Selection and inhibition mechanisms for human voluntary action decisions

One can choose between action alternatives that have no apparent difference in their outcomes. Such voluntary action decisions are associated with widespread frontal–parietal activation, and a tendency to inhibit the repetition of a previous action. However, the mechanism of initiating voluntary actions and the functions of different brain regions during this process remains largely unknown. Here, we combine computational modeling and functional magnetic resonance imaging to test the selection and inhibition mechanisms that mediate trial-to-trial voluntary action decisions. We fitted an optimized accumulator model to behavioral responses in a finger-tapping task in which participants were instructed to make chosen actions or specified actions. Model parameters derived from each individual were then applied to estimate the expected accumulated metabolic activity (EAA) engaged in every single trial. The EAA was associated with blood oxygenation level-dependent responses in a decision work that was maximal in the supplementary motor area and the caudal anterior cingulate cortex, consistent with a competitive accumulation-to-threshold mechanism for action decision by these regions. Furthermore, specific inhibition of the previous action's accumulator was related to the suppression of response repetition. This action-specific inhibition correlated with the activity of the right inferior frontal gyrus, when the option to repeat existed. Our findings suggest that human voluntary action decisions are mediated by complementary processes of intentional selection and inhibition

The role of the fornix in human navigational learning

Experiments on rodents have demonstrated that transecting the white matter fibre pathway linking the hippocampus with an array of cortical and subcortical structures - the fornix - impairs flexible navigational learning in the Morris Water Maze (MWM), as well as similar spatial learning tasks. While diffusion magnetic resonance imaging (dMRI) studies in humans have linked inter-individual differences in fornix microstructure to episodic memory abilities, its role in human spatial learning is currently unknown. We used high-angular resolution diffusion MRI combined with constrained spherical deconvolution-based tractography, to ask whether inter-individual differences in fornix microstructure in healthy young adults would be associated with spatial learning in a virtual reality navigation task. To efficiently capture individual learning across trials, we adopted a novel curve fitting approach to estimate a single index of learning rate. We found a statistically significant correlation between learning rate and the microstructure (mean diffusivity) of the fornix, but not that of a comparison tract linking occipital and anterior temporal cortices (the inferior longitudinal fasciculus, ILF). Further, this correlation remained significant when controlling for both hippocampal volume and participant gender. These findings extend previous animal studies by demonstrating the functional relevance of the fornix for human spatial learning in a virtual reality environment, and highlight the importance of a distributed neuroanatomical network, underpinned by key white matter pathways, such as the fornix, in complex spatial behaviour

+microstate: A MATLAB toolbox for brain microstate analysis in sensor and cortical EEG/MEG

+microstate is a MATLAB toolbox for brain functional microstate analysis. It builds upon previous EEG microstate literature and toolboxes by including algorithms for source-space microstate analysis. +microstate includes codes for performing individual- and group-level brain microstate analysis in resting-state and task-based data including event-related potentials/fields. Functions are included to visualise and perform statistical analysis of microstate sequences, including novel advanced statistical approaches such as statistical testing for associated functional connectivity patterns, cluster-permutation topographic ANOVAs, and analysis of microstate probabilities in response to stimuli. Additionally, codes for simulating microstate sequences and their associated M/EEG data are included in the toolbox, which can be used to generate artificial data with ground truth microstates and to validate the methodology. +microstate integrates with widely used toolboxes for M/EEG processing including Fieldtrip, SPM, LORETA/sLORETA, EEGLAB, and Brainstorm to aid with accessibility, and includes wrappers for pre-existing toolboxes for brain-state estimation such as Hidden Markov modelling (HMM-MAR) and independent component analysis (FastICA) to aid with direct comparison with these techniques. In this paper, we first introduce +microstate before subsequently performing example analyses using open access datasets to demonstrate and validate the methodology. MATLAB live scripts for each of these analyses are included in +microstate, to act as a tutorial and to aid with reproduction of the results presented in this manuscript

A large-scale brain network mechanism for increased seizure propensity in Alzheimer’s disease

People with Alzheimer’s disease (AD) are 6-10 times more likely to develop seizures than the healthy aging population. Leading hypotheses largely consider hyperexcitability of local cortical tissue as primarily responsible for increased seizure prevalence in AD. However, in the general population of people with epilepsy, large-scale brain network organization additionally plays a role in determining seizure likelihood and phenotype. Here, we propose that alterations to large-scale brain network organization seen in AD may contribute to increased seizure likelihood. To test this hypothesis, we combine computational modelling with electrophysiological data using an approach that has proved informative in clinical epilepsy cohorts without AD. EEG was recorded from 21 people with probable AD and 26 healthy controls. At the time of EEG acquisition, all participants were free from seizures. Whole brain functional connectivity derived from source-reconstructed EEG recordings was used to build subject-specific brain network models of seizure transitions. As cortical tissue excitability was increased in the simulations, AD simulations were more likely to transition into seizures than simulations from healthy controls, suggesting an increased group-level probability of developing seizures at a future time for AD participants. We subsequently used the model to assess seizure propensity of different regions across the cortex. We found the most important regions for seizure generation were those typically burdened by amyloid-beta at the early stages of AD, as previously reported by in-vivo and post-mortem staging of amyloid plaques. Analysis of these spatial distributions also give potential insight into mechanisms of increased susceptibility to generalized (as opposed to focal) seizures in AD vs controls. This research suggests avenues for future studies testing patients with seizures, e.g. co-morbid AD/epilepsy patients, and comparisons with PET and MRI scans to relate regional seizure propensity with AD pathologies

MEG cortical microstates: Spatiotemporal characteristics, dynamic functional connectivity and stimulus-evoked responses

EEG microstate analysis is an approach to study brain states and their fast transitions in healthy cognition and disease. A key limitation of conventional microstate analysis is that it must be performed at the sensor level, and therefore gives limited anatomical insight. Here, we generalise the microstate methodology to be applicable to source-reconstructed electrophysiological data. Using simulations of a neural-mass network model, we first established the validity and robustness of the proposed method. Using MEG resting-state data, we uncovered ten microstates with distinct spatial distributions of cortical activation. Multivariate pattern analysis demonstrated that source-level microstates were associated with distinct functional connectivity patterns. We further demonstrated that the occurrence probability of MEG microstates were altered by auditory stimuli, exhibiting a hyperactivity of the microstate including the auditory cortex. Our results support the use of source-level microstates as a method for investigating brain dynamic activity and connectivity at the millisecond scale

Novel Application of Melt Extrusion and Additive Manufacturing on Developing Diverse Dosages

New drug product development is a time consuming and costly process. One of the significant challenges is the poor aqueous solubility of many active pharmaceutical ingredients (APIs). Among those techniques, hot-melt extrusion(HME) is optimal for pharmaceutical solid dispersion development because of it free of using an organic solvent, easy scale up, and suitable for continuous processing with ensured optimal quality control

Spatiotemporal dynamics in human visual cortex rapidly encode the emotional content of faces

Recognizing emotion in faces is important in human interaction and survival, yet existing studies do not paint a consistent picture of the neural representation supporting this task. To address this, we collected magnetoencephalography (MEG) data while participants passively viewed happy, angry and neutral faces. Using time-resolved decoding of sensor-level data, we show that responses to angry faces can be discriminated from happy and neutral faces as early as 90 ms after stimulus onset and only 10 ms later than faces can be discriminated from scrambled stimuli, even in the absence of differences in evoked responses. Time-resolved relevance patterns in source space track expression-related information from the visual cortex (100 ms) to higher-level temporal and frontal areas (200–500 ms). Together, our results point to a system optimised for rapid processing of emotional faces and preferentially tuned to threat, consistent with the important evolutionary role that such a system must have played in the development of human social interactions

Breaking Deadlocks: Reward Probability and Spontaneous Preference Shape Voluntary Decisions and Electrophysiological Signals in Humans

Choosing between equally valued options is a common conundrum, for which classical decision theories predicted a prolonged response time (RT). This contrasts with the notion that an optimal decision maker in a stable environment should make fast and random choices, as the outcomes are indifferent. Here, we characterize the neurocognitive processes underlying such voluntary decisions by integrating cognitive modelling of behavioral responses and EEG recordings in a probabilistic reward task. Human participants performed binary choices between pairs of unambiguous cues associated with identical reward probabilities at different levels. Higher reward probability accelerated RT, and participants chose one cue faster and more frequent over the other at each probability level. The behavioral effects on RT persisted in simple reactions to single cues. By using hierarchical Bayesian parameter estimation for an accumulator model, we showed that the probability and preference effects were independently associated with changes in the speed of evidence accumulation, but not with visual encoding or motor execution latencies. Time-resolved MVPA of EEG-evoked responses identified significant representations of reward certainty and preference as early as 120 ms after stimulus onset, with spatial relevance patterns maximal in middle central and parietal electrodes. Furthermore, EEG-informed computational modelling showed that the rate of change between N100 and P300 event-related potentials modulated accumulation rates on a trial-by-trial basis. Our findings suggest that reward probability and spontaneous preference collectively shape voluntary decisions between equal options, providing a mechanism to prevent indecision or random behavior

The pre-supplementary motor area achieves inhibitory control by modulating response thresholds

The pre-supplementary motor area (pre-SMA) is central for the initiation and inhibition of voluntary action. For the execution of action, the pre-SMA optimises the decision of which action to choose by adjusting the thresholds for the required evidence for each choice. However, it remains unclear how the pre-SMA contributes to action inhibition. Here, we use computational modelling of a stop/no-go task, performed by an adult with a focal lesion in the pre-SMA, and 52 age-matched controls. We show that the patient required more time to successfully inhibit an action (longer stop-signal reaction time) but was faster in terms of go reaction times. Computational modelling revealed that the patient's failure to stop was explained by a significantly lower response threshold for initiating an action, as compared to controls, suggesting that the patient needed less evidence before committing to an action. A similarly specific impairment was also observed for the decision of which action to choose. Together, our results suggest that dynamic threshold modulation may be a general mechanism by which the pre-SMA exerts its control over voluntary action

The interindividual variability of multimodal brain connectivity maintains spatial heterogeneity and relates to tissue microstructure

Humans differ from each other in a wide range of biometrics, but to what extent brain connectivity varies between individuals remains largely unknown. By combining diffusion-weighted imaging (DWI) and magnetoencephalography (MEG), this study characterizes the inter-subject variability (ISV) of multimodal brain connectivity. Structural connectivity is characterized by higher ISV in association cortices including the core multiple-demand network and lower ISV in the sensorimotor cortex. MEG ISV exhibits frequency-dependent signatures, and the extent of MEG ISV is consistent with that of structural connectivity ISV in selective macroscopic cortical clusters. Across the cortex, the ISVs of structural connectivity and beta-band MEG functional connectivity are negatively associated with cortical myelin content indexed by the quantitative T1 relaxation rate measured by high-resolution 7 T MRI. Furthermore, MEG ISV from alpha to gamma bands relates to the hindrance and restriction of the white-matter tissue estimated by DWI microstructural models. Our findings depict the inter-relationship between the ISV of brain connectivity from multiple modalities, and highlight the role of tissue microstructure underpinning the ISV