Resting-state functional connectivity in children cooled for neonatal encephalopathy.

Therapeutic hypothermia improves outcomes following neonatal hypoxic-ischaemic encephalopathy, reducing cases of death and severe disability such as cerebral palsy compared with normothermia management. However, when cooled children reach early school-age, they have cognitive and motor impairments which are associated with underlying alterations to brain structure and white matter connectivity. It is unknown whether these differences in structural connectivity are associated with differences in functional connectivity between cooled children and healthy controls. Resting-state functional MRI has been used to characterize static and dynamic functional connectivity in children, both with typical development and those with neurodevelopmental disorders. Previous studies of resting-state brain networks in children with hypoxic-ischaemic encephalopathy have focussed on the neonatal period. In this study, we used resting-state fMRI to investigate static and dynamic functional connectivity in children aged 6-8 years who were cooled for neonatal hypoxic-ischaemic without cerebral palsy [n = 22, median age (interquartile range) 7.08 (6.85-7.52) years] and healthy controls matched for age, sex and socioeconomic status [n = 20, median age (interquartile range) 6.75 (6.48-7.25) years]. Using group independent component analysis, we identified 31 intrinsic functional connectivity networks consistent with those previously reported in children and adults. We found no case-control differences in the spatial maps of these intrinsic connectivity networks. We constructed subject-specific static functional connectivity networks by measuring pairwise Pearson correlations between component time courses and found no case-control differences in functional connectivity after false discovery rate correction. To study the time-varying organization of resting-state networks, we used sliding window correlations and deep clustering to investigate dynamic functional connectivity characteristics. We found k = 4 repetitively occurring functional connectivity states, which exhibited no case-control differences in dwell time, fractional occupancy or state functional connectivity matrices. In this small cohort, the spatiotemporal characteristics of resting-state brain networks in cooled children without severe disability were too subtle to be differentiated from healthy controls at early school-age, despite underlying differences in brain structure and white matter connectivity, possibly reflecting a level of recovery of healthy resting-state brain function. To our knowledge, this is the first study to investigate resting-state functional connectivity in children with hypoxic-ischaemic encephalopathy beyond the neonatal period and the first to investigate dynamic functional connectivity in any children with hypoxic-ischaemic encephalopathy.

Simultaneous cortical, subcortical, and brainstem mapping of sensory activation.

Non-painful tactile sensory stimuli are processed in the cortex, subcortex, and brainstem. Recent functional magnetic resonance imaging (fMRI) studies have highlighted the value of whole-brain, systems-level investigation for examining pain processing. However, whole-brain fMRI studies are uncommon, in part due to challenges with signal to noise when studying the brainstem. Furthermore, the differentiation of small sensory brainstem structures such as the cuneate and gracile nuclei necessitates high resolution imaging. To address this gap in systems-level sensory investigation, we employed a whole-brain, multi-echo fMRI acquisition at 3T with multi-echo independent component analysis (ME-ICA) denoising and brainstem-specific modeling to enable detection of activation across the entire sensory system. In healthy participants, we examined patterns of activity in response to non-painful brushing of the right hand, left hand, and right foot, and found the expected lateralization, with distinct cortical and subcortical responses for upper and lower limb stimulation. At the brainstem level, we were able to differentiate the small, adjacent cuneate and gracile nuclei, corresponding to hand and foot stimulation respectively. Our findings demonstrate that simultaneous cortical, subcortical, and brainstem mapping at 3T could be a key tool to understand the sensory system in both healthy individuals and clinical cohorts with sensory deficits.

Spinal fMRI demonstrates segmental organisation of functionally connected networks in the cervical spinal cord: A test-retest reliability study.

Resting functional magnetic resonance imaging (fMRI) studies have identified intrinsic spinal cord activity, which forms organised motor (ventral) and sensory (dorsal) resting-state networks. However, to facilitate the use of spinal fMRI in, for example, clinical studies, it is crucial to first assess the reliability of the method, particularly given the unique anatomical, physiological, and methodological challenges associated with acquiring the data. Here, we characterise functional connectivity relationships in the cervical cord and assess their between-session test-retest reliability in 23 young healthy volunteers. Resting-state networks were estimated in two ways (1) by estimating seed-to-voxel connectivity maps and (2) by calculating seed-to-seed correlations. Seed regions corresponded to the four grey matter horns (ventral/dorsal and left/right) of C5-C8 segmental levels. Test-retest reliability was assessed using the intraclass correlation coefficient. Spatial overlap of clusters derived from seed-to-voxel analysis between sessions was examined using Dice coefficients. Following seed-to-voxel analysis, we observed distinct unilateral dorsal and ventral organisation of cervical spinal resting-state networks that was largely confined in the rostro-caudal extent to each spinal segmental level, with more sparse connections observed between segments. Additionally, strongest correlations were observed between within-segment ipsilateral dorsal-ventral connections, followed by within-segment dorso-dorsal and ventro-ventral connections. Test-retest reliability of these networks was mixed. Reliability was poor when assessed on a voxelwise level, with more promising indications of reliability when examining the average signal within clusters. Reliability of correlation strength between seeds was highly variable, with the highest reliability achieved in ipsilateral dorsal-ventral and dorso-dorsal/ventro-ventral connectivity. However, the spatial overlap of networks between sessions was excellent. We demonstrate that while test-retest reliability of cervical spinal resting-state networks is mixed, their spatial extent is similar across sessions, suggesting that these networks are characterised by a consistent spatial representation over time.

Ultradian hydrocortisone replacement alters neuronal processing, emotional ambiguity, affect and fatigue in adrenal insufficiency: The PULSES trial.

BACKGROUND: Primary adrenal insufficiency (PAI) mortality and morbidity remain unacceptably high, possibly arising as glucocorticoid replacement does not replicate natural physiology. A pulsatile subcutaneous pump can closely replicate cortisol's circadian and ultradian rhythm. OBJECTIVES: To assess the effect of pump therapy on quality of life, mood, functional neuroimaging, behavioural/cognitive responses, sleep and metabolism. METHODS: A 6-week randomised, crossover, double-blinded and placebo-controlled feasibility study of usual dose hydrocortisone in PAI administered as either pulsed subcutaneous or standard care in Bristol, United Kingdom (ISRCTN67193733). Participants were stratified by adrenal insufficiency type. All participants who received study drugs are included in the analysis. The primary outcome, the facial expression recognition task (FERT), occurred at week 6. RESULTS: Between December 2014 and 2017, 22 participants were recruited - 20 completed both arms, and 21 were analysed. The pump was well-tolerated. No change was seen in the FERT primary outcome; however, there were subjective improvements in fatigue and mood. Additionally, functional magnetic resonance imaging revealed differential neural processing to emotional cues and visual stimulation. Region of interest analysis identified the left amygdala and insula, key glucocorticoid-sensitive regions involved in emotional ambiguity. FERT post hoc analysis confirmed this response. There were four serious adverse events (AE): three intercurrent illnesses requiring hospitalisation (1/3, 33.3% pump) and a planned procedure (1/1, 100% pump). There was a small number of expected AEs: infusion site bruising/itching (3/5, 60% pump), intercurrent illness requiring extra (3/7, 42% pump) and no extra (4/6, 66% pump) steroid. CONCLUSIONS: These findings support the administration of hormone therapy that mimics physiology.

Reliability of resting-state functional connectivity in the human spinal cord: Assessing the impact of distinct noise sources.

The investigation of spontaneous fluctuations of the blood-oxygen-level-dependent (BOLD) signal has recently been extended from the brain to the spinal cord, where it has stimulated interest from a clinical perspective. A number of resting-state functional magnetic resonance imaging (fMRI) studies have demonstrated robust functional connectivity between the time series of BOLD fluctuations in bilateral dorsal horns and between those in bilateral ventral horns, in line with the functional neuroanatomy of the spinal cord. A necessary step prior to extension to clinical studies is assessing the reliability of such resting-state signals, which we aimed to do here in a group of 45 healthy young adults at the clinically prevalent field strength of 3T. When investigating connectivity in the entire cervical spinal cord, we observed fair to good reliability for dorsal-dorsal and ventral-ventral connectivity, whereas reliability was poor for within- and between-hemicord dorsal-ventral connectivity. Considering how prone spinal cord fMRI is to noise, we extensively investigated the impact of distinct noise sources and made two crucial observations: removal of physiological noise led to a reduction in functional connectivity strength and reliability - due to the removal of stable and participant-specific noise patterns - whereas removal of thermal noise considerably increased the detectability of functional connectivity without a clear influence on reliability. Finally, we also assessed connectivity within spinal cord segments and observed that while the pattern of connectivity was similar to that of whole cervical cord, reliability at the level of single segments was consistently poor. Taken together, our results demonstrate the presence of reliable resting-state functional connectivity in the human spinal cord even after thoroughly accounting for physiological and thermal noise, but at the same time urge caution if focal changes in connectivity (e.g. due to segmental lesions) are to be studied, especially in a longitudinal manner.

Mammillary body abnormalities and cognitive outcomes in children cooled for neonatal encephalopathy.

AIM: To evaluate mammillary body abnormalities in school-age children without cerebral palsy treated with therapeutic hypothermia for neonatal hypoxic-ischaemic encephalopathy (cases) and matched controls, and associations with cognitive outcome, hippocampal volume, and diffusivity in the mammillothalamic tract (MTT) and fornix. METHOD: Mammillary body abnormalities were scored from T1-weighted magnetic resonance imaging (MRI) in 32 cases and 35 controls (median age [interquartile range] 7 years [6 years 7 months-7 years 7 months] and 7 years 4 months [6 years 7 months-7 years 7 months] respectively). Cognition was assessed using the Wechsler Intelligence Scale for Children, Fourth Edition. Hippocampal volume (normalized by total brain volume) was measured from T1-weighted MRI. Radial diffusivity and fractional anisotropy were measured in the MTT and fornix, from diffusion-weighted MRI using deterministic tractography. RESULTS: More cases than controls had mammillary body abnormalities (34% vs 0%; p < 0.001). Cases with abnormal mammillary bodies had lower processing speed (p = 0.016) and full-scale IQ (p = 0.028) than cases without abnormal mammillary bodies, and lower scores than controls in all cognitive domains (p < 0.05). Cases with abnormal mammillary bodies had smaller hippocampi (left p = 0.016; right p = 0.004) and increased radial diffusivity in the right MTT (p = 0.004) compared with cases without mammillary body abnormalities. INTERPRETATION: Cooled children with mammillary body abnormalities at school-age have reduced cognitive scores, smaller hippocampi, and altered MTT microstructure compared with those without mammillary body abnormalities, and matched controls. WHAT THIS PAPER ADDS: Cooled children are at higher risk of mammillary body abnormalities than controls. Abnormal mammillary bodies are associated with reduced cognitive scores and smaller hippocampi. Abnormal mammillary bodies are associated with altered mammillothalamic tract diffusivity.

Development of the corpus callosum and cognition after neonatal encephalopathy.

OBJECTIVE: Neonatal imaging studies report corpus callosum abnormalities after neonatal hypoxic-ischaemic encephalopathy (HIE), but corpus callosum development and relation to cognition in childhood are unknown. Using magnetic resonance imaging (MRI), we examined the relationship between corpus callosum size, microstructure and cognitive and motor outcomes at early school-age children cooled for HIE (cases) without cerebral palsy compared to healthy, matched controls. A secondary aim was to examine the impact of HIE-related neonatal brain injury on corpus callosum size, microstructure and growth. METHODS: Participants aged 6-8 years underwent MRI, the Movement Assessment Battery for Children Second Edition and Wechsler Intelligence Scale for Children Fourth Edition. Cross-sectional area, volume, fractional anisotropy and radial diffusivity of the corpus callosum and five subdivisions were measured. Multivariable regression was used to assess associations between total motor score, full-scale IQ (FSIQ) and imaging metrics. RESULTS: Adjusting for age, sex and intracranial volume, cases (N = 40) compared to controls (N = 39) demonstrated reduced whole corpus callosum area (ß = -26.9, 95% confidence interval [CI] = -53.17, -0.58), volume (ß = -138.5, 95% CI = -267.54, -9.56), fractional anisotropy and increased radial diffusivity (P < 0.05) within segments II-V. In cases, segment V area (ß = 0.18, 95% CI = 0.004, 0.35), volume (ß = 0.04, 95% CI = 0.001, 0.079), whole corpus callosum fractional anisotropy (ß = 13.8 95% CI = 0.6, 27.1) and radial diffusivity (ß = -11.3, 95% CI = -22.22, -0.42) were associated with FSIQ. Growth of the corpus callosum was restricted in cases with a FSIQ ≤85, and volume was reduced in cases with mild neonatal multifocal injury compared to white matter injury alone. INTERPRETATION: Following neonatal HIE, morphological and microstructural changes in the corpus callosum are associated with reduced cognitive function at early school age.

Brain volumes and functional outcomes in children without cerebral palsy after therapeutic hypothermia for neonatal hypoxic-ischaemic encephalopathy.

AIM: To investigate whether brain volumes were reduced in children aged 6 to 8 years without cerebral palsy, who underwent therapeutic hypothermia for neonatal hypoxic-ischaemic encephalopathy (patients), and matched controls, and to examine the relation between subcortical volumes and functional outcome. METHOD: We measured regional brain volumes in 31 patients and 32 controls (median age 7 years and 7 years 2 months respectively) from T1-weighted magnetic resonance imaging (MRI). We assessed cognition using the Wechsler Intelligence Scales for Children, Fourth Edition and motor ability using the Movement Assessment Battery for Children, Second Edition (MABC-2). RESULTS: Patients had lower volume of whole-brain grey matter, white matter, pallidi, hippocampi, and thalami than controls (false discovery rate-corrected p < 0.05). Differences in subcortical grey-matter volumes were not independent of total brain volume (TBV). In patients, hippocampal and thalamic volumes correlated with full-scale IQ (hippocampi, r = 0.477, p = 0.010; thalami, r = 0.452, p = 0.016) and MABC-2 total score (hippocampi, r = 0.526, p = 0.004; thalami, r = 0.505, p = 0.006) independent of age, sex, and TBV. No significant correlations were found in controls. In patients, cortical injury on neonatal MRI was associated with reduced volumes of hippocampi (p = 0.001), thalami (p = 0.002), grey matter (p = 0.015), and white matter (p = 0.013). INTERPRETATION: Children who underwent therapeutic hypothermia have reduced whole-brain grey and white-matter volumes, with associations between hippocampal and thalamic volumes and functional outcomes.

Reliability of task-based fMRI in the dorsal horn of the human spinal cord.

The application of functional magnetic resonance imaging (fMRI) to the human spinal cord is still a relatively small field of research and faces many challenges. Here we aimed to probe the limitations of task-based spinal fMRI at 3T by investigating the reliability of spinal cord blood oxygen level dependent (BOLD) responses to repeated nociceptive stimulation across two consecutive days in 40 healthy volunteers. We assessed the test-retest reliability of subjective ratings, autonomic responses, and spinal cord BOLD responses to short heat pain stimuli (1s duration) using the intraclass correlation coefficient (ICC). At the group level, we observed robust autonomic responses as well as spatially specific spinal cord BOLD responses at the expected location, but no spatial overlap in BOLD response patterns across days. While autonomic indicators of pain processing showed good-to-excellent reliability, both ß-estimates and z-scores of task-related BOLD responses showed poor reliability across days in the target region (gray matter of the ipsilateral dorsal horn). When taking into account the sensitivity of gradient-echo echo planar imaging (GE-EPI) to draining vein signals by including the venous plexus in the analysis, we observed BOLD responses with good reliability across days. Taken together, these results demonstrate that heat pain stimuli as short as one second are able to evoke a robust and spatially specific BOLD response, which is however strongly variable within participants across time, resulting in low reliability in the dorsal horn gray matter. Further improvements in data acquisition and analysis techniques are thus necessary before event-related spinal cord fMRI as used here can be reliably employed in longitudinal designs or clinical settings.

Automated slice-specific z-shimming for functional magnetic resonance imaging of the human spinal cord.

Functional magnetic resonance imaging (fMRI) of the human spinal cord faces many challenges, such as signal loss due to local magnetic field inhomogeneities. This issue can be addressed with slice-specific z-shimming, which compensates for the dephasing effect of the inhomogeneities using a slice-specific gradient pulse. Here, we aim to address outstanding issues regarding this technique by evaluating its effects on several aspects that are directly relevant for spinal fMRI and by developing two automated procedures in order to improve upon the time-consuming and subjective nature of manual selection of z-shims: one procedure finds the z-shim that maximizes signal intensity in each slice of an EPI reference-scan and the other finds the through-slice field inhomogeneity for each EPI-slice in field map data and calculates the required compensation gradient moment. We demonstrate that the beneficial effects of z-shimming are apparent across different echo times, hold true for both the dorsal and ventral horn, and are also apparent in the temporal signal-to-noise ratio (tSNR) of EPI time-series data. Both of our automated approaches were faster than the manual approach, lead to significant improvements in gray matter tSNR compared to no z-shimming and resulted in beneficial effects that were stable across time. While the field-map-based approach performed slightly worse than the manual approach, the EPI-based approach performed as well as the manual one and was furthermore validated on an external corticospinal data-set (N > 100). Together, automated z-shimming may improve the data quality of future spinal fMRI studies and lead to increased reproducibility in longitudinal studies.

Sensory and motor electrophysiological mapping of the cerebellum in humans.

Cerebellar damage during posterior fossa surgery in children can lead to ataxia and risk of cerebellar mutism syndrome. Compartmentalisation of sensorimotor and cognitive functions within the cerebellum have been demonstrated in animal electrophysiology and human imaging studies. Electrophysiological monitoring was carried out under general anaesthesia to assess the limb sensorimotor representation within the human cerebellum for assessment of neurophysiological integrity to reduce the incidence of surgical morbidities. Thirteen adult and paediatric patients undergoing posterior fossa surgery were recruited. Sensory evoked field potentials were recorded in response to mapping (n = 8) to electrical stimulation of limb nerves or muscles. For motor mapping (n = 5), electrical stimulation was applied to the surface of the cerebellum and evoked EMG responses were sought in facial and limb muscles. Sensory evoked potentials were found in two patients (25%). Responses were located on the surface of the right inferior posterior cerebellum to stimulation of the right leg in one patient, and on the left inferior posterior lobe in another patient to stimulation of left forearm. No evoked EMG responses were found for the motor mapping. The present study identifies challenges with using neurophysiological methods to map functional organization within the human cerebellum and considers ways to improve success.

Central pain modulatory mechanisms of attentional analgesia are preserved in fibromyalgia.

ABSTRACT: Fibromyalgia is a prevalent pain condition that is associated with cognitive impairments including in attention, memory, and executive processing. It has been proposed that fibromyalgia may be caused by altered central pain processing characterised by a loss of endogenous pain modulation. We tested whether attentional analgesia, where cognitive engagement diminishes pain percept, was attenuated in patients with fibromyalgia (n = 20) compared with matched healthy controls (n = 20). An individually calibrated, attentional analgesia paradigm with a 2 × 2 factorial design was used with brain and brainstem-focussed functional magnetic resonance imaging. Patients with fibromyalgia had both lower heat pain thresholds and speeds in a visual attention task. When this was taken into account for both attentional task and thermal stimulation, both groups exhibited an equivalent degree of attentional analgesia. Functional magnetic resonance imaging analysis showed similar patterns of activation in the main effects of pain and attention in the brain and brainstem (with the sole exceptions of increased activation in the control group in the frontopolar cortex and the ipsilateral locus coeruleus). The attentional analgesic effect correlated with activity in the periaqueductal gray and rostral ventromedial medulla. These findings indicate that patients with fibromyalgia can engage the descending pain modulatory system if the attentional task and noxious stimulus intensity are appropriately titrated.

An Age-Specific Atlas for Delineation of White Matter Pathways in Children Aged 6-8 Years.

Introduction: Diffusion magnetic resonance imaging (MRI) allows noninvasive assessment of white matter connectivity in typical development and of changes due to brain injury or pathology. Probabilistic white matter atlases allow diffusion metrics to be measured in specific white matter pathways, and are a critical component in spatial normalization for group analysis. However, given the known developmental changes in white matter it may be suboptimal to use an adult template when assessing data acquired from children. Methods: By averaging subject-specific fiber bundles from 28 children aged from 6 to 8 years, we created an age-specific probabilistic white matter atlas for 12 major white matter tracts. Using both the newly developed and Johns Hopkins adult atlases, we compared the atlas with subject-specific fiber bundles in two independent validation cohorts, assessing accuracy in terms of volumetric overlap and measured diffusion metrics. Results: Our age-specific atlas gave better overall performance than the adult atlas, achieving higher volumetric overlap with subject-specific fiber tracking and higher correlation of fractional anisotropy (FA) measurements with those measured from subject-specific fiber bundles. Specifically, estimates of FA values for corticospinal tract, uncinate fasciculus, forceps minor, cingulate gyrus part of the cingulum, and anterior thalamic radiation were all significantly more accurate when estimated with an age-specific atlas. Discussion: The age-specific atlas allows delineation of white matter tracts in children aged 6-8 years, without the need for tractography, more accurately than when normalizing to an adult atlas. To our knowledge, this is the first publicly available probabilistic atlas of white matter tracts for this age group.

Motor function and white matter connectivity in children cooled for neonatal encephalopathy.

Therapeutic hypothermia reduces the incidence of severe motor disability, such as cerebral palsy, following neonatal hypoxic-ischaemic encephalopathy. However, cooled children without cerebral palsy at school-age demonstrate motor deficits and altered white matter connectivity. In this study, we used diffusion-weighted imaging to investigate the relationship between white matter connectivity and motor performance, measured using the Movement Assessment Battery for Children-2, in children aged 6-8 years treated with therapeutic hypothermia for neonatal hypoxic-ischaemic encephalopathy at birth, who did not develop cerebral palsy (cases), and matched typically developing controls. Correlations between total motor scores and diffusion properties in major white matter tracts were assessed in 33 cases and 36 controls. In cases, significant correlations (FDR-corrected P < 0.05) were found in the anterior thalamic radiation bilaterally (left: r = 0.513; right: r = 0.488), the cingulate gyrus part of the left cingulum (r = 0.588), the hippocampal part of the left cingulum (r = 0.541), and the inferior fronto-occipital fasciculus bilaterally (left: r = 0.445; right: r = 0.494). No significant correlations were found in controls. We then constructed structural connectivity networks, for 22 cases and 32 controls, in which nodes represent brain regions and edges were determined by probabilistic tractography and weighted by fractional anisotropy. Analysis of whole-brain network metrics revealed correlations (FDR-corrected P < 0.05), in cases, between total motor scores and average node strength (r = 0.571), local efficiency (r = 0.664), global efficiency (r = 0.677), clustering coefficient (r = 0.608), and characteristic path length (r = -0.652). No significant correlations were found in controls. We then investigated edge-level association with motor function using the network-based statistic. This revealed subnetworks which exhibited group differences in the association between motor outcome and edge weights, for total motor scores (P = 0.0109) as well as for balance (P = 0.0245) and manual dexterity (P = 0.0233) domain scores. All three of these subnetworks comprised numerous frontal lobe regions known to be associated with motor function, including the superior frontal gyrus and middle frontal gyrus. The subnetwork associated with total motor scores was highly left-lateralised. These findings demonstrate an association between impaired motor function and brain organisation in school-age children treated with therapeutic hypothermia for neonatal hypoxic-ischaemic encephalopathy.

Disrupted brain connectivity in children treated with therapeutic hypothermia for neonatal encephalopathy.

Therapeutic hypothermia following neonatal encephalopathy due to birth asphyxia reduces death and cerebral palsy. However, school-age children without cerebral palsy treated with therapeutic hypothermia for neonatal encephalopathy still have reduced performance on cognitive and motor tests, attention difficulties, slower reaction times and reduced visuo-spatial processing abilities compared to typically developing controls. We acquired diffusion-weighted imaging data from school-age children without cerebral palsy treated with therapeutic hypothermia for neonatal encephalopathy at birth, and a matched control group. Voxelwise analysis (33 cases, 36 controls) confirmed reduced fractional anisotropy in widespread areas of white matter in cases, particularly in the fornix, corpus callosum, anterior and posterior limbs of the internal capsule bilaterally and cingulum bilaterally. In structural brain networks constructed using probabilistic tractography (22 cases, 32 controls), graph-theoretic measures of strength, local and global efficiency, clustering coefficient and characteristic path length were found to correlate with IQ in cases but not controls. Network-based statistic analysis implicated brain regions involved in visuo-spatial processing and attention, aligning with previous behavioural findings. These included the precuneus, thalamus, left superior parietal gyrus and left inferior temporal gyrus. Our findings demonstrate that, despite the manifest successes of therapeutic hypothermia, brain development is impaired in these children.

Parallel cortical-brainstem pathways to attentional analgesia.

Pain demands attention, yet pain can be reduced by focusing attention elsewhere. The neural processes involved in this robust psychophysical phenomenon, attentional analgesia, are still being defined. Our previous fMRI study linked activity in the brainstem triad of locus coeruleus (LC), rostral ventromedial medulla (RVM) and periaqueductal grey (PAG) with attentional analgesia. Here we identify and model the functional interactions between these regions and the cortex in healthy human subjects (n = 57), who received painful thermal stimuli whilst simultaneously performing a visual attention task. RVM activity encoded pain intensity while contralateral LC activity correlated with attentional analgesia. Psycho-Physiological Interaction analysis and Dynamic Causal Modelling identified two parallel paths between forebrain and brainstem. These connections are modulated by attentional demand: a bidirectional anterior cingulate cortex (ACC) - right-LC loop, and a top-down influence of task on ACC-PAG-RVM. By recruiting discrete brainstem circuits, the ACC is able to modulate nociceptive input to reduce pain in situations of conflicting attentional demand.

Cerebral Blood Flow Response to Simulated Hypovolemia in Essential Hypertension: A Magnetic Resonance Imaging Study.

Hypertension is associated with raised cerebral vascular resistance and cerebrovascular remodeling. It is currently unclear whether the cerebral circulation can maintain cerebral blood flow (CBF) during reductions in cardiac output (CO) in hypertensive patients thereby avoiding hypoperfusion of the brain. We hypothesized that hypertension would impair the ability to effectively regulate CBF during simulated hypovolemia. In the present study, 39 participants (13 normotensive, 13 controlled, and 13 uncontrolled hypertensives; mean age±SD, 55±10 years) underwent lower body negative pressure (LBNP) at -20, -40, and -50 mmHg to decrease central blood volume. Phase-contrast MR angiography was used to measure flow in the basilar and internal carotid arteries, as well as the ascending aorta. CBF and CO decreased during LBNP (P<0.0001). Heart rate increased during LBNP, reaching significance at -50 mmHg (P<0.0001). There was no change in mean arterial pressure during LBNP (P=0.3). All participants showed similar reductions in CBF (P=0.3, between groups) and CO (P=0.7, between groups) during LBNP. There was no difference in resting CBF between the groups (P=0.36). In summary, during reductions in CO induced by hypovolemic stress, mean arterial pressure is maintained but CBF declines indicating that CBF is dependent on CO in middle-aged normotensive and hypertensive volunteers. Hypertension is not associated with impairments in the CBF response to reduced CO.

Sensorimotor, language, and working memory representation within the human cerebellum.

The cerebellum is involved in a wide range of behaviours. A key organisational principle from animal studies is that somatotopically corresponding sensory input and motor output reside in the same cerebellar cortical areas. However, compelling evidence for a similar arrangement in humans and whether it extends to cognitive functions is lacking. To address this, we applied cerebellar optimised whole-brain functional MRI in 20 healthy subjects. To assess spatial overlap within the sensorimotor and cognitive domains, we recorded activity to a sensory stimulus (vibrotactile) and a motor task; the Sternberg verbal working memory (VWM) task; and a verb generation paradigm. Consistent with animal data, sensory and motor activity overlapped with a somatotopic arrangement in ipsilateral areas of the anterior and posterior cerebellum. During the maintenance phase of the Sternberg task, a positive linear relationship between VWM load and activity was observed in right Lobule VI, extending into Crus I bilaterally. Articulatory movement gave rise to bilateral activity in medial Lobule VI. A conjunction of two independent language tasks localised activity during verb generation in right Lobule VI-Crus I, which overlapped with activity during VWM. These results demonstrate spatial compartmentalisation of sensorimotor and cognitive function in the human cerebellum, with each area involved in more than one aspect of a given behaviour, consistent with an integrative function. Sensorimotor localisation was uniform across individuals, but the representation of cognitive tasks was more variable, highlighting the importance of individual scans for mapping higher order functions within the cerebellum.

Keeping track of 'alternative facts': The neural correlates of processing misinformation corrections.

Upon receiving a correction, initially presented misinformation often continues to influence people's judgment and reasoning. Whereas some researchers believe that this so-called continued influence effect of misinformation (CIEM) simply arises from the insufficient encoding and integration of corrective claims, others assume that it arises from a competition between the correct information and the initial misinformation in memory. To examine these possibilities, we conducted two functional magnetic resonance imaging (fMRI) studies. In each study, participants were asked to (a) read a series of brief news reports that contained confirmations or corrections of prior information and (b) evaluate whether subsequently presented memory probes matched the reports' correct facts rather than the initial misinformation. Both studies revealed that following correction-containing news reports, participants struggled to refute mismatching memory probes, especially when they referred to initial misinformation (as opposed to mismatching probes with novel information). We found little evidence, however, that the encoding of confirmations and corrections produced systematic neural processing differences indicative of distinct encoding strategies. Instead, we discovered that following corrections, participants exhibited increased activity in the left angular gyrus and the bilateral precuneus in response to mismatching memory probes that contained prior misinformation, compared to novel mismatch probes. These findings favour the notion that people's susceptibility to the CIEM arises from the concurrent retention of both correct and incorrect information in memory.

Exploring the neural substrates of misinformation processing.

It is well known that information that is initially thought to be correct but then revealed to be false, often continues to influence human judgement and decision making despite people being aware of the retraction. Yet little research has examined the underlying neural substrates of this phenomenon, which is known as the 'continued influence effect of misinformation' (CIEM). It remains unclear how the human brain processes critical information that retracts prior claims. To address this question in further detail, 26 healthy adults underwent functional magnetic resonance imaging (fMRI) while listening to brief narratives which either involved a retraction of prior information or not. Following each narrative, subjects' comprehension of the narrative, including their inclination to rely on retracted information, was probed. As expected, it was found that retracted information continued to affect participants' narrative-related reasoning. In addition, the fMRI data indicated that the continued influence of retracted information may be due to a breakdown of narrative-level integration and coherence-building mechanisms implemented by the precuneus and posterior cingulate gyrus.