The Effects of Noninvasive Vagus Nerve Stimulation on Fatigue in Participants With Primary Sjögren's Syndrome.

OBJECTIVES: Fatigue is one of the most important symptoms needing improvement in Primary Sjögren's syndrome (PSS). Previous data from our group suggest that noninvasive stimulation of the vagus nerve (nVNS) may improve symptoms of fatigue. This experimental medicine study uses the gammaCore device (electroCore) and a sham device to investigate the relationship between nVNS and fatigue in PSS, and to explore potential mechanisms involved. MATERIALS AND METHODS: Forty participants with PSS were randomly assigned to use active (n = 20) or sham (n = 20) nVNS devices twice daily for 54 days in a double-blind manner. Patient-reported measures of fatigue were collected at baseline and day 56: Profile of Fatigue (PRO-F)-Physical, PRO-F-Mental and Visual Analogue Scale of abnormal fatigue (fVAS). Neurocognitive tests, immunologic responses, electroencephalography alpha reactivity, muscle acidosis, and heart rate variability were compared between devices from baseline to day 56 using analysis of covariance. RESULTS: PRO-F-Physical, PRO-F-Mental, and fVAS scores were significantly reduced at day 56 in the active group only (p = 0.02, 0.02, and 0.04, respectively). Muscle bioenergetics and heart rate variability showed no change between arms. There were significant improvements in digit span and a neurocognitive test (p = 0.03), and upon acute nVNS stimulation, frontal region alpha reactivity showed a significant negative relationship with fatigue scores in the active group (p < 0.01). CONCLUSIONS: We observed significant improvements in three measures of fatigue at day 56 with the active device but not the sham device. Directly after device use, fatigue levels correlate with measures of alpha reactivity, suggesting modulation of cholinergic system integrity as a mechanism of action for nVNS.

Investigation of structural brain changes in Charles Bonnet Syndrome.

BACKGROUND AND OBJECTIVES: In Charles Bonnet Syndrome (CBS), visual hallucinations (VH) are experienced by people with sight loss due to eye disease or lesional damage to early visual pathways. The aim of this cross-sectional study was to investigate structural brain changes using magnetic resonance imaging (MRI) in CBS. METHODS: Sixteen CBS patients, 17 with eye disease but no VH, and 19 normally sighted people took part. Participants were imaged on a 3T scanner, with 1 mm resolution T1 weighted structural imaging, and diffusion tensor imaging with 64 diffusion directions. RESULTS: The three groups were well matched for age, sex and cognitive scores (MMSE). The two eye disease groups were matched on visual acuity. Compared to the sighted controls, we found reduced grey matter in the occipital cortex in both eye disease groups. We also found reductions of fractional anisotropy and increased diffusivity in widespread areas, including occipital tracts, the corpus callosum, and the anterior thalamic radiation. We did not find any significant differences between the eye disease participants with VH versus without VH, but did observe a negative association between hippocampal volume and VH severity in the CBS group. DISCUSSION: Our findings suggest that although there are cortical and subcortical effects associated with sight loss, structural changes do not explain the occurrence of VHs. CBS may relate instead to connectivity or excitability changes in brain networks linked to vision.

Connectivity-Guided Theta Burst Transcranial Magnetic Stimulation Versus Repetitive Transcranial Magnetic Stimulation for Treatment-Resistant Moderate to Severe Depression: Magnetic Resonance Imaging Protocol and SARS-CoV-2-Induced Changes for a Randomized Double-blind Controlled Trial.

BACKGROUND: Depression is a substantial health and economic burden. In approximately one-third of patients, depression is resistant to first-line treatment; therefore, it is essential to find alternative treatments. Transcranial magnetic stimulation (TMS) is a neuromodulatory treatment involving the application of magnetic pulses to the brain that is approved in the United Kingdom and the United States in treatment-resistant depression. This trial aims to compare the clinical effectiveness, cost-effectiveness, and mechanism of action of standard treatment repetitive TMS (rTMS) targeted at the F3 electroencephalogram site with a newer treatment-a type of TMS called theta burst stimulation (TBS) targeted based on measures of functional brain connectivity. This protocol outlines brain imaging acquisition and analysis for the Brain Imaging Guided Transcranial Magnetic Stimulation in Depression (BRIGhTMIND) study trial that is used to create personalized TMS targets and answer the proposed mechanistic hypotheses. OBJECTIVE: The aims of the imaging arm of the BRIGhTMIND study are to identify functional and neurochemical brain signatures indexing the treatment mechanisms of rTMS and connectivity-guided intermittent theta burst TMS and to identify imaging-based markers predicting response to treatment. METHODS: The study is a randomized double-blind controlled trial with 1:1 allocation to either 20 sessions of TBS or standard rTMS. Multimodal magnetic resonance imaging (MRI) is acquired for each participant at baseline (before TMS treatment) with T1-weighted and task-free functional MRI during rest used to estimate TMS targets. For participants enrolled in the mechanistic substudy, additional diffusion-weighted sequences are acquired at baseline and at posttreatment follow-up 16 weeks after treatment randomization. Core data sets of T1-weighted and task-free functional MRI during rest are acquired for all participants and are used to estimate TMS targets. Additional sequences of arterial spin labeling, magnetic resonance spectroscopy, and diffusion-weighted images are acquired depending on the recruitment site for mechanistic evaluation. Standard rTMS treatment is targeted at the F3 electrode site over the left dorsolateral prefrontal cortex, whereas TBS treatment is guided using the coordinate of peak effective connectivity from the right anterior insula to the left dorsolateral prefrontal cortex. Both treatment targets benefit from the level of MRI guidance, but only TBS is provided with precision targeting based on functional brain connectivity. RESULTS: Recruitment began in January 2019 and is ongoing. Data collection is expected to continue until January 2023. CONCLUSIONS: This trial will determine the impact of precision MRI guidance on rTMS treatment and assess the neural mechanisms underlying this treatment in treatment-resistant depressed patients. TRIAL REGISTRATION: ISRCTN Registry ISRCTN19674644; https://www.isrctn.com/ISRCTN19674644. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/31925.

Motion correction of free-breathing magnetic resonance renography using model-driven registration.

INTRODUCTION: Model-driven registration (MDR) is a general approach to remove patient motion in quantitative imaging. In this study, we investigate whether MDR can effectively correct the motion in free-breathing MR renography (MRR). MATERIALS AND METHODS: MDR was generalised to linear tracer-kinetic models and implemented using 2D or 3D free-form deformations (FFD) with multi-resolution and gradient descent optimization. MDR was evaluated using a kidney-mimicking digital reference object (DRO) and free-breathing patient data acquired at high temporal resolution in multi-slice 2D (5 patients) and 3D acquisitions (8 patients). Registration accuracy was assessed using comparison to ground truth DRO, calculating the Hausdorff distance (HD) between ground truth masks with segmentations and visual evaluation of dynamic images, signal-time courses and parametric maps (all data). RESULTS: DRO data showed that the bias and precision of parameter maps after MDR are indistinguishable from motion-free data. MDR led to reduction in HD (HDunregistered = 9.98 ± 9.76, HDregistered = 1.63 ± 0.49). Visual inspection showed that MDR effectively removed motion effects in the dynamic data, leading to a clear improvement in anatomical delineation on parametric maps and a reduction in motion-induced oscillations on signal-time courses. DISCUSSION: MDR provides effective motion correction of MRR in synthetic and patient data. Future work is needed to compare the performance against other more established methods.

A 4D flow cardiovascular magnetic resonance study of flow asymmetry and haemodynamic quantity correlations in the pulmonary artery.

OBJECTIVE: In this paper we elucidate the asymmetric flow pattern and the haemodynamic quantity distributions and correlations in the pulmonary artery (PA) vasculature in healthy adults having structurally normal hearts, to provide reference on the flow characteristics in the PA and the right ventricle. APPROACH: Velocity data are acquired non-invasively from 18 healthy volunteers by 4D flow magnetic resonance imaging, resolved to 20 phases with spatial resolution 3 × 3 × 3 mm3. Interpolation is applied to improve the accuracy in quantifying haemodynamic quantities including kinetic energy, rotational energy, helicity and energy dissipation rate. These quantities are volumetrically normalised to remove size dependency, representing densities or local intensity. MAIN RESULTS: Flow asymmetry in the PA is quantified in terms of all the flow dynamic quantities and their correlations. The right PA has larger diameter and higher peak stroke velocity than the left PA. It also has the highest rotational energy intensity. Counter-rotating helical streams in the main PA appear to be associated with the unidirectional helical flow noticed in the left and the right PA near the peak systole. SIGNIFICANCE: This study provides a fundamental basis of normal flow in the PA. It implies the validity to use these flow pattern-related quantitative measures to aid with the identification of abnormal PA flow non-invasively, specifically for detecting abnormalities in the pulmonary circulation and response to therapy, where haemodynamic flow is commonly characterised by increased vortical and helical formations.

Effect of Levothyroxine on Left Ventricular Ejection Fraction in Patients With Subclinical Hypothyroidism and Acute Myocardial Infarction: A Randomized Clinical Trial.

Importance: Thyroid hormones play a key role in modulating myocardial contractility. Subclinical hypothyroidism in patients with acute myocardial infarction is associated with poor prognosis. Objective: To evaluate the effect of levothyroxine treatment on left ventricular function in patients with acute myocardial infarction and subclinical hypothyroidism. Design, Setting, and Participants: A double-blind, randomized clinical trial conducted in 6 hospitals in the United Kingdom. Patients with acute myocardial infarction including ST-segment elevation and non-ST-segment elevation were recruited between February 2015 and December 2016, with the last participant being followed up in December 2017. Interventions: Levothyroxine treatment (n = 46) commencing at 25 µg titrated to aim for serum thyrotropin levels between 0.4 and 2.5 mU/L or identical placebo (n = 49), both provided in capsule form, once daily for 52 weeks. Main Outcomes and Measures: The primary outcome measure was left ventricular ejection fraction at 52 weeks, assessed by magnetic resonance imaging, adjusted for age, sex, type of acute myocardial infarction, affected coronary artery territory, and baseline left ventricular ejection fraction. Secondary measures were left ventricular volumes, infarct size (assessed in a subgroup [n = 60]), adverse events, and patient-reported outcome measures of health status, health-related quality of life, and depression. Results: Among the 95 participants randomized, the mean (SD) age was 63.5 (9.5) years, 72 (76.6%) were men, and 65 (69.1%) had ST-segment elevation myocardial infarction. The median serum thyrotropin level was 5.7 mU/L (interquartile range, 4.8-7.3 mU/L) and the mean (SD) free thyroxine level was 1.14 (0.16) ng/dL. The primary outcome measurements at 52 weeks were available in 85 patients (89.5%). The mean left ventricular ejection fraction at baseline and at 52 weeks was 51.3% and 53.8%, respectively, in the levothyroxine group compared with 54.0% and 56.1%, respectively, in the placebo group (adjusted difference in groups, 0.76% [95% CI, -0.93% to 2.46%]; P = .37). None of the 6 secondary outcomes showed a significant difference between the levothyroxine and placebo treatment groups. There were 15 (33.3%) and 18 (36.7%) cardiovascular adverse events in the levothyroxine and placebo groups, respectively. Conclusions and Relevance: In this preliminary study involving patients with subclinical hypothyroidism and acute myocardial infarction, treatment with levothyroxine, compared with placebo, did not significantly improve left ventricular ejection fraction after 52 weeks. These findings do not support treatment of subclinical hypothyroidism in patients with acute myocardial infarction. Trial Registration: isrctn.org Identifier: http://www.isrctn.com/ISRCTN52505169.

The role of flow rotation in the adult right atrium: a 4D flow cardiovascular magnetic resonance study.

OBJECTIVE: In healthy adults, the right atrium (RA) serves as a reservoir for the systemic flow return from the superior vena cava (SVC) and inferior vena cava (IVC), preparing the two flows to be transferred to the right ventricle (RV) and pulmonary circulation. This study aims to quantify the haemodynamics of the RA and the associated SVC and IVC inflows, which have not been fully understood to date. APPROACH: Eighteen adults with structurally normal hearts underwent 4D flow magnetic resonance imaging. The cardiac cycle was resolved to 20 temporal phases with a spatial resolution of 3 × 3 × 3 mm3. Analysis included objective visualisation of the flow structures in the RA identified by three different vortex identification criteria, kinetic energy (KE), enstrophy and dissipation. KE and helicity flux were also assessed in both caval veins. MAIN RESULTS: Vortex identification methods confirmed that in the majority of participants the blood flow from the caval veins filling the RA during ventricular systole is not chaotic, but rather forms an organised pattern of a single coherent forward turning vortex structure. Thirteen participants displayed a single vortex flow structure, four showed multiple vortices and one had a helical flow pattern without a clear vortex structure. A strong positive correlation exists between the flow KE and enstrophy density. SIGNIFICANCE: This suggests that flow energy in the RA is mainly rotational, part of which is convected by the highly helical SVC and IVC inflows. Multiple vortices tend to be associated with higher dissipation rates in the central RA region due to turbulence. The rotational nature of the flow in the RA maintains KE better than non-rotational flow. RA flow characteristics are highly related to the helicity content in the caval veins, as well as the KE flux intensity. Lower caval helicity or IVC KE flux dominance tends to favour single vortex formation while the opposite tends to lead to multiple vortices or the rare helical flow patterns. Atria lacking single vortex flow are inclined to have a larger energy input from atrial contraction.

Metabolic effects of bezafibrate in mitochondrial disease.

Mitochondrial disorders affect 1/5,000 and have no cure. Inducing mitochondrial biogenesis with bezafibrate improves mitochondrial function in animal models, but there are no comparable human studies. We performed an open-label observational experimental medicine study of six patients with mitochondrial myopathy caused by the m.3243A>G MTTL1 mutation. Our primary aim was to determine the effects of bezafibrate on mitochondrial metabolism, whilst providing preliminary evidence of safety and efficacy using biomarkers. The participants received 600-1,200 mg bezafibrate daily for 12 weeks. There were no clinically significant adverse events, and liver function was not affected. We detected a reduction in the number of complex IV-immunodeficient muscle fibres and improved cardiac function. However, this was accompanied by an increase in serum biomarkers of mitochondrial disease, including fibroblast growth factor 21 (FGF-21), growth and differentiation factor 15 (GDF-15), plus dysregulation of fatty acid and amino acid metabolism. Thus, although potentially beneficial in short term, inducing mitochondrial biogenesis with bezafibrate altered the metabolomic signature of mitochondrial disease, raising concerns about long-term sequelae.

Reduced occipital GABA in Parkinson disease with visual hallucinations.

OBJECTIVE: To investigate the relationship between visual hallucinations in Parkinson disease (PD) and levels of γ-aminobutyric acid (GABA) in the primary visual cortex. METHODS: We utilized magnetic resonance spectroscopy to investigate occipital GABA levels in 36 participants with PD, 19 with and 17 without complex visual hallucinations, together with 20 healthy controls without hallucinations. In addition, we acquired T1-weighted MRI, whole-brain fMRI during a visual task, and diffusion tensor imaging. RESULTS: We found lower GABA+/creatine in PD with visual hallucinations (0.091 ± 0.010) vs those without (0.101 ± 0.010) and controls (0.099 ± 0.010) (F2,49 = 4.5; p = 0.016). Reduced gray matter in the hallucinations group was also observed in the anterior temporal lobe. Although there were widespread reductions in white matter integrity in the visual hallucinations group, this was no longer significant after controlling for cognitive function. CONCLUSIONS: The data suggest that reduced levels of GABA are associated with visual hallucinations in PD and implicate changes to the ventral visual stream in the genesis of visual hallucinations. Modulation of visual cortical excitability through, for example, pharmacologic intervention, may be a promising treatment avenue to explore.

Skeletal muscle mitochondrial oxidative phosphorylation function in idiopathic pulmonary arterial hypertension: in vivo and in vitro study.

Mitochondrial dysfunction within the pulmonary vessels has been shown to contribute to the pathology of idiopathic pulmonary arterial hypertension (IPAH). We investigated the hypothesis of whether impaired exercise capacity observed in IPAH patients is in part due to primary mitochondrial oxidative phosphorylation (OXPHOS) dysfunction in skeletal muscle. This could lead to potentially new avenues of treatment beyond targeting the pulmonary vessels. Nine clinically stable participants with IPAH underwent cardiopulmonary exercise testing, in vivo and in vitro assessment of mitochondrial function by 31P-magnetic resonance spectroscopy (31P-MRS) and laboratory muscle biopsy analysis. 31P-MRS showed abnormal skeletal muscle bioenergetics with prolonged recovery times of phosphocreatine and abnormal muscle pH handling. Histochemistry and quadruple immunofluorescence performed on muscle biopsies showed normal function and subunit protein abundance of the complexes within the OXPHOS system. Our findings suggest that there is no primary mitochondrial OXPHOS dysfunction but raises the possibility of impaired oxygen delivery to the mitochondria affecting skeletal muscle bioenergetics during exercise.

Variance components associated with long-echo-time MR spectroscopic imaging in human brain at 1.5T and 3T.

OBJECT: Magnetic resonance spectroscopic imaging (MRSI) is increasingly used in medicine and clinical research. Previous reliability studies have used small samples and focussed on limited aspects of variability; information regarding 1.5T versus 3T performance is lacking. The aim of the present work was to measure the inter-session, intra-session, inter-subject, within-brain and residual variance components using both 1.5T and 3T MR scanners. MATERIALS AND METHODS: Eleven healthy volunteers were invited for MRSI scanning on three occasions at both 1.5T and 3T, with four scans acquired at each visit. We measured variance components, correcting for grey matter and white matter content of voxels, of metabolite peak areas and peak area ratios. RESULTS: Residual variance was in general the largest component at 1.5T (8.6-24.6%), while within-brain variation was the largest component at 3T (12.0-24.7%). Inter-subject variation was around 5%, while inter- and intra-session variance were both generally small. CONCLUSION: Multiple variance contributions associated with MRSI measurements were quantified and the performance of 1.5T and 3T MRI scanners compared using data from the same group of subjects. Residual error is much lower at 3T, but other variance components remain important.

Left ventricular functional, structural and energetic effects of normal aging: Comparison with hypertension.

OBJECTIVES: Both aging and hypertension are significant risk factors for heart failure in the elderly. The purpose of this study was to determine how aging, with and without hypertension, affects left ventricular function. METHODS: Cross-sectional study of magnetic resonance imaging and 31P spectroscopy-based measurements of left ventricular structure, global function, strains, pulse wave velocity, high energy phosphate metabolism in 48 normal subjects and 40 treated hypertensive patients (though no other cardiovascular disease or diabetes) stratified into 3 age deciles from 50-79 years. RESULTS: Normal aging was associated with significant increases in systolic blood pressure, vascular stiffness, torsion, and impaired diastolic function (all P<0.05). Age-matched hypertension exacerbated the effects of aging on systolic pressure, and diastolic function. Hypertension alone, and not aging, was associated with increased left ventricular mass index, reduced energetic reserve, reduced longitudinal shortening and increased endocardial circumferential shortening (all P<0.05). Multiple linear regression analysis showed that these unique hypertensive features were significantly related to systolic blood pressure (P<0.05). CONCLUSIONS: 1) Hypertension adds to the age-related changes in systolic blood pressure and diastolic function; 2) hypertension is uniquely associated with changes in several aspects of left ventricular structure, function, systolic strains, and energetics; and 3) these uniquely hypertensive-associated parameters are related to the level of systolic blood pressure and so are potentially modifiable.

4D flow MRI assessment of right atrial flow patterns in the normal heart - influence of caval vein arrangement and implications for the patent foramen ovale.

AIM: To investigate atrial flow patterns in the normal adult heart, to explore whether caval vein arrangement and patency of the foramen ovale (PFO) may be associated with flow pattern. MATERIALS AND METHODS: Time-resolved, three-dimensional velocity encoded magnetic resonance imaging (4D flow) was employed to assess atrial flow patterns in thirteen healthy subjects (6 male, 40 years, range 25-50) and thirteen subjects (6 male, 40 years, range 21-50) with cryptogenic stroke and patent foramen ovale (CS-PFO). Right atrial flow was defined as vortical, helico-vortical, helical and multiple vortices. Time-averaged and peak systolic and diastolic flows in the caval and pulmonary veins and their anatomical arrangement were compared. RESULTS: A spectrum of right atrial flow was observed across the four defined categories. The right atrial flow patterns were strongly associated with the relative position of the caval veins. Right atrial flow patterns other than vortical were more common (p = 0.015) and the separation between the superior and inferior vena cava greater (10±5mm versus 3±3mm, p = 0.002) in the CS-PFO group. In the left atrium all subjects except one had counter-clockwise vortical flow. Vortex size varied and was associated with left lower pulmonary vein flow (systolic r = 0.61, p = 0.001, diastolic r = 0.63 p = 0.002). A diastolic vortex was less common and time-averaged left atrial velocity was greater in the CS-PFO group (17±2cm/sec versus 15±1, p = 0.048). One CS-PFO subject demonstrated vortical retrograde flow in the descending aortic arch; all other subjects had laminar descending aortic flow. CONCLUSION: Right atrial flow patterns in the normal heart are heterogeneous and are associated with the relative position of the caval veins. Patterns, other than 'typical' vortical flow, are more prevalent in the right atrium of those with cryptogenic stroke in the context of PFO. Left atrial flow patterns are more homogenous in normal hearts and show a relationship with flow arising from the left pulmonary veins.

Normal age-related changes in left ventricular function: Role of afterload and subendocardial dysfunction.

BACKGROUND: In normal ageing, both vascular and ventricular properties change, and how these affect left ventricular function is not clear. METHODS: 96 subjects (ages 20-79) without cardiovascular disease underwent cardiac magnetic resonance (MR) imaging for measurement of global function, diastolic function (E/A ratio), MR tagging for measurement of torsion to shortening ratio (TSR, ratio of epicardial torsion to endocardial circumferential shortening, with increase in TSR suggesting subendocardial dysfunction relative to the subepicardium), and phase contrast MR imaging measurement of central aortic pulse wave velocity (PWV). The Vicorder device was used to measure carotid to femoral PWV. RESULTS: Univariate correlations established that the 4 principal age-related changes in the left ventricular function were: 1) diastolic function: E/A ratio (r: -0.61, p<0.00001); 2) global systolic function: cardiac output (r: -0.49, p<0.00001), 3) structure: end-diastolic volume index (r: -0.39, p<0.0001), and 4) systolic strains: TSR (r: 0.49, p<0.0001). Multiple linear regression analysis showed that age was the dominant factor in predicting changes in cardiac output and E/A ratio (both p<0.01). Increased TSR was significantly related to reduced cardiac output and end-diastolic volume index (p<0.05 and p<0.01 respectively). Measures of vascular stiffness were not significantly related to any of these variables, but increased effective arterial elastance (afterload) was significantly related to reduced E/A ratio (p<0.05). CONCLUSIONS: In this group of normal ageing subjects, afterload but not vascular stiffness is significantly related to diastolic dysfunction. Increased TSR, suggesting relative subendocardial dysfunction, has a significant role in reductions of cardiac output and end-diastolic volume index.

Measurement of pulse wave velocity in normal ageing: comparison of Vicorder and magnetic resonance phase contrast imaging.

BACKGROUND: Pulse wave velocity is an important measure of cardiovascular risk, and can be measured by several different techniques. We compared age-related changes in pulse wave velocity derived from carotid and femoral artery waveforms using the Vicorder device and descending thoracic aorta time velocity curves using phase contrast magnetic resonance imaging (MRI) in a group of normal healthy volunteers, without cardiovascular disease, aged between 20 and 79 years. METHODS: Eighty subjects underwent same-day measurements of Vicorder and MRI pulse wave velocity measurements. RESULTS: Both Vicorder and MRI-based pulse wave velocity measurements were significantly increased with age (R = 0.59 and 0.57 respectively, both P < 0.0001). Vicorder and MRI pulse wave velocities were also significantly related to each other (R = 0.27, P < 0.05), and Bland Altman plots showed that on average Vicorder measurements were 1.6 m/s greater than MRI. In 5% of cases, agreement between the values of the two techniques were above and below 2 standard deviations, and these were at higher levels of pulse wave velocities. Multiple linear stepwise regression analysis confirmed highly significant relationships of both techniques to age (both P < 0.0001), and MRI was also significantly related to heart rate (P = 0.006) but Vicorder was not. CONCLUSIONS: Both Vicorder and MRI perform similarly in detecting age-related changes in pulse wave velocity. Thus, the choice of using one or the other will depend on other aspects of the investigation, such as the need for portability favouring Vicorder, or need for additional cardiovascular imaging favouring MRI. TRIAL REGISTRATION: ClinicalTrials.Gov identifier NCT01504828.

High intensity intermittent exercise improves cardiac structure and function and reduces liver fat in patients with type 2 diabetes: a randomised controlled trial.

AIMS/HYPOTHESIS: Cardiac disease remains the leading cause of mortality in type 2 diabetes, yet few strategies to target cardiac dysfunction have been developed. This randomised controlled trial aimed to investigate high intensity intermittent training (HIIT) as a potential therapy to improve cardiac structure and function in type 2 diabetes. The impact of HIIT on liver fat and metabolic control was also investigated. METHODS: Using an online random allocation sequence, 28 patients with type 2 diabetes (metformin and diet controlled) were randomised to 12 weeks of HIIT (n = 14) or standard care (n = 14). Cardiac structure and function were measured by 3.0 T MRI and tagging. Liver fat was determined by 1H-magnetic resonance spectroscopy and glucose control by an OGTT. MRI analysis was performed by an observer blinded to group allocation. All study procedures took place in Newcastle upon Tyne, UK. RESULTS: Five patients did not complete the study and were therefore excluded from analysis: this left 12 HIIT and 11 control patients for the intention-to-treat analysis. Compared with controls, HIIT improved cardiac structure (left ventricular wall mass 104 ± 17 g to 116 ± 20 g vs. 107 ± 25 g to 105 ± 25 g, p < 0.05) and systolic function (stroke volume 76 ± 16 ml to 87 ± 19 ml vs. 79 ± 14 ml to 75 ± 15 ml, p < 0.01). Early diastolic filling rates increased (241 ± 84 ml/s to 299 ± 89 ml/s vs. 250 ± 44 ml/s to 251 ± 47 ml/s, p < 0.05) and peak torsion decreased (8.1 ± 1.8° to 6.9 ± 1.6° vs. 7.1 ± 2.2° to 7.6 ± 1.9°, p < 0.05) in the treatment group. Following HIIT, there was a 39% relative reduction in liver fat (p < 0.05) and a reduction in HbA1c (7.1 ± 1.0% [54.5 mmol/mol] to 6.8 ± 0.9% [51.3 mmol/mol] vs. 7.2 ± 0.5% [54.9 mmol/mol] to 7.4 ± 0.7% [57.0 mmol/mol], p < 0.05). Changes in liver fat correlated with changes in HbA1c (r = 0.70, p < 0.000) and 2 h glucose (r = 0.57, p < 0.004). No adverse events were recorded. CONCLUSIONS/INTERPRETATION: This is the first study to demonstrate improvements in cardiac structure and function, along with the greatest reduction in liver fat, to be recorded following an exercise intervention in type 2 diabetes. HIIT should be considered by clinical care teams as a therapy to improve cardiometabolic risk in patients with type 2 diabetes. TRIAL REGISTRATION: www.isrctn.com 78698481 FUNDING: : Medical Research Council.

Human Auditory Cortex Neurochemistry Reflects the Presence and Severity of Tinnitus.

It is not known why tinnitus occurs in some cases of hearing damage but not others. Abnormalities of excitation-inhibition balance could influence whether tinnitus develops and its severity if it does. Animal models of hearing damage, which also produce tinnitus based on behavioral evidence, have identified abnormalities of GABAergic inhibition, both cortically and subcortically. However, the precise relationships of GABA inhibitory changes to tinnitus itself, as opposed to other consequences of hearing damage, remain uncertain. Here, we used magnetic resonance spectroscopy to non-invasively quantify GABA in the left (LAC) and right (RAC) auditory cortices of a group of 14 patients with lateralized tinnitus (eight left ear) and 14 controls matched for age, sex, and hearing. We also explored the potential relationships with other brain metabolites (i.e., choline, N-acetylaspartate, and creatine). The presence of tinnitus was associated with a reduction in auditory cortex GABA concentration. Regardless of tinnitus laterality, post hoc testing indicated reductions that were significant in RAC and nonsignificant in LAC. Tinnitus severity and hearing loss were correlated positively with RAC choline but not GABA. We discuss the results in the context of current models of tinnitus and methodological constraints. SIGNIFICANCE STATEMENT: Permanently affecting one in seven adults, tinnitus lacks both widely effective treatments and adequate understanding of its brain mechanisms. Existing animal models represent tinnitus that may not be distinguishable from homeostatic responses to the auditory insults used to induce it. Human studies can be well controlled in this regard but are usually not (with few even matching control subjects for hearing loss) and are limited in scope as a result of relying solely on non-invasive recording techniques. Here, we exploit recent advances in non-invasive spectroscopic techniques to establish, in a human study tightly controlled for hearing loss and hyperacusis, that tinnitus is associated with a significant reduction in auditory cortex GABA concentration, which has implications for understanding and treatment of the condition.

Proton spectroscopic imaging of brain metabolites in basal ganglia of healthy older adults.

OBJECT: We sought to measure brain metabolite levels in healthy older people. MATERIALS AND METHODS: Spectroscopic imaging at the level of the basal ganglia was applied in 40 participants aged 73-74 years. Levels of the metabolites N-acetyl aspartate (NAA), choline, and creatine were determined in "institutional units" (IU) corrected for T1 and T2 relaxation effects. Structural imaging enabled determination of grey matter (GM), white matter (WM), and cerebrospinal fluid content. ANOVA analysis was carried out for voxels satisfying quality criteria. RESULTS: Creatine levels were greater in GM than WM (57 vs. 44 IU, p < 0.001), whereas choline and NAA levels were greater in WM than GM [13 vs. 10 IU (p < 0.001) and 76 versus 70 IU (p = 0.03), respectively]. The ratio of NAA/cre was greater in WM than GM (2.1 vs. 1.4, p = 0.001) as was that of cho/cre (0.32 vs. 0.16, p < 0.001). A low voxel yield was due to brain atrophy and the difficulties of shimming over an extended region of brain. CONCLUSION: This study addresses the current lack of information on brain metabolite levels in older adults. The normal features of ageing result in a substantial loss of reliable voxels and should be taken into account when planning studies. Improvements in shimming are also required before the methods can be applied more widely.

Reliability of MRSI brain temperature mapping at 1.5 and 3 T.

MRSI permits the non-invasive mapping of brain temperature in vivo, but information regarding its reliability is lacking. We obtained MRSI data from 31 healthy male volunteers [age range, 22-40 years; mean ± standard deviation (SD), 30.5 ± 5.0 years]. Eleven subjects (age range, 23-40 years; mean ± SD, 30.5 ± 5.2 years) were invited to receive four point-resolved spectroscopy MRSI scans on each of 3 days in both 1.5-T (TR/TE = 1000/144 ms) and 3-T (TR/TE = 1700/144 ms) clinical scanners; a further 20 subjects (age range, 22-40 years; mean ± SD, 30.5 ± 4.9 years) were scanned on a single occasion at 3 T. Data were fitted in the time domain to determine the water-N-acetylaspartate chemical shift difference, from which the temperature was estimated. Temperature data were analysed using a linear mixed effects model to determine variance components and systematic temperature changes during the scanning sessions. To characterise the effects of instrumental drift on apparent MRSI brain temperature, a temperature-controlled phantom was constructed and scanned on multiple occasions. Components of apparent in vivo temperature variability at 1.5 T/3 T caused by inter-subject (0.18/0.17 °C), inter-session (0.18/0.15 °C) and within-session (0.36/0.14 °C) effects, as well as voxel-to-voxel variation (0.59/0.54 °C), were determined. There was a brain cooling effect during in vivo MRSI of 0.10 °C [95% confidence interval (CI): -0.110, -0.094 °C; p < 0.001] and 0.051 °C (95% CI: -0.054, -0.048 °C; p < 0.001) per scan at 1.5 T and 3 T, respectively, whereas phantom measurements revealed minimal drift in apparent MRSI temperature relative to fibre-optic temperature measurements. The mean brain temperature at 3 T was weakly associated with aural (R = 0.55, p = 0.002) and oral (R = 0.62, p < 0.001) measurements of head temperature. In conclusion, the variability associated with MRSI brain temperature mapping was quantified. Repeatability was somewhat higher at 3 T than at 1.5 T, although subtle spatial and temporal variations in apparent temperature were demonstrated at both field strengths. Such data should assist in the efficient design of future clinical studies.