Evaluating synthetic neuroimaging data augmentation for automatic brain tumour segmentation with a deep fully-convolutional network.

Gliomas observed in medical images require expert neuro-radiologist evaluation for treatment planning and monitoring, motivating development of intelligent systems capable of automating aspects of tumour evaluation. Deep learning models for automatic image segmentation rely on the amount and quality of training data. In this study we developed a neuroimaging synthesis technique to augment data for training fully-convolutional networks (U-nets) to perform automatic glioma segmentation. We used StyleGAN2-ada to simultaneously generate fluid-attenuated inversion recovery (FLAIR) magnetic resonance images and corresponding glioma segmentation masks. Synthetic data were successively added to real training data (n = 2751) in fourteen rounds of 1000 and used to train U-nets that were evaluated on held-out validation (n = 590) and test sets (n = 588). U-nets were trained with and without geometric augmentation (translation, zoom and shear), and Dice coefficients were computed to evaluate segmentation performance. We also monitored the number of training iterations before stopping, total training time, and time per iteration to evaluate computational costs associated with training each U-net. Synthetic data augmentation yielded marginal improvements in Dice coefficients (validation set +0.0409, test set +0.0355), whereas geometric augmentation improved generalization (standard deviation between training, validation and test set performances of 0.01 with, and 0.04 without geometric augmentation). Based on the modest performance gains for automatic glioma segmentation we find it hard to justify the computational expense of developing a synthetic image generation pipeline. Future work may seek to optimize the efficiency of synthetic data generation for augmentation of neuroimaging data.

Blind source separation of event-related potentials using a recurrent neural network.

Event-related potentials (ERPs) are a superposition of electric potential differences generated by neurophysiological activity associated with psychophysical events. Spatiotemporal dissociation of these signal sources can supplement conventional ERP analysis and improve source localization. However, results from established source separation methods applied to ERPs can be challenging to interpret. Hence, we have developed a recurrent neural network (RNN) method for blind source separation. The RNN transforms input step pulse signals representing events into corresponding ERP difference waveforms. Source waveforms are obtained from penultimate layer units and scalp maps are obtained from feed-forward output layer weights that project these source waveforms onto EEG electrode amplitudes. An interpretable, sparse source representation is achieved by incorporating L1 regularization of signals obtained from the penultimate layer of the network during training. This RNN method was applied to four ERP difference waveforms (MMN, N170, N400, P3) from the open-access ERP CORE database, and independent component analysis (ICA) was applied to the same data for comparison. The RNN decomposed these ERPs into eleven spatially and temporally separate sources that were less noisy, tended to be more ERP-specific, and were less similar to each other than ICA-derived sources. The RNN sources also had less ambiguity between source waveform amplitude, scalp potential polarity, and equivalent current dipole orientation than ICA sources. In conclusion, the proposed RNN blind source separation method can be effectively applied to grand-average ERP difference waves and holds promise for further development as a computational model of event-related neural signals.

Conceptual structure of emotions.

Theories of semantic organization have historically prioritized investigation of concrete concepts pertaining to inanimate objects and natural kinds. As a result, accounts of the conceptual representation of emotions have almost exclusively focused on their juxtaposition with concrete concepts. The present study aims to fill this gap by deriving a large set of normative feature data for emotion concepts and assessing similarities and differences between the featural representation of emotion, nonemotion abstract, and concrete concepts. We hypothesized that differences between the experience of emotions (e.g., happiness and sadness) and the experience of other abstract concepts (e.g., equality and tyranny), specifically regarding the relative importance of interoceptive states, might drive distinctions in the dimensions along which emotion concepts are represented. We also predicted, based on constructionist views of emotion, that emotion concepts might demonstrate more variability in their representation than concrete and other abstract concepts. Participants listed features which we coded into discrete categories and contrasted the feature distributions across conceptual types. Analyses revealed statistically significant differences in the distribution of features among the category types by condition. We also examined variability in the features generated, finding that, contrary to expectation, emotion concepts were associated with less variability. Our results reflect subtle differences between the structure of emotion concepts and the structure of, not only concrete concepts, but also other abstract concepts. We interpret these findings in the context of our sample, which was restricted to native English speakers, and discuss the importance of validating these findings across speakers of different languages. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Localized estimation of electromagnetic sources underlying event-related fields using recurrent neural networks.

Objective. To use a recurrent neural network (RNN) to reconstruct neural activity responsible for generating noninvasively measured electromagnetic signals.Approach. Output weights of an RNN were fixed as the lead field matrix from volumetric source space computed using the boundary element method with co-registered structural magnetic resonance images and magnetoencephalography (MEG). Initially, the network was trained to minimise mean-squared-error loss between its outputs and MEG signals, causing activations in the penultimate layer to converge towards putative neural source activations. Subsequently, L1 regularisation was applied to the final hidden layer, and the model was fine-tuned, causing it to favour more focused activations. Estimated source signals were then obtained from the outputs of the last hidden layer. We developed and validated this approach with simulations before applying it to real MEG data, comparing performance with beamformers, minimum-norm estimate, and mixed-norm estimate source reconstruction methods.Main results. The proposed RNN method had higher output signal-to-noise ratios and comparable correlation and error between estimated and simulated sources. Reconstructed MEG signals were also equal or superior to the other methods regarding their similarity to ground-truth. When applied to MEG data recorded during an auditory roving oddball experiment, source signals estimated with the RNN were generally biophysically plausible and consistent with expectations from the literature.Significance. This work builds on recent developments of RNNs for modelling event-related neural responses by incorporating biophysical constraints from the forward model, thus taking a significant step towards greater biological realism and introducing the possibility of exploring how input manipulations may influence localised neural activity.

Integrity of input verbal short-term memory ability predicts naming accuracy in aphasia.

Background: Contemporary models of aphasia predominantly attribute lexical retrieval deficits to impaired access and/or maintenance of semantic, lexical, and phonological representations of words. A central hypothesis of language-emergent models of verbal short-term memory (STM) is that temporary storage and maintenance of verbal information arises from activation of linguistic representations in long-term memory. This close relationship between short-term retention and linguistic representations has prompted accounts of aphasia that include impairments to both these components. Aims: We investigated associations between measures of input semantic and phonological verbal STM and corresponding output processing measures. We hypothesised that both input and output functions of verbal STM rely on a common substrate (i.e., temporary activation and maintenance of long-term linguistic representations). Methods & Procedure: Twenty adults with aphasia completed a series of semantic and phonological probe spans. Results were compared with naming performance in immediate and delayed conditions. The data were analysed using correlations, principal components analysis and linear regressions. Results & Discussion: Input semantic and phonological verbal STM abilities were predictive of naming accuracy. Greater input semantic and phonological STM spans were associated with fewer semantic and phonological naming errors. Latent factors identified by principal components analysis of probe span data were consistent with a two-step interactive model of word retrieval. Probe spans measuring access to semantic and initial consonant-vowel representations aligned with lexical-semantic abilities (lexical-semantic factor). Probe spans assessing access to the rhyme component of a word measured lexical-phonological abilities (lexical-phonological factor). The principal components analysis indicated that stronger lexical-semantic abilities were associated with fewer semantic and nonword errors, and stronger lexical phonological abilities were associated with fewer formal and unrelated errors. In addition, our results were consistent with models that postulate serial access to phonology, proceeding from initial to final phonemes. The span measuring access to initial consonant-vowel was associated with lexical selection, while the span measuring access to rhyme information was associated with phonological selection. Conclusion: Performance on input semantic and phonological tasks predicts accuracy of picture naming performance and types of errors made by people with aphasia. These results indicate overlap in input and output semantic and phonological processing, which must be accounted for in models of lexical processing. These findings also have implications for approaches to diagnosis and treatments for lexical comprehension and production that capitalise on the overlap of input and output processing.

Bigram semantic distance as an index of continuous semantic flow in natural language: Theory, tools, and applications.

Much of our understanding of word meaning has been informed through studies of single words. High-dimensional semantic space models have recently proven instrumental in elucidating connections between words. Here we show how bigram semantic distance can yield novel insights into conceptual cohesion and topic flow when computed over continuous language samples. For example, "Cats drink milk" is comprised of an ordered vector of bigrams (cat-drink, drink-milk). Each of these bigrams has a unique semantic distance. These distances in turn may provide a metric of dispersion or the flow of concepts as language unfolds. We offer an R-package ("semdistflow") that transforms any user-specified language transcript into a vector of ordered bigrams, appending two metrics of semantic distance to each pair. We validated these distance metrics on a continuous stream of simulated verbal fluency data assigning predicted switch markers between alternating semantic clusters (animals, musical instruments, fruit). We then generated bigram distance norms on a large sample of text and demonstrated applications of the technique to a classic work of short fiction, To Build a Fire (London, 1908). In one application, we showed that bigrams spanning sentence boundaries are punctuated by jumps in the semantic distance. We discuss the promise of this technique for characterizing semantic processing in real-world narratives and for bridging findings at the single word level with macroscale discourse analyses. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Neural correlates of face perception modeled with a convolutional recurrent neural network.

Objective.Event-related potential (ERP) sensitivity to faces is predominantly characterized by an N170 peak that has greater amplitude and shorter latency when elicited by human faces than images of other objects. We aimed to develop a computational model of visual ERP generation to study this phenomenon which consisted of a three-dimensional convolutional neural network (CNN) connected to a recurrent neural network (RNN).Approach.The CNN provided image representation learning, complimenting sequence learning of the RNN for modeling visually-evoked potentials. We used open-access data from ERP Compendium of Open Resources and Experiments (40 subjects) to develop the model, generated synthetic images for simulating experiments with a generative adversarial network, then collected additional data (16 subjects) to validate predictions of these simulations. For modeling, visual stimuli presented during ERP experiments were represented as sequences of images (time x pixels). These were provided as inputs to the model. By filtering and pooling over spatial dimensions, the CNN transformed these inputs into sequences of vectors that were passed to the RNN. The ERP waveforms evoked by visual stimuli were provided to the RNN as labels for supervised learning. The whole model was trained end-to-end using data from the open-access dataset to reproduce ERP waveforms evoked by visual events.Main results.Cross-validation model outputs strongly correlated with open-access (r= 0.98) and validation study data (r= 0.78). Open-access and validation study data correlated similarly (r= 0.81). Some aspects of model behavior were consistent with neural recordings while others were not, suggesting promising albeit limited capacity for modeling the neurophysiology of face-sensitive ERP generation.Significance.The approach developed in this work is potentially of significant value for visual neuroscience research, where it may be adapted for multiple contexts to study computational relationships between visual stimuli and evoked neural activity.

Give me a break! Unavoidable fatigue effects in cognitive pupillometry.

Pupillometry has a rich history in the study of perception and cognition. One perennial challenge is that the magnitude of the task-evoked pupil response diminishes over the course of an experiment, a phenomenon we refer to as a fatigue effect. Reducing fatigue effects may improve sensitivity to task effects and reduce the likelihood of confounds due to systematic physiological changes over time. In this paper, we investigated the degree to which fatigue effects could be ameliorated by experimenter intervention. In Experiment 1, we assigned participants to one of three groups-no breaks, kinetic breaks (playing with toys, but no social interaction), or chatting with a research assistant-and compared the pupil response across conditions. In Experiment 2, we additionally tested the effect of researcher observation. Only breaks including social interaction significantly reduced the fatigue of the pupil response across trials. However, in all conditions we found robust evidence for fatigue effects: that is, regardless of protocol, the task-evoked pupil response was substantially diminished (at least 60%) over the duration of the experiment. We account for the variance of fatigue effects in our pupillometry data using multiple common statistical modeling approaches (e.g., linear mixed-effects models of peak, mean, and baseline pupil diameters, as well as growth curve models of time-course data). We conclude that pupil attenuation is a predictable phenomenon that should be accommodated in our experimental designs and statistical models.

SymCog: An open-source toolkit for assessing human symbolic cognition.

Symbol systems have a profound influence on human behavior, spanning countless modalities such as natural language, clothing styles, monetary systems, and gestural conventions (e.g., handshaking). Selective impairments in understanding and manipulating symbols are collectively known as asymbolia. Here we address open questions about the nature of asymbolia in the context of both historical and contemporary approaches to human symbolic cognition. We describe a tripartite perspective on symbolic cognition premised upon (1) mental representation of a concept, (2) a stored pool of symbols segregated from their respective referents, and (3) fast and accurate mapping between concepts and symbols. We present an open-source toolkit for assessing symbolic knowledge premised upon matching animated video depictions of abstract concepts to their corresponding verbal and nonverbal symbols. Animations include simple geometric shapes (e.g., filled circles, squares) moving in semantically meaningful ways. For example, a rectangle bending under the implied weight of a large square denotes "heaviness." We report normative data for matching words and images to these target animations. In a second norming study, participants rated target animations across a range of semantic dimensions (e.g., valence, dominance). In a third study, we normed a set of concepts familiar to American English speakers but lacking verbal labels (e.g., the feeling of a Sunday evening). We describe how these tools may be used to assess human symbolic processing and identify asymbolic deficits across the span of human development.

A Guided Tutorial on Modelling Human Event-Related Potentials with Recurrent Neural Networks.

In cognitive neuroscience research, computational models of event-related potentials (ERP) can provide a means of developing explanatory hypotheses for the observed waveforms. However, researchers trained in cognitive neurosciences may face technical challenges in implementing these models. This paper provides a tutorial on developing recurrent neural network (RNN) models of ERP waveforms in order to facilitate broader use of computational models in ERP research. To exemplify the RNN model usage, the P3 component evoked by target and non-target visual events, measured at channel Pz, is examined. Input representations of experimental events and corresponding ERP labels are used to optimize the RNN in a supervised learning paradigm. Linking one input representation with multiple ERP waveform labels, then optimizing the RNN to minimize mean-squared-error loss, causes the RNN output to approximate the grand-average ERP waveform. Behavior of the RNN can then be evaluated as a model of the computational principles underlying ERP generation. Aside from fitting such a model, the current tutorial will also demonstrate how to classify hidden units of the RNN by their temporal responses and characterize them using principal component analysis. Statistical hypothesis testing can also be applied to these data. This paper focuses on presenting the modelling approach and subsequent analysis of model outputs in a how-to format, using publicly available data and shared code. While relatively less emphasis is placed on specific interpretations of P3 response generation, the results initiate some interesting discussion points.

Recurrent Neural Network Model of Human Event-related Potentials in Response to Intensity Oddball Stimulation.

The mismatch negativity (MMN) component of the human event-related potential (ERP) is frequently interpreted as a sensory prediction-error signal. However, there is ambiguity concerning the neurophysiology underlying hypothetical prediction and prediction-error signalling components, and whether these can be dissociated from overlapping obligatory components of the ERP that are sensitive to physical properties of sounds. In the present study, a hierarchical recurrent neural network (RNN) was fitted to ERP data from 38 subjects. After training the model to reproduce ERP waveforms evoked by 80 dB standard and 70 dB deviant stimuli, it was used to simulate a response to 90 dB deviant stimuli. Internal states of the RNN effectively combined to generate synthetic ERPs, where individual hidden units are loosely analogous to population-level sources. Model behaviour was characterised using principal component analysis of stimulus condition, layer, and individual unit responses. Hidden units were categorised according to their temporal response fields, and statistically significant differences among stimulus conditions were observed for amplitudes of units peaking in the 0-75 ms (P50), 75-125 ms (N1), and 250-400 ms (N3) latency ranges, surprisingly not including the measurement window of MMN. The model demonstrated opposite polarity changes in MMN amplitude produced by falling (70 dB) and rising (90 dB) intensity deviant stimuli, consistent with loudness dependence of sensory ERP components. This modelling study suggests that loudness dependence is a principal driver of intensity MMN, and future studies ought to clarify the distinction between loudness dependence, adaptation and prediction-error signalling.

Modelling mouse auditory response dynamics along a continuum of consciousness using a deep recurrent neural network.

Objective.Understanding neurophysiological changes that accompany transitions between anaesthetized and conscious states is a key objective of anesthesiology and consciousness science. This study aimed to characterize the dynamics of auditory-evoked potential morphology in mice along a continuum of consciousness.Approach.Epidural field potentials were recorded from above the primary auditory cortices of two groups of laboratory mice: urethane-anaesthetized (A,n= 14) and conscious (C,n= 17). Both groups received auditory stimulation in the form of a repeated pure-tone stimulus, before and after receiving 10 mg kg-1i.p. ketamine (AK and CK). Evoked responses were then ordered by ascending sample entropy into AK, A, CK, and C, considered to reflect physiological correlates of awareness. These data were used to train a recurrent neural network (RNN) with an input parameter encoding state. Model outputs were compared with grand-average event-related potential (ERP) waveforms. Subsequently, the state parameter was varied to simulate changes in the ERP that occur during transitions between states, and relationships with dominant peak amplitudes were quantified.Main results.The RNN synthesized output waveforms that were in close agreement with grand-average ERPs for each group (r2> 0.9,p< 0.0001). Varying the input state parameter generated model outputs reflecting changes in ERP morphology predicted to occur between states. Positive peak amplitudes within 25-50 ms, and negative peak amplitudes within 50-75 ms post-stimulus-onset, were found to display a sigmoidal characteristic during the transition from anaesthetized to conscious states. In contrast, negative peak amplitudes within 0-25 ms displayed greater linearity.Significance.This study demonstrates a method for modelling changes in ERP morphology that accompany transitions between states of consciousness using an RNN. In future studies, this approach may be applied to human data to support the clinical use of ERPs to predict transition to consciousness.

Identifying Obviously Artificial Medical Images Produced by a Generative Adversarial Network.

Synthetic medical images have an important role to play in developing data-driven medical image processing systems. Using a relatively small amount of patient data to train generative models that can produce an abundance of additional samples could bridge the gap towards big-data in niche medical domains. These generative models are evaluated in terms of the synthetic data they generate using the Visual Turing Test (VTT), Fréchet Inception Distance (FID), and other metrics. However, these are generally interpreted at the group level, and do not measure the artificiality of individual synthetic images. The present study attempts to address the challenge of automatically identifying artificial images that are obviously-artificial-looking, which may be necessary for filtering out poorly constructed synthetic images that might otherwise deteriorate the performance of assimilating systems. Synthetic computed tomography (CT) images from a progressively-grown generative adversarial network (PGGAN) were evaluated with a VTT and their image embeddings were analyzed for correlation with artificiality. Images categorized as obviously-artificial (≥0. 7 probability of being rated as fake) were classified using a battery of algorithms. The top-performing classifier, a support vector machine, exhibited accuracy of 75.5%, sensitivity of 0.743, and specificity of 0.769. This is an encouraging result that suggests a potential approach for validating synthetic medical image datasets. Clinical Relevance - Next-generation medical AI systems for image processing will utilize synthetic images produced by generative models. This paper presents an approach towards verifying artificial image legibility for quality-control before being deployed for these purposes.

An Electric Circuit Model of Central Auditory Processing that Replicates Low-level Features of the Mouse Mismatch Response.

Neurophysiology research using animals is often necessary to further our understanding of particular areas of medical interest. Human mismatch negativity (MMN) is one such area, where animal models are used to explore underlying mechanisms more invasively and with greater precision than typically possible with human subjects. Computational models can supplement these efforts by providing abstractions that lead to new insights and drive hypotheses. This study aims to establish whether a mouse mismatch response (MMR) analogous to human MMN can be modelled using electric circuit theory. Input to the auditory cortex was modelled as a step function multiplied by a frequency-dependent weighting designed to reflect spectral hearing sensitivity. Afferent sensory responses were modelled using a resistor-capacitor (RC) network, while bidirectional (bottom-up and top-down) responses were modelled using a resistor-inductor-capacitor (RLC) network. Synthetic EEG was combined with RC and RLC circuit currents in response to simulated sequences of auditory input, which comprised duration and frequency oddball paradigms. Two different states of awareness were considered: i) anaesthetized, including only the RC circuit, and ii) conscious, including both RC and RLC circuits. Event-related potential waveforms were obtained from ten simulated experiments for each oddball paradigm and state. These were qualitatively and quantitatively compared with data from a previous in-vivo study, and the model was deemed to successfully replicate low-level features of the mouse central auditory response. Clinical Relevance - Abnormal MMN is believed to reflect pathological changes associated with psychiatric disease. Maximizing the effectiveness of this biomarker will require a greater understanding of the specific cause(s) of these abnormalities. This study presents a computational model that can account for differences between responses to duration and frequency oddball paradigms, which is particularly significant for clinical MMN research.

Decoding violated sensory expectations from the auditory cortex of anaesthetised mice: Hierarchical recurrent neural network depicts separate 'danger' and 'safety' units.

The ability to respond appropriately to sensory information received from the external environment is among the most fundamental capabilities of central nervous systems. In the auditory domain, processes underlying this behaviour are studied by measuring auditory-evoked electrophysiology during sequences of sounds with predetermined regularities. Identifying neural correlates of ensuing auditory novelty responses is supported by research in experimental animals. In the present study, we reanalysed epidural field potential recordings from the auditory cortex of anaesthetised mice during frequency and intensity oddball stimulation. Multivariate pattern analysis (MVPA) and hierarchical recurrent neural network (RNN) modelling were adopted to explore these data with greater resolution than previously considered using conventional methods. Time-wise and generalised temporal decoding MVPA approaches revealed previously underestimated asymmetry between responses to sound-level transitions in the intensity oddball paradigm, in contrast with tone frequency changes. After training, the cross-validated RNN model architecture with four hidden layers produced output waveforms in response to simulated auditory inputs that were strongly correlated with grand-average auditory-evoked potential waveforms (r2 > .9). Units in hidden layers were classified based on their temporal response properties and characterised using principal component analysis and sample entropy. These demonstrated spontaneous alpha rhythms, sound onset and offset responses and putative 'safety' and 'danger' units activated by relatively inconspicuous and salient changes in auditory inputs, respectively. The hypothesised existence of corresponding biological neural sources is naturally derived from this model. If proven, this could have significant implications for prevailing theories of auditory processing.

Semantic flow and its relation to controlled semantic retrieval deficits in the narrative production of people with aphasia.

Aphasia has had a profound influence on our understanding of how language is instantiated within the human brain. Historically, aphasia has yielded an in vivo model for elucidating the effects of impaired lexical-semantic access on language comprehension and production. Aphasiology has focused intensively on single word dissociations. Yet, less is known about the integrity of combinatorial semantic processes required to construct well-formed narratives. Here we addressed the question of how controlled lexical-semantic retrieval deficits (a hallmark of aphasia) might compound over the course of longer narratives. We specifically examined word-by-word flow of taxonomic vs. thematic semantic distance in the storytelling narratives of individuals with chronic post-stroke aphasia (n = 259) relative to age-matched controls (n = 203). We first parsed raw transcribed narratives into content words and computed inter-word semantic distances for every running pair of words in each narrative (N = 232,490 word transitions). The narratives of people with aphasia showed significant reductions in taxonomic and thematic semantic distance relative to controls. Both distance metrics were strongly predictive of offline measures of semantic impairment and aphasia severity. Since individuals with aphasia often exhibit perseverative language output (i.e., repetitions), we performed additional analyses with repetitions excluded. When repetitions were excluded, group differences in semantic distances persisted and thematic distance was still predictive of semantic impairment, although some findings changed. These results demonstrate the cumulative impact of deficits in controlled word retrieval over the course of narrative production. We discuss the nature of semantic flow between words as a novel metric of characterizing discourse and elucidating the nature of lexical-semantic access impairment in aphasia at multiword levels.

Eyetracking during picture naming predicts future vocabulary dropout in progressive anomia.

The dynamic and unpredictable nature of expressive vocabulary dropout in progressive anomia presents a challenge for language intervention. We evaluated whether eye gaze patterns during naming could predict anomia for the same items in the near future. We tracked naming accuracy and gaze patterns as patients with semantic (n = 7) or logopenic (n = 2) variants of Primary Progressive Aphasia or amnestic Alzheimer's Disease (n = 1), named photographs of people and objects. Patients were tested three or more times spaced roughly evenly over an average duration of 19.1 months. Target words named accurately at baseline were retrospectively coded as either known (i.e., consistently named) or vulnerable (i.e., inaccurately or inconsistently named) based on naming accuracy over the study interval. We extracted gaze data corresponding to successful naming attempts and implemented logistic mixed effects models to determine whether common gaze measures could predict each word's naming status as known or vulnerable. More visual fixations and greater visual fixation dispersion predicted later anomia. These findings suggest that eye tracking may yield a biomarker of the robustness of particular target words to future expressive vocabulary dropout. We discuss the potential utility of this finding for optimizing treatment for progressive anomia.

Generation and characterization of three induced pluripotent stem cell lines (NUIGi046-A, NUIGi046-B, NUIGi046-C) from a 51-year-old healthy individual.

Skin punch biopsy was donated by a healthy 51-year-old Caucasian male and the dermal fibroblasts were reprogrammed into human induced pluripotent stem cell (hiPSC) lines by using non-integrative Sendai viruses expressing OCT4, SOX2, KLF4 and c-MYC. Three iPSC lines (NUIGi046-A, NUIGi046-B, NUIGi046-C) highly expressed the pluripotent markers and were capable of differentiating into cells of endodermal, mesodermal, and ectodermal origin. These iPSCs can be offered as controls and in combination with genome-editing and three-dimensional (3D) system. They may be used for human disease modelling and drug screening.

Roving oddball paradigm elicits sensory gating, frequency sensitivity, and long-latency response in common marmosets.

Mismatch negativity (MMN) is a candidate biomarker for neuropsychiatric disease. Understanding the extent to which it reflects cognitive deviance-detection or purely sensory processes will assist practitioners in making informed clinical interpretations. This study compares the utility of deviance-detection and sensory-processing theories for describing MMN-like auditory responses of a common marmoset monkey during roving oddball stimulation. The following exploratory analyses were performed on an existing dataset: responses during the transition and repetition sequence of the roving oddball paradigm (standard -> deviant/S1 -> S2 -> S3) were compared; long-latency potentials evoked by deviant stimuli were examined using a double-epoch waveform subtraction; effects of increasing stimulus repetitions on standard and deviant responses were analyzed; and transitions between standard and deviant stimuli were divided into ascending and descending frequency changes to explore contributions of frequency-sensitivity. An enlarged auditory response to deviant stimuli was observed. This decreased exponentially with stimulus repetition, characteristic of sensory gating. A slow positive deflection was viewed over approximately 300-800 ms after the deviant stimulus, which is more difficult to ascribe to afferent sensory mechanisms. When split into ascending and descending frequency transitions, the resulting difference waveforms were disproportionally influenced by descending frequency deviant stimuli. This asymmetry is inconsistent with the general deviance-detection theory of MMN. These findings tentatively suggest that MMN-like responses from common marmosets are predominantly influenced by rapid sensory adaptation and frequency preference of the auditory cortex, while deviance-detection may play a role in long-latency activity.

NRXN1α+/- is associated with increased excitability in ASD iPSC-derived neurons.

BACKGROUND: NRXN1 deletions are identified as one of major rare risk factors for autism spectrum disorder (ASD) and other neurodevelopmental disorders. ASD has 30% co-morbidity with epilepsy, and the latter is associated with excessive neuronal firing. NRXN1 encodes hundreds of presynaptic neuro-adhesion proteins categorized as NRXN1α/ß/γ. Previous studies on cultured cells show that the short NRXN1ß primarily exerts excitation effect, whereas the long NRXN1α which is more commonly deleted in patients involves in both excitation and inhibition. However, patient-derived models are essential for understanding functional consequences of NRXN1α deletions in human neurons. We recently derived induced pluripotent stem cells (iPSCs) from five controls and three ASD patients carrying NRXN1α+/- and showed increased calcium transients in patient neurons. METHODS: In this study we investigated the electrophysiological properties of iPSC-derived cortical neurons in control and ASD patients carrying NRXN1α+/- using patch clamping. Whole genome RNA sequencing was carried out to further understand the potential underlying molecular mechanism. RESULTS: NRXN1α+/- cortical neurons were shown to display larger sodium currents, higher AP amplitude and accelerated depolarization time. RNASeq analyses revealed transcriptomic changes with significant upregulation glutamatergic synapse and ion channels/transporter activity including voltage-gated potassium channels (GRIN1, GRIN3B, SLC17A6, CACNG3, CACNA1A, SHANK1), which are likely to couple with the increased excitability in NRXN1α+/- cortical neurons. CONCLUSIONS: Together with recent evidence of increased calcium transients, our results showed that human NRXN1α+/- isoform deletions altered neuronal excitability and non-synaptic function, and NRXN1α+/- patient iPSCs may be used as an ASD model for therapeutic development with calcium transients and excitability as readouts.