Visual mismatch negativity to masked stimuli presented at very brief presentation rates

Mismatch Negativity (MMN) has been characterised as a ‘pre-attentive’ component of an event-related potential (ERP) that is related to discrimination and error prediction processes. The aim of the current experiment was to establish whether visual MMN could be recorded to briefly presented, backward and forward masked visual stimuli, given both below and above levels of subjective experience. Evidence of visual MMN elicitation in the absence of the ability to consciously report stimuli would provide strong evidence for the automaticity of the visual MMN mechanism. Using an oddball paradigm, two stimuli that differed in orientation from each other, an + and an x were presented on a computer screen. Electroencephalogram (EEG) was recorded from nine participants (six females), mean age 21.4 years. Results showed that for stimuli that were effectively masked at 7ms presentation, there was little variation in the ERPs evoked to standard and deviant stimuli or in the subtraction waveform employed to delineate the visual MMN. At 14 ms stimulus presentation, when participants were able to report stimulus presence, an enhanced negativity at around 175 ms and 305 ms was observed to the deviant and was evident in the subtraction waveform. Although some of the difference observed in the ERPs can be attributed to stimulus characteristics, the use of a ‘lonely’ deviant protocol revealed attenuated visual MMN components at 14 ms stimulus presentation. Overall, results suggest that some degree of conscious attention is required before visual MMN components emerge, suggesting visual MMN is not an entirely pre-attentive process

Reverse translation of the rodent 5C-CPT reveals that the impaired attention of people with schizophrenia is similar to scopolamine-induced deficits in mice.

Attentional dysfunction in schizophrenia (SZ) is a core deficit that contributes to multiple cognitive deficits and the resulting functional disability. However, developing procognitive therapeutics for neuropsychiatric disorders have been limited by a 'translational gap'--a lack of cognitive paradigms having cross-species translational validity and relevance. The present study was designed to perform an initial validation of the cross-species homology of the 5-choice Continuous Performance Test (5C-CPT) in healthy nonpsychiatric comparison subjects (NCS), SZ patients and mice under pharmacologic challenge. The 5C-CPT performance in SZ patients (n=20) was compared with age-matched NCS (n=23). The effects of the general muscarinic receptor antagonist scopolamine on mice (n=21) performing the 5C-CPT were also assessed. SZ subjects exhibited significantly impaired attention in the 5C-CPT, driven by reduced target detection over time and nonsignificantly increased impulsive responding. Similarly, scopolamine significantly impaired attention in mice, driven by reduced target detection and nonsignificantly increased impulsive responding. Scopolamine also negatively affected accuracy and speed of responding in mice, although these measures failed to differentiate SZ vs. NCS. Thus, mice treated with scopolamine exhibited similar impairments in vigilance as seen in SZ, although the differences between the behavioral profiles warrant further study. The availability of rodent and human versions of this paradigm provides an opportunity to: (1) investigate the neuroanatomic, neurochemical and genomic architecture of abnormalities in attention observed in clinical populations such as SZ; (2) develop and refine animal models of cognitive impairments; and (3) improve cross-species translational testing for the development of treatments for these impairments

Characterization of spatio-temporal epidural event-related potentials for mouse models of psychiatric disorders

Distinctive features in sensory event-related potentials (ERPs) are endophenotypic biomarkers of psychiatric disorders, widely studied using electroencephalographic (EEG) methods in humans and model animals. Despite the popularity and unique significance of the mouse as a model species in basic research, existing EEG methods applicable to mice are far less powerful than those available for humans and large animals. We developed a new method for multi-channel epidural ERP characterization in behaving mice with high precision, reliability and convenience and report an application to time-domain ERP feature characterization of the Sp4 hypomorphic mouse model for schizophrenia. Compared to previous methods, our spatio-temporal ERP measurement robustly improved the resolving power of key signatures characteristic of the disease model. The high performance and low cost of this technique makes it suitable for high-throughput behavioral and pharmacological studies

Neurophysiologic measures of target engagement predict response to auditory-based cognitive training in treatment refractory schizophrenia

Cognitive impairment is a core feature of schizophrenia and a strong predictor of psychosocial disability. Auditory-based targeted cognitive training (TCT) aims to enhance verbal learning and other domains of cognitive functioning through "bottom-up" tuning of the neural systems underlying early auditory information processing (EAIP). Although TCT has demonstrated efficacy at the group level, individual response to TCT varies considerably, with nearly half of patients showing little-to-no benefit. EEG measures of EAIP, mismatch negativity (MMN) and P3a, are sensitive to the neural systems engaged by TCT exercises and might therefore predict clinical outcomes after a full course of treatment. This study aimed to determine whether initial malleability of MMN and P3a to 1-h of auditory-based TCT predicts improvements in verbal learning and clinical symptom reduction following a full (30-h) course of TCT. Treatment refractory patients diagnosed with schizophrenia were randomly assigned to receive treatment-as-usual (TAU; n = 22) or TAU augmented with TCT (n = 23). Results indicated that malleability (i.e., change from baseline after the initial 1-h dose of TCT) of MMN and P3a predicted improvements in verbal learning as well as decreases in the severity of positive symptoms. Examination of MMN and P3a malleability in patients after their first dose of TCT can be used to predict clinical response to a full course of treatment and shows promise for future biomarker-informed treatment assignment

Gradient sensing in defined chemotactic fields

Cells respond to a variety of secreted molecules by modifying their physiology, growth patterns, and behavior. Motile bacteria and eukaryotic cells can sense extracellular chemoattractants and chemorepellents and alter their movement. In this way fibroblasts and leukocytes can find their ways to sites of injury and cancer cells can home in on sites that are releasing growth factors. Social amoebae such as Dictyostelium are chemotactic to cAMP which they secrete several hours after they have initiated development. These eukaryotic cells are known to be able to sense extremely shallow gradients but the processes underlying their exquisite sensitivity are still largely unknown. In this study we determine the responses of developed cells of Dictyostelium discoideum to stable linear gradients of cAMP of varying steepness generated in 2 µm deep gradient chambers of microfluidic devices. The gradients are generated by molecular diffusion between two 50 µm deep flow-through channels, one of which is perfused with a solution of cAMP and the other with buffer, serving as continuously replenished source and sink. These low ceiling gradient chambers constrained the cells in the vertical dimension, facilitatin