Effects of synaptic and myelin plasticity on learning in a network of Kuramoto phase oscillators.

Models of learning typically focus on synaptic plasticity. However, learning is the result of both synaptic and myelin plasticity. Specifically, synaptic changes often co-occur and interact with myelin changes, leading to complex dynamic interactions between these processes. Here, we investigate the implications of these interactions for the coupling behavior of a system of Kuramoto oscillators. To that end, we construct a fully connected, one-dimensional ring network of phase oscillators whose coupling strength (reflecting synaptic strength) as well as conduction velocity (reflecting myelination) are each regulated by a Hebbian learning rule. We evaluate the behavior of the system in terms of structural (pairwise connection strength and conduction velocity) and functional connectivity (local and global synchronization behavior). We find that adaptive myelination is able to both functionally decouple structurally connected oscillators as well as to functionally couple structurally disconnected oscillators. With regard to the latter, we find that for conditions in which a system limited to synaptic plasticity develops two distinct clusters both structurally and functionally, additional adaptive myelination allows for functional communication across these structural clusters. These results confirm that network states following learning may be different when myelin plasticity is considered in addition to synaptic plasticity, pointing toward the relevance of integrating both factors in computational models of learning.

Alpha power indexes task-related networks on large and small scales: A multimodal ECoG study in humans and a non-human primate.

Performing different tasks, such as generating motor movements or processing sensory input, requires the recruitment of specific networks of neuronal populations. Previous studies suggested that power variations in the alpha band (8-12Hz) may implement such recruitment of task-specific populations by increasing cortical excitability in task-related areas while inhibiting population-level cortical activity in task-unrelated areas (Klimesch et al., 2007; Jensen and Mazaheri, 2010). However, the precise temporal and spatial relationships between the modulatory function implemented by alpha oscillations and population-level cortical activity remained undefined. Furthermore, while several studies suggested that alpha power indexes task-related populations across large and spatially separated cortical areas, it was largely unclear whether alpha power also differentially indexes smaller networks of task-related neuronal populations. Here we addressed these questions by investigating the temporal and spatial relationships of electrocorticographic (ECoG) power modulations in the alpha band and in the broadband gamma range (70-170Hz, indexing population-level activity) during auditory and motor tasks in five human subjects and one macaque monkey. In line with previous research, our results confirm that broadband gamma power accurately tracks task-related behavior and that alpha power decreases in task-related areas. More importantly, they demonstrate that alpha power suppression lags population-level activity in auditory areas during the auditory task, but precedes it in motor areas during the motor task. This suppression of alpha power in task-related areas was accompanied by an increase in areas not related to the task. In addition, we show for the first time that these differential modulations of alpha power could be observed not only across widely distributed systems (e.g., motor vs. auditory system), but also within the auditory system. Specifically, alpha power was suppressed in the locations within the auditory system that most robustly responded to particular sound stimuli. Altogether, our results provide experimental evidence for a mechanism that preferentially recruits task-related neuronal populations by increasing cortical excitability in task-related cortical areas and decreasing cortical excitability in task-unrelated areas. This mechanism is implemented by variations in alpha power and is common to humans and the non-human primate under study. These results contribute to an increasingly refined understanding of the mechanisms underlying the selection of the specific neuronal populations required for task execution.

Areas V1 and V2 show microsaccade-related 3-4-Hz covariation in gamma power and frequency.

Neuronal gamma-band synchronization (25-80 Hz) in visual cortex appears sustained and stable during prolonged visual stimulation when investigated with conventional averages across trials. However, recent studies in macaque visual cortex have used single-trial analyses to show that both power and frequency of gamma oscillations exhibit substantial moment-by-moment variation. This has raised the question of whether these apparently random variations might limit the functional role of gamma-band synchronization for neural processing. Here, we studied the moment-by-moment variation in gamma oscillation power and frequency, as well as inter-areal gamma synchronization, by simultaneously recording local field potentials in V1 and V2 of two macaque monkeys. We additionally analyzed electrocorticographic V1 data from a third monkey. Our analyses confirm that gamma-band synchronization is not stationary and sustained but undergoes moment-by-moment variations in power and frequency. However, those variations are neither random and nor a possible obstacle to neural communication. Instead, the gamma power and frequency variations are highly structured, shared between areas and shaped by a microsaccade-related 3-4-Hz theta rhythm. Our findings provide experimental support for the suggestion that cross-frequency coupling might structure and facilitate the information flow between brain regions.

Parametric variation of gamma frequency and power with luminance contrast: A comparative study of human MEG and monkey LFP and spike responses.

Gamma oscillations contribute significantly to the manner in which neural activity is bound into functional assemblies. The mechanisms that underlie the human gamma response, however, are poorly understood. Previous computational models of gamma rely heavily on the results of invasive recordings in animals, and it is difficult to assess whether these models hold in humans. Computational models of gamma predict specific changes in gamma spectral response with increased excitatory drive. Hence, differences and commonalities between spikes, LFPs and MEG in the spectral responses to changes in excitatory drive can lead to a refinement of existing gamma models. We compared gamma spectral responses to varying contrasts in a monkey dataset acquired previously (Roberts et al., 2013) with spectral responses to similar contrast variations in a new human MEG dataset. We found parametric frequency shifts with increasing contrast in human MEG at the single-subject and the single-trial level, analogous to those observed in the monkey. Additionally, we observed parametric modulations of spectral asymmetry, consistent across spikes, LFP and MEG. However, while gamma power scaled linearly with contrast in MEG, it saturated at high contrasts in both the LFP and spiking data. Thus, while gamma frequency changes to varying contrasts were comparable across spikes, LFP and MEG, gamma power changes were not. This indicates that gamma frequency may be a more stable parameter across scales of measurements and species than gamma power. The comparative approach undertaken here represents a fruitful path towards a better understanding of gamma oscillations in the human brain.

Canonical finger-numeral configurations facilitate the processing of Arabic numerals in adults: An Event-Related Potential study.

Various studies claim that early-learned, culture-typical (canonical) finger configurations used to communicate or represent numerosity, have stronger connections to numerical concepts stored in long-term memory than cultural-unfamiliar finger configurations, thereby allowing for faster access to their numerical meaning. The current study investigated whether presentation of canonical finger configurations gesturing numerosities 1-4 or 6-9 would facilitate young adults' behavioral and neural processing of Arabic numerals. Thirty-one adults performed a number comparison task in which they had to decide whether simultaneously presented Arabic numerals and canonical or non-canonical finger configurations showed the same or a different numerosity, while measuring their performance and Event-Related Potentials (ERPs). The results showed faster responses when comparisons involved canonical (versus non-canonical) finger configurations, but only on numerosity-congruent trials where finger configuration and Arabic numeral matched in number identity. Canonical, and small-number finger configurations 1-4 in general (irrespective of their canonicity), also elicited enhanced amplitude of the early right-parietal P2p, and the later centro-parietal P3 on numerosity-congruent trials. We suggest these P2p and P3 findings respectively reflect facilitated numerical access and easier categorization of canonical finger-numeral configurations. The current results provide behavioral and neurophysiological evidence for the embodiment of culture-specific, canonical, finger-numeral configurations, and their link with other number representations in the adult brain, likely emerging from their more frequent use in daily life communication and/or in early childhood during number symbol acquisition.

Frequency-specific transcranial neuromodulation of alpha power alters visuospatial attention performance.

Transcranial alternating current stimulation (tACS) at 10 Hz has been shown to modulate spatial attention. However, the frequency-specificity and the oscillatory changes underlying this tACS effect are still largely unclear. Here, we applied high-definition tACS at individual alpha frequency (IAF), two control frequencies (IAF+/-2Hz) and sham to the left posterior parietal cortex and measured its effects on visuospatial attention performance and offline alpha power (using electroencephalography, EEG). We revealed a behavioural and electrophysiological stimulation effect relative to sham for IAF but not control frequency stimulation conditions: there was a leftward lateralization of alpha power for IAF tACS, which differed from sham for the first out of three minutes following tACS. At a high value of this EEG effect (moderation effect), we observed a leftward attention bias relative to sham. This effect was task-specific, i.e., it could be found in an endogenous attention but not in a detection task. Only in the IAF tACS condition, we also found a correlation between the magnitude of the alpha lateralization and the attentional bias effect. Our results support a functional role of alpha oscillations in visuospatial attention and the potential of tACS to modulate it. The frequency-specificity of the effects suggests that an individualization of the stimulation frequency is necessary in heterogeneous target groups with a large variation in IAF.

Antioxidant treatment ameliorates prefrontal hypomyelination and cognitive deficits in a rat model of schizophrenia.

Cognitive dysfunction in schizophrenia (SZ) is thought to arise from neurodevelopmental abnormalities that include interneuron hypomyelination in the prefrontal cortex (PFC). Here we report that RNA-sequencing of the medial (m)PFC of the APO-SUS rat model with SZ-relevant cognitive inflexibility revealed antioxidant metabolism as the most-enriched differentially expressed pathway. Antioxidant-related gene expression was altered throughout postnatal development and preceded hypomyelination. Furthermore, reduced glutathione levels and increased mitochondria numbers were observed in the mPFC. Strikingly, chronic treatment with the glutathione precursor N-acetylcysteine (NAC) from postnatal days 5-90 restored not only antioxidant-related mRNA expression and mitochondria numbers, but also myelin-related mRNA expression and mPFC-dependent cognitive dysfunction, while blood glutathione levels remained unaffected. The promyelinating effect of NAC was at least partly due to a positive effect on oligodendrocyte lineage progression. Together, our findings highlight that oxidative stress may contribute to cognitive symptoms in the APO-SUS rat model of SZ and encourage antioxidant therapy in early phases of SZ.

Mechanisms of directed attention in the human extrastriate cortex as revealed by functional MRI.

A typical scene contains many different objects, but the capacity of the visual system to process multiple stimuli at a given time is limited. Thus, attentional mechanisms are required to select relevant objects from among the many objects competing for visual processing. Evidence from functional magnetic resonance imaging (MRI) in humans showed that when multiple stimuli are present simultaneously in the visual field, their cortical representations within the object recognition pathway interact in a competitive, suppressive fashion. Directing attention to one of the stimuli counteracts the suppressive influence of nearby stimuli. This mechanism may serve to filter out irrelevant information in cluttered visual scenes.

Increased activity in human visual cortex during directed attention in the absence of visual stimulation.

When subjects direct attention to a particular location in a visual scene, responses in the visual cortex to stimuli presented at that location are enhanced, and the suppressive influences of nearby distractors are reduced. What is the top-down signal that modulates the response to an attended versus an unattended stimulus? Here, we demonstrate increased activity related to attention in the absence of visual stimulation in extrastriate cortex when subjects covertly directed attention to a peripheral location expecting the onset of visual stimuli. Frontal and parietal areas showed a stronger signal increase during this expectation than did visual areas. The increased activity in visual cortex in the absence of visual stimulation may reflect a top-down bias of neural signals in favor of the attended location, which derives from a fronto-parietal network.

Loss of attentional stimulus selection after extrastriate cortical lesions in macaques.

Many objects in natural visual scenes compete for attention. To identify the neural mechanisms necessary for visual attention, we made restricted lesions, affecting different quadrants of the visual field but leaving one quadrant intact, in extrastriate cortical areas V4 and TEO of two monkeys. Monkeys were trained to discriminate the orientation of a target grating surrounded by distracters. As distracter contrast increased, performance deteriorated in quadrants affected by V4 and TEO lesions, but not in the normal quadrant. Performance in affected quadrants was restored by increasing the contrast of the target relative to distracters. Thus, without V4 and TEO, visual attention is 'captured' by strong stimuli, regardless of their behavioral relevance.

Epitope regions on U1 small nuclear RNA recognized by anti-U1RNA-specific autoantibodies.

Autoantibodies specifically directed to U1RNA were found in patients suffering from systemic lupus erythematosus (SLE) overlap syndromes. To obtain more insight in the mechanism responsible for this U1RNA-specific antibody formation and to use the antibodies eventually as a tool to study U1RNA-protein (U1RNP) interactions, the B cell epitopes on U1RNA were mapped. Using in vitro synthesized domains of U1RNA, the main epitope regions were found in stemloops II and IV. Furthermore, 3'-end or 5'-end truncation of both stemloop II and stemloop IV showed that the conformation of the stemloops is critical for antibody recognition. Mutant studies on both stemloops indicated that in the case of stemloop II the stem is the main antigenic region, whereas in stemloop IV, the loop (E-loop) is a main target. The results of this study support the idea that the anti-U1RNA autoantibody could be the result of a process driven by the human U1RNP complex itself (antigen-driven process).

Orientation discrimination in the cat: its cortical locus. I. Areas 17 and 18.

An elementary unit of visual pattern and form perception is thought to be the orientation of edges; this element has been studied extensively by neurophysiologists using oriented line segments or bars. These same stimuli have been used in the present study to measure threshold discriminations in cats before and after cortical lesions of areas 17 and/or 18. Control experiments showed that the discriminations were made by using a single cue, orientation, and that other stimulus parameters, width, length and contrast of the bar, were optimized. The extent of the lesions was evaluated anatomically from cell and fiber stained sections through cortex and thalamus, matched to retinotopic maps of Tusa et al. (Cortical Sensory Organization, Vol. 2, Humana Press, pp. 1-31, '81) and Sanderson (Journal of Comparative Neurology 143:101-118, '71), and physiologically from visual field position of receptive fields of cells recorded in areas neighboring the lesions. Lesions involving area 17 and large parts of area 18 produced a marked deficit in orientation discrimination which included a loss in retention, and after retraining a substantial increase in thresholds for up to 3 years when tested with long bars. There was no recovery of discrimination when the animals were tested with short bars. Lesions which involved area 17 plus small parts of 18, or lesions of areas 18 and 19, produced no retention deficit and resulted in an increase in thresholds only at low contrast and narrow width. These experiments revealed an excellent correlation between lesion locus and size and behavioral deficit. They indicate that the cortical representation of bar orientation used for discrimination is distributed within and across areas 17 and 18. The spread of the distribution depends on other stimulus parameters such as bar width and length. Furthermore the experiments show that neither the most narrowly tuned cells nor the X-cell system is required for fine orientation discrimination of a long bar.

Orientation discrimination in the cat: its cortical locus II. Extrastriate cortical areas.

Luminance-defined edges or bars are among the basic units of visual analysis: a "primitive" component of perception. We have utilized this stimulus in a psychophysical study of bar orientation discrimination in the cat before and after selective lesions in visual cortical areas. The cortices have been divided on the basis of their connectivity into three tiers. Tier I refers to areas 17 and 18, tier II includes areas that receive directly from tier I, and tier III includes those areas that receive directly from tier II. Previous studies (Vandenbussche et al. [1991] J. Comp. Neurol. 305:632-658) have shown that the discrimination of bar orientation depends heavily upon the integrity of areas 17 and 18 (tier I). The present study indicates that several extrastriate areas in tiers II and III contribute to this discrimination task. Our data suggest that the anterior medial lateral suprasylvian, the posterior lateral lateral suprasylvian (tier II), and the anterior lateral lateral suprasylvian (tier III) areas are most likely to contribute to bar orientation discrimination.

Speeding up visual discrimination learning in cats by differential exposure of positive and negative stimuli.

We have developed an adaptive training method which considerably reduces the total time required to train cats to threshold in an orientation discrimination task. During training, the animals are given greater exposure in time to the positive stimulus compared to the negative one. Therefore, this method has been coined the differential exposure method (DEM). The greater exposure to the positive stimulus reduces the number of errors an animal commits during training and thereby enhances speed of learning. Indeed, with the DEM, 34 daily sessions sufficed to train cats to threshold for 2 different reference orientations. Furthermore, the DEM was effective not only for simple stimuli such as real bars but also for complex stimuli such as illusory contours. Finally, the DEM was equally effective for training naive cats which had undergone large visual cortical lesions as it was for normal animals.

Staircase procedure and constant stimuli method in cat psychophysics.

We measured 73.5% correct just noticeable differences (JNDs) in bar orientation with the method of constant stimuli and with a Wetherill and Levitt staircase procedure, using a total of 25 cats. For the same number of trials per threshold assessment, the variability of the threshold remained independent of the testing method used. However, the JNDs measured using the method of constant stimuli were significantly influenced by the range of the orientation differences (ODs) utilized for measuring the JND. This effect was particularly large in incompletely trained cats, but it also was significant in extensively trained subjects. On the other hand, staircase threshold measurements were not affected by the starting OD, independently of how well the animals had been trained. This shows that the staircase procedure is a more efficient instrument with which to measure JNDs in orientation than is the method of constant stimuli. With the staircase procedure, we found that the JNDs measured at oblique reference orientations did not exceed those measured at principal reference orientations (no oblique effect). Two earlier studies from this laboratory using the method of constant stimuli did report an oblique effect. Our data suggest that this oblique effect might stem from a less efficient training at the right oblique reference orientation in these studies, combined with a relatively inefficient testing procedure such as the constant stimuli method.

Illusory contour orientation discrimination in the cat.

We present the first evidence that a non-human species (the cat) is able to discriminate the orientation of illusory contours. Following Vogels and Orban45, we used two types of illusory contours. In one type, the illusory contour was defined by a number of contour-inducing semicircles, of which the endpoints were separated by a gap. In the other pattern, the inducing semicircles were shifted in phase along their diameter and their endpoints were aligned along the contour. Just noticeable differences in orientation were measured (at the 73.5% correct level), using a Wetherill and Levitt49 staircase procedure. Values in the order of 11 degrees were obtained when using the first type of illusory contour. Just noticeable differences with the second type were in the order of 17 degrees. Reducing the salience of the illusory contour, whether by scrambling the contour, or by decreasing the number or the contrast of inducing semicircles, systematically increased discrimination thresholds.

Texture segregation in the cat: a parametric study.

We have investigated how different texture parameters affect texture segregation in the cat, and which strategies cats use to solve the segregation task. Five cats were presented with stimuli consisting of two adjacent panels. One side contained a square area of a particular texture embedded in a different background texture; the other side was filled with only the background texture. The animal's task was to detect at which side the texture difference was presented. Sensitivity for the texture difference was assessed by making one aspect of the texture (in most instances the size of the texture elements) dependent upon performance by means of a staircase procedure. Among the most prominent parametric effects are those of density and element position randomization. In general, segregation was optimal at intermediate densities and deteriorated at larger and smaller densities. Element position randomization caused a slight but systematic decrease in segregation performance. Furthermore, we found texture elements at the border between different textures to be of primary importance for segregation. Which strategy the animals used for solving the segregation task depended upon the presence of random figure/background reversals in subsequent stimulus presentations during training. The animals learned to detect texture differences if these reversals were present, and without reversals, they learned to identify the particular texture in the target square. Interestingly, parameter dependencies of segregation did not depend upon the detection strategy used. We have speculated that the two different strategies used by the cats to solve the segregation tasks are related to different hierarchical levels of texture segregation which can be traced back to different stages of texture processing in human models of segregation performance.

Perceptual filling-in: a parametric study.

We studied perceptual filling-in during maintained peripheral viewing of a uniform gray or red figure presented on a large textured background. Changes in the figure's size, shape, and eccentricity caused variations in the time required for filling-in that could be predicted from the size of its cortical projection within early visual areas. The data suggest that the time which elapsed before the figure was filled-in by its background reflects the time required for figure-ground segregation to fail, rather than a slow spread of the background across the figure. Our findings reveal interactions between surface segregation and filling-in which may be at the basis of normal surface perception.