Lloyd Gregory - Academia.edu (original) (raw)

Papers by Lloyd Gregory

Exploring relationships for visceral and somatic pain with autonomic control and personality

Pain, 2009

The autonomic nervous system (ANS) integrates afferent and motor activity for homeostatic process... more The autonomic nervous system (ANS) integrates afferent and motor activity for homeostatic processes including pain. The aim of the study was to compare hitherto poorly characterised relations between brainstem autonomic control and personality in response to visceral and somatic pain. Eighteen healthy subjects (16 females, mean age 34) had recordings during rest and pain of heart rate (HR), cardiac vagal tone (CVT), cardiac sensitivity to baroreflex (CSB), skin conductance level (SC), cardiac sympathetic index (CSI) and mean blood pressure (MBP). Visceral pain was induced by balloon distension in proximal (PB) and distal (DB) oesophagus and somatic pain by nail-bed pressure (NBP). Eight painful stimuli were delivered at each site and unpleasantness and intensity measured. Personality was profiled with the Big Five inventory. (1) Oesophageal intubation evoked "fight-flight" responses: HR and sympathetic (CSI, SC, MBP) elevation with parasympathetic (CVT) withdrawal (p<0.05). (2) Pain at all sites evoked novel parasympathetic/sympathetic co-activation with elevated HR but vasodepression (all p<0.05). (3) Personality traits correlated with slope of distal oesophageal pain-related CVT changes wherein more neurotic-introvert subjects had greater positive pain-related CVT slope change (neuroticism r 0.8, p<0.05; extroversion r -0.5, p<0.05). Pain-evoked heart rate increases were mediated by parasympathetic and sympathetic co-activation - a novel finding in humans but recently described in mammals too. Visceral pain-related parasympathetic change correlated with personality. ANS defence responses are nuanced and may relate to personality type for visceral pain. Clinical relevance of these findings warrants further exploration.

Neuropsychologia, 2002

Functional magnetic resonance imaging (fMRI) was used to examine whether (1) verbal associative e... more Functional magnetic resonance imaging (fMRI) was used to examine whether (1) verbal associative encoding activates the medial temporal lobes (MTL) and related regions more than non-associative encoding, (2) verbal associative novelty is related to enhanced MTL activation, and (3) verbal item novelty is related to enhanced MTL activation and, if so, whether these activations are in different or overlapping sites. No increase in MTL activation was found during verbal associative encoding relative to non-associative encoding, although associative encoding was related to a relative increase in activation in the posterior cingulate cortex. In contrast, verbal associative novelty was found to activate the MTL and posterior cingulate cortex. Verbal item novelty did not significantly activate any brain region. The verbal associative novelty-related effect occurred despite subjects having little awareness of associative novelty. The verbal associative novelty-related activation in the MTL may be related either to unconscious novelty detection or to a priming effect at encoding. We argue that if the priming explanation is correct then this may account for our failure to observe an associative encoding MTL activation.

Psychosomatic Medicine, 2010

Objective: Anxiety at the time of gastrointestinal injury or inflammation increases the risk of d... more Objective: Anxiety at the time of gastrointestinal injury or inflammation increases the risk of developing visceral hyperalgesia. Distal esophageal acidification induces hyperalgesia in the non-acid exposed proximal esophagus, due to the sensitization of spinal dorsal horn neurones. The objective was to determine whether anxiety influences acid-induced hyperalgesia. Methods: A total of 19 healthy volunteers (n ϭ 12 females; age, 22-57 years; mean, 35.7 years) completed a 10-minute mood induction paradigm (anxiety or neutral) with autonomic monitoring (visit 1). On visits 2 and 3, pain thresholds to electrical stimulation, in milliamperes (mA), were determined in the proximal esophagus and foot (control) before and after a 30-minute infusion of 0.15 M of hydrochloric acid. During esophageal acid infusion, the subjects randomly received anxiety or neutral mood induction with autonomic monitoring, in a crossover design. Anxiety and pain ratings were recorded pre and post infusion. Results: Visit 1: Anxiety induction increased anxiety scores (p Ͻ .001), mean arterial pressure (p Ͻ .001), and cardiac sympathetic index (p ϭ .007), and reduced parasympathetic measures (cardiac vagal tone [p ϭ .05] and cardiac sensitivity to baroreflex [p ϭ .006)]). Visit 2: Anxiety induction conferred greater acid-induced hyperalgesia compared with neutral (Ϫ4.9 mA versus 2.7 mA, p ϭ .009, analysis of covariance). No differences in autonomic measures were found during acid infusion with anxiety or neutral mood induction. Conclusions: Anxiety induction increases acid-induced esophageal hyperalgesia; anxiety, thus, facilitates central sensitization in the esophagus. Our studies provide a new model for studying the effects of anxiety on esophageal hyperalgesia and may allow testing of therapeutic strategies to reduce this effect.

NeuroImage, 1996

Many ''higher-order'' mental functions are subserved by large-scale neurocognitive networks compr... more Many ''higher-order'' mental functions are subserved by large-scale neurocognitive networks comprising several spatially distributed and functionally specialized brain regions. We here report statistical and graphical methods of functional magnetic resonance imaging data analysis which can be used to elucidate the functional relationships (i.e., connectivity and distance) between elements of a neurocognitive network in a single subject. Data were acquired from a normal right-handed volunteer during periodic performance of a task which demanded visual and semantic processing of words and subvocalization of a decision about the meaning of each word. Major regional foci of activation were identified (by sinusoidal regression modeling and spatiotemporal randomization tests) in left extrastriate cortex, angular gyrus, supramarginal gyrus, superior and middle temporal gyri, lateral premotor cortex, and Broca's area. Principal component (PC) analysis was initially undertaken by singular value decomposition (SVD) of the ''raw'' time series observed at 170 activated voxels. This revealed a large functional distance (negative connectivity) between visual processing systems and all other brain regions in the space of the first PC. SVD of a matrix of fitted time series, and a matrix of six sinusoidal regression parameters estimated at each activated voxel, were developed as less noisy (more informative) alternatives to SVD of the ''raw'' data. Canonical variate analysis of denoised data was then used to clarify functional relationships between the major regional foci. Visual input analysis systems (extrastriate cortex and angular gyrus) were colocalized in the space of the first canonical variate (CV) and significantly separated from all other brain regions. Semantic analysis systems (supramarginal and temporal gyri) were colocalized and significantly separated in the space of the second CV from the subvocal output system (Broca's area). These results are provisionally interpreted in terms of underlying hemodynamic events and cognitive psychological theory.

Nature Neuroscience, 2002

In synesthesia, a stimulus in one sensory modality triggers, involuntarily and automatically, a s... more In synesthesia, a stimulus in one sensory modality triggers, involuntarily and automatically, a sensation in another: thus, in 'colored hearing' , hearing words induces sensations of color 1. Positron-emission tomography (PET) has shown in colored-hearing synesthetes the activation by speech of regions of visual association cortex not activated in controls, without significant activation of lower visual areas, including areas V1, V2 or V4/V8 (ref. 2). If synesthetic color experience is similar to true color percepts, however, one can more specifically predict activation of the human 'color center' , called V4 (refs. 3, 4) or V8 (ref. 5). Using the greater spatial resolution and sensitivity of fMRI, we tested this prediction by comparing brain activation patterns elicited by spoken words versus tones in synesthetes and controls. We also determined whether primary visual cortex (areas V1 and V2) was active during colored-hearing synesthesia. Lack of V1/V2 activity would suggest the generation of conscious visual percepts without contribution from primary visual cortex 6-8. Specifically, we compared the activation pattern in synesthetes hearing words to those observed in response to seen colors both in a group of non-synesthetes for whom the latter data were already 9 available (Experiment 1) and, in a within-subject design, in synesthetes themselves (Experiment 2). To control for the possibility that synesthetes might have an unusual topography of the visual areas, we also compared the regions activated by seen colors in these subjects and in non-synesthetes. In Experiment 3, we investigated whether normal subjects imagining colors show activation of a similar kind to that observed when synesthetes spontaneously

Magnetic Resonance Imaging, 1997

Magnetic resonance imaging gives high quality images of the urinary bladder with excellent contra... more Magnetic resonance imaging gives high quality images of the urinary bladder with excellent contrast. We report here the first application of dynamic, multi-slice, echo planar imaging to a study of urinary bladder emptying. Changes in urinary bladder volumes and rates of urine expulsion from the bladder have been measured simultaneously with bladder pressure. The method shows promise for clinical applications involving compromised bladder function, for reappraising bladder contraction strength-volume relationships, and for investigating the rate of change of length, three-dimensional shape, and wall tension in different parts of the bladder during micturition.

Journal of Investigative Dermatology, 2009

Psoriasis produces significant psychosocial disability; however, little is understood about the n... more Psoriasis produces significant psychosocial disability; however, little is understood about the neurocognitive mechanisms that mediate the adverse consequences of the social stigma associated with visible skin lesions, such as disgusted facial expressions of others. Both the feeling of disgust and the observation of disgust in others are known to activate the insula cortex. We investigated whether the social impact of psoriasis is associated with altered cognitive processing of disgust using (i) a covert recognition of faces task conducted using functional magnetic resonance imaging (fMRI) and (ii) the facial expression recognition task (FERT), a decision-making task, conducted outside the scanner to assess the ability to recognize overtly different intensities of disgust. Thirteen right-handed male patients with psoriasis and 13 age-matched male controls were included. In the fMRI study, psoriasis patients had significantly (Po0.005) smaller signal responses to disgusted faces in the bilateral insular cortex compared with healthy controls. These data were corroborated by FERT, in that patients were less able than controls to identify all intensities of disgust tested. We hypothesize that patients with psoriasis, in this case male patients, develop a coping mechanism to protect them from stressful emotional responses by blocking the processing of disgusted facial expressions.

Journal of Clinical Investigation, 2011

Although a relationship between emotional state and feeding behavior is known to exist, the inter... more Although a relationship between emotional state and feeding behavior is known to exist, the interactions between signaling initiated by stimuli in the gut and exteroceptively generated emotions remain incompletely understood. Here, we investigated the interaction between nutrient-induced gut-brain signaling and sad emotion induced by musical and visual cues at the behavioral and neural level in healthy nonobese subjects undergoing functional magnetic resonance imaging. Subjects received an intragastric infusion of fatty acid solution or saline during neutral or sad emotion induction and rated sensations of hunger, fullness, and mood. We found an interaction between fatty acid infusion and emotion induction both in the behavioral readouts (hunger, mood) and at the level of neural activity in multiple pre-hypothesized regions of interest. Specifically, the behavioral and neural responses to sad emotion induction were attenuated by fatty acid infusion. These findings increase our understanding of the interplay among emotions, hunger, food intake, and meal-induced sensations in health, which may have important implications for a wide range of disorders, including obesity, eating disorders, and depression. Conflict of interest: The authors have declared that no conflict of interest exists.

Gastroenterology, 2003

Despite the recent growth in studies on the central processing of visceral sensations, the test-r... more Despite the recent growth in studies on the central processing of visceral sensations, the test-retest reliability of the neural correlates of visceral sensation remain unclear. In order to test the variance between scan sessions, at the group level, volunteers underwent a modified boxcar functional magnetic resonance imaging (fMRI) experiment, involving periods of non-painful and painful oesophageal stimulation on three separate occasions. Painful stimulation produced robust activation in many cerebral regions previously associated with visceral processing. Non-painful stimulation activated a similar network but showed greater variability between scans.

S1808 Exploring the Neural Processing of Visceral Sensations: the Influence of Sensory, Emotional and Cognitive Factors

Gastroenterology, 2008

Gastroenterology, 2000

We present a method to gradually compute a smaller and smaller unsatisfiable core of a propositio... more We present a method to gradually compute a smaller and smaller unsatisfiable core of a propositional formula by minimizing proofs of unsatisfiability. The goal is to compute a minimal unsatisfiable core that is relatively small compared to other minimal unsatisfiable cores of the same formula. We try to achieve this goal by postponing deletion of arbitrary clauses from the formula as long as possible-in contrast to existing minimal unsatisfiable core algorithms. We applied this method to reduce the smallest known unit-distance graph with chromatic number 5 from 553 vertices and 2 720 edges to 529 vertices and 2 670 edges.

Defining the Role of Cholecystokinin in the Lipid-Induced Human Brain Activation Matrix

Gastroenterology, 2010

In human beings, as in most vertebrates, the release of the intestinal peptide cholecystokinin (C... more In human beings, as in most vertebrates, the release of the intestinal peptide cholecystokinin (CCK) by ingested food plays a major role both in digestion and the regulation of further food intake, but the changes in brain function and their underlying activation mechanisms remain unknown. Our aim was to explore, using a novel physiologic magnetic resonance imaging approach, the temporospatial brain activation matrix, in response to ingestion of a lipid meal and, by use of a CCK-1 receptor antagonist, to define the role of CCK in this activation. We studied, in 19 healthy subjects, the brain activation responses to ingested lipid (dodecanoic acid) or saline (control) with magnetic resonance imaging. Gallbladder volume, plasma CCK levels, and subjective hunger and fullness scores were also recorded. The experiment was then repeated, with and without prior administration of the CCK-1 receptor antagonist dexloxiglumide (600 mg orally) with a controlled, randomized order, latin-square design. Ingested lipid activated bilaterally a matrix of brain areas, particularly the brain stem, pons, hypothalamus, and also cerebellum and motor cortical areas. These activations were abolished by dexloxiglumide, indicating a CCK-mediated pathway, independent of any nutrient-associated awareness cues. The identification of these activations now defines the lipid-activated brain matrix and provides a means by which the gut-derived homeostatic mechanisms of food regulation can be distinguished from secondary sensory and hedonic cues, thereby providing a new approach to exploring aberrant human gastrointestinal responses and eating behavior.

Gastroenterology, 2010

for bitter taste receptors, T2R, and the gustatory G proteins, α-gustducin and α-transducin are e... more for bitter taste receptors, T2R, and the gustatory G proteins, α-gustducin and α-transducin are expressed by the oral cavity and the gastrointestinal mucosa and may be part of a wide chemosensing system of luminal contents. Aim: To investigate whether T2R agonists may affect ghrelin release and consequently food intake and gastric emptying. Methods: The co-localisation of ghrelin with α-gustducin and α-transducin was investigated by double immunofluorescence staining of sections of the mouse stomach. Mice were fasted for 16h and gavaged with a bitter taste receptor agonist mixture (denatonium benzoate(10mM), phenylthiocarbamide(10mM), 6-propyl-2-thiouracil (5mM), quinine (1,5mM), D-[-]salicin (5mM)). Blood samples were taken at several time points (0-40 min) after gavage and plasma ghrelin levels were determined by radioimmunoassay. Food intake after administration of bitter taste receptor agonists was monitored and the effect on gastric emptying was determined by the 13 C octanoic breath test. Results: Several ghrelin positive cells were co-localized with α-gustducin and α-transducin in enteroendocrine cells of the mouse corpus. Oral gavage of the bitter taste receptor agonist mixture resulted in a time-dependent increase in plasma total ghrelin levels: from 1295±105 pg/ml (0 min) to 1583±181 pg/ml (20 min), 2196±93 pg/ml (30 min) and 2892±268 pg/ml (40 min). Plasma octanoyl ghrelin levels also increased from 72±7 pg/ml to 231±49 pg/ml (40 min). The increase in plasma ghrelin levels after gavage of T2R agonists was accompanied by a significant increase in food intake during the first half hour (saline: 1.35 ± 0.09; T2R agonists: 1.61±0.07 g/h). During the following 4 hours food intake was dramatically decreased by 71% in T2R agonists-treated mice compared to 31% in saline-treated mice. Gastric half emptying time (T 1/2) decreased in parallel after oral gavage of T2R agonists from 123±6 min to 315±72 min. In GHSR-/mice the decrease in T 1/2 was even more pronounced (from 145±12 min to 1177±379 min). Conclusion: Oral administration of bitter taste receptor agonists induces an increase in plasma ghrelin levels which results in a temporary increase in food intake. This is followed by pronounced decrease in food intake which may be due to a prominent delay in gastric emptying which also involves activation of ghrelin receptors to counterbalance the effect.

302 Effects of Distraction on Brain Activity Following Painful Visceral Stimulation

European Journal of Pain, 2006

neuromatrix. However, the influence of negative emotion on the brain processing of painful viscer... more neuromatrix. However, the influence of negative emotion on the brain processing of painful visceral sensation has yet to be investigated. The aim of this study was to address this issue. Methods: 12 healthy volunteers participated in the study. fMRI images were acquired during two experimental runs in which volunteers received phasic non-painful and painful distensions to the oesophagus under a) negative mood induction and b) neutral mood induction. Results: Brain activation following painful stimulation increased during negative mood induction in the anterior cingulate cortex (ACC, BA24 & BA32), anterior insula, inferior frontal gyrus and SMA. All significant increases (compared to neutral mood and pain) were located in the right hemisphere of the brain. During non-painful stimulation and negative mood, significant increases in brain activity were localised to the right anterior insula, ACC (BA24 & BA32), as well as bilateral posterior cingulate. Conclusions: The results of this study suggest a possible right-hemispheric dominance in the processing of affective motivational components of oesophageal sensation. In accordance with previous literature, increased activation of the right anterior insula during negative emotion suggests this region may be involved in interoceptive processes related to self-evaluation of the negative component of a painful experience.

301 Imaging Brain Processing of Painful Visceral Sensation During Negative Mood Induction

European Journal of Pain, 2006

Results: Sensory descriptors selected from the SF McGill were significantly different (p< 0.05... more Results: Sensory descriptors selected from the SF McGill were significantly different (p< 0.05) between the muscle and cutaneous pain conditions. FMRI analysis demonstrates activation of the ‘pain matrix’ in both conditions. This was bilateral during cutaneous pain however predominantly contralateral during the muscle pain condition. Conclusion: Characteristics of experimental muscle and intradermal pain, induced by the same method are different and may be differentiated through the SF McGill questionnaire. Initial fMRI results suggest patterns of brain activity associated with muscle and skin pain also differ and warrant further investigation.

Brain, 2003

Sensory experience is in¯uenced by emotional context. Although perception of emotion and unpleasa... more Sensory experience is in¯uenced by emotional context. Although perception of emotion and unpleasant visceral sensation are associated with activation within the insula and dorsal and ventral anterior cingulate gyri (ACG), regions important for attention to and perception of sensory and emotional information, the neural mechanisms underlying the effect of emotional context upon visceral sensation remain unexplored. Using functional MRI, we examined neural responses to phasic, non-painful oesophageal sensation (OS) in eight healthy subjects (seven male; age range 27±36 years) either during neutral or negative emotional contexts produced, respectively, by presentation of neutral or fearful facial expressions. Activation within right insular and bilateral dorsal ACG was signi®cantly greater (P < 0.01) during OS with fearful than with neutral faces. In a second experiment, we measured anxiety, discomfort and neural responses in eight healthy male subjects (age range 22±41 years) to phasic, non-painful OS during presentation of faces depicting either low, moderate or high intensities of fear. Signi®cantly greater (P < 0.01) discomfort, anxiety and activation predominantly within the left dorsal ACG and bilateral anterior insulae occurred with high-intensity compared with low-intensity expressions. Clusters of voxels were also detected in this region, which exhibited a positive correlation between subjective behaviour and blood oxygenation level-dependent effect (P < 0.05). We report the ®rst evidence for a modulation of neural responses, and perceived discomfort during, non-painful visceral stimulation by the intensity of the negative emotional context in which the stimulation occurs, and suggest a mechanism for the effect of negative context on symptoms in functional pain disorders.

Brain Research, 2003

Most neuroprotective compounds that appear promising in the pre-clinical phase of testing are sub... more Most neuroprotective compounds that appear promising in the pre-clinical phase of testing are subsequently dismissed as relatively ineffective when entered into large-scale clinical trials. Many pre-clinical studies of potential neuroprotective candidates evaluate efficacy in only one or possibly two different models of ischaemia. In this study we examined the effects of 1,2-trifluoromethylphenyl imidazole (TRIM), a novel neuronal nitric oxide synthase (nNOS) inhibitor, in three models of cerebral ischaemia (global gerbil, global rat and focal rat). In addition, to follow the progression of the pathology, we also compared traditional histology methods with more advanced magnetic resonance imaging (MRI) as endpoint measures for neurological damage and neuroprotection. TRIM (50 mg/kg i.p.) prevented ischaemia-induced hippocampal damage following global ischaemia in gerbils when administered before or immediately post-occlusion, but failed to protect when administration was delayed until 30 min post-occlusion. Further studies indicated that the compound (administered at 50 mg/kg, i.p., immediately after occlusion) also protected in a rat four-vessel occlusion (4-VO) model using both histological and diffusion-weighted (DW) imaging techniques. In a final study, TRIM (50 mg/kg i.p. 30 min after occlusion) provided a significant reduction in infarct volume at 4 and 24 h as measured using diffusion-weighted (DW) and proton density (PD)weighted magnetic resonance imaging (MRI). This was confirmed using histological techniques. These studies confirm that nNOS inhibitors may have utility in stroke and provide evidence that combined magnetic resonance and histological methods can provide a powerful method of assessing neuronal damage in rodent models of cerebral ischaemia.

Brain and Cognition, 2006

Background: People with autism or Asperger Syndrome (AS) show altered patterns of brain activity ... more Background: People with autism or Asperger Syndrome (AS) show altered patterns of brain activity during visual search and emotion recognition tasks. Autism and AS are genetic conditions and parents may show the 'broader autism phenotype.' Aims: (1) To test if parents of children with AS show atypical brain activity during a visual search and an empathy task; (2) to test for sex diVerences during these tasks at the neural level; (3) to test if parents of children with autism are hyper-masculinized, as might be predicted by the 'extreme male brain' theory. Method: We used fMRI during a visual search task (the Embedded Figures Test (EFT)) and an emotion recognition test (the 'Reading the Mind in the Eyes' (or Eyes) test). Sample: Twelve parents of children with AS, vs. 12 sex-matched controls. Design: Factorial analysis was used to map main eVects of sex, group (parents vs. controls), and sex £ group interaction on brain function. An ordinal ANOVA also tested for regions of brain activity where females > males > fathers D mothers, to test for parental hyper-masculinization. Results on EFT task: Female controls showed more activity in extrastriate cortex than male controls, and both mothers and fathers showed even less activity in this area than sex-matched controls. There were no diVerences in group activation between mothers and fathers of children with AS. The ordinal ANOVA identiWed two speciWc regions in visual cortex (right and left, respectively) that showed the pattern Females > Males > Fathers D Mothers, both in BA 19. Results on Eyes task: Male controls showed more activity in the left inferior frontal gyrus than female controls, and both mothers and fathers showed even more activity in this area compared to sex-matched controls. Female controls showed greater bilateral inferior frontal activation than males. This was not seen when comparing mothers to males, or mothers to fathers. The ordinal ANOVA identiWed two speciWc regions that showed the pattern Females > Males > Mothers D Fathers: left medial temporal gyrus (BA 21) and left dorsolateral prefrontal cortex (BA 44). Conclusions: Parents of children with AS show atypical brain function during both visual search and emotion recognition, in the direction of hyper-masculinization of the brain. Because of the small sample size, and lack of age-matching between parents and controls, such results constitute a pilot study that needs replicating with larger samples.

BMC Pediatrics, 2008

Background: Infants born at extreme prematurity are at high risk of developmental disability. A m... more Background: Infants born at extreme prematurity are at high risk of developmental disability. A major risk factor for disability is having a low level of thyroid hormone described as hypothyroxinaemia, which is recognised to be a frequent phenomenon in these infants. Derangements of critical thyroid function during the sensitive window in prematurity when early development occurs, may have a range of long term effects for brain development. Further research in preterm infants using neuroimaging techniques will increase our understanding of the specificity of the effects of hypothyroxinaemia on the developing foetal brain. This is an explanatory double blinded randomised controlled trial which is aimed to assess the effect of thyroid hormone supplementation on brain size, key brain structures, extent of myelination, white matter integrity and vessel morphology, somatic growth and the hypothalamic-pituitary-adrenal axis. Methods: The study is a multi-centred double blinded randomised controlled trial of thyroid hormone supplementation in babies born below 28 weeks' gestation. All infants will receive either levothyroxine or placebo until 32 weeks corrected gestational age. The primary outcomes will be width of the sub-arachnoid space measured using cranial ultrasound and head circumference at 36 weeks corrected gestational age. The secondary outcomes will be thyroid hormone concentrations, the hypothalamic pituitary axis status and auxological data between birth and expected date of delivery; thyroid gland volume, brain size, volumes of key brain structures, extent of myelination and brain vessel morphology at expected date of delivery and markers of morbidity

Exploring relationships for visceral and somatic pain with autonomic control and personality

Pain, 2009

The autonomic nervous system (ANS) integrates afferent and motor activity for homeostatic process... more The autonomic nervous system (ANS) integrates afferent and motor activity for homeostatic processes including pain. The aim of the study was to compare hitherto poorly characterised relations between brainstem autonomic control and personality in response to visceral and somatic pain. Eighteen healthy subjects (16 females, mean age 34) had recordings during rest and pain of heart rate (HR), cardiac vagal tone (CVT), cardiac sensitivity to baroreflex (CSB), skin conductance level (SC), cardiac sympathetic index (CSI) and mean blood pressure (MBP). Visceral pain was induced by balloon distension in proximal (PB) and distal (DB) oesophagus and somatic pain by nail-bed pressure (NBP). Eight painful stimuli were delivered at each site and unpleasantness and intensity measured. Personality was profiled with the Big Five inventory. (1) Oesophageal intubation evoked &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;fight-flight&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; responses: HR and sympathetic (CSI, SC, MBP) elevation with parasympathetic (CVT) withdrawal (p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.05). (2) Pain at all sites evoked novel parasympathetic/sympathetic co-activation with elevated HR but vasodepression (all p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.05). (3) Personality traits correlated with slope of distal oesophageal pain-related CVT changes wherein more neurotic-introvert subjects had greater positive pain-related CVT slope change (neuroticism r 0.8, p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.05; extroversion r -0.5, p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.05). Pain-evoked heart rate increases were mediated by parasympathetic and sympathetic co-activation - a novel finding in humans but recently described in mammals too. Visceral pain-related parasympathetic change correlated with personality. ANS defence responses are nuanced and may relate to personality type for visceral pain. Clinical relevance of these findings warrants further exploration.

Neuropsychologia, 2002

Functional magnetic resonance imaging (fMRI) was used to examine whether (1) verbal associative e... more Functional magnetic resonance imaging (fMRI) was used to examine whether (1) verbal associative encoding activates the medial temporal lobes (MTL) and related regions more than non-associative encoding, (2) verbal associative novelty is related to enhanced MTL activation, and (3) verbal item novelty is related to enhanced MTL activation and, if so, whether these activations are in different or overlapping sites. No increase in MTL activation was found during verbal associative encoding relative to non-associative encoding, although associative encoding was related to a relative increase in activation in the posterior cingulate cortex. In contrast, verbal associative novelty was found to activate the MTL and posterior cingulate cortex. Verbal item novelty did not significantly activate any brain region. The verbal associative novelty-related effect occurred despite subjects having little awareness of associative novelty. The verbal associative novelty-related activation in the MTL may be related either to unconscious novelty detection or to a priming effect at encoding. We argue that if the priming explanation is correct then this may account for our failure to observe an associative encoding MTL activation.

Psychosomatic Medicine, 2010

Objective: Anxiety at the time of gastrointestinal injury or inflammation increases the risk of d... more Objective: Anxiety at the time of gastrointestinal injury or inflammation increases the risk of developing visceral hyperalgesia. Distal esophageal acidification induces hyperalgesia in the non-acid exposed proximal esophagus, due to the sensitization of spinal dorsal horn neurones. The objective was to determine whether anxiety influences acid-induced hyperalgesia. Methods: A total of 19 healthy volunteers (n ϭ 12 females; age, 22-57 years; mean, 35.7 years) completed a 10-minute mood induction paradigm (anxiety or neutral) with autonomic monitoring (visit 1). On visits 2 and 3, pain thresholds to electrical stimulation, in milliamperes (mA), were determined in the proximal esophagus and foot (control) before and after a 30-minute infusion of 0.15 M of hydrochloric acid. During esophageal acid infusion, the subjects randomly received anxiety or neutral mood induction with autonomic monitoring, in a crossover design. Anxiety and pain ratings were recorded pre and post infusion. Results: Visit 1: Anxiety induction increased anxiety scores (p Ͻ .001), mean arterial pressure (p Ͻ .001), and cardiac sympathetic index (p ϭ .007), and reduced parasympathetic measures (cardiac vagal tone [p ϭ .05] and cardiac sensitivity to baroreflex [p ϭ .006)]). Visit 2: Anxiety induction conferred greater acid-induced hyperalgesia compared with neutral (Ϫ4.9 mA versus 2.7 mA, p ϭ .009, analysis of covariance). No differences in autonomic measures were found during acid infusion with anxiety or neutral mood induction. Conclusions: Anxiety induction increases acid-induced esophageal hyperalgesia; anxiety, thus, facilitates central sensitization in the esophagus. Our studies provide a new model for studying the effects of anxiety on esophageal hyperalgesia and may allow testing of therapeutic strategies to reduce this effect.

NeuroImage, 1996

Many ''higher-order'' mental functions are subserved by large-scale neurocognitive networks compr... more Many ''higher-order'' mental functions are subserved by large-scale neurocognitive networks comprising several spatially distributed and functionally specialized brain regions. We here report statistical and graphical methods of functional magnetic resonance imaging data analysis which can be used to elucidate the functional relationships (i.e., connectivity and distance) between elements of a neurocognitive network in a single subject. Data were acquired from a normal right-handed volunteer during periodic performance of a task which demanded visual and semantic processing of words and subvocalization of a decision about the meaning of each word. Major regional foci of activation were identified (by sinusoidal regression modeling and spatiotemporal randomization tests) in left extrastriate cortex, angular gyrus, supramarginal gyrus, superior and middle temporal gyri, lateral premotor cortex, and Broca's area. Principal component (PC) analysis was initially undertaken by singular value decomposition (SVD) of the ''raw'' time series observed at 170 activated voxels. This revealed a large functional distance (negative connectivity) between visual processing systems and all other brain regions in the space of the first PC. SVD of a matrix of fitted time series, and a matrix of six sinusoidal regression parameters estimated at each activated voxel, were developed as less noisy (more informative) alternatives to SVD of the ''raw'' data. Canonical variate analysis of denoised data was then used to clarify functional relationships between the major regional foci. Visual input analysis systems (extrastriate cortex and angular gyrus) were colocalized in the space of the first canonical variate (CV) and significantly separated from all other brain regions. Semantic analysis systems (supramarginal and temporal gyri) were colocalized and significantly separated in the space of the second CV from the subvocal output system (Broca's area). These results are provisionally interpreted in terms of underlying hemodynamic events and cognitive psychological theory.

Nature Neuroscience, 2002

In synesthesia, a stimulus in one sensory modality triggers, involuntarily and automatically, a s... more In synesthesia, a stimulus in one sensory modality triggers, involuntarily and automatically, a sensation in another: thus, in 'colored hearing' , hearing words induces sensations of color 1. Positron-emission tomography (PET) has shown in colored-hearing synesthetes the activation by speech of regions of visual association cortex not activated in controls, without significant activation of lower visual areas, including areas V1, V2 or V4/V8 (ref. 2). If synesthetic color experience is similar to true color percepts, however, one can more specifically predict activation of the human 'color center' , called V4 (refs. 3, 4) or V8 (ref. 5). Using the greater spatial resolution and sensitivity of fMRI, we tested this prediction by comparing brain activation patterns elicited by spoken words versus tones in synesthetes and controls. We also determined whether primary visual cortex (areas V1 and V2) was active during colored-hearing synesthesia. Lack of V1/V2 activity would suggest the generation of conscious visual percepts without contribution from primary visual cortex 6-8. Specifically, we compared the activation pattern in synesthetes hearing words to those observed in response to seen colors both in a group of non-synesthetes for whom the latter data were already 9 available (Experiment 1) and, in a within-subject design, in synesthetes themselves (Experiment 2). To control for the possibility that synesthetes might have an unusual topography of the visual areas, we also compared the regions activated by seen colors in these subjects and in non-synesthetes. In Experiment 3, we investigated whether normal subjects imagining colors show activation of a similar kind to that observed when synesthetes spontaneously

Magnetic Resonance Imaging, 1997

Magnetic resonance imaging gives high quality images of the urinary bladder with excellent contra... more Magnetic resonance imaging gives high quality images of the urinary bladder with excellent contrast. We report here the first application of dynamic, multi-slice, echo planar imaging to a study of urinary bladder emptying. Changes in urinary bladder volumes and rates of urine expulsion from the bladder have been measured simultaneously with bladder pressure. The method shows promise for clinical applications involving compromised bladder function, for reappraising bladder contraction strength-volume relationships, and for investigating the rate of change of length, three-dimensional shape, and wall tension in different parts of the bladder during micturition.

Journal of Investigative Dermatology, 2009

Psoriasis produces significant psychosocial disability; however, little is understood about the n... more Psoriasis produces significant psychosocial disability; however, little is understood about the neurocognitive mechanisms that mediate the adverse consequences of the social stigma associated with visible skin lesions, such as disgusted facial expressions of others. Both the feeling of disgust and the observation of disgust in others are known to activate the insula cortex. We investigated whether the social impact of psoriasis is associated with altered cognitive processing of disgust using (i) a covert recognition of faces task conducted using functional magnetic resonance imaging (fMRI) and (ii) the facial expression recognition task (FERT), a decision-making task, conducted outside the scanner to assess the ability to recognize overtly different intensities of disgust. Thirteen right-handed male patients with psoriasis and 13 age-matched male controls were included. In the fMRI study, psoriasis patients had significantly (Po0.005) smaller signal responses to disgusted faces in the bilateral insular cortex compared with healthy controls. These data were corroborated by FERT, in that patients were less able than controls to identify all intensities of disgust tested. We hypothesize that patients with psoriasis, in this case male patients, develop a coping mechanism to protect them from stressful emotional responses by blocking the processing of disgusted facial expressions.

Journal of Clinical Investigation, 2011

Although a relationship between emotional state and feeding behavior is known to exist, the inter... more Although a relationship between emotional state and feeding behavior is known to exist, the interactions between signaling initiated by stimuli in the gut and exteroceptively generated emotions remain incompletely understood. Here, we investigated the interaction between nutrient-induced gut-brain signaling and sad emotion induced by musical and visual cues at the behavioral and neural level in healthy nonobese subjects undergoing functional magnetic resonance imaging. Subjects received an intragastric infusion of fatty acid solution or saline during neutral or sad emotion induction and rated sensations of hunger, fullness, and mood. We found an interaction between fatty acid infusion and emotion induction both in the behavioral readouts (hunger, mood) and at the level of neural activity in multiple pre-hypothesized regions of interest. Specifically, the behavioral and neural responses to sad emotion induction were attenuated by fatty acid infusion. These findings increase our understanding of the interplay among emotions, hunger, food intake, and meal-induced sensations in health, which may have important implications for a wide range of disorders, including obesity, eating disorders, and depression. Conflict of interest: The authors have declared that no conflict of interest exists.

Gastroenterology, 2003

Despite the recent growth in studies on the central processing of visceral sensations, the test-r... more Despite the recent growth in studies on the central processing of visceral sensations, the test-retest reliability of the neural correlates of visceral sensation remain unclear. In order to test the variance between scan sessions, at the group level, volunteers underwent a modified boxcar functional magnetic resonance imaging (fMRI) experiment, involving periods of non-painful and painful oesophageal stimulation on three separate occasions. Painful stimulation produced robust activation in many cerebral regions previously associated with visceral processing. Non-painful stimulation activated a similar network but showed greater variability between scans.

S1808 Exploring the Neural Processing of Visceral Sensations: the Influence of Sensory, Emotional and Cognitive Factors

Gastroenterology, 2008

Gastroenterology, 2000

We present a method to gradually compute a smaller and smaller unsatisfiable core of a propositio... more We present a method to gradually compute a smaller and smaller unsatisfiable core of a propositional formula by minimizing proofs of unsatisfiability. The goal is to compute a minimal unsatisfiable core that is relatively small compared to other minimal unsatisfiable cores of the same formula. We try to achieve this goal by postponing deletion of arbitrary clauses from the formula as long as possible-in contrast to existing minimal unsatisfiable core algorithms. We applied this method to reduce the smallest known unit-distance graph with chromatic number 5 from 553 vertices and 2 720 edges to 529 vertices and 2 670 edges.

Defining the Role of Cholecystokinin in the Lipid-Induced Human Brain Activation Matrix

Gastroenterology, 2010

In human beings, as in most vertebrates, the release of the intestinal peptide cholecystokinin (C... more In human beings, as in most vertebrates, the release of the intestinal peptide cholecystokinin (CCK) by ingested food plays a major role both in digestion and the regulation of further food intake, but the changes in brain function and their underlying activation mechanisms remain unknown. Our aim was to explore, using a novel physiologic magnetic resonance imaging approach, the temporospatial brain activation matrix, in response to ingestion of a lipid meal and, by use of a CCK-1 receptor antagonist, to define the role of CCK in this activation. We studied, in 19 healthy subjects, the brain activation responses to ingested lipid (dodecanoic acid) or saline (control) with magnetic resonance imaging. Gallbladder volume, plasma CCK levels, and subjective hunger and fullness scores were also recorded. The experiment was then repeated, with and without prior administration of the CCK-1 receptor antagonist dexloxiglumide (600 mg orally) with a controlled, randomized order, latin-square design. Ingested lipid activated bilaterally a matrix of brain areas, particularly the brain stem, pons, hypothalamus, and also cerebellum and motor cortical areas. These activations were abolished by dexloxiglumide, indicating a CCK-mediated pathway, independent of any nutrient-associated awareness cues. The identification of these activations now defines the lipid-activated brain matrix and provides a means by which the gut-derived homeostatic mechanisms of food regulation can be distinguished from secondary sensory and hedonic cues, thereby providing a new approach to exploring aberrant human gastrointestinal responses and eating behavior.

Gastroenterology, 2010

for bitter taste receptors, T2R, and the gustatory G proteins, α-gustducin and α-transducin are e... more for bitter taste receptors, T2R, and the gustatory G proteins, α-gustducin and α-transducin are expressed by the oral cavity and the gastrointestinal mucosa and may be part of a wide chemosensing system of luminal contents. Aim: To investigate whether T2R agonists may affect ghrelin release and consequently food intake and gastric emptying. Methods: The co-localisation of ghrelin with α-gustducin and α-transducin was investigated by double immunofluorescence staining of sections of the mouse stomach. Mice were fasted for 16h and gavaged with a bitter taste receptor agonist mixture (denatonium benzoate(10mM), phenylthiocarbamide(10mM), 6-propyl-2-thiouracil (5mM), quinine (1,5mM), D-[-]salicin (5mM)). Blood samples were taken at several time points (0-40 min) after gavage and plasma ghrelin levels were determined by radioimmunoassay. Food intake after administration of bitter taste receptor agonists was monitored and the effect on gastric emptying was determined by the 13 C octanoic breath test. Results: Several ghrelin positive cells were co-localized with α-gustducin and α-transducin in enteroendocrine cells of the mouse corpus. Oral gavage of the bitter taste receptor agonist mixture resulted in a time-dependent increase in plasma total ghrelin levels: from 1295±105 pg/ml (0 min) to 1583±181 pg/ml (20 min), 2196±93 pg/ml (30 min) and 2892±268 pg/ml (40 min). Plasma octanoyl ghrelin levels also increased from 72±7 pg/ml to 231±49 pg/ml (40 min). The increase in plasma ghrelin levels after gavage of T2R agonists was accompanied by a significant increase in food intake during the first half hour (saline: 1.35 ± 0.09; T2R agonists: 1.61±0.07 g/h). During the following 4 hours food intake was dramatically decreased by 71% in T2R agonists-treated mice compared to 31% in saline-treated mice. Gastric half emptying time (T 1/2) decreased in parallel after oral gavage of T2R agonists from 123±6 min to 315±72 min. In GHSR-/mice the decrease in T 1/2 was even more pronounced (from 145±12 min to 1177±379 min). Conclusion: Oral administration of bitter taste receptor agonists induces an increase in plasma ghrelin levels which results in a temporary increase in food intake. This is followed by pronounced decrease in food intake which may be due to a prominent delay in gastric emptying which also involves activation of ghrelin receptors to counterbalance the effect.

302 Effects of Distraction on Brain Activity Following Painful Visceral Stimulation

European Journal of Pain, 2006

neuromatrix. However, the influence of negative emotion on the brain processing of painful viscer... more neuromatrix. However, the influence of negative emotion on the brain processing of painful visceral sensation has yet to be investigated. The aim of this study was to address this issue. Methods: 12 healthy volunteers participated in the study. fMRI images were acquired during two experimental runs in which volunteers received phasic non-painful and painful distensions to the oesophagus under a) negative mood induction and b) neutral mood induction. Results: Brain activation following painful stimulation increased during negative mood induction in the anterior cingulate cortex (ACC, BA24 & BA32), anterior insula, inferior frontal gyrus and SMA. All significant increases (compared to neutral mood and pain) were located in the right hemisphere of the brain. During non-painful stimulation and negative mood, significant increases in brain activity were localised to the right anterior insula, ACC (BA24 & BA32), as well as bilateral posterior cingulate. Conclusions: The results of this study suggest a possible right-hemispheric dominance in the processing of affective motivational components of oesophageal sensation. In accordance with previous literature, increased activation of the right anterior insula during negative emotion suggests this region may be involved in interoceptive processes related to self-evaluation of the negative component of a painful experience.

301 Imaging Brain Processing of Painful Visceral Sensation During Negative Mood Induction

European Journal of Pain, 2006

Results: Sensory descriptors selected from the SF McGill were significantly different (p< 0.05... more Results: Sensory descriptors selected from the SF McGill were significantly different (p< 0.05) between the muscle and cutaneous pain conditions. FMRI analysis demonstrates activation of the ‘pain matrix’ in both conditions. This was bilateral during cutaneous pain however predominantly contralateral during the muscle pain condition. Conclusion: Characteristics of experimental muscle and intradermal pain, induced by the same method are different and may be differentiated through the SF McGill questionnaire. Initial fMRI results suggest patterns of brain activity associated with muscle and skin pain also differ and warrant further investigation.

Brain, 2003

Sensory experience is in¯uenced by emotional context. Although perception of emotion and unpleasa... more Sensory experience is in¯uenced by emotional context. Although perception of emotion and unpleasant visceral sensation are associated with activation within the insula and dorsal and ventral anterior cingulate gyri (ACG), regions important for attention to and perception of sensory and emotional information, the neural mechanisms underlying the effect of emotional context upon visceral sensation remain unexplored. Using functional MRI, we examined neural responses to phasic, non-painful oesophageal sensation (OS) in eight healthy subjects (seven male; age range 27±36 years) either during neutral or negative emotional contexts produced, respectively, by presentation of neutral or fearful facial expressions. Activation within right insular and bilateral dorsal ACG was signi®cantly greater (P < 0.01) during OS with fearful than with neutral faces. In a second experiment, we measured anxiety, discomfort and neural responses in eight healthy male subjects (age range 22±41 years) to phasic, non-painful OS during presentation of faces depicting either low, moderate or high intensities of fear. Signi®cantly greater (P < 0.01) discomfort, anxiety and activation predominantly within the left dorsal ACG and bilateral anterior insulae occurred with high-intensity compared with low-intensity expressions. Clusters of voxels were also detected in this region, which exhibited a positive correlation between subjective behaviour and blood oxygenation level-dependent effect (P < 0.05). We report the ®rst evidence for a modulation of neural responses, and perceived discomfort during, non-painful visceral stimulation by the intensity of the negative emotional context in which the stimulation occurs, and suggest a mechanism for the effect of negative context on symptoms in functional pain disorders.

Brain Research, 2003

Most neuroprotective compounds that appear promising in the pre-clinical phase of testing are sub... more Most neuroprotective compounds that appear promising in the pre-clinical phase of testing are subsequently dismissed as relatively ineffective when entered into large-scale clinical trials. Many pre-clinical studies of potential neuroprotective candidates evaluate efficacy in only one or possibly two different models of ischaemia. In this study we examined the effects of 1,2-trifluoromethylphenyl imidazole (TRIM), a novel neuronal nitric oxide synthase (nNOS) inhibitor, in three models of cerebral ischaemia (global gerbil, global rat and focal rat). In addition, to follow the progression of the pathology, we also compared traditional histology methods with more advanced magnetic resonance imaging (MRI) as endpoint measures for neurological damage and neuroprotection. TRIM (50 mg/kg i.p.) prevented ischaemia-induced hippocampal damage following global ischaemia in gerbils when administered before or immediately post-occlusion, but failed to protect when administration was delayed until 30 min post-occlusion. Further studies indicated that the compound (administered at 50 mg/kg, i.p., immediately after occlusion) also protected in a rat four-vessel occlusion (4-VO) model using both histological and diffusion-weighted (DW) imaging techniques. In a final study, TRIM (50 mg/kg i.p. 30 min after occlusion) provided a significant reduction in infarct volume at 4 and 24 h as measured using diffusion-weighted (DW) and proton density (PD)weighted magnetic resonance imaging (MRI). This was confirmed using histological techniques. These studies confirm that nNOS inhibitors may have utility in stroke and provide evidence that combined magnetic resonance and histological methods can provide a powerful method of assessing neuronal damage in rodent models of cerebral ischaemia.

Brain and Cognition, 2006

Background: People with autism or Asperger Syndrome (AS) show altered patterns of brain activity ... more Background: People with autism or Asperger Syndrome (AS) show altered patterns of brain activity during visual search and emotion recognition tasks. Autism and AS are genetic conditions and parents may show the 'broader autism phenotype.' Aims: (1) To test if parents of children with AS show atypical brain activity during a visual search and an empathy task; (2) to test for sex diVerences during these tasks at the neural level; (3) to test if parents of children with autism are hyper-masculinized, as might be predicted by the 'extreme male brain' theory. Method: We used fMRI during a visual search task (the Embedded Figures Test (EFT)) and an emotion recognition test (the 'Reading the Mind in the Eyes' (or Eyes) test). Sample: Twelve parents of children with AS, vs. 12 sex-matched controls. Design: Factorial analysis was used to map main eVects of sex, group (parents vs. controls), and sex £ group interaction on brain function. An ordinal ANOVA also tested for regions of brain activity where females > males > fathers D mothers, to test for parental hyper-masculinization. Results on EFT task: Female controls showed more activity in extrastriate cortex than male controls, and both mothers and fathers showed even less activity in this area than sex-matched controls. There were no diVerences in group activation between mothers and fathers of children with AS. The ordinal ANOVA identiWed two speciWc regions in visual cortex (right and left, respectively) that showed the pattern Females > Males > Fathers D Mothers, both in BA 19. Results on Eyes task: Male controls showed more activity in the left inferior frontal gyrus than female controls, and both mothers and fathers showed even more activity in this area compared to sex-matched controls. Female controls showed greater bilateral inferior frontal activation than males. This was not seen when comparing mothers to males, or mothers to fathers. The ordinal ANOVA identiWed two speciWc regions that showed the pattern Females > Males > Mothers D Fathers: left medial temporal gyrus (BA 21) and left dorsolateral prefrontal cortex (BA 44). Conclusions: Parents of children with AS show atypical brain function during both visual search and emotion recognition, in the direction of hyper-masculinization of the brain. Because of the small sample size, and lack of age-matching between parents and controls, such results constitute a pilot study that needs replicating with larger samples.

BMC Pediatrics, 2008

Background: Infants born at extreme prematurity are at high risk of developmental disability. A m... more Background: Infants born at extreme prematurity are at high risk of developmental disability. A major risk factor for disability is having a low level of thyroid hormone described as hypothyroxinaemia, which is recognised to be a frequent phenomenon in these infants. Derangements of critical thyroid function during the sensitive window in prematurity when early development occurs, may have a range of long term effects for brain development. Further research in preterm infants using neuroimaging techniques will increase our understanding of the specificity of the effects of hypothyroxinaemia on the developing foetal brain. This is an explanatory double blinded randomised controlled trial which is aimed to assess the effect of thyroid hormone supplementation on brain size, key brain structures, extent of myelination, white matter integrity and vessel morphology, somatic growth and the hypothalamic-pituitary-adrenal axis. Methods: The study is a multi-centred double blinded randomised controlled trial of thyroid hormone supplementation in babies born below 28 weeks' gestation. All infants will receive either levothyroxine or placebo until 32 weeks corrected gestational age. The primary outcomes will be width of the sub-arachnoid space measured using cranial ultrasound and head circumference at 36 weeks corrected gestational age. The secondary outcomes will be thyroid hormone concentrations, the hypothalamic pituitary axis status and auxological data between birth and expected date of delivery; thyroid gland volume, brain size, volumes of key brain structures, extent of myelination and brain vessel morphology at expected date of delivery and markers of morbidity