In memory of Professor Iain Wilkinson: cognitive and neuroimaging endophenotypes in a consanguineous schizophrenia multiplex family.

BACKGROUND: Schizophrenia endophenotypes may help elucidate functional effects of genetic risk variants in multiply affected consanguineous families that segregate recessive risk alleles of large effect size. We studied the association between a schizophrenia risk locus involving a 6.1Mb homozygous region on chromosome 13q22-31 in a consanguineous multiplex family and cognitive functioning, haemodynamic response and white matter integrity using neuroimaging. METHODS: We performed CANTAB neuropsychological testing on four affected family members (all homozygous for the risk locus), ten unaffected family members (seven homozygous and three heterozygous) and ten healthy volunteers, and tested neuronal responses on fMRI during an n-back working memory task, and white matter integrity on diffusion tensor imaging (DTI) on four affected and six unaffected family members (four homozygous and two heterozygous) and three healthy volunteers. For cognitive comparisons we used a linear mixed model (Kruskal-Wallis) test, followed by posthoc Dunn's pairwise tests with a Bonferroni adjustment. For fMRI analysis, we counted voxels exceeding the p < 0.05 corrected threshold. DTI analysis was observational. RESULTS: Family members with schizophrenia and unaffected family members homozygous for the risk haplotype showed attention (p < 0.01) and working memory deficits (p < 0.01) compared with healthy controls; a neural activation laterality bias towards the right prefrontal cortex (voxels reaching p < 0.05, corrected) and observed lower fractional anisotropy in the anterior cingulate cortex and left dorsolateral prefrontal cortex. CONCLUSIONS: In this family, homozygosity at the 13q risk locus was associated with impaired cognition, white matter integrity, and altered laterality of neural activation.

Assessment of the Precision in Measuring Glutathione at 3 T With a MEGA-PRESS Sequence in Primary Motor Cortex and Occipital Cortex.

BACKGROUND: Glutathione (GSH) is an important brain antioxidant and a number of studies have reported its measurement by edited and nonedited localized 1 H spectroscopy techniques within a range of applications in healthy volunteers and disease states. Good test-retest reproducibility is key when assessing the efficacy of treatments aimed at modulating GSH levels within the central nervous system or when noninvasively assessing changes in GSH content over time. PURPOSE: To evaluate the intraday (in vitro and in vivo) and 1-month apart (in vivo) test-retest reproducibility of GSH measurements from GSH-edited MEGA-PRESS acquisitions at 3 T in a phantom and in the brain of a cohort of middle-aged and older healthy volunteers. STUDY TYPE: Prospective. SUBJECTS/PHANTOMS: A phantom containing physiological concentrations of GSH and metabolites with overlapping spectral signatures and 10 healthy volunteers (4 F, 6 M, 55 ± 14 years old). FIELD STRENGTH/SEQUENCE: GSH-edited spectra were acquired at 3 T using the MEGA-PRESS sequence. ASSESSMENT: The phantom was scanned twice and the healthy subjects were scanned three times (on two separate days, 1 month apart). GSH was quantified from each acquisition, with the in vivo voxels placed at the primary motor cortex (PMC) and the occipital cortex (OCC). STATISTICAL TESTS: Mean coefficients of variation (CV) were used to assess short-term (in vitro and in vivo) and longer-term (in vivo) test-retest reproducibility. RESULTS: In vitro, the CV was 2.3%. In vivo, the mean intraday CV was 3.3% in the PMC and 2.4% in the OCC, while the CVs at 1 month apart were 4.6% in the PMC and 7.8% in the OCC. DATA CONCLUSION: GSH-edited MEGA-PRESS spectroscopy allows measurement of GSH with excellent precision. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 2.

Somatosensory network functional connectivity differentiates clinical pain phenotypes in diabetic neuropathy.

AIMS/HYPOTHESIS: The aim of this work was to investigate whether different clinical pain phenotypes of diabetic polyneuropathy (DPN) are distinguished by functional connectivity at rest. METHODS: This was an observational, cohort study of 43 individuals with painful DPN, divided into irritable (IR, n = 10) and non-irritable (NIR, n = 33) nociceptor phenotypes using the German Research Network of Neuropathic Pain quantitative sensory testing protocol. In-situ brain MRI included 3D T1-weighted anatomical and 6 min resting-state functional MRI scans. Subgroup differences in resting-state functional connectivity in brain regions involved with somatic (thalamus, primary somatosensory cortex, motor cortex) and non-somatic (insular and anterior cingulate cortices) pain processing were examined. Multidimensional reduction of MRI datasets was performed using a machine-learning approach to classify individuals into each clinical pain phenotype. RESULTS: Individuals with the IR nociceptor phenotype had significantly greater thalamic-insular cortex (p false discovery rate [FDR] = 0.03) and reduced thalamus-somatosensory cortex functional connectivity (p-FDR = 0.03). We observed a double dissociation such that self-reported neuropathic pain score was more associated with greater thalamus-insular cortex functional connectivity (r = 0.41; p = 0.01) whereas more severe nerve function deficits were more related to lower thalamus-somatosensory cortex functional connectivity (r = -0.35; p = 0.03). Machine-learning group classification performance to identify individuals with the NIR nociceptor phenotype achieved an accuracy of 0.92 (95% CI 0.08) and sensitivity of 90%. CONCLUSIONS/INTERPRETATION: This study demonstrates differences in functional connectivity in nociceptive processing brain regions between IR and NIR phenotypes in painful DPN. We also establish proof of concept for the utility of multimodal MRI as a biomarker for painful DPN by using a machine-learning approach to classify individuals into sensory phenotypes.

Magnetic resonance spectroscopy reveals mitochondrial dysfunction in amyotrophic lateral sclerosis.

Mitochondrial dysfunction is postulated to be central to amyotrophic lateral sclerosis (ALS) pathophysiology. Evidence comes primarily from disease models and conclusive data to support bioenergetic dysfunction in vivo in patients is currently lacking. This study is the first to assess mitochondrial dysfunction in brain and muscle in individuals living with ALS using 31P-magnetic resonance spectroscopy (MRS), the modality of choice to assess energy metabolism in vivo. We recruited 20 patients and 10 healthy age and gender-matched control subjects in this cross-sectional clinico-radiological study. 31P-MRS was acquired from cerebral motor regions and from tibialis anterior during rest and exercise. Bioenergetic parameter estimates were derived including: ATP, phosphocreatine, inorganic phosphate, adenosine diphosphate, Gibbs free energy of ATP hydrolysis (ΔGATP), phosphomonoesters, phosphodiesters, pH, free magnesium concentration, and muscle dynamic recovery constants. Linear regression was used to test for associations between brain data and clinical parameters (revised amyotrophic functional rating scale, slow vital capacity, and upper motor neuron score) and between muscle data and clinico-neurophysiological measures (motor unit number and size indices, force of contraction, and speed of walking). Evidence for primary dysfunction of mitochondrial oxidative phosphorylation was detected in the brainstem where ΔGATP and phosphocreatine were reduced. Alterations were also detected in skeletal muscle in patients where resting inorganic phosphate, pH, and phosphomonoesters were increased, whereas resting ΔGATP, magnesium, and dynamic phosphocreatine to inorganic phosphate recovery were decreased. Phosphocreatine in brainstem correlated with respiratory dysfunction and disability; in muscle, energy metabolites correlated with motor unit number index, muscle power, and speed of walking. This study provides in vivo evidence for bioenergetic dysfunction in ALS in brain and skeletal muscle, which appears clinically and electrophysiologically relevant. 31P-MRS represents a promising technique to assess the pathophysiology of mitochondrial function in vivo in ALS and a potential tool for future clinical trials targeting bioenergetic dysfunction.

Painful and Painless Diabetic Neuropathies: What Is the Difference?

PURPOSE OF REVIEW: The prevalence of diabetes mellitus and its chronic complications are increasing to epidemic proportions. This will unfortunately result in massive increases in diabetic distal symmetrical polyneuropathy (DPN) and its troublesome sequelae, including disabling neuropathic pain (painful-DPN), which affects around 25% of patients with diabetes. Why these patients develop neuropathic pain, while others with a similar degree of neuropathy do not, is not clearly understood. This review will look at recent advances that may shed some light on the differences between painful and painless-DPN. RECENT FINDINGS: Gender, clinical pain phenotyping, serum biomarkers, brain imaging, genetics, and skin biopsy findings have been reported to differentiate painful- from painless-DPN. Painful-DPN seems to be associated with female gender and small fiber dysfunction. Moreover, recent brain imaging studies have found neuropathic pain signatures within the central nervous system; however, whether this is the cause or effect of the pain is yet to be determined. Further research is urgently required to develop our understanding of the pathogenesis of pain in DPN in order to develop new and effective mechanistic treatments for painful-DPN.

Frequency and phase correction for multiplexed edited MRS of GABA and glutathione.

PURPOSE: Detection of endogenous metabolites using multiplexed editing substantially improves the efficiency of edited magnetic resonance spectroscopy. Multiplexed editing (i.e., performing more than one edited experiment in a single acquisition) requires a tailored, robust approach for correction of frequency and phase offsets. Here, a novel method for frequency and phase correction (FPC) based on spectral registration is presented and compared against previously presented approaches. METHODS: One simulated dataset and 40 γ-aminobutyric acid-/glutathione-edited HERMES datasets acquired in vivo at three imaging centers were used to test four FPC approaches: no correction; spectral registration; spectral registration with post hoc choline-creatine alignment; and multistep FPC. The performance of each routine for the simulated dataset was assessed by comparing the estimated frequency/phase offsets against the known values, whereas the performance for the in vivo data was assessed quantitatively by calculation of an alignment quality metric based on choline subtraction artifacts. RESULTS: The multistep FPC approach returned corrections that were closest to the true values for the simulated dataset. Alignment quality scores were on average worst for no correction, and best for multistep FPC in both the γ-aminobutyric acid- and glutathione-edited spectra in the in vivo data. CONCLUSIONS: Multistep FPC results in improved correction of frequency/phase errors in multiplexed γ-aminobutyric acid-/glutathione-edited magnetic resonance spectroscopy experiments. The optimal FPC strategy is experiment-specific, and may even be dataset-specific. Magn Reson Med 80:21-28, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Imaging muscle as a potential biomarker of denervation in motor neuron disease.

OBJECTIVE: To assess clinical, electrophysiological and whole-body muscle MRI measurements of progression in patients with motor neuron disease (MND), as tools for future clinical trials, and to probe pathophysiological mechanisms in vivo. METHODS: A prospective, longitudinal, observational, clinicoelectrophysiological and radiological cohort study was performed. Twenty-nine patients with MND and 22 age-matched and gender-matched healthy controls were assessed with clinical measures, electrophysiological motor unit number index (MUNIX) and T2-weighted whole-body muscle MRI, at first clinical presentation and 4 months later. Between-group differences and associations were assessed using age-adjusted and gender-adjusted multivariable regression models. Within-subject longitudinal changes were assessed using paired t-tests. Patterns of disease spread were modelled using mixed-effects multivariable regression, assessing associations between muscle relative T2 signal and anatomical adjacency to site of clinical onset. RESULTS: Patients with MND had 30% higher relative T2 muscle signal than controls at baseline (all regions mean, 95% CI 15% to 45%, p<0.001). Higher T2 signal was associated with greater overall disability (coefficient -0.009, 95% CI -0.017 to -0.001, p=0.023) and with clinical weakness and lower MUNIX in multiple individual muscles. Relative T2 signal in bilateral tibialis anterior increased over 4 months in patients with MND (right: 10.2%, 95% CI 2.0% to 18.4%, p=0.017; left: 14.1%, 95% CI 3.4% to 24.9%, p=0.013). Anatomically, contiguous disease spread on MRI was not apparent in this model. CONCLUSIONS: Whole-body muscle MRI offers a new approach to objective assessment of denervation over short timescales in MND and enables investigation of patterns of disease spread in vivo. Muscles inaccessible to conventional clinical and electrophysiological assessment may be investigated using this methodology.

Evaluation of wave delivery methodology for brain MRE: Insights from computational simulations.

PURPOSE: MR elastography (MRE) of the brain is being explored as a biomarker of neurodegenerative disease such as dementia. However, MRE measures for healthy brain have varied widely. Differing wave delivery methodologies may have influenced this, hence finite element-based simulations were performed to explore this possibility. METHODS: The natural frequencies of a series of cranial models were calculated, and MRE-associated vibration was simulated for different wave delivery methods at varying frequency, using simple isotropic viscoelastic material models for the brain. Displacement fields and the corresponding brain constitutive properties estimated by standard inversion techniques were compared across delivery methods and frequencies. RESULTS: The delivery methods produced widely different MRE displacement fields and inversions. Furthermore, resonances at natural frequencies influenced the displacement patterns. Consequently, some delivery methods led to lower inversion errors than others, and the error on the storage modulus varied by up to 11% between methods. CONCLUSION: Wave delivery has a considerable impact on brain MRE reliability. Assuming small variations in brain biomechanics, as recently reported to accompany neurodegenerative disease (e.g., 7% for Alzheimer's disease), the effect of wave delivery is important. Hence, a consensus should be established on a consistent methodology to ensure diagnostic and prognostic consistency. Magn Reson Med 78:341-356, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Magnetic resonance elastography of the brain: An in silico study to determine the influence of cranial anatomy.

PURPOSE: Magnetic resonance elastography (MRE) of the brain has demonstrated potential as a biomarker of neurodegenerative disease such as dementia but requires further evaluation. Cranial anatomical features such as the falx cerebri and tentorium cerebelli membranes may influence MRE measurements through wave reflection and interference and tissue heterogeneity at their boundaries. We sought to determine the influence of these effects via simulation. METHODS: MRE-associated mechanical stimulation of the brain was simulated using steady state harmonic finite element analysis. Simulations of geometrical models and anthropomorphic brain models derived from anatomical MRI data of healthy individuals were compared. Constitutive parameters were taken from MRE measurements for healthy brain. Viscoelastic moduli were reconstructed from the simulated displacement fields and compared with ground truth. RESULTS: Interference patterns from reflections and heterogeneity resulted in artifacts in the reconstructions of viscoelastic moduli. Artifacts typically occurred in the vicinity of boundaries between different tissues within the cranium, with a magnitude of 10%-20%. CONCLUSION: Given that MRE studies for neurodegenerative disease have reported only marginal variations in brain elasticity between controls and patients (e.g., 7% for Alzheimer's disease), the predicted errors are a potential confound to the development of MRE as a biomarker of dementia and other neurodegenerative diseases. Magn Reson Med 76:645-662, 2016. © 2015 Wiley Periodicals, Inc.

Discrimination of voice gender in the human auditory cortex.

Discerning a speaker's gender from their voice is a basic and crucial aspect of human communication. Voice pitch height, the perceptual correlate of fundamental frequency, is higher in females and provides a cue for gender discrimination. However, male and female voices are also differentiated by multiple other spectral and temporal characteristics, including mean formant frequency and spectral flux. The robust perceptual segregation of male and female voices is thought to result from processing the combination of discriminating features, which in neural terms may correspond to early sound object analysis occurring in non-primary auditory cortex. However, the specific mechanism for gender perception has been unclear. Here, using functional magnetic resonance imaging, we show that discrete sites in non-primary auditory cortex are differentially activated by male and female voices, with female voices consistently evoking greater activation in the upper bank of the superior temporal sulcus and posterior superior temporal plane. This finding was observed at the individual subject-level in all 24 subjects. The neural response was highly specific: no auditory regions were more activated by male than female voices. Further, the activation associated with female voices was 1) larger than can be accounted for by a sole effect of fundamental frequency, 2) not due to psychological attribution of female gender and 3) unaffected by listener gender. These results demonstrate that male and female voices are represented as distinct auditory objects in the human brain, with the mechanism for gender discrimination being a gender-dependent activation-level cue in non-primary auditory cortex.

Reduced Thalamic Gamma Aminobutyric Acid (GABA) in Painless but not Painful Diabetic Peripheral Neuropathy.

Alterations in the structure, function, and microcirculation of the thalamus, a key brain region involved in pain pathways, have previously been demonstrated in patients with Painless- and Painful-diabetic peripheral neuropathy (DPN). However, thalamic neurotransmitter levels including GABA (inhibitory neurotransmitter) and glutamate (excitatory neurotransmitter) in different DPN phenotypes are not known. We performed a Magnetic Resonance Spectroscopy study and quantified GABA and glutamate levels within the thalamus, in a carefully characterised cohort of participants with Painless- and Painful-DPN. Participants with DPN (Painful- and Painless combined) had a significantly lower GABA:H2O ratio compared to those without DPN (Healthy volunteers [HV] and diabetes without DPN [No-DPN]). Participants with Painless-DPN had the lowest GABA:H2O ratio, which reached significance compared with HV and No-DPN, but not Painful-DPN. There was no difference in GABA:H2O in Painful-DPN compared with all other groups. A significant correlation with GABA:H2O and neuropathy severity was also seen. This study demonstrates that lower levels of thalamic GABA in participants with Painless-DPN may reflect neuroplasticity due to reduced afferent pain impulses. Whereas partially preserved levels of GABA in Painful-DPN may indicate that central GABAergic pathways are involved in the mechanisms of neuropathic pain in diabetes.

Magnetic resonance imaging biomarkers in patients with progressive ataxia: current status and future direction.

A diagnostic challenge commonly encountered in neurology is that of an adult patient presenting with ataxia. The differential is vast and clinical assessment alone may not be sufficient due to considerable overlap between different causes of ataxia. Magnetic resonance (MR)-based biomarkers such as voxel-based morphometry, MR spectroscopy, diffusion-weighted and diffusion-tensor imaging and functional MR imaging are gaining great attention for their potential as indicators of disease. A number of studies have reported correlation with clinical severity and underlying pathophysiology, and in some cases, MR imaging has been shown to allow differentiation of conditions causing ataxia. However, despite recent advances, their sensitivity and specificity vary. In addition, questions remain over their validity and reproducibility, especially when applied in routine clinical practice. This article extensively reviews the current literature regarding MR-based biomarkers for the patient with predominantly adult-onset ataxia. Imaging features characteristic of a particular ataxia are provided and features differentiating ataxia groups and subgroups are discussed. Finally, discussion will turn to the feasibility of applying these biomarkers in routine clinical practice.

Magnetic resonance imaging of the central nervous system in diabetic neuropathy.

Diabetic 'peripheral' neuropathy (DPN) is one of the common sequelae to the development of both type-1 and type-2 diabetes mellitus. Neuropathy has a major negative impact on quality of life. Abnormalities in both peripheral vasculature and nerve function are well documented and, in addition, evidence is emerging regarding changes within the central nervous system (CNS) that are concomitant with the presence of DPN. The often-resistant nature of DPN to medical treatment highlights the need to understand the role of the CNS in neuropathic symptomatology and progression, as this may modulate therapeutic approaches. Advanced neuroimaging techniques, especially those that can provide quantitative measures of structure and function, can provide objective markers of CNS status. With that comes great potential for not only furthering our understanding of involvement of the CNS in neuropathic etiology but also most importantly aiding the development of new and more effective, targeted, analgesic interventions.

Differentiating core and co-opted mechanisms in calculation: the neuroimaging of calculation in aphasia.

The role of language in exact calculation is the subject of debate. Some behavioral and functional neuroimaging investigations of healthy participants suggest that calculation requires language resources. However, there are also reports of individuals with severe aphasic language impairment who retain calculation ability. One possibility in resolving these discordant findings is that the neural basis of calculation has undergone significant reorganization in aphasic calculators. Using fMRI, we examined brain activations associated with exact addition and subtraction in two patients with severe agrammatic aphasia and retained calculation ability. Behavior and brain activations during two-digit addition and subtraction were compared to those of a group of 11 healthy, age-matched controls. Behavioral results confirmed that both patients retained calculation ability. Imaging findings revealed individual differences in processing, but also a similar activation pattern across patients and controls in bilateral parietal cortices. Patients differed from controls in small areas of increased activation in peri-lesional regions, a shift from left fronto-temporal activation to the contralateral region, and increased activations in bilateral superior parietal regions. Our results suggest that bilateral parietal cortex represents the core of the calculation network and, while healthy controls may recruit language resources to support calculation, these mechanisms are not mandatory in adult cognition.

Understanding MRI: basic MR physics for physicians.

More frequently hospital clinicians are reviewing images from MR studies of their patients before seeking formal radiological opinion. This practice is driven by a multitude of factors, including an increased demand placed on hospital services, the wide availability of the picture archiving and communication system, time pressures for patient treatment (eg, in the management of acute stroke) and an inherent desire for the clinician to learn. Knowledge of the basic physical principles behind MRI is essential for correct image interpretation. This article, written for the general hospital physician, describes the basic physics of MRI taking into account the machinery, contrast weighting, spin- and gradient-echo techniques and pertinent safety issues. Examples provided are primarily referenced to neuroradiology reflecting the subspecialty for which MR currently has the greatest clinical application.

Magnetic resonance spectroscopy of the brain.

Proton magnetic resonance (MR) spectroscopy of the brain is a non-invasive, in vivo technique that allows investigation into regional chemical environments. Its complementary use with MR imaging sequences provides valuable insights into brain tumour characteristics, progression and response to treatment. Additionally, its sensitivity to brain dysfunction in the presence of apparently normal structural imaging has galvanised interest in its use as a biomarker of neurodegenerative disorders such as Alzheimer's disease. Accordingly, its integration into clinical imaging protocols within many neuroscience centres throughout the world is increasing. This growing attention is encouraging but if the potential of MR spectroscopy is to be realised, fundamental questions need to be addressed, such as reproducibility of the technique and the biochemistry that underpins the neurometabolites measured. Failure to resolve these issues will continue to hinder the extent and accuracy of conclusions that can be drawn from its data. In this review we discuss the issues regarding MR spectroscopy in the brain with particular attention paid to its technique. Key examples of current clinical applications are provided and future directions are discussed.

Structural Brain Alterations in Key Somatosensory and Nociceptive Regions in Diabetic Peripheral Neuropathy.

OBJECTIVE: Despite increasing evidence demonstrating structural and functional alterations within the central nervous system in diabetic peripheral neuropathy (DPN), the neuroanatomical correlates of painful and painless DPN have yet to be identified. Focusing on structural MRI, the aims of this study were to 1) define the brain morphological alterations in painful and painless DPN and 2) explore the relationships between brain morphology and clinical/neurophysiological assessments. RESEARCH DESIGN AND METHODS: A total of 277 participants with type 1 and 2 diabetes (no DPN [n = 57], painless DPN [n = 77], painful DPN [n = 77]) and 66 healthy volunteers (HVs) were enrolled. All underwent detailed clinical/neurophysiological assessment and brain 3T MRI. Participants with painful DPN were subdivided into the irritable (IR) nociceptor and nonirritable (NIR) nociceptor phenotypes using the German Research Network on Neuropathic Pain protocol. Cortical reconstruction and volumetric segmentation were performed with FreeSurfer software and voxel-based morphometry implemented in FSL. RESULTS: Both participants with painful and painless DPN showed a significant reduction in primary somatosensory and motor cortical thickness compared with HVs (P = 0.02; F[3,275] = 3.36) and participants with no DPN (P = 0.01; F[3,275] = 3.80). Somatomotor cortical thickness correlated with neurophysiological measures of DPN severity. There was also a reduction in ventrobasal thalamic nuclei volume in both painless and painful DPN. Participants with painful DPN with the NIR nociceptor phenotype had reduced primary somatosensory cortical, posterior cingulate cortical, and thalamic volume compared with the IR nociceptor phenotype. CONCLUSIONS: In this largest neuroimaging study in DPN to date, we demonstrated significant structural alterations in key somatomotor/nociceptive brain regions specific to painless DPN and painful DPN, including the IR and NIR nociceptor phenotypes.

Should we be 'nervous' about coeliac disease? Brain abnormalities in patients with coeliac disease referred for neurological opinion.

OBJECTIVES: To examine the extent of brain abnormality in patients with coeliac disease referred for neurological opinion and evaluate MR imaging sequences as biomarkers for neurological dysfunction, given the lack of readily available serological markers of neurological disease in this cohort. METHODS: Retrospective examination of a consecutive cohort of patients (n = 33, mean age = 44 ± 13 years (range 19-64)) with biopsy proven coeliac disease referred for neurological opinion. Patients were divided into subgroups based on their primary neurological complaint (balance disturbance, headache and sensory loss). 3T MR was used to evaluate differences in brain grey matter density, cerebellar volume, cerebellar neurochemistry and white matter abnormalities (WMAs) between subjects and controls. RESULTS: Cerebellar volume was significantly less in the patient group than in controls (6.9 ± 0.7% vs 7.4 ± 0.9% of total intracranial volume, p<0.05). Significantly less grey matter density was found in multiple brain regions, both above and below the tentorium cerebelli, than in controls (p<0.05). 12 (36%) patients demonstrated WMAs unexpected for the patient's age, with the highest incidence occurring in the headache subgroup. This subgroup averaged almost twice the number of WMAs per MR imaging than the subgroup with balance disturbance and six times more than the subgroup with sensory loss. CONCLUSION: Patients with established coeliac disease referred for neurological opinion show significant brain abnormality on MR imaging. MR imaging may provide valuable biomarkers of disease in this patient cohort.

Preservation of thalamic neuronal function may be a prerequisite for pain perception in diabetic neuropathy: A magnetic resonance spectroscopy study.

Introduction: In this study, we used proton Magnetic Resonance Spectroscopy (1H-MRS) to determine the neuronal function in the thalamus and primary somatosensory (S1) cortex in different subgroups of DPN, including subclinical- and painful-DPN. Method: One-hundred and ten people with type 1 diabetes [20 without DPN (no-DPN); 30 with subclinical-DPN; 30 with painful-DPN; and 30 with painless-DPN] and 20 healthy volunteers, all of whom were right-handed men, were recruited and underwent detailed clinical and neurophysiological assessments. Participants underwent Magnetic Resonance Imaging at 1.5 Tesla with two 1H-MRS spectra obtained from 8 ml cubic volume voxels: one placed within left thalamus to encompass the ventro-posterior lateral sub-nucleus and another within the S1 cortex. Results: In the thalamus, participants with painless-DPN had a significantly lower NAA:Cr ratio [1.55 + 0.22 (mean ± SD)] compared to all other groups [HV (1.80 ± 0.23), no-DPN (1.85 ± 0.20), sub-clinical DPN (1.79 ± 0.23), painful-DPN (1.75 ± 0.19), ANOVA p < 0.001]. There were no significant group differences in S1 cortical neurometabolites. Conclusion: In this largest cerebral MRS study in DPN, thalamic neuronal dysfunction was found in advanced painless-DPN with preservation of function in subclinical- and painful-DPN. Furthermore, there was a preservation of neuronal function within the S1 cortex in all subgroups of DPN. Therefore, there may be a proximo-distal gradient to central nervous system alterations in painless-DPN, with thalamic neuronal dysfunction occurring only in established DPN. Moreover, these results further highlight the manifestation of cerebral alterations between painful- and painless-DPN whereby preservation of thalamic function may be a prerequisite for neuropathic pain in DPN.

The role of the cerebellum in sub- and supraliminal error correction during sensorimotor synchronization: evidence from fMRI and TMS.

Our ability to interact physically with objects in the external world critically depends on temporal coupling between perception and movement (sensorimotor timing) and swift behavioral adjustment to changes in the environment (error correction). In this study, we investigated the neural correlates of the correction of subliminal and supraliminal phase shifts during a sensorimotor synchronization task. In particular, we focused on the role of the cerebellum because this structure has been shown to play a role in both motor timing and error correction. Experiment 1 used fMRI to show that the right cerebellar dentate nucleus and primary motor and sensory cortices were activated during regular timing and during the correction of subliminal errors. The correction of supraliminal phase shifts led to additional activations in the left cerebellum and right inferior parietal and frontal areas. Furthermore, a psychophysiological interaction analysis revealed that supraliminal error correction was associated with enhanced connectivity of the left cerebellum with frontal, auditory, and sensory cortices and with the right cerebellum. Experiment 2 showed that suppression of the left but not the right cerebellum with theta burst TMS significantly affected supraliminal error correction. These findings provide evidence that the left lateral cerebellum is essential for supraliminal error correction during sensorimotor synchronization.