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1.
Mol Pharm ; 21(4): 1553-1562, 2024 Apr 01.
Article in English | MEDLINE | ID: mdl-38440796

ABSTRACT

Oral dosage forms are the most widely and frequently used formulations to deliver active pharmaceutical ingredients (APIs), due to their ease of administration and noninvasiveness. Knowledge of intragastric release rates and gastric mixing is crucial for predicting the API release profile, especially for immediate release formulations. However, knowledge of the intragastric fate of oral dosage forms in vivo to date is limited, particularly for dosage forms administered when the stomach is in the fed state. An improved understanding of gastric food processing, dosage form location, disintegration times, and food effects is essential for greater understanding for effective API formulation design. In vitro standard and controlled modeling has played a significant role in predicting the behavior of dosage forms in vivo. However, discrepancies are reported between in vitro and in vivo disintegration times, with these discrepancies being greatest in the fed state. Studying the fate of a dosage form in vivo is a challenging process, usually requiring the use of invasive methods, such as intubation. Noninvasive, whole body imaging techniques can however provide unique insights into this process. A scoping review was performed systematically to identify and critically appraise published studies using MRI to visualize oral solid dosage forms in vivo in healthy human subjects. The review identifies that so far, an all-purpose robust contrast agent or dosage form type has not been established for dosage form visualization and disintegration studies in the gastrointestinal system. Opportunities have been identified for future studies, with particular focus on characterizing dosage form disintegration for development after the consumption food, as exemplified by the standard Food and Drug Administration (FDA) high fat meal.


Subject(s)
Gastrointestinal Tract , Stomach , Humans , Administration, Oral , Stomach/diagnostic imaging , Contrast Media , Magnetic Resonance Imaging/methods , Dosage Forms , Solubility , Tablets
2.
Cogn Neurosci ; : 1-29, 2024 Feb 21.
Article in English | MEDLINE | ID: mdl-38384107

ABSTRACT

Learning regularities in the environment is a fundament of human cognition, which is supported by a network of brain regions that include the hippocampus. In two experiments, we assessed the effects of selective bilateral damage to human hippocampal subregion CA3, which was associated with autobiographical episodic amnesia extending ~50 years prior to the damage, on the ability to recognize complex, deterministic event sequences presented either in a spatial or a non-spatial configuration. In contrast to findings from related paradigms, modalities, and homologue species, hippocampal damage did not preclude recognition memory for an event sequence studied and tested at four spatial locations, whereas recognition memory for an event sequence presented at a single location was at chance. In two additional experiments, recognition memory for novel single-items was intact, whereas the ability to recognize novel single-items in a different location from that presented at study was at chance. The results are at variance with a general role of the hippocampus in the learning and recognition of complex event sequences based on non-adjacent spatial and temporal dependencies. We discuss the impact of the results on established theoretical accounts of the hippocampal contributions to implicit sequence learning and episodic memory.

3.
medRxiv ; 2024 Apr 02.
Article in English | MEDLINE | ID: mdl-38260410

ABSTRACT

Structural brain aging has demonstrated strong inter-individual heterogeneity and mirroring patterns with brain development. However, due to the lack of large-scale longitudinal neuroimaging studies, most of the existing research focused on the cross-sectional changes of brain aging. In this investigation, we present a data-driven approach that incorporate both cross-sectional changes and longitudinal trajectories of structural brain aging and identified two brain aging patterns among 37,013 healthy participants from UK Biobank. Participants with accelerated brain aging also demonstrated accelerated biological aging, cognitive decline and increased genetic susceptibilities to major neuropsychiatric disorders. Further, by integrating longitudinal neuroimaging studies from a multi-center adolescent cohort, we validated the "last in, first out" mirroring hypothesis and identified brain regions with manifested mirroring patterns between brain aging and brain development. Genomic analyses revealed risk loci and genes contributing to accelerated brain aging and delayed brain development, providing molecular basis for elucidating the biological mechanisms underlying brain aging and related disorders.

4.
PLoS One ; 19(1): e0296311, 2024.
Article in English | MEDLINE | ID: mdl-38165858

ABSTRACT

Recent magnetic resonance imaging (MRI) studies showed that colonic volumes in children are different between health and functional constipation. The length of the colon has however been rarely measured and principally using unphysiological colon preparations or cadaver studies. The main objective of this study was to measure the length of the undisturbed colon in children with functional constipation (FC) and healthy controls. Here, the colon of 19 healthy controls (10-18 years old) and 16 children with FC (7-18 years old) was imaged using MRI. Different regions of the colon (ascending, transverse, descending, and sigmoid-rectum) were first segmented manually on the MRI images. Three-dimensional skeletonization image analysis methods were then used to reduce the regions of interest to a central, measurable line. Total colon length (corrected for body surface area) in healthy controls was 56±2 cm/m2 (mean±SEM). Total colon length was significantly longer in children with FC 69±3 cm/m2 compared to controls (p = 0.0037). The colon regions showing the largest differences between groups were the ascending colon (p = 0.0479) and the sigmoid-rectum (p = 0.0003). In a linear regression model, there was a positive significant correlation between total colon length and age (R = 0.45, p = 0.0064), height (R = 0.49, p = 0.0031), weight (R = 0.46, p = 0.0059) and colon volume (R = 0.4543, p = 0.0061). Our findings showed significant differences in colon lengths between healthy controls and children with constipation. A new objective diagnostic imaging endpoint such as colon length may help to improve knowledge of colon morphology and function and, in turn, understanding of colon functional pathology.


Subject(s)
Colon , Constipation , Humans , Child , Adolescent , Colon/pathology , Colon, Sigmoid , Rectum , Magnetic Resonance Imaging/methods
5.
NMR Biomed ; 37(1): e5032, 2024 Jan.
Article in English | MEDLINE | ID: mdl-37654051

ABSTRACT

Parallel transmit MRI at 7 T has increasingly been adopted in research projects and provides increased signal-to-noise ratios and novel contrasts. However, the interactions of fields in the body need to be carefully considered to ensure safe scanning. Recent advances in physically flexible body coils have allowed for high-field abdominal imaging, but the effects of increased variability on energy deposition need further exploration. The aim of this study was to assess the impact of subject geometry, respiration phase and coil positioning on the specific absorption rate (SAR). Ten healthy subjects (body mass index [BMI] = 25 ± 5 kg m-2 ) were scanned (at 3 T) during exhale breath-hold and images used to generate body models. Seven of these subjects were also scanned during inhale. Simplifications of the coil and body models were first explored, and then finite-difference time-domain simulations were run with a typical eight-channel parallel transmit coil positioned over the abdomen. Simulations were used to generate 10 g averaged SAR (SAR10g ) maps across 100,000 phase settings, and the worst-case scenario 10 g averaged SAR (wocSAR10g ) was identified using trigonometric maximisation. The average maximum SAR10g across the 10 subjects with 1 W input power per channel was 1.77 W kg-1 . Hotspots were always close to the body surface near the muscle wall boundary. The wocSAR10g across the 10 subjects ranged from 2.3 to 3.2 W kg-1 and was inversely correlated to fat volume percentage (R = 8) and BMI (R = 0.6). The coefficient of variation values in SAR10g due to variations in subject geometry, respiration phase and realistic coil repositioning were 12%, 4% and 12%, respectively. This study found that the variability due to realistic coil repositioning was similar to the variability due to differing healthy subject geometries for abdominal imaging. This is important as it suggests that population-based modelling is likely to be more useful than individual modelling in setting safe thresholds for abdominal imaging.


Subject(s)
Magnetic Resonance Imaging , Radio Waves , Humans , Phantoms, Imaging , Magnetic Resonance Imaging/methods , Abdomen/diagnostic imaging , Respiration
7.
Nat Commun ; 14(1): 4684, 2023 08 15.
Article in English | MEDLINE | ID: mdl-37582920

ABSTRACT

Smoking of cigarettes among young adolescents is a pressing public health issue. However, the neural mechanisms underlying smoking initiation and sustenance during adolescence, especially the potential causal interactions between altered brain development and smoking behaviour, remain elusive. Here, using large longitudinal adolescence imaging genetic cohorts, we identify associations between left ventromedial prefrontal cortex (vmPFC) gray matter volume (GMV) and subsequent self-reported smoking initiation, and between right vmPFC GMV and the maintenance of smoking behaviour. Rule-breaking behaviour mediates the association between smaller left vmPFC GMV and smoking behaviour based on longitudinal cross-lagged analysis and Mendelian randomisation. In contrast, smoking behaviour associated longitudinal covariation of right vmPFC GMV and sensation seeking (especially hedonic experience) highlights a potential reward-based mechanism for sustaining addictive behaviour. Taken together, our findings reveal vmPFC GMV as a possible biomarker for the early stages of nicotine addiction, with implications for its prevention and treatment.


Subject(s)
Gray Matter , Tobacco Use Disorder , Humans , Adolescent , Gray Matter/diagnostic imaging , Magnetic Resonance Imaging/methods , Prefrontal Cortex/diagnostic imaging , Smoking/adverse effects , Brain
8.
NMR Biomed ; 36(11): e5001, 2023 Nov.
Article in English | MEDLINE | ID: mdl-37452522

ABSTRACT

The z-spectrum contains many pools with different exchange rates and T2 values, which can make it difficult to interpret in vivo data and complicates the design of experiments aimed at providing sensitivity to one pool. This work aims to characterise the main pools observable with MRI at 7T in the human brain. To achieve this, we acquired z-spectra at multiple saturation powers in the human brain at 7T. We used simulations to optimise the use of particle swarm optimisation (PSO) to fit these data, validating this approach using further simulations and creatine phantoms. We then used the PSO to fit data from grey and white matter for the pool size, exchange rate, and T2 of five proton pools (magnetisation transfer, amides, amines, nuclear Overhauser enhancement NOE-3.5ppm and NOE-1.7ppm in addition to water). We then devised an approach for using PSO to fit z-spectra while limiting the computational burden, and we investigated the sensitivity of the fit to T2 and k for three overlapping pools. We used this to measure the exchange rate of creatine and to show that it varied with temperature, as expected. In the brain we measured a significantly larger pool size in white matter than in grey matter for the magnetisation transfer pool and the NOE-3.5ppm pool. For all other parameters we found no significant difference between grey and white matter. We showed that PSO can be used to fit z-spectra acquired at a range of B1 to provide information about peak position, amplitude, exchange rate, and T2 in vivo in the human brain. These data could provide more sensitivity to change in some clinical conditions and will also provide key information for further experimental design.


Subject(s)
Brain Neoplasms , Creatine , Humans , Brain/diagnostic imaging , Gray Matter , Algorithms , Magnetic Resonance Imaging
9.
J Am Acad Child Adolesc Psychiatry ; 62(1): 48-58, 2023 01.
Article in English | MEDLINE | ID: mdl-35714839

ABSTRACT

OBJECTIVE: Adolescence is a critical period for circadian rhythm, with a strong shift toward eveningness around age 14. Also, eveningness in adolescence has been found to predict later onset of depressive symptoms. However, no previous study has investigated structural variations associated with chronotype in early adolescence and how this adds to the development of depressive symptoms. METHOD: Assessment of 128 community-based adolescents (51% girls) at age 14 and 19 years was performed. Using whole-brain voxel-based morphometry, baseline (at age 14) regional gray matter volumes (GMVs), follow-up (at age 19) regional GMVs, and longitudinal changes (between 14 and 19) associated with Morningness/Eveningness Scale in Children score and sleep habits at baseline were measured. The association of GMV with depressive symptoms at 19 years was studied, and the role of potential clinical and genetic factors as mediators and moderators was assessed. RESULTS: Higher eveningness was associated with larger GMV in the right medial prefrontal cortex at ages 14 and 19 in the whole sample. GMV in this region related to depressive symptoms at age 19 in catechol-O-methyltransferase (COMT) Val/Val, but not in Met COMT, carriers. Larger GMV also was observed in the right fusiform gyrus at age 14, which was explained by later wake-up time during weekends. CONCLUSION: In adolescence, eveningness and its related sleep habits correlated with distinct developmental patterns. Eveningness was specifically associated with GMV changes in the medial prefrontal cortex; this could serve as a brain vulnerability factor for later self-reported depressive symptoms in COMT Val/Val carriers.


Subject(s)
Catechol O-Methyltransferase , Depression , Adolescent , Female , Humans , Male , Young Adult , Brain/diagnostic imaging , Catechol O-Methyltransferase/genetics , Chronotype , Depression/diagnostic imaging , Sleep , Surveys and Questionnaires
11.
Elife ; 112022 05 26.
Article in English | MEDLINE | ID: mdl-35616520

ABSTRACT

Alcohol misuse during adolescence (AAM) has been associated with disruptive development of adolescent brains. In this longitudinal machine learning (ML) study, we could predict AAM significantly from brain structure (T1-weighted imaging and DTI) with accuracies of 73 -78% in the IMAGEN dataset (n∼1182). Our results not only show that structural differences in brain can predict AAM, but also suggests that such differences might precede AAM behavior in the data. We predicted 10 phenotypes of AAM at age 22 using brain MRI features at ages 14, 19, and 22. Binge drinking was found to be the most predictable phenotype. The most informative brain features were located in the ventricular CSF, and in white matter tracts of the corpus callosum, internal capsule, and brain stem. In the cortex, they were spread across the occipital, frontal, and temporal lobes and in the cingulate cortex. We also experimented with four different ML models and several confound control techniques. Support Vector Machine (SVM) with rbf kernel and Gradient Boosting consistently performed better than the linear models, linear SVM and Logistic Regression. Our study also demonstrates how the choice of the predicted phenotype, ML model, and confound correction technique are all crucial decisions in an explorative ML study analyzing psychiatric disorders with small effect sizes such as AAM.


Subject(s)
Alcoholism , White Matter , Adolescent , Brain/diagnostic imaging , Corpus Callosum , Ethanol , Humans , Magnetic Resonance Imaging/methods
12.
J Am Acad Child Adolesc Psychiatry ; 61(8): 1050-1061, 2022 08.
Article in English | MEDLINE | ID: mdl-34954028

ABSTRACT

OBJECTIVE: Children experiencing attention-deficit/hyperactivity disorder (ADHD) symptoms may retain symptoms into adulthood, but little is known about the underlying mechanism. METHOD: To identify biomarkers of persistent ADHD symptom development, we carried out whole-brain analyses of neuroimaging data during the anticipation phase of the Monetary-Incentive-Delay (MID) task in 1,368 adolescents recruited by the IMAGEN Consortium at age 14 years, whose behavioral measurements were followed up longitudinally at age 16. In particular, we focused on comparing individuals with persistent high ADHD symptoms at both ages 14 and 16 years to unaffected control individuals, but also exploring which individuals demonstrating symptom remission (with high ADHD symptoms at age 14 but much reduced at age 16). RESULTS: We identified reduced activations in the medial frontal cortex and the thalamus during reward anticipation as neuro-biomarkers for persistent ADHD symptoms across time. The genetic relevance of the above findings was further supported by the associations of the polygenic risk scores of ADHD with both the persistent and control status and the activations of both brain regions. Furthermore, in an exploratory analysis, the thalamic activation might also help to distinguish persons with persistent ADHD from those remitted in both an exploratory sample (odds ratio = 9.43, p < .001) and an independent generalization sample (odds ratio = 4.64, p = .003). CONCLUSION: Using a well-established and widely applied functional magnetic resonance imaging task, we have identified neural biomarkers that could discriminate ADHD symptoms that persist throughout adolescence from controls and potentially those likely to remit during adolescent development as well.


Subject(s)
Attention Deficit Disorder with Hyperactivity , Adolescent , Adult , Attention Deficit Disorder with Hyperactivity/genetics , Brain , Brain Mapping/methods , Child , Humans , Magnetic Resonance Imaging , Reward
13.
J Cyst Fibros ; 21(3): 502-505, 2022 05.
Article in English | MEDLINE | ID: mdl-34922853

ABSTRACT

People with cystic fibrosis (CF) experience digestive symptoms but the mechanisms are incompletely understood. Here we explore causes and consequences of slower gastrointestinal transit using magnetic resonance imaging (MRI). Twelve people with CF and 12 healthy controls, matched for age and gender, underwent MRI scans, both fasted and after standardised meals, over 6.5 h. Fasted small bowel motility scores were lower in CF than in controls. No difference in ascending colon chyme T1 was detected. The difference in texture between small bowel and colon contents, seen in health, was diminished in CF. The ascending colon in CF participants had an abnormal appearance compared to controls. MRI offers unique potential to evaluate gut luminal content, colonic mucosa and intestinal motor activity. These new data support the theoretical cycle of desiccation, dysmotility and delayed transit as a cause of gastrointestinal symptoms in CF.


Subject(s)
Cystic Fibrosis , Gastrointestinal Motility , Gastrointestinal Tract , Gastrointestinal Transit , Humans , Magnetic Resonance Imaging
14.
Diagnostics (Basel) ; 11(11)2021 Nov 17.
Article in English | MEDLINE | ID: mdl-34829482

ABSTRACT

Perianal Crohn's Disease (pCD) is a common manifestation of Crohn's Disease. Absence of reliable disease measures makes disease monitoring unreliable. Qualitative MRI has been increasingly used for diagnosing and monitoring pCD and has shown potential for assessing response to treatment. Quantitative MRI sequences, such as diffusion-weighted imaging (DWI), dynamic contrast enhancement (DCE) and magnetisation transfer (MT), along with T2 relaxometry, offer opportunities to improve diagnostic capability. Quantitative MRI sequences (DWI, DCE, MT and T2) were used in a cohort of 25 pCD patients before and 12 weeks after biological therapy at two different field strengths (1.5 and 3 T). Disease activity was measured with the Perianal Crohn's Disease Activity index (PDAI) and serum C-reactive protein (CRP). Diseased tissue areas on MRI were defined by a radiologist. A baseline model to predict outcome at 12 weeks was developed. No differences were seen in the quantitative MR measured in the diseased tissue regions from baseline to 12 weeks; however, PDAI and CRP decreased. Baseline PDAI, CRP, T2 relaxometry and surgical history were found to have a moderate ability to predict response after 12 weeks of biological treatment. Validation in larger cohorts with MRI and clinical measures are needed in order to further develop the model.

15.
Pharmaceutics ; 13(9)2021 Aug 27.
Article in English | MEDLINE | ID: mdl-34575420

ABSTRACT

Dietary lipids and some pharmaceutical lipid excipients can facilitate the targeted delivery of drugs to the intestinal lymphatics. Here, the feasibility of magnetic resonance imaging (MRI) for imaging lipid uptake into the intestinal lymphatics was assessed, shedding light on which lymph nodes can be targeted using this approach. Three healthy male volunteers were scanned at 3.0 T at baseline, 120, 180, 240, and 300 min post high-fat meal. A sagittal multi-slice image was acquired using a diffusion-weighted whole-body imaging sequence with background suppression (DWIBS) (pre inversion TI = 260 ms). Changes in area, major, and minor axis length were compared at each time point. Apparent diffusion coefficient (ADC) was calculated (b = 0 and 600 s/mm2) across eight slices. An average of 22 nodes could be visualised across all time points. ADC increased at 120 and 180 min compared to the baseline in all three participants by an average of 9.2% and 6.8%, respectively. In two participants, mean node area and major axis lengths increased at 120 and 180 min relative to the baseline. In conclusion, the method described shows potential for repeated lymph node measurements and the tracking of lipid uptake into the lymphatics. Further studies should focus on methodology optimisation in a larger cohort.

16.
Diagnostics (Basel) ; 11(6)2021 May 28.
Article in English | MEDLINE | ID: mdl-34071217

ABSTRACT

BACKGROUND: Functional constipation in children is common. Management of this condition can be challenging and is often based on symptom reports. Increased, objective knowledge of colonic volume changes in constipation compared to health could provide additional information. However, very little data on paediatric colonic volume is available except from methods that are invasive or require unphysiological colonic preparations. OBJECTIVES: (1) To measure volumes of the undisturbed colon in children with functional constipation (FC) using magnetic resonance imaging (MRI) and provide initial normal range values for healthy controls, and (2) to investigate possible correlation of colonic volume with whole gut transit time (WGTT). METHODS: Total and regional (ascending, transverse, descending, sigmoid, and rectum) colon volumes were measured from MRI images of 35 participants aged 7-18 years (16 with FC and 19 healthy controls), and corrected for body surface area. Linear regression was used to explore the relationship between total colon volume and WGTT. RESULTS: Total colonic volume was significantly higher, with a median (interquartile range) of 309 mL (243-384 mL) for the FC group than for the healthy controls of 227 mL (180-263 mL). The largest increase between patients and controls was in the sigmoid colon-rectum region. In a linear regression model, there was a positive significant correlation between total colonic volume and WGTT (R = 0.56, p = 0.0005). CONCLUSIONS: This initial study shows increased volumes of the colon in children with FC, in a physiological state, without use of any bowel preparation. Increased knowledge of colonic morphology may improve understanding of FC in this age group and help to direct treatment.

17.
MAGMA ; 34(6): 791-804, 2021 Dec.
Article in English | MEDLINE | ID: mdl-34089407

ABSTRACT

OBJECTIVE: Quantitative Magnetic Resonance Imaging sequences have been investigated as objective imaging biomarkers of fibrosis and inflammation in Crohn's disease. AIM: To determine the repeatability and inter- and intra-observer agreement of these measures in the prepared small bowel wall. METHODS: Ten healthy participants were scanned at 3 T on 2 separate occasions using T1 and T2 relaxometry, IVIM-DWI and MT sequences. Test-retest repeatability was assessed using the coefficient of variation (CoV) and intra-class correlation coefficients (ICCs) were used to evaluate the intra- and inter-observer agreement RESULTS: Test-retest repeatability in the bowel wall was excellent for apparent diffusion coefficient (ADC), magnetisation transfer ratio (MTR), T1, and diffusion coefficient D (CoV 5%, 7%, 8%, and 10%, respectively), good for perfusion fraction (PF) (CoV 20%) and acceptable for T2 (CoV 21%). Inter-observer agreement was good for the T2, D and ADC (ICC = 0.89, 0.86, 0.76, respectively) and moderate for T1 (ICC = 0.55). Intra-observer agreement was similar to inter-observer agreement. DISCUSSION: This study showed variable results between the different parameters measured. Test-retest repeatability was at least acceptable for all parameters except pseudo-diffusion coefficient D*. Good inter- and intra-observer agreement was obtained for T2, ADC and D, with these parameters performing best in this technical validation study.


Subject(s)
Diffusion Magnetic Resonance Imaging , Magnetic Resonance Imaging , Healthy Volunteers , Humans , Prospective Studies , Reproducibility of Results
18.
Magn Reson Med ; 86(2): 611-624, 2021 08.
Article in English | MEDLINE | ID: mdl-33749010

ABSTRACT

PURPOSE: Achieving a desired RF transmit field ( B1+ ) in small regions of interest is critical for single-voxel MRS at ultrahigh field. Radio-frequency (RF) shimming, using parallel transmission, requires B1+ mapping and optimization, which limits its ease of use. This work aimed to generate calibration-free RF shims for predefined target regions of interest, which can be applied to any participant, to produce a desired absolute magnitude B1+ (| B1+ |). METHODS: The RF shims were found offline by joint optimization on a database comprising B1+ maps from 11 subjects, considering regions of interest in occipital cortex, hippocampus and posterior cingulate, as well as whole brain. The | B1+ | achieved was compared with a tailored shimming approach, and MR spectra were acquired using tailored and calibration-free shims in 4 participants. Global and local 10g specific-absorption-rate deposition were estimated using Duke and Ella dielectric models. RESULTS: There was no difference in the mean | B1+ | produced using calibration-free versus tailored RF shimming in the occipital cortex (p = .15), hippocampus (p = .5), or posterior cingulate (p = .98), although differences were observed in the RMS error | B1+ |. Spectra acquired using calibration-free shims had similar SNR and low residual water signal. Under identical power settings, specific-absorption-rate deposition was lower compared with operating in quadrature mode. For example, the total head specific absorption rate was around 35% less for the occipital cortex. CONCLUSION: This work demonstrates that static RF shims, optimized offline for small regions, avoid the need for B1+ mapping and optimization for each region of interest and participant. Furthermore, power settings may be increased when using calibration-free shims, to better take advantage of RF shimming.


Subject(s)
Magnetic Resonance Imaging , Radio Waves , Brain/diagnostic imaging , Calibration , Head , Humans
19.
J Magn Reson Imaging ; 53(5): 1422-1431, 2021 05.
Article in English | MEDLINE | ID: mdl-33331088

ABSTRACT

BACKGROUND: Increased small bowel permeability leads to bacterial translocation, associated with significant morbidity and mortality. Biomarkers are needed to evaluate these changes in vivo, stratify an individual's risk, and evaluate the efficacy of interventions. MRI is an established biomarker of small bowel inflammation. PURPOSE: To characterize changes in the small bowel with quantitative MRI measures associated with increased permeability induced by indomethacin. STUDY TYPE: Prospective single-center, double-blind, two-way crossover provocation study. SUBJECTS: A provocation cohort (22 healthy volunteers) and intrasubject reproducibility cohort (8 healthy volunteers). FIELD STRENGTH/SEQUENCE: 2D balanced turbo field echo sequences to measure small bowel wall thickness, T2 , and motility acquired at 3T. ASSESSMENT: Participants were randomized to receive indomethacin or placebo prior to assessment. After a minimum 2-week washout, measures were repeated with the alternative allocation. MR measures (wall thickness, T2 , motility) at each study visit were compared to the reference standard 2-hour lactulose/mannitol urinary excretion ratio (LMR) test performed by a lab technician. All analyses were performed blind. STATISTICAL TESTS: Normality was tested (Shapiro-Wilk's test). Paired testing (Student's t-test or Wilcoxon) determined the significance of paired differences with indomethacin provocation. Pearson's correlation coefficient compared significant measures with indomethacin provocation to LMR. Intrasubject (intraclass correlation) and interrater variability (Bland-Altman) were assessed. RESULTS: Indomethacin provocation induced a significant increase in LMR compared to placebo (P < 0.05) and a significant increase in small bowel T2 (0.12 seconds compared to placebo 0.07 seconds, P < 0.05). Small bowel wall thickness (P = 0.17) and motility (P = 0.149) showed no significant change. T2 and LMR were positively correlated (r = 0.68, P < 0.05). T2 measurements were robust to interobserver (intraclass correlation 0.89) and intrasubject variability (Bland-Altman bias of 0.005 seconds, 95% confidence interval [CI] -0.04 to +0.05 seconds, and 0.0006 seconds, 95% CI -0.05 to +0.06 seconds). DATA CONCLUSION: MR measures of small bowel wall T2 were significantly increased following indomethacin provocation and correlated with 2-hour LMR test results. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY STAGE: 2.


Subject(s)
Intestine, Small , Magnetic Resonance Imaging , Humans , Intestine, Small/diagnostic imaging , Permeability , Prospective Studies , Reproducibility of Results
20.
PLoS One ; 15(11): e0241441, 2020.
Article in English | MEDLINE | ID: mdl-33175860

ABSTRACT

OBJECTIVE: The gastrointestinal environment in which drug products need to disintegrate before the drug can dissolve and be absorbed has not been studied in detail due to limitations, especially invasiveness of existing techniques. Minimal in vivo data is available on undisturbed gastrointestinal motility to improve relevance of predictive dissolution models and in silico tools such as physiologically-based pharmacokinetic models. Recent advances in magnetic resonance imaging methods could provide novel data and insights that can be used as a reference to validate and, if necessary, optimize these models. The conventional method for measuring gastrointestinal motility is via a manometric technique involving intubation. Nevertheless, it is feasible to measure gastrointestinal motility with magnetic resonance imaging. The aim of this study was is to develop and validate a magnetic resonance imaging method using the most recent semi-automated analysis method against concomitant perfused manometry method. MATERIAL AND METHODS: Eighteen healthy fasted participants were recruited for this study. The participants were intubated with a water-perfused manometry catheter. Subsequently, stomach motility was assessed by cine-MRI acquired at intervals, of 3.5min sets, at coronal oblique planes through the abdomen and by simultaneous water perfused manometry, before and after administration of a standard bioavailability / bioequivalence 8 ounces (~240mL) drink of water. The magnetic resonance imaging motility images were analysed using Spatio-Temporal Motility analysis STMM techniques. The area under the curve of the gastric motility contractions was calculated for each set and compared between techniques. The study visit was then repeated one week later. RESULTS: Data from 15 participants was analysed. There was a good correlation between the MRI antral motility plots area under the curve and corresponding perfused manometry motility area under the curve (r = 0.860) during both antral contractions and quiescence. CONCLUSION: Non-invasive dynamic magnetic resonance imaging of gastric antral motility coupled with recently developed, semi-automated magnetic resonance imaging data processing techniques correlated well with simultaneous, 'gold standard' water perfused manometry. This will be particularly helpful for research purposes related to oral absorption where the absorption of a drug is highly depending on the underlying gastrointestinal processes such as gastric emptying, gastrointestinal motility and availability of residual fluid volumes. CLINICAL TRIAL: This trial was registered at ClinicalTrials.gov as NCT03191045.


Subject(s)
Fasting/physiology , Gastrointestinal Motility/physiology , Healthy Volunteers , Magnetic Resonance Imaging , Manometry , Pyloric Antrum/diagnostic imaging , Pyloric Antrum/physiology , Water/pharmacology , Adult , Area Under Curve , Biological Availability , Female , Gastrointestinal Motility/drug effects , Humans , Male , Middle Aged , Muscle Contraction/physiology , Pyloric Antrum/drug effects , Therapeutic Equivalency , Time Factors , Young Adult
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