Causal Evidence for the Multiple Demand Network in Change Detection: Auditory Mismatch Magnetoencephalography across Focal Neurodegenerative Diseases.

The multiple demand (MD) system is a network of fronto-parietal brain regions active during the organization and control of diverse cognitive operations. It has been argued that this activation may be a nonspecific signal of task difficulty. However, here we provide convergent evidence for a causal role for the MD network in the "simple task" of automatic auditory change detection, through the impairment of top-down control mechanisms. We employ independent structure-function mapping, dynamic causal modeling (DCM), and frequency-resolved functional connectivity analyses of MRI and magnetoencephalography (MEG) from 75 mixed-sex human patients across four neurodegenerative syndromes [behavioral variant fronto-temporal dementia (bvFTD), nonfluent variant primary progressive aphasia (nfvPPA), posterior cortical atrophy (PCA), and Alzheimer's disease mild cognitive impairment with positive amyloid imaging (ADMCI)] and 48 age-matched controls. We show that atrophy of any MD node is sufficient to impair auditory neurophysiological response to change in frequency, location, intensity, continuity, or duration. There was no similar association with atrophy of the cingulo-opercular, salience or language networks, or with global atrophy. MD regions displayed increased functional but decreased effective connectivity as a function of neurodegeneration, suggesting partially effective compensation. Overall, we show that damage to any of the nodes of the MD network is sufficient to impair top-down control of sensation, providing a common mechanism for impaired change detection across dementia syndromes.SIGNIFICANCE STATEMENT Previous evidence for fronto-parietal networks controlling perception is largely associative and may be confounded by task difficulty. Here, we use a preattentive measure of automatic auditory change detection [mismatch negativity (MMN) magnetoencephalography (MEG)] to show that neurodegeneration in any frontal or parietal multiple demand (MD) node impairs primary auditory cortex (A1) neurophysiological response to change through top-down mechanisms. This explains why the impaired ability to respond to change is a core feature across dementias, and other conditions driven by brain network dysfunction, such as schizophrenia. It validates theoretical frameworks in which neurodegenerating networks upregulate connectivity as partially effective compensation. The significance extends beyond network science and dementia, in its construct validation of dynamic causal modeling (DCM), and human confirmation of frequency-resolved analyses of animal neurodegeneration models.

GABAergic cortical network physiology in frontotemporal lobar degeneration.

The clinical syndromes caused by frontotemporal lobar degeneration are heterogeneous, including the behavioural variant frontotemporal dementia (bvFTD) and progressive supranuclear palsy. Although pathologically distinct, they share many behavioural, cognitive and physiological features, which may in part arise from common deficits of major neurotransmitters such as γ-aminobutyric acid (GABA). Here, we quantify the GABAergic impairment and its restoration with dynamic causal modelling of a double-blind placebo-controlled crossover pharmaco-magnetoencephalography study. We analysed 17 patients with bvFTD, 15 patients with progressive supranuclear palsy, and 20 healthy age- and gender-matched controls. In addition to neuropsychological assessment and structural MRI, participants undertook two magnetoencephalography sessions using a roving auditory oddball paradigm: once on placebo and once on 10 mg of the oral GABA reuptake inhibitor tiagabine. A subgroup underwent ultrahigh-field magnetic resonance spectroscopy measurement of GABA concentration, which was reduced among patients. We identified deficits in frontotemporal processing using conductance-based biophysical models of local and global neuronal networks. The clinical relevance of this physiological deficit is indicated by the correlation between top-down connectivity from frontal to temporal cortex and clinical measures of cognitive and behavioural change. A critical validation of the biophysical modelling approach was evidence from parametric empirical Bayes analysis that GABA levels in patients, measured by spectroscopy, were related to posterior estimates of patients' GABAergic synaptic connectivity. Further evidence for the role of GABA in frontotemporal lobar degeneration came from confirmation that the effects of tiagabine on local circuits depended not only on participant group, but also on individual baseline GABA levels. Specifically, the phasic inhibition of deep cortico-cortical pyramidal neurons following tiagabine, but not placebo, was a function of GABA concentration. The study provides proof-of-concept for the potential of dynamic causal modelling to elucidate mechanisms of human neurodegenerative disease, and explains the variation in response to candidate therapies among patients. The laminar- and neurotransmitter-specific features of the modelling framework, can be used to study other treatment approaches and disorders. In the context of frontotemporal lobar degeneration, we suggest that neurophysiological restoration in selected patients, by targeting neurotransmitter deficits, could be used to bridge between clinical and preclinical models of disease, and inform the personalized selection of drugs and stratification of patients for future clinical trials.

GABA-ergic Dynamics in Human Frontotemporal Networks Confirmed by Pharmaco-Magnetoencephalography.

To bridge the gap between preclinical cellular models of disease and in vivo imaging of human cognitive network dynamics, there is a pressing need for informative biophysical models. Here we assess dynamic causal models (DCM) of cortical network responses, as generative models of magnetoencephalographic observations during an auditory oddball roving paradigm in healthy adults. This paradigm induces robust perturbations that permeate frontotemporal networks, including an evoked 'mismatch negativity' response and transiently induced oscillations. Here, we probe GABAergic influences in the networks using double-blind placebo-controlled randomized-crossover administration of the GABA reuptake inhibitor, tiagabine (oral, 10 mg) in healthy older adults. We demonstrate the facility of conductance-based neural mass mean-field models, incorporating local synaptic connectivity, to investigate laminar-specific and GABAergic mechanisms of the auditory response. The neuronal model accurately recapitulated the observed magnetoencephalographic data. Using parametric empirical Bayes for optimal model inversion across both drug sessions, we identify the effect of tiagabine on GABAergic modulation of deep pyramidal and interneuronal cell populations. We found a transition of the main GABAergic drug effects from auditory cortex in standard trials to prefrontal cortex in deviant trials. The successful integration of pharmaco- magnetoencephalography with dynamic causal models of frontotemporal networks provides a potential platform on which to evaluate the effects of disease and pharmacological interventions.SIGNIFICANCE STATEMENT Understanding human brain function and developing new treatments require good models of brain function. We tested a detailed generative model of cortical microcircuits that accurately reproduced human magnetoencephalography, to quantify network dynamics and connectivity in frontotemporal cortex. This approach identified the effect of a test drug (GABA-reuptake inhibitor, tiagabine) on neuronal function (GABA-ergic dynamics), opening the way for psychopharmacological studies in health and disease with the mechanistic precision afforded by generative models of the brain.

iElectrodes: A Comprehensive Open-Source Toolbox for Depth and Subdural Grid Electrode Localization.

The localization of intracranial electrodes is a fundamental step in the analysis of invasive electroencephalography (EEG) recordings in research and clinical practice. The conclusions reached from the analysis of these recordings rely on the accuracy of electrode localization in relationship to brain anatomy. However, currently available techniques for localizing electrodes from magnetic resonance (MR) and/or computerized tomography (CT) images are time consuming and/or limited to particular electrode types or shapes. Here we present iElectrodes, an open-source toolbox that provides robust and accurate semi-automatic localization of both subdural grids and depth electrodes. Using pre- and post-implantation images, the method takes 2-3 min to localize the coordinates in each electrode array and automatically number the electrodes. The proposed pre-processing pipeline allows one to work in a normalized space and to automatically obtain anatomical labels of the localized electrodes without neuroimaging experts. We validated the method with data from 22 patients implanted with a total of 1,242 electrodes. We show that localization distances were within 0.56 mm of those achieved by experienced manual evaluators. iElectrodes provided additional advantages in terms of robustness (even with severe perioperative cerebral distortions), speed (less than half the operator time compared to expert manual localization), simplicity, utility across multiple electrode types (surface and depth electrodes) and all brain regions.

Getting over the bursary blues.

The decision to scrap bursaries will discourage people from applying for degree courses.

Convergent evidence for hierarchical prediction networks from human electrocorticography and magnetoencephalography.

We propose that sensory inputs are processed in terms of optimised predictions and prediction error signals within hierarchical neurocognitive models. The combination of non-invasive brain imaging and generative network models has provided support for hierarchical frontotemporal interactions in oddball tasks, including recent identification of a temporal expectancy signal acting on prefrontal cortex. However, these studies are limited by the need to invert magnetoencephalographic or electroencephalographic sensor signals to localise activity from cortical 'nodes' in the network, or to infer neural responses from indirect measures such as the fMRI BOLD signal. To overcome this limitation, we examined frontotemporal interactions estimated from direct cortical recordings from two human participants with cortical electrode grids (electrocorticography - ECoG). Their frontotemporal network dynamics were compared to those identified by magnetoencephalography (MEG) in forty healthy adults. All participants performed the same auditory oddball task with standard tones interspersed with five deviant tone types. We normalised post-operative electrode locations to standardised anatomic space, to compare across modalities, and inverted the MEG to cortical sources using the estimated lead field from subject-specific head models. A mismatch negativity signal in frontal and temporal cortex was identified in all subjects. Generative models of the electrocorticographic and magnetoencephalographic data were separately compared using the free-energy estimate of the model evidence. Model comparison confirmed the same critical features of hierarchical frontotemporal networks in each patient as in the group-wise MEG analysis. These features included bilateral, feedforward and feedback frontotemporal modulated connectivity, in addition to an asymmetric expectancy driving input on left frontal cortex. The invasive ECoG provides an important step in construct validation of the use of neural generative models of MEG, which in turn enables generalisation to larger populations. Together, they give convergent evidence for the hierarchical interactions in frontotemporal networks for expectation and processing of sensory inputs.

How narratives can change nursing practice.

This series has explored the value of patient narratives in enabling nurses to reflect on how their practice is perceived by, and affects, patients and their families. This article describes how two student learning disability nurses used patient and carer narratives to highlight the effect of a hospital trust's lack of toilet provision for people with physical impairments, using the stories to persuade the trust to develop appropriate facilities.

Starting out - What do you do when a trip to the loo is anything but bog standard?

During my nurse training, I was in a lecture, listening to a woman describing the problems she and her son experienced using the loo in outpatients. Her son had profound multiple learning disabilities, and what should have been a simple matter of gaining access to a toilet became a physical, and emotional, struggle.

Hierarchical Organization of Frontotemporal Networks for the Prediction of Stimuli across Multiple Dimensions.

Brain function can be conceived as a hierarchy of generative models that optimizes predictions of sensory inputs and minimizes "surprise." Each level of the hierarchy makes predictions of neural events at a lower level in the hierarchy, which returns a prediction error when these expectations are violated. We tested the generalization of this hypothesis to multiple sequential deviations, and we identified the most likely organization of the network that accommodates deviations in temporal structure of stimuli. Magnetoencephalography of healthy human participants during an auditory paradigm identified prediction error responses in bilateral primary auditory cortex, superior temporal gyrus, and lateral prefrontal cortex for deviation by frequency, intensity, location, duration, and silent gap. We examined the connectivity between cortical sources using a set of 21 generative models that embedded alternate hypotheses of frontotemporal network dynamics. Bayesian model selection provided evidence for two new features of functional network organization. First, an expectancy signal provided input to the prefrontal cortex bilaterally, related to the temporal structure of stimuli. Second, there are functionally significant lateral connections between superior temporal and/or prefrontal cortex. The results support a predictive coding hypothesis but go beyond previous work in demonstrating the generalization to multiple concurrent stimulus dimensions and the evidence for a temporal expectancy input at the higher level of the frontotemporal hierarchy. We propose that this framework for studying the brain's response to unexpected events is not limited to simple sensory tasks but may also apply to the neurocognitive mechanisms of higher cognitive functions and their disorders.

Preceptor development: providing effective feedback, part 2.

An integral part of providing effective feedback to pharmacy residents occurs during the evaluation process. Residency evaluation involves measuring and documenting performance as it relates to standardized residency outcomes, goals, and learning objectives. Evaluations may be formative or summative and include the preceptor's evaluation of the resident's performance, the resident's self-assessments, and the resident's evaluation of the preceptor and learning experience. Evaluations are more structured than feedback, and they involve documentation of the verbal feedback that was provided throughout the learning experience. This article will focus on the preceptor's role in providing effective resident evaluations based on specific learning activities.

Residency scramble: program directors' experiences with the Pharmacy Online Residency Centralized Application Service.

PURPOSE: Residency program directors' perceptions of the scramble process in 2013 using the Pharmacy Online Residency Centralized Application Service (PhORCAS) were evaluated. METHODS: After the ASHP Resident Matching Program ("Match") results were released in 2013, programs were asked to not extend offers to applicants until the following Monday, allowing a week for programs and applicants to evaluate their options and make the best decisions. A survey consisting of open-ended and structured response questions was sent electronically to 1905 program directors. Adherence to the recommended one-week moratorium before extending an offer to applicants for unmatched positions was also assessed. RESULTS: A total of 531 completed surveys were returned (28.2% response rate). Programs with 119 of the 133 unmatched postgraduate year 1 positions were represented in the results. The ma jority of directors were satisfied with the use of PhORCAS overall, rating it easier (60.3%) or at least the same (24.8%) as processes used in the past. Programs with unmatched positions thought using PhORCAS made it easier to fill positions (64.5%). Sixty percent of program directors contacted applicants the week after the Match. Most directors (79%) followed the recommendation of waiting until April 1 or later to make offers; however, 49% thought others did not follow the guidelines. Program directors offered many concerns about the stressful nature of the scramble process and offered several recommendations for improvement. CONCLUSION: Residency program directors found that the use of PhORCAS and guidelines from the ASHP Commission on Credentialing improved the scramble process and facilitated the filling of unmatched residency positions.

Real-time peer review: an innovative feature to an evidence-based practice conference.

Many health sciences librarians as well as other professionals attend conferences on a regular basis. This study sought to link an innovative peer review process of presented research papers to long-term conference outcomes in the peer-reviewed professional journal literature. An evidence-based conference included a proof-of-concept study to gauge the long-term outcomes from research papers presented during the program. Real-time peer review recommendations from the conference were linked to final versions of articles published in the peer-reviewed literature. The real-time peer review feedback served as the basis for further mentoring to guide prospective authors toward publishing their research results. These efforts resulted in the publication of two of the four research papers in the peer-viewed literature. A third presented paper appeared in a blog because the authors wanted to disseminate their findings more quickly than through the journal literature. The presenters of the fourth paper never published their study. Real-time peer review from this study can be adapted to other professional conferences that include presented research papers.

Preceptor development: providing effective feedback.

Feedback plays a significant role in precepting and is indispensable in residency training. As described by the Accreditation Council for Graduate Medical Education, the goal of any postgraduate residency program is to prepare individual trainees to function as qualified practitioners. Although feedback and evaluations have traditionally been synonymous, our goal is to differentiate the two and describe the role of each within resident performance. The goal of this article is to provide preceptors with the tools to provide timely, effective, and quality feedback to residents on a regular basis. Although the focus of this article is on residency training, these concepts can be utilized in student rotations as well.

Optimizing the customized residency plan.

Residents and residency program directors (RPDs) understand that the goal of the residency year is to earn a residency certificate through achievement of established goals and objectives. The customized residency plan provides a map for the resident and RPD to follow throughout the course of the residency year, helping to keep everyone on track to accomplish the established goals and objectives of the program. It also provides information that allows preceptors to take the individual resident's plan into consideration when customizing a learning experience. This article will focus on the process for developing a customized residency plan and implementing it over the course of the residency year.