Adolescents on psychotropic treatment displayed longer corrected QT intervals than unmedicated controls when they rose rapidly from the supine position.

AIM: Psychotropic medication can contribute to arrhythmia and identifying individuals at risk is crucial. This Swedish study compared the corrected QT (QTc) intervals of adolescents on psychotropic medication with unmedicated controls, when supine and after rising rapidly. METHODS: The study was carried out at Östersund County Hospital in March 2022 and February to March 2023. It comprised 16 cases, aged 10-17 years and 28 controls. QTc intervals were measured with electrocardiography and calculated using Bazett's and Fridericia's formulas. Univariate and multiple linear regressions were used to assess differences in QTc intervals between the cases and controls and across sex, age and body mass index. RESULTS: The mean QTc interval when supine, calculated with Bazett's formula, was longer for the adolescents on psychotropic medication than the controls (p = 0.046). The same was true for the mean QTc interval after rising rapidly from the supine position, calculated with both Bazett's formula (p = 0.009) and Fridericia's formula (p = 0.007). Mean QTc intervals varied by sex and age groups. Psychotropic medication prolonged QTc intervals, particularly in girls. CONCLUSION: Longer QTc intervals were found in adolescents on psychotropic medication, particularly after rising rapidly from the supine position.

Disrupted Attention to Other's Eyes is Linked to Symptoms of ADHD in Childhood.

Attention-deficit/hyperactivity disorder (ADHD) is associated with impaired social interaction. Other's eyes are important for understanding the social world. Here, we examined concurrent and longitudinal links between attention to other's eyes and symptoms of ADHD and comorbid externalizing and internalizing symptoms. Eighty-two 8 to 13-year-old children (40% with ADHD) participated. The latency to a first gaze shift to and away from the eye region of human faces, when primed to look at either the eyes or the mouth, was recorded with eye tracking. Parents rated ADHD, externalizing and internalizing symptoms at the time of testing and at 2-year follow-up. The results show that longer looking at the eyes before reorienting was specifically associated with concurrent and future symptoms of inattention, even when accounting for comorbid symptoms. We conclude that the temporal microstructure of attention to other's eyes is altered in children with symptoms of ADHD, which may contribute to social impairments.

Dynamics of retinotopic spatial attention revealed by multifocal MEG.

Visual focal attention is both fast and spatially localized, making it challenging to investigate using human neuroimaging paradigms. Here, we used a new multivariate multifocal mapping method with magnetoencephalography (MEG) to study how focal attention in visual space changes stimulus-evoked responses across the visual field. The observer's task was to detect a color change in the target location, or at the central fixation. Simultaneously, 24 regions in visual space were stimulated in parallel using an orthogonal, multifocal mapping stimulus sequence. First, we used univariate analysis to estimate stimulus-evoked responses in each channel. Then we applied multivariate pattern analysis to look for attentional effects on the responses. We found that attention to a target location causes two spatially and temporally separate effects. Initially, attentional modulation is brief, observed at around 60-130 ms post stimulus, and modulates responses not only at the target location but also in adjacent regions. A later modulation was observed from around 200 ms, which was specific to the location of the attentional target. The results support the idea that focal attention employs several processing stages and suggest that early attentional modulation is less spatially specific than late.

MutT homologue 1 (MTH1) catalyzes the hydrolysis of mutagenic O6-methyl-dGTP.

Nucleotides in the free pool are more susceptible to nonenzymatic methylation than those protected in the DNA double helix. Methylated nucleotides like O6-methyl-dGTP can be mutagenic and toxic if incorporated into DNA. Removal of methylated nucleotides from the nucleotide pool may therefore be important to maintain genome integrity. We show that MutT homologue 1 (MTH1) efficiently catalyzes the hydrolysis of O6-methyl-dGTP with a catalytic efficiency similar to that for 8-oxo-dGTP. O6-methyl-dGTP activity is exclusive to MTH1 among human NUDIX proteins and conserved through evolution but not found in bacterial MutT. We present a high resolution crystal structure of human and zebrafish MTH1 in complex with O6-methyl-dGMP. By microinjecting fertilized zebrafish eggs with O6-methyl-dGTP and inhibiting MTH1 we demonstrate that survival is dependent on active MTH1 in vivo. O6-methyl-dG levels are higher in DNA extracted from zebrafish embryos microinjected with O6-methyl-dGTP and inhibition of O6-methylguanine-DNA methyl transferase (MGMT) increases the toxicity of O6-methyl-dGTP demonstrating that O6-methyl-dGTP is incorporated into DNA. MTH1 deficiency sensitizes human cells to the alkylating agent Temozolomide, a sensitization that is more pronounced upon MGMT inhibition. These results expand the cellular MTH1 function and suggests MTH1 also is important for removal of methylated nucleotides from the nucleotide pool.

Perception and Processing of Faces in the Human Brain Is Tuned to Typical Feature Locations.

UNLABELLED: Faces are salient social stimuli whose features attract a stereotypical pattern of fixations. The implications of this gaze behavior for perception and brain activity are largely unknown. Here, we characterize and quantify a retinotopic bias implied by typical gaze behavior toward faces, which leads to eyes and mouth appearing most often in the upper and lower visual field, respectively. We found that the adult human visual system is tuned to these contingencies. In two recognition experiments, recognition performance for isolated face parts was better when they were presented at typical, rather than reversed, visual field locations. The recognition cost of reversed locations was equal to ∼60% of that for whole face inversion in the same sample. Similarly, an fMRI experiment showed that patterns of activity evoked by eye and mouth stimuli in the right inferior occipital gyrus could be separated with significantly higher accuracy when these features were presented at typical, rather than reversed, visual field locations. Our findings demonstrate that human face perception is determined not only by the local position of features within a face context, but by whether features appear at the typical retinotopic location given normal gaze behavior. Such location sensitivity may reflect fine-tuning of category-specific visual processing to retinal input statistics. Our findings further suggest that retinotopic heterogeneity might play a role for face inversion effects and for the understanding of conditions affecting gaze behavior toward faces, such as autism spectrum disorders and congenital prosopagnosia. SIGNIFICANCE STATEMENT: Faces attract our attention and trigger stereotypical patterns of visual fixations, concentrating on inner features, like eyes and mouth. Here we show that the visual system represents face features better when they are shown at retinal positions where they typically fall during natural vision. When facial features were shown at typical (rather than reversed) visual field locations, they were discriminated better by humans and could be decoded with higher accuracy from brain activity patterns in the right occipital face area. This suggests that brain representations of face features do not cover the visual field uniformly. It may help us understand the well-known face-inversion effect and conditions affecting gaze behavior toward faces, such as prosopagnosia and autism spectrum disorders.

Glycans Confer Specificity to the Recognition of Ganglioside Receptors by Botulinum Neurotoxin A.

The highly poisonous botulinum neurotoxins, produced by the bacterium Clostridium botulinum, act on their hosts by a high-affinity association to two receptors on neuronal cell surfaces as the first step of invasion. The glycan motifs of gangliosides serve as initial coreceptors for these protein complexes, whereby a membrane protein receptor is bound. Herein we set out to characterize the carbohydrate minimal binding epitope of the botulinum neurotoxin serotype A. By means of ligand-based NMR spectroscopy, X-ray crystallography, computer simulations, and isothermal titration calorimetry, a screening of ganglioside analogues together with a detailed characterization of various carbohydrate ligand complexes with the toxin were accomplished. We show that the representation of the glycan epitope to the protein affects the details of binding. Notably, both branches of the oligosaccharide GD1a can associate to botulinum neurotoxin serotype A when expressed as individual trisaccharides. It is, however, the terminal branch of GD1a as well as this trisaccharide motif alone, corresponding to the sialyl-Thomsen-Friedenreich antigen, that represents the active ligand epitope, and these compounds bind to the neurotoxin with a high degree of predisposition but with low affinities. This finding does not correlate with the oligosaccharide moieties having a strong contribution to the total affinity, which was expected to be the case. We here propose that the glycan part of the ganglioside receptors mainly provides abundance and specificity, whereas the interaction with the membrane itself and protein receptor brings about the strong total binding of the toxin to the neuronal membrane.

Radial Frequency Analysis of Contour Shapes in the Visual Cortex.

Cumulative psychophysical evidence suggests that the shape of closed contours is analysed by means of their radial frequency components (RFC). However, neurophysiological evidence for RFC-based representations is still missing. We investigated the representation of radial frequency in the human visual cortex with functional magnetic resonance imaging. We parametrically varied the radial frequency, amplitude and local curvature of contour shapes. The stimuli evoked clear responses across visual areas in the univariate analysis, but the response magnitude did not depend on radial frequency or local curvature. Searchlight-based, multivariate representational similarity analysis revealed RFC specific response patterns in areas V2d, V3d, V3AB, and IPS0. Interestingly, RFC-specific representations were not found in hV4 or LO, traditionally associated with visual shape analysis. The modulation amplitude of the shapes did not affect the responses in any visual area. Local curvature, SF-spectrum and contrast energy related representations were found across visual areas but without similar specificity for visual area that was found for RFC. The results suggest that the radial frequency of a closed contour is one of the cortical shape analysis dimensions, represented in the early and mid-level visual areas.

Contextual and social cues may dominate natural visual search.

A framework where only the size of the functional visual field of fixations can vary is hardly able to explain natural visual-search behavior. In real-world search tasks, context guides eye movements, and task-irrelevant social stimuli may capture the gaze.

From evoked potentials to cortical currents: Resolving V1 and V2 components using retinotopy constrained source estimation without fMRI.

Despite evoked potentials' (EP) ubiquity in research and clinical medicine, insights are limited to gross brain dynamics as it remains challenging to map surface potentials to their sources in specific cortical regions. Multiple sources cancellation due to cortical folding and cross-talk obscures close sources, e.g. between visual areas V1 and V2. Recently retinotopic functional magnetic resonance imaging (fMRI) responses were used to constrain source locations to assist separating close sources and to determine cortical current generators. However, an fMRI is largely infeasible for routine EP investigation. We developed a novel method that replaces the fMRI derived retinotopic layout (RL) by an approach where the retinotopy and current estimates are generated from EEG or MEG signals and a standard clinical T1-weighted anatomical MRI. Using the EEG-RL, sources were localized to within 2 mm of the fMRI-RL constrained localized sources. The EEG-RL also produced V1 and V2 current waveforms that closely matched the fMRI-RL's (n = 2) r(1,198) = 0.99, P < 0.0001. Applying the method to subjects without fMRI (n = 4) demonstrates it generates waveforms that agree closely with the literature. Our advance allows investigators with their current EEG or MEG systems to create a library of brain models tuned to individual subjects' cortical folding in retinotopic maps, and should be applicable to auditory and somatosensory maps. The novel method developed expands EP's ability to study specific brain areas, revitalizing this well-worn technique. Hum Brain Mapp 37:1696-1709, 2016. © 2016 Wiley Periodicals, Inc.

Visual representations are dominated by intrinsic fluctuations correlated between areas.

Intrinsic cortical dynamics are thought to underlie trial-to-trial variability of visually evoked responses in animal models. Understanding their function in the context of sensory processing and representation is a major current challenge. Here we report that intrinsic cortical dynamics strongly affect the representational geometry of a brain region, as reflected in response-pattern dissimilarities, and exaggerate the similarity of representations between brain regions. We characterized the representations in several human visual areas by representational dissimilarity matrices (RDMs) constructed from fMRI response-patterns for natural image stimuli. The RDMs of different visual areas were highly similar when the response-patterns were estimated on the basis of the same trials (sharing intrinsic cortical dynamics), and quite distinct when patterns were estimated on the basis of separate trials (sharing only the stimulus-driven component). We show that the greater similarity of the representational geometries can be explained by coherent fluctuations of regional-mean activation within visual cortex, reflecting intrinsic dynamics. Using separate trials to study stimulus-driven representations revealed clearer distinctions between the representational geometries: a Gabor wavelet pyramid model explained representational geometry in visual areas V1-3 and a categorical animate-inanimate model in the object-responsive lateral occipital cortex.

Structure and activity of botulinum neurotoxin X.

Botulinum neurotoxins (BoNTs) are the most potent toxins known and are used to treat an increasing number of medical disorders. All BoNTs are naturally co-expressed with a protective partner protein (NTNH) with which they form a 300 kDa complex, to resist acidic and proteolytic attack from the digestive tract. We have previously identified a new botulinum neurotoxin serotype, BoNT/X, that has unique and therapeutically attractive properties. We present the cryo-EM structure of the BoNT/X-NTNH/X complex at 3.1 Å resolution. Unexpectedly, the BoNT/X complex is stable and protease resistant at both neutral and acidic pH and disassembles only in alkaline conditions. Using the stabilizing effect of NTNH, we isolated BoNT/X and showed that it has very low potency both in vitro and in vivo . Given the high catalytic activity and translocation efficacy of BoNT/X, low activity of the full toxin is likely due to the receptor-binding domain, which presents weak ganglioside binding and exposed hydrophobic surfaces.

Unconscious and conscious processing of color rely on activity in early visual cortex: a TMS study.

Chromatic information is processed by the visual system both at an unconscious level and at a level that results in conscious perception of color. It remains unclear whether both conscious and unconscious processing of chromatic information depend on activity in the early visual cortex or whether unconscious chromatic processing can also rely on other neural mechanisms. In this study, the contribution of early visual cortex activity to conscious and unconscious chromatic processing was studied using single-pulse TMS in three time windows 40-100 msec after stimulus onset in three conditions: conscious color recognition, forced-choice discrimination of consciously invisible color, and unconscious color priming. We found that conscious perception and both measures of unconscious processing of chromatic information depended on activity in early visual cortex 70-100 msec after stimulus presentation. Unconscious forced-choice discrimination was above chance only when participants reported perceiving some stimulus features (but not color).

Unconscious response priming by shape depends on geniculostriate visual projection.

It has been suggested that unconscious visual processing of some stimulus features might occur without the contribution of early visual cortex (V1/V2). In the present study, the causal role of V1/V2 in unconscious processing of simple shapes in intact human brain was studied by applying transcranial magnetic stimulation (TMS) on early visual cortex or lateral occipital cortex (LO) while observers performed a metacontrast-masked response priming task with arrow figures as visual stimuli. Magnetic stimulation of V1/V2 impaired masked priming 30-90 ms after the onset of the prime. Stimulation of LO reduced the magnitude of masked priming at 90-120 ms, but this effect occurred only in the early parts of the priming experiment. A control task measuring the visibility of masked primes indicated that the orientation of masked primes could not be consciously discriminated and that TMS did not influence the conscious visibility of the primes indirectly by reducing the effectiveness of the mask in the critical time windows. We conclude that feedforward sweep of processing from V1/V2 (30-90 ms) to LO (90 ms and above) is necessary for unconscious priming of shape, whereas conscious perception requires also the contribution of recurrent (feedback) processing.

Eye movement behavior in a real-world virtual reality task reveals ADHD in children.

Eye movements and other rich data obtained in virtual reality (VR) environments resembling situations where symptoms are manifested could help in the objective detection of various symptoms in clinical conditions. In the present study, 37 children with attention deficit hyperactivity disorder and 36 typically developing controls (9-13 y.o) played a lifelike prospective memory game using head-mounted display with inbuilt 90 Hz eye tracker. Eye movement patterns had prominent group differences, but they were dispersed across the full performance time rather than associated with specific events or stimulus features. A support vector machine classifier trained on eye movement data showed excellent discrimination ability with 0.92 area under curve, which was significantly higher than for task performance measures or for eye movements obtained in a visual search task. We demonstrated that a naturalistic VR task combined with eye tracking allows accurate prediction of attention deficits, paving the way for precision diagnostics.

Representation of cross-frequency spatial phase relationships in human visual cortex.

An image patch can be locally decomposed into sinusoidal waves of different orientations, spatial frequencies, amplitudes, and phases. The local phase information is essential for perception, because important visual features like edges emerge at locations of maximal local phase coherence. Detection of phase coherence requires integration of spatial frequency information across multiple spatial scales. Models of early visual processing suggest that the visual system should implement phase-sensitive pooling of spatial frequency information in the identification of broadband edges. We used functional magnetic resonance imaging (fMRI) adaptation to look for phase-sensitive neural responses in the human visual cortex. We found sensitivity to the phase difference between spatial frequency components in all studied visual areas, including the primary visual cortex (V1). Control experiments demonstrated that these results were not explained by differences in contrast or position. Next, we compared fMRI responses for broadband compound grating stimuli with congruent and random phase structures. All studied visual areas showed stronger responses for the stimuli with congruent phase structure. In addition, selectivity to phase congruency increased from V1 to higher-level visual areas along both the ventral and dorsal streams. We conclude that human V1 already shows phase-sensitive pooling of spatial frequencies, but only higher-level visual areas might be capable of pooling spatial frequency information across spatial scales typical for broadband natural images.

Neuronavigated TMS of early visual cortex eliminates unconscious processing of chromatic stimuli.

Some neurological patients with primary visual cortex (V1) lesions can guide their behavior based on stimuli presented to their blind visual field. One example of this phenomenon is the ability to discriminate colors in the absence of awareness. These so-called patients with blindsight must have a neural pathway that bypasses V1, explaining their ability to unconsciously process stimuli. The pathways that have been most often hypothesized to be the cause of blindsight connect lateral geniculate nucleus (LGN) or superior colliculus (SC) to extrastriate cortex, most likely V5, and parietal areas. To test if similar pathways function in neurologically healthy individuals or if unconscious processing depends on early visual cortex, we disturbed the visibility of a chromatic stimulus with metacontrast masking (Experiment 1) or neuronavigated transcranial magnetic stimulation (TMS) of early visual cortex, exact target being retinotopically mapped V1 (Experiment 2). We measured unconscious processing using the redundant target effect (RTE), which is the speeding up of reaction times in response to dual stimuli compared with one stimulus, when the task is to respond to any number of stimuli. An unconscious chromatic RTE was found when the visibility of the redundant chromatic stimulus was suppressed with a visual mask. When TMS was targeted to the correct retinotopic location of V1, and conscious perception of the redundant chromatic stimulus suppressed, the RTE was eliminated. Whether the elimination of unconscious RTE during TMS was exclusively due to disruption of V1 activity, or whether it was due to the possible interference with processing in V2 or even V3, is discussed. Based on our results and converging evidence from previous studies, we conclude that unconscious processing of chromatic information depends on the early visual cortex, in neurologically healthy participants.

Rapid Invariant Encoding of Scene Layout in Human OPA.

Successful visual navigation requires a sense of the geometry of the local environment. How do our brains extract this information from retinal images? Here we visually presented scenes with all possible combinations of five scene-bounding elements (left, right, and back walls; ceiling; floor) to human subjects during functional magnetic resonance imaging (fMRI) and magnetoencephalography (MEG). The fMRI response patterns in the scene-responsive occipital place area (OPA) reflected scene layout with invariance to changes in surface texture. This result contrasted sharply with the primary visual cortex (V1), which reflected low-level image features of the stimuli, and the parahippocampal place area (PPA), which showed better texture than layout decoding. MEG indicated that the texture-invariant scene layout representation is computed from visual input within ∼100 ms, suggesting a rapid computational mechanism. Taken together, these results suggest that the cortical representation underlying our instant sense of the environmental geometry is located in the OPA.

Quantitative multifocal fMRI shows active suppression in human V1.

Multifocal functional magnetic resonance imaging has recently been introduced as an alternative method for retinotopic mapping, and it enables effective functional localization of multiple regions-of-interest in the visual cortex. In this study we characterized interactions in V1 with spatially and temporally identical stimuli presented alone, or as a part of a nine-region multifocal stimulus. We compared stimuli at different contrasts, collinear and orthogonal orientations and spatial frequencies one octave apart. Results show clear attenuation of BOLD signal from the central region in the multifocal condition. The observed modulation in BOLD signal could be produced either by neural suppression resulting from stimulation of adjacent regions of visual field, or alternatively by hemodynamic saturation or stealing effects in V1. However, we find that attenuation of the central response persists through a range of contrasts, and that its strength varies with relative orientation and spatial frequency of the central and surrounding stimulus regions, indicating active suppression mechanisms of neural origin. Our results also demonstrate that the extent of the signal spreading is commensurate with the extent of the horizontal connections in primate V1.

Decreased behavioral activation following caffeine, amphetamine and darkness in A3 adenosine receptor knock-out mice.

We have examined behavioral consequences of genetic deletion of the adenosine A3 receptors in mice. The open field behavior of A3 adenosine receptor knock-out (A3R KO) mice was investigated both under basal conditions and after stimulation with psychostimulants. Adolescent (21 day-old) and adult A3R KO males showed an increase in overall motor activity compared to wild type (WT) males, but the type of activity differed. The motor activity, especially rearing, was also higher in A3R KO compared to WT adult females. A3 receptors have a low affinity for caffeine and it was therefore surprising to find a decreased response to stimulation with either caffeine or amphetamine in A3R KO as compared to WT mice in males as well as females. Telemetry recordings also showed a significantly smaller increase in activity upon darkness in A3R KO. There were no compensatory changes in the mRNA expression of any other adenosine receptor subtypes (A1, A2A and A2B) or any changes in dopamine D1 and D2 receptor binding in A3R KO brains. Challenge with the developmental toxicant methylmercury (1 microM in drinking water) during pregnancy and lactation did not cause any behavioral alterations in adolescent and adult WT female offspring. In contrast, the A3R KO female offspring displayed changes in locomotion indicating an interaction between perinatal methylmercury and adenosine A3 receptors. In conclusion, despite low expression of A3 receptors in wild type mouse brain we observed several behavioral consequences of genetic elimination of the adenosine A3 receptors. The possibility that this is due to a role of A3 receptors in development is discussed.

Spatial frequency tuning in human retinotopic visual areas.

Human medial occipital cortex comprises multiple visual areas, each with a distinct retinotopic representation of visual environment. We measured spatial frequency (SF) tuning curves with functional magnetic resonance imaging (fMRI) and found consistent differences between these areas. Areas V1, V2, VP, V3, V4v, and V3A were all band-pass tuned, with progressively lower SF optima in V1, V2, and V3A. In VP and V3, the SF optima were similar to optima in V2, whereas V4v showed more individual variation and scattered SF representations on the cortical surface. Area V5+ showed low-pass SF tuning. In each area, the SF optimum declined with increasing eccentricity. After accounting for the cortical magnification, the cortical extent of the optimal spatial wavelengths was approximately constant across eccentricity in V1, which suggests an anatomical constraint for the optimal SF, and this extent is actually comparable to the extent of horizontal connections within primate V1. The optimal spatial wavelengths in the visual field are also of similar extent to the spatial summation fields of macaque V1. The progressive decline in the SF tuning from V1 to V2 and V3A is compatible with the view that these areas represent visual information at different spatial scales.