Genomic testing in neurology.

Genomic testing has been available for neurological conditions for decades. However, in recent years, there has been a significant change in its availability, range and cost, as well as improvements in the technology and knowledge that underpin how the genome is interrogated. Neurologists can encounter a wide range of genetic conditions, and so their understanding of genomic testing is fundamental to modern clinical practice.

General Framework to Quantitatively Predict Pharmacokinetic Induction Drug-Drug Interactions Using In Vitro Data.

INTRODUCTION: Metabolic inducers can expose people with polypharmacy to adverse health outcomes. A limited fraction of potential drug-drug interactions (DDIs) have been or can ethically be studied in clinical trials, leaving the vast majority unexplored. In the present study, an algorithm has been developed to predict the induction DDI magnitude, integrating data related to drug-metabolising enzymes. METHODS: The area under the curve ratio (AUCratio) resulting from the DDI with a victim drug in the presence and absence of an inducer (rifampicin, rifabutin, efavirenz, or carbamazepine) was predicted from various in vitro parameters and then correlated with the clinical AUCratio (N = 319). In vitro data including fraction unbound in plasma, substrate specificity and induction potential for cytochrome P450s, phase II enzymes and uptake, and efflux transporters were integrated. To represent the interaction potential, the in vitro metabolic metric (IVMM) was generated by combining the fraction of substrate metabolised by each hepatic enzyme of interest with the corresponding in vitro fold increase in enzyme activity (E) value for the inducer. RESULTS: Two independent variables were deemed significant and included in the algorithm: IVMM and fraction unbound in plasma. The observed and predicted magnitudes of the DDIs were categorised accordingly: no induction, mild, moderate, and strong induction. DDIs were assumed to be well classified if the predictions were in the same category as the observations, or if the ratio between these two was < 1.5-fold. This algorithm correctly classified 70.5% of the DDIs. CONCLUSION: This research presents a rapid screening tool to identify the magnitude of potential DDIs utilising in vitro data which can be highly advantageous in early drug development.

Neurofeedback Training versus Treatment-as-Usual for Alcohol Dependence: Results of an Early-Phase Randomized Controlled Trial and Neuroimaging Correlates.

INTRODUCTION: Alcohol dependence is one of the most common substance use disorders, and novel treatment options are urgently needed. Neurofeedback training (NFT) based on real-time functional magnetic resonance imaging (rtf-MRI) has emerged as an attractive candidate for add-on treatments in psychiatry, but its use in alcohol dependence has not been formally investigated in a clinical trial. We investigated the use of rtfMRI-based NFT to prevent relapse in alcohol dependence. METHODS: Fifty-two alcohol-dependent patients from the UK who had completed a detoxification program were randomly assigned to a treatment group (receiving rtfMRI NFT in addition to standard care) or the control group (receiving standard care only). At baseline, alcohol consumption was assessed as the primary outcome measure and a variety of psychological, behavioral, and neural parameters as secondary outcome measures to determine feasibility and secondary training effects. Participants in the treatment group underwent 6 NFT sessions over 4 months and were trained to downregulate their brain activation in the salience network in the presence of alcohol stimuli and to upregulate frontal activation in response to pictures related to positive goals. Four, 8, and 12 months after baseline assessment, both groups were followed up with a battery of clinical and psychometric tests. RESULTS: Primary outcome measures showed very low relapse rates for both groups. Analysis of neural secondary outcome measures indicated that the majority of patients modulated the salience system in the desired directions, by decreasing activity in response to alcohol stimuli and increasing activation in response to positive goals. The intervention had a good safety and acceptability profile. CONCLUSION: We demonstrated that rtfMRI-neurofeedback targeting hyperactivity of the salience network in response to alcohol cues is feasible in currently abstinent patients with alcohol dependence.

Graded fMRI Neurofeedback Training of Motor Imagery in Middle Cerebral Artery Stroke Patients: A Preregistered Proof-of-Concept Study.

Ischemic stroke of the middle cerebral artery (MCA), a major brain vessel that supplies the primary motor and premotor cortex, is one of the most common causes for severe upper limb impairment. Currently available motor rehabilitation training largely lacks satisfying efficacy with over 70% of stroke survivors showing residual upper limb dysfunction. Motor imagery-based functional magnetic resonance imaging neurofeedback (fMRI-NF) has been suggested as a potential therapeutic technique to improve motor impairment in stroke survivors. In this preregistered proof-of-concept study (https://osf.io/y69jc/), we translated graded fMRI-NF training, a new paradigm that we have previously studied in healthy participants, to first-time MCA stroke survivors with residual mild to severe impairment of upper limb motor function. Neurofeedback was provided from the supplementary motor area (SMA) targeting two different neurofeedback target levels (low and high). We hypothesized that MCA stroke survivors will show (1) sustained SMA-region of interest (ROI) activation and (2) a difference in SMA-ROI activation between low and high neurofeedback conditions during graded fMRI-NF training. At the group level, we found only anecdotal evidence for these preregistered hypotheses. At the individual level, we found anecdotal to moderate evidence for the absence of the hypothesized graded effect for most subjects. These null findings are relevant for future attempts to employ fMRI-NF training in stroke survivors. The study introduces a Bayesian sequential sampling plan, which incorporates prior knowledge, yielding higher sensitivity. The sampling plan was preregistered together with a priori hypotheses and all planned analysis before data collection to address potential publication/researcher biases. Unforeseen difficulties in the translation of our paradigm to a clinical setting required some deviations from the preregistered protocol. We explicitly detail these changes, discuss the accompanied additional challenges that can arise in clinical neurofeedback studies, and formulate recommendations for how these can be addressed. Taken together, this work provides new insights about the feasibility of motor imagery-based graded fMRI-NF training in MCA stroke survivors and serves as a first example for comprehensive study preregistration of an (fMRI) neurofeedback experiment.

Exon-focused targeted oligonucleotide microarray design increases detection of clinically relevant variants across multiple NHS genomic centres.

In recent years, chromosomal microarrays have been widely adopted by clinical diagnostic laboratories for postnatal constitutional genome analysis and have been recommended as the first-line test for patients with intellectual disability, developmental delay, autism and/or congenital abnormalities. Traditionally, array platforms have been designed with probes evenly spaced throughout the genome and increased probe density in regions associated with specific disorders with a resolution at the level of whole genes or multiple exons. However, this level of resolution often cannot detect pathogenic intragenic deletions or duplications, which represent a significant disease-causing mechanism. Therefore, new high-resolution oligonucleotide comparative genomic hybridisation arrays (oligo-array CGH) have been developed with probes targeting single exons of disease relevant genes. Here we present a retrospective study on 27,756 patient samples from a consortium of state-funded diagnostic UK genomic centres assayed by either oligo-array CGH of a traditional design (Cytosure ISCA v2) or by an oligo-array CGH with enhanced exon-level coverage of genes associated with developmental disorders (CytoSure Constitutional v3). The new targeted design used in Cytosure v3 array has been designed to capture intragenic aberrations that would have been missed on the v2 array. To assess the relative performance of the two array designs, data on a subset of samples (n = 19,675), generated only by laboratories using both array designs, were compared. Our results demonstrate that the new high-density exon-focused targeted array design that uses updated information from large scale genomic studies is a powerful tool for detection of intragenic deletions and duplications that leads to a significant improvement in diagnostic yield.

The role of the pre-commissural fornix in episodic autobiographical memory and simulation.

Neuropsychological and functional magnetic resonance imaging evidence suggests that the ability to vividly remember our personal past, and imagine future scenarios, involves two closely connected regions: the hippocampus and ventromedial prefrontal cortex (vmPFC). Despite evidence of a direct anatomical connection from hippocampus to vmPFC, it is unknown whether hippocampal-vmPFC structural connectivity supports both past- and future-oriented episodic thinking. To address this, we applied a novel deterministic tractography protocol to diffusion-weighted magnetic resonance imaging (dMRI) data from a group of healthy young adult humans who undertook an adapted past-future autobiographical interview (portions of this data were published in Hodgetts et al., 2017a). This tractography protocol enabled distinct subdivisions of the fornix, detected previously in axonal tracer studies, to be reconstructed in vivo, namely the pre-commissural (connecting the hippocampus to vmPFC) and post-commissural (linking the hippocampus and medial diencephalon) fornix. As predicted, we found that inter-individual differences in pre-commissural - but not post-commissural - fornix microstructure (fractional anisotropy) were significantly correlated with the episodic richness of both past and future autobiographical narratives. Notably, these results held when controlling for non-episodic narrative content, verbal fluency, and grey matter volumes of the hippocampus and vmPFC. This study provides novel evidence that reconstructing events from one's personal past, and constructing possible future events, involves a distinct, structurally-instantiated hippocampal-vmPFC pathway.

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.

On the sensitivity of event-related potentials to retrieval mode.

Event-related potential (ERP) signatures of preparation to retrieve episodic memories have been identified in several studies. A common finding is relatively more positive-going ERP activity over right-frontal sites when people prepare for episodic rather than semantic retrieval. This activity has been linked to the process of retrieval mode - a retrieval set that ensures subsequent events are treated as cues for episodic retrieval. This experiment was designed to test one explanation for why this putative index of retrieval mode was not observed in two recent experiments. Towards this end, ERPs were recorded time-locked to different task-cues indicating which of two retrieval tasks participants should prepare to complete. Each task-cue was followed by a retrieval-cue that required a memory judgment. Departures from the designs of the two studies in which null ERP results were obtained were intra-trial timings and the order in which task cues were presented. Frequentist statistics revealed that ERPs elicited by the task-cues did index preparation to retrieve. The topographies of these activities, however, did not overlap markedly with that of the putative index of retrieval mode reported previously. Bayesian analyses, moreover, provided little compelling evidence for a signature of retrieval mode. These outcomes prompt consideration of how ERP sensitivities to preparatory retrieval processing should be characterized.

The BOLD response in primary motor cortex and supplementary motor area during kinesthetic motor imagery based graded fMRI neurofeedback.

There is increasing interest in exploring the use of functional MRI neurofeedback (fMRI-NF) as a therapeutic technique for a range of neurological conditions such as stroke and Parkinson's disease (PD). One main therapeutic potential of fMRI-NF is to enhance volitional control of damaged or dysfunctional neural nodes and networks via a closed-loop feedback model using mental imagery as the catalyst of self-regulation. The choice of target node/network and direction of regulation (increase or decrease activity) are central design considerations in fMRI-NF studies. Whilst it remains unclear whether the primary motor cortex (M1) can be activated during motor imagery, the supplementary motor area (SMA) has been robustly activated during motor imagery. Such differences in the regulation potential between primary and supplementary motor cortex are important because these areas can be differentially affected by a stroke or PD, and the choice of fMRI-NF target and grade of self-regulation of activity likely have substantial influence on the clinical effects and cost effectiveness of NF-based interventions. In this study we therefore investigated firstly whether healthy subjects would be able to achieve self-regulation of the hand-representation areas of M1 and the SMA using fMRI-NF training. There was a significant decrease in M1 neural activity during fMRI-NF, whereas SMA neural activity was increased, albeit not with the predicated graded effect. This study has important implications for fMRI-NF protocols that employ motor imagery to modulate activity in specific target regions of the brain and to determine how they may be tailored for neurorehabilitation.

On the Antecedents of an Electrophysiological Signature of Retrieval Mode.

It has been proposed that people employ a common set of sustained operations (retrieval mode) when preparing to remember different kinds of episodic information. In two experiments, however, there was no evidence for the pattern of brain activity commonly assumed to index these operations. In both experiments event-related potentials (ERPs) were recorded time-locked to alternating preparatory cues signalling that participants should prepare for different retrieval tasks. One cue signalled episodic retrieval: remember the location where the object was presented in a prior study phase. The other signalled semantic retrieval: identify the location where the object is most commonly found (Experiment 1) or identify the typical size of the object (Experiment 2). In both experiments, only two trials of the same task were completed in succession. This enabled ERP contrasts between 'repeat' trials (the cue on the preceding trial signalled the same retrieval task), and 'switch' trials (the cue differed from the preceding trial). There were differences between the ERPs elicited by the preparatory task cues in Experiment 1 only: these were evident only on switch trials and comprised more positive-going activity over right-frontal scalp for the semantic than for the episodic task. These findings diverge from previous outcomes where the activity differentiating cues signalling preparation for episodic or semantic retrieval has been restricted to right-frontal scalp sites, comprising more positive-going activity for the episodic than for the semantic task. While these findings are consistent with the view that there is not a common set of operations engaged when people prepare to remember different kinds of episodic information, an alternative account is offered here, which is that these outcomes are a consequence of structural and temporal components of the experiment designs.

Are cattle dangerous to walkers? A scoping review.

Anecdotal evidence suggests that people coming into contact with cattle while participating in outdoor pursuits can sustain severe, even fatal injuries. This has negative implications for farmers, cattle and the public. This study outlines findings from a review of published literature, UK media reports and internet guidelines currently available to the UK public for walking near cattle. A total of 54 cattle attacks were reported in the UK media from 1 January 1993 to 31 May 2013; approximately one-quarter resulted in fatality and two-thirds involved dogs. Walking with dogs among cows, particularly with calves present, was a problematic context. Twenty pieces of commonly occurring advice were found within various guidelines. However, there are no definitive approved guidelines, no published studies describing the prevalence of cattle attacks on members of the public and no system in place to document them. Attacks by cattle are underinvestigated and further work should assess their public health impact.

Complex coupled metabolic and prokaryotic community responses to increasing temperatures in anaerobic marine sediments: critical temperatures and substrate changes.

The impact of temperature (0-80°C) on anaerobic biogeochemical processes and prokaryotic communities in marine sediments (tidal flat) was investigated in slurries for up to 100 days. Temperature had a non-linear effect on biogeochemistry and prokaryotes with rapid changes over small temperature intervals. Some activities (e.g. methanogenesis) had multiple 'windows' within a large temperature range (∼10 to 80°C). Others, including acetate oxidation, had maximum activities within a temperature zone, which varied with electron acceptor [metal oxide (up to ∼34°C) and sulphate (up to ∼50°C)]. Substrates for sulphate reduction changed from predominantly acetate below, and H2 above, a 43°C critical temperature, along with changes in activation energies and types of sulphate-reducing Bacteria. Above ∼43°C, methylamine metabolism ceased with changes in methanogen types and increased acetate concentrations (>1 mM). Abundances of uncultured Archaea, characteristic of deep marine sediments (e.g. MBGD Euryarchaeota, 'Bathyarchaeota') changed, indicating their possible metabolic activity and temperature range. Bacterial cell numbers were consistently higher than archaeal cells and both decreased above ∼15°C. Substrate addition stimulated activities, widened some activity temperature ranges (methanogenesis) and increased bacterial (×10) more than archaeal cell numbers. Hence, additional organic matter input from climate-related eutrophication may amplify the impact of temperature increases on sedimentary biogeochemistry.

Archaeal community diversity and abundance changes along a natural salinity gradient in estuarine sediments.

Archaea are widespread in marine sediments, but their occurrence and relationship with natural salinity gradients in estuarine sediments is not well understood. This study investigated the abundance and diversity of Archaea in sediments at three sites [Brightlingsea (BR), Alresford (AR) and Hythe (HY)] along the Colne Estuary, using quantitative real-time PCR (qPCR) of 16S rRNA genes, DNA hybridization, Archaea 16S rRNA and mcrA gene phylogenetic analyses. Total archaeal 16S rRNA abundance in sediments were higher in the low-salinity brackish sediments from HY (2-8 × 10(7) 16S rRNA gene copies cm(-3)) than the high-salinity marine sites from BR and AR (2 × 10(4)-2 × 10(7) and 4 × 10(6)-2 × 10(7) 16S rRNA gene copies cm(-3), respectively), although as a proportion of the total prokaryotes Archaea were higher at BR than at AR or HY. Phylogenetic analysis showed that members of the 'Bathyarchaeota' (MCG), Thaumarchaeota and methanogenic Euryarchaeota were the dominant groups of Archaea. The composition of Thaumarchaeota varied with salinity, as only 'marine' group I.1a was present in marine sediments (BR). Methanogen 16S rRNA genes from low-salinity sediments at HY were dominated by acetotrophic Methanosaeta and putatively hydrogentrophic Methanomicrobiales, whereas the marine site (BR) was dominated by mcrA genes belonging to methylotrophic Methanococcoides, versatile Methanosarcina and methanotrophic ANME-2a. Overall, the results indicate that salinity and associated factors play a role in controlling diversity and distribution of Archaea in estuarine sediments.

Electrophysiological evidence for retrieval mode immediately after a task switch.

It has been suggested that retrieving episodic information can involve adopting a cognitive state or set: retrieval mode. In a series of studies, an event-related potential (ERP) index of retrieval mode has been identified in designs which cue participants on a trial-by-trial basis to switch between preparing for and then completing an episodic or non-episodic retrieval task. However, a confound in these studies is that along with task type the content of what is to be retrieved has varied. Here we examined whether the ERP index of retrieval mode remains when the contents of an episodic and non-episodic task are highly similar - both requiring a location judgement. In the episodic task participants indicated the screen location where words had been shown in a prior study phase (left/right/new); whereas in the perceptual task they indicated the current screen location of the word (top/middle/bottom). Consistent with previous studies the ERPs elicited while participants prepared for episodic retrieval were more positive-going at right-frontal sites than when they prepared for the perceptual task. This index was observed, however, on the first trial after participants had switched tasks, rather than on the second trial, as has been observed previously. Potential reasons for this are discussed, including the critical manipulation of similarity in contents between tasks, as well as the use of a predictable cue sequence.

Effects of speed and accuracy instructions on performance in a visual search task by children with good or poor attention.

Children rated by teachers as having good or poor attention ability carried out a visual search task in which they were required to find a series of targets in a complex display. Different groups were told to concentrate on either speed or accuracy. Previous studies using this task have consistently shown that children rated as having poor attention make more errors (false alarms to non-targets in the display), but do not differ in the time to make a correct response; this result was replicated. Though the instructions produced wide differences in speed and error rates in the expected directions, these differences were similar in both attention groups and the differences in error rates between the two groups remained unchanged. It is suggested that these findings are not compatible with the view that children with poor attention make errors primarily due to fast impulsive responding, nor with an explanation in terms of slower processing of the input by such children. An alternative explanation of the high error rates in such children is offered in terms of weak executive function resulting in poor ability to inhibit false alarms to non-targets.