Introducing the Concept of Sanctuary Sites in Ischemic Stroke.

BACKGROUND: The topography of arterial territories has been defined using digital maps of supratentorial infarcts. Regions with a high probability of infarction (Pi) exist in the deep compartment due to a paucity of collaterals. However, less attention has been given to regions with a low Pi. METHODS: Using published digital maps, patients with cortical stroke and documented vessel occlusion were included. Infarcts from T2-weighted magnetic resonance images were segmented and registered onto a standard brain template (Montreal Neurological Institute 152). Segmented magnetic resonance images were averaged to yield the Pi at a voxel level. The overall Pi for the combined arterial territories was calculated to ensure that Pi was in the range of 0 to 1. Sanctuary sites were identified as regions with Pi <0.1. RESULTS: There were 154 patients (63% men; median age, 69 years; and interquartile range, 57-78 years). The magnetic resonance imaging scan used for segmentation was performed at a median interval of 35 (interquartile range, 3-66) days after stroke onset. Sanctuary sites were present in the frontal (gyrus rectus, the paracentral lobule, and orbitofrontal and precentral gyrus), parietal (postcentral, supramarginal, and angular gyrus, superior and inferior parietal lobule, and precuneus and posterior cingulate), and occipital cortex (cuneus, middle, and superior occipital gyrus). CONCLUSIONS: We propose that following vessel occlusion, there are cortical regions with a low Pi, which we termed sanctuary sites. The anatomic basis for this observation is the compensatory capacity of leptomeningeal collaterals.

Measures of Subjective Memory for People with Epilepsy: A Systematic Review of Measurement Properties.

People with epilepsy frequently express concern about the burden of memory problems in their everyday lives. Self-report memory questionnaires may provide valuable insight into individuals' perceptions of their everyday memory performance and changes over time. Yet, despite their potential utility, the measurement properties of self-report memory questionnaires have not been evaluated in epilepsy. This systematic review aimed to provide a critical appraisal of the measurement properties of self-report memory questionnaires for adults with epilepsy. Following protocol registration (PROSPERO CRD42020210967), a systematic search of PubMed, EMBASE, Web of Science, CINAHL, and PsychInfo from database inception until 27 May 2021 was conducted. Eligible studies were published in English-language peer-reviewed journals, recruited adults with epilepsy, and reported on the development or evaluation of the measurement properties of a self-report memory questionnaire. The COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) methodology was used to evaluate each study of a measurement property, and results were qualitatively synthesised. In total, 80 articles and one test manual were located containing 153 studies of measurement properties pertinent to 23 self-report memory questionnaires. Overall, no scale could be recommended outright for the evaluation of subjective memory symptoms in adults with epilepsy. This was due to the near absence of dedicated content validation studies relevant to this population and shortcomings in the methodology and scientific reporting of available studies of structural validity. Recommendations to support the advancement and psychometric validation of self-report memory questionnaires for people with epilepsy are provided.

Improved dynamic distortion correction for fMRI using single-echo EPI and a readout-reversed first image (REFILL).

The boundaries between tissues with different magnetic susceptibilities generate inhomogeneities in the main magnetic field which change over time due to motion, respiration and system instabilities. The dynamically changing field can be measured from the phase of the fMRI data and corrected. However, methods for doing so need multi-echo data, time-consuming reference scans and/or involve error-prone processing steps, such as phase unwrapping, which are difficult to implement robustly on the MRI host. The improved dynamic distortion correction method we propose is based on the phase of the single-echo EPI data acquired for fMRI, phase offsets calculated from a triple-echo, bipolar reference scan of circa 3-10 s duration using a method which avoids the need for phase unwrapping and an additional correction derived from one EPI volume in which the readout direction is reversed. This Reverse-Encoded First Image and Low resoLution reference scan (REFILL) approach is shown to accurately measure B0 as it changes due to shim, motion and respiration, even with large dynamic changes to the field at 7 T, where it led to a > 20% increase in time-series signal to noise ratio compared to data corrected with the classic static approach. fMRI results from REFILL-corrected data were free of stimulus-correlated distortion artefacts seen when data were corrected with static field mapping. The method is insensitive to shim changes and eddy current differences between the reference scan and the fMRI time series, and employs calculation steps that are simple and robust, allowing most data processing to be performed in real time on the scanner image reconstruction computer. These improvements make it feasible to routinely perform dynamic distortion correction in fMRI.

Social Cognition in Temporal and Frontal Lobe Epilepsy: Systematic Review, Meta-analysis, and Clinical Recommendations.

OBJECTIVE: Despite the importance of social cognitive functions to mental health and social adjustment, examination of these functions is absent in routine assessment of epilepsy patients. Thus, this review aims to provide a comprehensive overview of the literature on four major aspects of social cognition among temporal and frontal lobe epilepsy, which is a critical step toward designing new interventions. METHOD: Papers from 1990 to 2021 were reviewed and examined for inclusion in this study. After the deduplication process, a systematic review and meta-analysis of 44 and 40 articles, respectively, involving 113 people with frontal lobe epilepsy and 1482 people with temporal lobe epilepsy were conducted. RESULTS: Our results indicated that while patients with frontal or temporal lobe epilepsy have difficulties in all aspects of social cognition relative to nonclinical controls, the effect sizes were larger for theory of mind (g = .95), than for emotion recognition (g = .69) among temporal lobe epilepsy group. The frontal lobe epilepsy group exhibited significantly greater impairment in emotion recognition compared to temporal lobe. Additionally, people with right temporal lobe epilepsy (g =  1.10) performed more poorly than those with a left-sided (g = .90) seizure focus, specifically in the theory of mind domain. CONCLUSIONS: These data point to a potentially important difference in the severity of deficits within the emotion recognition and theory of mind abilities depending on the laterlization of seizure side. We also suggest a guide for the assessment of impairments in social cognition that can be integrated into multidisciplinary clinical evaluation for people with epilepsy.

Generalisation of continuous time random walk to anomalous diffusion MRI models with an age-related evaluation of human corpus callosum.

Diffusion MRI measures of the human brain provide key insight into microstructural variations across individuals and into the impact of central nervous system diseases and disorders. One approach to extract information from diffusion signals has been to use biologically relevant analytical models to link millimetre scale diffusion MRI measures with microscale influences. The other approach has been to represent diffusion as an anomalous transport process and infer microstructural information from the different anomalous diffusion equation parameters. In this study, we investigated how parameters of various anomalous diffusion models vary with age in the human brain white matter, particularly focusing on the corpus callosum. We first unified several established anomalous diffusion models (the super-diffusion, sub-diffusion, quasi-diffusion and fractional Bloch-Torrey models) under the continuous time random walk modelling framework. This unification allows a consistent parameter fitting strategy to be applied from which meaningful model parameter comparisons can be made. We then provided a novel way to derive the diffusional kurtosis imaging (DKI) model, which is shown to be a degree two approximation of the sub-diffusion model. This link between the DKI and sub-diffusion models led to a new robust technique for generating maps of kurtosis and diffusivity using the sub-diffusion parameters ßSUB and DSUB. Superior tissue contrast is achieved in kurtosis maps based on the sub-diffusion model. 7T diffusion weighted MRI data for 65 healthy participants in the age range 19-78 years was used in this study. Results revealed that anomalous diffusion model parameters α and ß have shown consistent positive correlation with age in the corpus callosum, indicating α and ß are sensitive to tissue microstructural changes in ageing.

Salience and default-mode network connectivity during threat and safety processing in older adults.

The appropriate assessment of threat and safety is important for decision-making but might be altered in old age due to neurobiological changes. The literature on threat and safety processing in older adults is sparse and it is unclear how healthy ageing affects the brain's functional networks associated with affective processing. We measured skin conductance responses as an indicator of sympathetic arousal and used functional magnetic resonance imaging and independent component analysis to compare young and older adults' functional connectivity in the default mode (DMN) and salience networks (SN) during a threat conditioning and extinction task. While our results provided evidence for differential threat processing in both groups, they also showed that functional connectivity within the SN - but not the DMN - was weaker during threat processing in older compared to young adults. This reduction of within-network connectivity was accompanied by an age-related decrease in low frequency spectral power in the SN and a reduction in inter-network connectivity between the SN and DMN during threat and safety processing. Similarly, we found that skin conductance responses were generally lower in older compared to young adults. Our results are the first to demonstrate age-related changes in brain activation during aversive conditioning and suggest that the ability to adaptively filter affective information is reduced in older adults.

Synthesis, isolation and characterisation of fluorinated-benzimidazoisoquinoline regioisomers.

A pair of novel fluorinated-benzimidazoisoquinoline regioisomers was synthesised and isolated. Initial structural characterisation and identification employed 1D proton, 1D carbon, correlated spectroscopy (COSY), heteronuclear single quantum coherence (HSQC), and heteronuclear multiple bond correlation (HMBC) nuclear magnetic resonance spectroscopy and mass spectrometry. However, the fluorinated regioisomers could not be differentiated using nuclear magnetic resonance (NMR) alone. Density functional theory calculations and single-crystal X-ray diffraction experiments were used to completely characterise and identify the compounds.

Investigation on the impact of three different quaternary methyl ammonium cartridges on the radiosynthetic yields of [18 F]fluoromethyl tosylate.

Our recent investigations for the radiosynthesis of [18 F]fluoromethyl tosylate have highlighted that choice of quaternary methyl ammonium (QMA) cartridge used during the radiosynthesis can significantly impact the radiochemical yields. Often the details of the QMA cartridge used in fluourine-18 syntheses are not fully described. However, our studies demonstrate that the type, the size, and nature (method by which it has been conditioned) of the QMA cartridge used during the radiosynthesis can make a significant impact in the labelling efficiency. This paper investigates the use of three QMA cartridges and demonstrates that radiochemical yield (decay corrected) of [18 F]fluoromethyl tosylate can increase from 46% to 60% by simply changing the QMA cartridge (and leaving all other reagents and labelling conditions exactly the same). These learnings may be applied to improve the radiochemical yields of a number of [18 F]-fluorinated tracers (and synthons), where the labelling step is base-sensitive to increase the radiochemical yield, thereby significantly benefiting the radiochemistry and nuclear medicine community. This paper also highlights the necessity of the radiochemistry community to ensure the details of QMA cartridges used in fluorine-18 chemistry are fully and accurately described, since this will improve the translation of radiochemical methods from one laboratory to another.

Synthesis of 18 F-radiolabeled diphenyl gallium dithiosemicarbazone using a novel halogen exchange method and in vivo biodistribution.

18 F-radiolabeled diphenyl gallium thiosemicarbazone was prepared by [18 F] fluoride exchange of a nitrato anion under mild conditions. The diphenyl gallium thiosemicarbazone chloride is easily prepared in gram quantities and can be used at room temperature in the presence of oxygen. The corresponding nitrate complex is prepared using silver nitrate in methanol solvent and can be stored under nitrogen for weeks before radiolabeling. The biodistribution of this new tracer was studied in mice using positron emission tomography (PET).

Evidence for a functional specialization of ventral anterior temporal lobe for language.

The controlled semantic cognition framework proposes that the ventral anterior temporal lobes (vATL) in the left and right hemisphere function as an integrated hub region supporting transmodal semantic representations. The clinical evidence for the transmodal function of vATL is largely based on studies of semantic dementia patients with severe anomia, who also show impaired performance on nonverbal tasks that involve the retrieval of knowledge about objects and their prototypical use, such as the production of tool use pantomimes. Yet, evidence from patients with apraxia and functional neuroimaging studies in healthy adults does not implicate vATL in pantomime production. We, therefore, compared semantic retrieval of object-action associations for overt verb and pantomime production from picture and word stimuli. Our results show that, independent of stimulus modality, the retrieval of object-action associations for verb, but not pantomime, production is related to activity in bilateral vATL. Bilateral vATL activation was also observed for meaningless verbal responses that did not require the retrieval of object-action associations. Taken together, our results suggest that bilateral vATL is not engaged in the retrieval of object-action associations per se, but rather supports semantic representations that are functionally specialized for language. These findings have implications for the semantic cognition framework and our understanding of the dependence of conceptual knowledge on language.

The 2018 correlative microscopy techniques roadmap.

Developments in microscopy have been instrumental to progress in the life sciences, and many new techniques have been introduced and led to new discoveries throughout the last century. A wide and diverse range of methodologies is now available, including electron microscopy, atomic force microscopy, magnetic resonance imaging, small-angle x-ray scattering and multiple super-resolution fluorescence techniques, and each of these methods provides valuable read-outs to meet the demands set by the samples under study. Yet, the investigation of cell development requires a multi-parametric approach to address both the structure and spatio-temporal organization of organelles, and also the transduction of chemical signals and forces involved in cell-cell interactions. Although the microscopy technologies for observing each of these characteristics are well developed, none of them can offer read-out of all characteristics simultaneously, which limits the information content of a measurement. For example, while electron microscopy is able to disclose the structural layout of cells and the macromolecular arrangement of proteins, it cannot directly follow dynamics in living cells. The latter can be achieved with fluorescence microscopy which, however, requires labelling and lacks spatial resolution. A remedy is to combine and correlate different readouts from the same specimen, which opens new avenues to understand structure-function relations in biomedical research. At the same time, such correlative approaches pose new challenges concerning sample preparation, instrument stability, region of interest retrieval, and data analysis. Because the field of correlative microscopy is relatively young, the capabilities of the various approaches have yet to be fully explored, and uncertainties remain when considering the best choice of strategy and workflow for the correlative experiment. With this in mind, the Journal of Physics D: Applied Physics presents a special roadmap on the correlative microscopy techniques, giving a comprehensive overview from various leading scientists in this field, via a collection of multiple short viewpoints.

An ontologically consistent MRI-based atlas of the mouse diencephalon.

In topological terms, the diencephalon lies between the hypothalamus and the midbrain. It is made up of three segments, prosomere 1 (pretectum), prosomere 2 (thalamus), and prosomere 3 (the prethalamus). A number of MRI-based atlases of different parts of the mouse brain have already been published, but none of them displays the segments the diencephalon and their component nuclei. In this study we present a new volumetric atlas identifying 89 structures in the diencephalon of the male C57BL/6J 12 week mouse. This atlas is based on an average of MR scans of 18 mouse brains imaged with a 16.4T scanner. This atlas is available for download at www.imaging.org.au/AMBMC. Additionally, we have created an FSL package to enable nonlinear registration of novel data sets to the AMBMC model and subsequent automatic segmentation.

Adaptive contextualization: A new role for the default mode network in affective learning.

Safety learning describes the ability to learn that certain cues predict the absence of a dangerous or threatening event. Although incidental observations of activity within the default mode network (DMN) during the processing of safety cues have been reported previously, there is as yet no evidence demonstrating that the DMN plays a functional rather than a corollary role in safety learning. Using functional magnetic resonance imaging and a Pavlovian fear conditioning and extinction paradigm, we investigated the neural correlates of danger and safety learning. Our results provide evidence for a functional role of the DMN by showing that (i) the DMN is activated by safety but not danger cues, (ii) the DMN is anti-correlated with a fear-processing network, and (iii) DMN activation increases with safety learning. Based on our results, we formulate a novel proposal, arguing that activity within the DMN supports the contextualization of safety memories, constrains the generalization of fear, and supports adaptive fear learning. Our findings have important implications for our understanding of affective and stress disorders, which are characterized by aberrant DMN activity, as they suggest that therapies targeting the DMN through mindfulness practice or brain stimulation might help prevent pathological over-generalization of fear associations. Hum Brain Mapp 38:1082-1091, 2017. © 2016 Wiley Periodicals, Inc.

Dynamic competition between large-scale functional networks differentiates fear conditioning and extinction in humans.

The high evolutionary value of learning when to respond to threats or when to inhibit previously learned associations after changing threat contingencies is reflected in dedicated networks in the animal and human brain. Recent evidence further suggests that adaptive learning may be dependent on the dynamic interaction of meta-stable functional brain networks. However, it is still unclear which functional brain networks compete with each other to facilitate associative learning and how changes in threat contingencies affect this competition. The aim of this study was to assess the dynamic competition between large-scale networks related to associative learning in the human brain by combining a repeated differential conditioning and extinction paradigm with independent component analysis of functional magnetic resonance imaging data. The results (i) identify three task-related networks involved in initial and sustained conditioning as well as extinction, and demonstrate that (ii) the two main networks that underlie sustained conditioning and extinction are anti-correlated with each other and (iii) the dynamic competition between these two networks is modulated in response to changes in associative contingencies. These findings provide novel evidence for the view that dynamic competition between large-scale functional networks differentiates fear conditioning from extinction learning in the healthy brain and suggest that dysfunctional network dynamics might contribute to learning-related neuropsychiatric disorders.

Genes influence the amplitude and timing of brain hemodynamic responses.

In functional magnetic resonance imaging (fMRI), the hemodynamic response function (HRF) reflects regulation of regional cerebral blood flow in response to neuronal activation. The HRF varies significantly between individuals. This study investigated the genetic contribution to individual variation in HRF using fMRI data from 125 monozygotic (MZ) and 149 dizygotic (DZ) twin pairs. The resemblance in amplitude, latency, and duration of the HRF in six regions in the frontal and parietal lobes was compared between MZ and DZ twin pairs. Heritability was estimated using an ACE (Additive genetic, Common environmental, and unique Environmental factors) model. The genetic influence on the temporal profile and amplitude of HRF was moderate to strong (24%-51%). The HRF may be used in the genetic analysis of diseases with a cerebrovascular etiology.

Selective channel combination of MRI signal phase.

PURPOSE: Signal magnitude can robustly be combined using the sum-of-squares approach. Methods have been developed to combine complex images. However, techniques based only on signal phase have not been developed and evaluated. THEORY AND METHODS: We performed simulations to demonstrate the effect of noise on coil combination. 32-channel 7 Tesla human gradient echo MRI brain data were collected. We combined phase images based on phase noise leading to spatially selective and coil selective combination of phase images. We compared our selective combination approach to optimal noise distribution and adaptive combination methods. RESULTS: We found that selective combination of signal phases leads to improved phase signal-to-noise ratio. Furthermore, a phase shift can be present in combined phase images introduced by the method used to combine multiple channel phases. CONCLUSION: Mapping of signal phase from ultra-high field MRI data undoubtedly provides a wealth of information about the ageing brain and the effects of neurodegenerative disorders. Measurement of signal phase is essential in frequency shift mapping and in quantitative susceptibility mapping. The method used to combine signal phase should be informed by an understanding of the noise distribution in signal phase at the individual channel level. Magn Reson Med 76:1469-1477, 2016. © 2015 International Society for Magnetic Resonance in Medicine.

Towards higher sensitivity and stability of axon diameter estimation with diffusion-weighted MRI.

Diffusion-weighted MRI is an important tool for in vivo and non-invasive axon morphometry. The ActiveAx technique utilises an optimised acquisition protocol to infer orientationally invariant indices of axon diameter and density by fitting a model of white matter to the acquired data. In this study, we investigated the factors that influence the sensitivity to small-diameter axons, namely the gradient strength of the acquisition protocol and the model fitting routine. Diffusion-weighted ex. vivo images of the mouse brain were acquired using 16.4-T MRI with high (Gmax of 300 mT/m) and ultra-high (Gmax of 1350 mT/m) gradient strength acquisitions. The estimated axon diameter indices of the mid-sagittal corpus callosum were validated using electron microscopy. In addition, a dictionary-based fitting routine was employed and evaluated. Axon diameter indices were closer to electron microscopy measures when higher gradient strengths were employed. Despite the improvement, estimated axon diameter indices (a lower bound of ~ 1.8 µm) remained higher than the measurements obtained using electron microscopy (~1.2 µm). We further observed that limitations of pulsed gradient spin echo (PGSE) acquisition sequences and axonal dispersion could also influence the sensitivity with which axon diameter indices could be estimated. Our results highlight the influence of acquisition protocol, tissue model and model fitting, in addition to gradient strength, on advanced microstructural diffusion-weighted imaging techniques. © 2016 The Authors. NMR in Biomedicine published by John Wiley & Sons Ltd.

Investigation of two- and three-bond carbon-hydrogen coupling constants in cinnamic acid based compounds.

Two- and three-bond coupling constants (2 JHC and 3 JHC ) were determined for a series of 12 substituted cinnamic acids using a selective 2D inphase/antiphase (IPAP)-single quantum multiple bond correlation (HSQMBC) and 1D proton coupled 13 C NMR experiments. The coupling constants from two methods were compared and found to give very similar values. The results showed coupling constant values ranging from 1.7 to 9.7 Hz and 1.0 to 9.6 Hz for the IPAP-HSQMBC and the direct 13 C NMR experiments, respectively. The experimental values of the coupling constants were compared with discrete density functional theory (DFT) calculated values and were found to be in good agreement for the 3 JHC . However, the DFT method under estimated the 2 JHC coupling constants. Knowing the limitations of the measurement and calculation of these multibond coupling constants will add confidence to the assignment of conformation or stereochemical aspects of complex molecules like natural products. Copyright © 2016 John Wiley & Sons, Ltd.

Comparison of experimental and DFT-calculated NMR chemical shifts of 2-amino and 2-hydroxyl substituted phenyl benzimidazoles, benzoxazoles and benzothiazoles in four solvents using the IEF-PCM solvation model.

A comparative study of experimental and calculated NMR chemical shifts of six compounds comprising 2-amino and 2-hydroxy phenyl benzoxazoles/benzothiazoles/benzimidazoles in four solvents is reported. The benzimidazoles showed interesting spectral characteristics, which are discussed. The proton and carbon chemical shifts were similar for all solvents. The largest chemical shift deviations were observed in benzene. The chemical shifts were calculated with density functional theory using a suite of four functionals and basis set combinations. The calculated chemical shifts revealed a good match to the experimentally observed values in most of the solvents. The mean absolute error was used as the primary metric. The use of an additional metric is suggested, which is based on the order of chemical shifts. The DP4 probability measures were also used to compare the experimental and calculated chemical shifts for each compound in the four solvents. Copyright © 2015 John Wiley & Sons, Ltd.

Brain tissue compartment density estimated using diffusion-weighted MRI yields tissue parameters consistent with histology.

We examined whether quantitative density measures of cerebral tissue consistent with histology can be obtained from diffusion magnetic resonance imaging (MRI). By incorporating prior knowledge of myelin and cell membrane densities, absolute tissue density values were estimated from relative intracellular and intraneurite density values obtained from diffusion MRI. The NODDI (neurite orientation distribution and density imaging) technique, which can be applied clinically, was used. Myelin density estimates were compared with the results of electron and light microscopy in ex vivo mouse brain and with published density estimates in a healthy human brain. In ex vivo mouse brain, estimated myelin densities in different subregions of the mouse corpus callosum were almost identical to values obtained from electron microscopy (diffusion MRI: 42 ± 6%, 36 ± 4%, and 43 ± 5%; electron microscopy: 41 ± 10%, 36 ± 8%, and 44 ± 12% in genu, body and splenium, respectively). In the human brain, good agreement was observed between estimated fiber density measurements and previously reported values based on electron microscopy. Estimated density values were unaffected by crossing fibers.