a rule, voluntary control is switched on when additional cognitive resources are needed. Even a rather complicated mental operation, such as the discrimination between concrete and abstract words, could be executed very rapidly and implicitly; explicit analysis being engaged only in more difficult tasks. Furthermore, these two different kinds of mental operations, i.e., automatic and conscious, are predominantly associated with two different kinds of memory: a recognition memory for implicit analysis, and an episodic memory for explicit functions. iii. Rearrangements of EEG rhythms underlie mental functions. Certain rhythmical patterns are related with definite types of mental activity. The dependence of one upon the other is rather pronounced and expressive, so it becomes possible to recognize the type of mental operation being performed in mind with few seconds of the ongoing EEG, provided that the analysis of rhythms is accomplished using an artificial neural network. iv. It is commonly recognized that the computer, in contrast to the living brain, can calculate, yet cannot understand [Penrose, R., 1996. Shadows of the Mind: A Search for the Missing Science of Consciousness New York, Oxford, Oxford University Press 480 pp.]. Comprehension implies the comparison of new and old information that requires the ability to search for associations, grouping similar objects together, and distinguishing different objects from one another. However, these functions may also be implemented on a computer. Still, it is believed that computers perform these complicated operations without genuine understanding. Evidently, comprehension additionally has to be based upon some biologically significant ground. It is hypothesized that the subjective feeling of understanding appears when current information is attributed to a definite need, which is scaled in sign (+/−) coordinates. This coordinate system ceases the brain calculations, when “comprehension” is reached, i.e., the acceptable level of need satisfaction is attained.

Aggression is a heterogeneous heritable psychological trait, also influenced by environmental factors. Previous studies, mostly conducted on male population, have found some associations of the aggression with the polymorphisms of genes, regulating the activity of serotonin (5-HT) in the brain. However, psychological as well as biochemical manifestations of the aggression are different in males and females. Our study aimed to investigate the association of 5-HTT gene polymorphism with different facets of aggression (BDHI) in females. Two groups: the synchronized swimming and non-athlete control, - were examined to study the possible modulation effect of sport on the association between 5-HTT gene polymorphism and aggression. It was found that in both groups the low-active 5-HTT polymorphism (SS) was associated with increased scores on Indirect Hostility scale and decreased scores on Negativism scale, compared to LL genotype. No interaction effect between sport and 5-HTT polymorphism was found. The higher percentage of LL-carriers and lower of LS-carriers in the synchronized swimming group compared to the control one was observed. This may be the sign of the importance of LL polymorphism of 5-HTT gene, previously associated with higher resistance to stress factors, for being an athlete, although this result has to be taken cautiously keeping in mind the stratification problem. Synchronized swimmers had lower scores on Assault, Negativism, Irritability and Verbal Hostility compared to age-matched control girls (in general and for each 5-HTT genotype separately), suggesting that they may have more matured emotional system (older control group has also lower scores on these scales).

In order to test the "serotonin" hypothesis of the genesis of central fatigue, we studied association between genotype and fatigue (3-hour mental workload consisting of information processing and logical task solution) using analysis of variance for different indices (well-being, activity, mood, mental fatigue index). It was concluded that young men with serotonin deficit (LL genotype) and girls with serotonin excess (S genotype) were less tolerant to long-lasting mental workload. Thus, we confirmed that the degree of central fatigue depends on the function of the serotonin system and revealed gender differences in adaptive capacities of carriers of different variants of serotonin transporter.

We studied the effect of angiotensin-converting enzyme gene polymorphism on human emotional state in humans (189 athletes and 212 volunteers not engaged in sport activity). The distribution of angiotensin-converting enzyme genotypes was estimated. The dependence of aggression on age, sex, and professional activity was evaluated. This polymorphism was associated with physical aggression in female synchronized swimmers. Physical aggression in II genotype carriers was lower than in D allele carriers. Our results indicate that individual differences in aggression depend on professional activity and are genetically determined.

Gamma oscillations are generated in networks of inhibitory fast-spiking (FS) parvalbumin-positive (PV) interneurons and pyramidal cells. In animals, gamma frequency is modulated by the velocity of visual motion; the effect of velocity has not been evaluated in humans. In this work, we have studied velocity-related modulations of gamma frequency in children using MEG/EEG. We also investigated whether such modulations predict the prominence of the “spatial suppression” effect (Tadin D, Lappin JS, Gilroy LA, Blake R. Nature 424: 312-315, 2003) that is thought to depend on cortical center-surround inhibitory mechanisms. MEG/EEG was recorded in 27 normal boys aged 8–15 yr while they watched high-contrast black-and-white annular gratings drifting with velocities of 1.2, 3.6, and 6.0°/s and performed a simple detection task. The spatial suppression effect was assessed in a separate psychophysical experiment. MEG gamma oscillation frequency increased while power decreased with increasing velocity of visual motion. In EEG, the effects were less reliable. The frequencies of the velocity-specific gamma peaks were 64.9, 74.8, and 87.1 Hz for the slow, medium, and fast motions, respectively. The frequency of the gamma response elicited during slow and medium velocity of visual motion decreased with subject age, whereas the range of gamma frequency modulation by velocity increased with age. The frequency modulation range predicted spatial suppression even after controlling for the effect of age. We suggest that the modulation of the MEG gamma frequency by velocity of visual motion reflects excitability of cortical inhibitory circuits and can be used to investigate their normal and pathological development in the human brain.

Visual search and oddball paradigms were combined to investigate memory for to-be-ignored color changes in a group of 12 healthy participants. The onset of unexpected color change of an irrelevant stimulus evoked two reliable ERP effects: a component of the event-related potential (ERP), similar to the visual mismatch negativity response (vMMN), with a latency of 120-160 ms and a posterior distribution over the left hemisphere and Late Fronto-Central Negativity (LFCN) with a latency of 320-400 ms, apparent at fronto-central electrodes and some posterior sites. Color change of that irrelevant stimulus also slowed identification of a visual target, indicating distraction. The amplitude of this color-change vMMN, but not LFCN, indexed this distraction effect. That is, electrophysiological and behavioral measures were correlated. The interval between visual scenes approximated 1 s (611-1629 ms), indicating that the brain's sensory memory for the color of the preceding visual scenes must persist for at least 600 ms. Therefore, in the case of the neural code for color, durable memory representations are formed in an obligatory manner. (C) 2014 Elsevier B.V. All rights reserved.

THIS STUDY AIMED TO EXAMINE EFFECT OF PHYSICAL EXERCISE ON MOTOR TIMING: personal, maximum and "once per second" tapping. The acute effect was examined by comparing the baseline tapping with that after acute exercise in 9 amateur athletes, 8 elite synchronous swimmers and 9 elite biathletes. Then the baseline tapping was compared among athletes of different sports and professional levels (15 elite biathletes, 27 elite cross-country skiers, 15 elite synchronous swimmers and 9 amateur wrestlers) with a control group (44 non-athletes) not involved in regular exercise to examine the sport-specific or long-term effects. Maximum and "once per second" tapping speed increased after acute physical exercise and were also faster in elite athletes compared to controls during the baseline condition. However, personal tapping tempo was not affected by exercise. In addition, physical exercise had no effects on the variability of the intertap interval. The accuracy of "once per second" tapping differentiates controls and amateur wrestlers from elite synchronous swimmers and skiers suggesting sport-specific adaptations to play a role. It is concluded that acute physical exercise selectively speeds up motor timing but does not affect its variability and accuracy, and this speeding-up is suggested to transfer into a long-term effect in elite athletes.

The incidence of SLC6A4 gene 5HTTLPR polymorphism alleles was evaluated in 223 male athletes engaged in endurance sports, the results were compared with those in 177 male nonathletes. Association between 5-HTTLPR genotypes and the effect of exhaustive treadmill running on simple and complex visual reactions and critical flicker frequency threshold was studied. We found that the incidence of LL genotype was significantly higher in athletes in comparison to nonathletes; after exercise, the velocity of visual reactions and critical flicker frequency increased; exercise did not change the velocity of complex visual reaction in LL-carriers, and increased it in SS-carriers. We conclude that exhausting treadmill running leads to facilitation sensory information processing in athletes and that SS-carriers are more susceptible to the effect of exhaustive treadmill running than LL-carriers.

Establishing links between experimental data, their models, and the neural substrates presents a permanent challenge for research in timing and time perception. This applies particularly to the problem of internal representation of temporal duration and its neural implementation. In this short communication we will report on progress achieved with the “lossy integration” model (also known as “klepsydra” model; Wackermann and Ehm, 2006) in interpretation of time perception data in the context of neurophysiological and neurobiological findings. In the pacemaker–gate–accumulator model (Zakay and Block, 1997), which is still considered as the standard model in the literature (Grondin, 2010), temporal durations are internally represented by cumulative pulse counts, A=t⋅f (t is the interval duration, f the effective pulse train frequency, and A is the number of pulses accumulated in the counter). Consequently, all variations in timing behavior or in a time perception task response can be accounted for by a change of the frequency f of pulses entering the counter. This gives the model its apparent elegance and universality, but is also its main weakness. Since the two hypothetical components, pacemaker and gate, are arranged serially, it is impossible to disentangle their effects. The effective frequency f may vary due to a change of the pacemaker fundamental frequency fP (e.g., in response to organismic, physiological factors), or due to a change of the gate throughput g (e.g., attentional, cognitive effects): f=fP⋅g (where g is a real number in the range from 0 to 1). By contrast, in the “klepsydra” model, (Wackermann and Ehm, 2006), temporal durations are represented by states of a lossy integrator; written in a differential form dAdt=f−κ⋅A. The inflow rate f corresponds to the pulse train frequency in the “standard” model (that the states are here continuous, rather than discrete quantities, is unimportant). The outflow rate, however, is determined by the momentary state of the accumulator A and a proportionality factor κ. Therefore, there are two loci of possible effects on internal time representation, the inflow and the outflow. The inflows can be studied only in relative terms, e.g., as inflow ratios between different experimental conditions; however, the loss rate κ can be determined numerically in given physical units (sec−1). To apply the model to the two tasks mostly used in our experimental studies – duration reproduction and duration discrimination in the supra-second range – we assume two such inflow–outflow units, each one allocated to one of the two temporal intervals to be compared. [Hence the name “dual klepsydra model” under which the model is known (Wackermann and Ehm, 2006).] Numerical procedures are available for estimating the value of κ directly from (individual or group-based) response functions in the reproduction task (Wackermann and Ehm, 2006), or indirectly, from points of subjective indifference determined by psychometric functions fitted to the data from the discrimination task (Wackermann and Spati, 2006). The lossy character of internal time representation is revealed by the progressive shortening of the reproduction response, or by the presentation order effect in the discrimination response (generally known as “subjective shortening” of past durations). Recent experiments supported the notion of the “loss rate” parameter κ as a stable individual characteristic of the subject, evidenced by the high test–retest reliability of the parameter κ obtained from duration discrimination data (Sysoeva et al., 2010) and duration reproduction data. Moreover, it was shown (Sysoeva et al., 2010) that carriers of genotypic variants related to the activity of the serotonergic (5-HT) transmitter system significantly differ in the “loss rate” parameter κ. These results suggest genetic determination of dynamic parameters of neural representation of time. Higher values of κ were found for the carriers of genotypes characterized by higher potential for 5-HT transmission: (1) lower 5-HT reuptake, known for the 5-HTTLPR SS polymorphism compared with LL, (2) lower 5-HT degradation, described for the “low expression” variant of MAOA VNTR gene compared with “high expression” variant, and (3) higher 5-HT2a receptor density, proposed for the TT polymorphism of 5-HT2a T102C gene compared with CC. Also, they fit well with findings in studies on effects of psychotropic substances affecting the serotonin subsystem. In a double-blind, placebo-controlled study, psilocybin – a serotonin (5-HT) 2A/1A receptor agonist – significantly increased parameter κ which is indicative of a higher “loss rate” of duration representation, observable by a stronger under-reproduction of temporal intervals (Wackermann et al., 2008). These convergent findings suggest an action path from 5-HT activity-related genes, via activity of 5-HT in the brain, to time perception. The psychopharmacological data also indicate that although the loss rate parameter is genetically determined, it can be temporally modified by influencing the 5-HT system. In a fMRI study, it was shown that parameter κ and the degree of self-rated impulsivity were associated with brain activation during the reproduction phase of the duration reproduction task; the activated brain areas were those related to motor execution as well as to the “core control network.” In particular, activation in these regions was positively correlated with the “loss rate” parameter κ (i.e., more pronounced under-reproduction of intervals), and with the subject's degree of impulsivity (Wittmann et al., 2011). During the encoding of duration in the reproduction task brain activation within bilateral posterior insula showed an accumulating pattern over time which peaked at the end of the interval (Wittmann et al., 2010). Based on the knowledge about insular cortex functioning it has been suggested that the integration of ascending body signals forms the basis for the representation of duration (Craig, 2009; Wittmann, 2009). This hypothesis is supported by recent observations of an association between the decrease of heart-beat frequency – indicative of an increase in parasympathetic activity – during the encoding of duration in individuals performing the duration reproduction task (Meissner and Wittmann, 2011). Interpreting these empirical findings in term of the klepsydra model, the flux of bodily signals into the posterior insular cortex could be interpreted as constituting the inflow component of the model. A more widespread network encompassing the “core control network” (Cole and Schneider, 2007) which would be associated with maintaining the representation of duration over time, can be related to the outflow component of the model, thus representing the “loss rate” of the leaky accumulator. The work reported above focused on effects of the loss component of the klepsydra model, as the “subjective shortening” is a striking phenomenon seen in duration reproduction or duration discrimination data in the supra-second region. Since these effects are omnipresent in the data (whether they are subject matter of study or not) they have to be taken into account to distinguish net effects of experimental manipulations. The klepsydraic model not only disentangles the inflow (accumulation) and outflow (loss) effects conceptually, but it also allows to separate these effects operationally. An example of this analytic strategy is given in the study of brightness–duration interaction in a duration discrimination task (Wackermann and Meyer-Blankenburg, 2009), where the net effect caused by the stimulus variation is superimposed on the main stimulus-independent effect of subjective shortening. Similar strategies should be applicable in studies intending to manipulate the hypothetical “inflows” by varying somatosensory or proprioceptive stimuli to test the “bodily signals flux” hypothesis. Summarizing: in the reported studies effects of natural variations or experimental manipulations on time perception were evaluated by means of a simple “lossy integration” model, which conceptually distinguishes between two components of the mechanism underlying internal representation of temporal durations: accumulation of internal “inflow” in the integrator, and a parallel “loss” of accumulated representation (“outflow”). It is suggested that the inflow is primarily derived from the ongoing stream of intero- and proprioceptive neural signals, while the outflow is related to low-level (synaptic?) mechanisms of neural signals transfer. Converging findings on neurophysiological or neurochemical effectors or correlates of time perception provide cumulative evidence for these working hypotheses. Therefore, we wish to draw the attention of the research community to this fruitful methodology, which promises to obtain new insights into human timing and time perception in experimental research as well as in studies of clinical populations.

Background The present study investigates neurobiological underpinnings of individual differences in time perception. Methodology Forty-four right-handed Russian Caucasian males (18–35 years old) participated in the experiment. The polymorphism of the genes related to the activity of serotonin (5-HT) and dopamine (DA)-systems (such as 5-HTT, 5HT2a, MAOA, DAT, DRD2, COMT) was determined upon the basis of DNA analysis according to a standard procedure. Time perception in the supra-second range (mean duration 4.8 s) was studied, using the duration discrimination task and parametric fitting of psychometric functions, resulting in individual determination of the point of subjective equality (PSE). Assuming the ‘dual klepsydra model’ of internal duration representation, the PSE values were transformed into equivalent values of the parameter (kappa), which is a measure of the ‘loss rate’ of the duration representation. An association between time representation parameters (PSE and , respectively) and 5-HT-related genes was found, but not with DA-related genes. Higher ‘loss rate’ () of the cumulative duration representation were found for the carriers of genotypes characterized by higher 5-HT transmission, i.e., 1) lower 5-HT reuptake, known for the 5-HTTLPR SS polymorphism compared with LL, 2) lower 5-HT degradation, described for the ‘low expression’ variant of MAOA VNTR gene compared with ‘high expression’ variant, and 3) higher 5-HT2a receptor density, proposed for the TT polymorphism of 5-HT2a T102C gene compared with CC. Conclusion Convergent findings of the present study and previous psychopharmacological studies suggest an action path from 5-HT-activity-related genes, via activity of 5-HT in the brain, to time perception. An involvement of the DA-system in the encoding of durations in the supra-second range is questioned.

Association of brain processes presumably underlying aggression with serotonin transporter gene polymorphism in men was studied. Carriers of more active gene variant are characterized by higher aggression index, increased component of brain potential mismatch negativity responsible for automatic difference detection, and decreased P300 component characterizing involuntary attention and cognitive control.

Genetic and psychological analysis of the relationships between catechol-O-methyltransferase Val158Met polymorphism and various types of aggressiveness was performed in 114 women. Dispersion analysis revealed significant association of ValVal genotype with elevated physical aggression.

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Most studies of semantic processing address changes in the late (300–800 msec) components of evoked potentials. However, recent years have seen the appearance of data showing that humans can perceive the sense of stimuli presented to them in significantly shorter periods of time. We report here studies of the mechanism of semantic analysis of written abstract and concrete words in four series of experiments: 1) reading of words on a monitor screen; 2) simple classification of all presented words into the categories “abstract” and “concrete;” 3) complex, i.e., selective classification of words written only in a specified color with a prompt as to which color would be used for the word; 4) complex classification of words of only a specified color without a prior prompt. Early (40–100 msec) differences in evoked brain potentials were seen on comparison of responses to abstract and concrete words, predominantly in the frontal areas in the case of simple reading of words and in the more dorsal areas in the case of tasks with simple classification. All cases of explicit classification of words were characterized by differences in late (450–700 msec) components in the left frontal zone. The results indicate the existence of two semantic systems: a rapid, implicit system associated with activation of the right frontal area, and a slow, explicit system of word classification which is predominantly associated with activity in the left frontal area. The relationship between the two systems is to a certain extent reciprocal: the rapid system can by inhibited by introduction of a word classification task.

Previous studies have repeatedly found that late (300-800 ms) components of event-related potentials (ERP) reflected semantic analysis, i.e. the differentiation between abstract and concrete words. However, the human brain may detect the meaning of the words much earlier. This study investigated the brain mechanisms of the processing of abstract and concrete written words in four experimental conditions: i) Simple Reading, during which volunteers were required to silently read words; ii) Simple Classification, during which volunteers were required to classify the presented word into the abstract and concrete categories; and iii) Cued and iv) Uncued Selective Classification conditions, during which subjects had to classify only the words typed in a particular colour. 19-channel EEG was recorded during the experiment from 13 subjects. The ERP to abstract and concrete words differed not only at the late but also at early (40-100 ms) latencies in the Simple Reading and Classification conditions, as well as for the words that should not be explicitly classified in the Cued Selective Classification condition. This means that semantic analysis can occur in a manner which is both very rapid and implicit. Moreover, increasing task demands can even suppress this rapid semantic analysis. The functional microstate analysis revealed a topographical difference in response to abstract and concrete words, which indicated that at least partly distinct brain networks are involved in the processing of words during both early (implicit differentiation) and late (explicit classification) latencies.