A preliminary study of dynamic neurochemical changes in the dorsolateral prefrontal cortex during working memory.

Working memory (WM) is one of the fundamental cognitive functions associated with the dorsolateral prefrontal cortex (DLPFC). However, the neurochemical mechanisms of WM, including the dynamic changes in neurometabolites such as glutamate and GABA in the DLPFC, remain unclear. Here, we investigated WM-related glutamate and GABA changes, alongside hemodynamic responses in the DLPFC, using a combination of functional magnetic resonance spectroscopy (fMRS) and functional magnetic resonance imaging (fMRI). During a WM task, we measured Glx (glutamate + glutamine) and GABA levels using GABA editing MEscher-GArwood Point REsolved Spectroscopy (MEGA-PRESS) sequence and blood-oxygen-level-dependent (BOLD) signal changes. In the DLPFC, we observed elevated Glx levels and increased BOLD signal changes during a 2-back task. Specifically, the Glx levels in the DLPFC were significantly higher during the 2-back task compared with fixation, although this difference was not significant when compared with a 0-back task. However, Glx levels during the 0-back task were higher than during fixation. Furthermore, there was a positive correlation between Glx levels in the DLPFC during the 2-back task and the corresponding BOLD signal changes. Notably, higher Glx increases were associated with increased DLPFC activation and lower WM task performance in individuals. No notable changes in DLPFC GABA levels were observed during WM processing. These findings suggest that the modulation of glutamatergic activity in the DLPFC may play a crucial role in both working memory processing and its associated performance outcomes.

Noise suppression of proton magnetic resonance spectroscopy improves paediatric brain tumour classification.

Proton magnetic resonance spectroscopy (1H-MRS) is increasingly used for clinical brain tumour diagnosis, but suffers from limited spectral quality. This retrospective and comparative study aims at improving paediatric brain tumour classification by performing noise suppression on clinical 1H-MRS. Eighty-three/forty-two children with either an ependymoma (ages 4.6 ± 5.3/9.3 ± 5.4), a medulloblastoma (ages 6.9 ± 3.5/6.5 ± 4.4), or a pilocytic astrocytoma (8.0 ± 3.6/6.3 ± 5.0), recruited from four centres across England, were scanned with 1.5T/3T short-echo-time point-resolved spectroscopy. The acquired raw 1H-MRS was quantified by using Totally Automatic Robust Quantitation in NMR (TARQUIN), assessed by experienced spectroscopists, and processed with adaptive wavelet noise suppression (AWNS). Metabolite concentrations were extracted as features, selected based on multiclass receiver operating characteristics, and finally used for identifying brain tumour types with supervised machine learning. The minority class was oversampled through the synthetic minority oversampling technique for comparison purposes. Post-noise-suppression 1H-MRS showed significantly elevated signal-to-noise ratios (P < .05, Wilcoxon signed-rank test), stable full width at half-maximum (P > .05, Wilcoxon signed-rank test), and significantly higher classification accuracy (P < .05, Wilcoxon signed-rank test). Specifically, the cross-validated overall and balanced classification accuracies can be improved from 81% to 88% overall and 76% to 86% balanced for the 1.5T cohort, whilst for the 3T cohort they can be improved from 62% to 76% overall and 46% to 56%, by applying Naïve Bayes on the oversampled 1H-MRS. The study shows that fitting-based signal-to-noise ratios of clinical 1H-MRS can be significantly improved by using AWNS with insignificantly altered line width, and the post-noise-suppression 1H-MRS may have better diagnostic performance for paediatric brain tumours.

Characterisation of paediatric brain tumours by their MRS metabolite profiles.

1H-magnetic resonance spectroscopy (MRS) has the potential to improve the noninvasive diagnostic accuracy for paediatric brain tumours. However, studies analysing large, comprehensive, multicentre datasets are lacking, hindering translation to widespread clinical practice. Single-voxel MRS (point-resolved single-voxel spectroscopy sequence, 1.5 T: echo time [TE] 23-37 ms/135-144 ms, repetition time [TR] 1500 ms; 3 T: TE 37-41 ms/135-144 ms, TR 2000 ms) was performed from 2003 to 2012 during routine magnetic resonance imaging for a suspected brain tumour on 340 children from five hospitals with 464 spectra being available for analysis and 281 meeting quality control. Mean spectra were generated for 13 tumour types. Mann-Whitney U-tests and Kruskal-Wallis tests were used to compare mean metabolite concentrations. Receiver operator characteristic curves were used to determine the potential for individual metabolites to discriminate between specific tumour types. Principal component analysis followed by linear discriminant analysis was used to construct a classifier to discriminate the three main central nervous system tumour types in paediatrics. Mean concentrations of metabolites were shown to differ significantly between tumour types. Large variability existed across each tumour type, but individual metabolites were able to aid discrimination between some tumour types of importance. Complete metabolite profiles were found to be strongly characteristic of tumour type and, when combined with the machine learning methods, demonstrated a diagnostic accuracy of 93% for distinguishing between the three main tumour groups (medulloblastoma, pilocytic astrocytoma and ependymoma). The accuracy of this approach was similar even when data of marginal quality were included, greatly reducing the proportion of MRS excluded for poor quality. Children's brain tumours are strongly characterised by MRS metabolite profiles readily acquired during routine clinical practice, and this information can be used to support noninvasive diagnosis. This study provides both key evidence and an important resource for the future use of MRS in the diagnosis of children's brain tumours.

Medio-dorsal thalamic dysconnectivity in chronic knee pain: A possible mechanism for negative affect and pain comorbidity.

The reciprocal interaction between pain and negative affect is acknowledged but pain-related alterations in brain circuits involved in this interaction, such as the mediodorsal thalamus (MDThal), still require a better understanding. We sought to investigate the relationship between MDThal circuitry, negative affect and pain severity in chronic musculoskeletal pain. For these analyses, participants with chronic knee pain (CKP, n = 74) and without (n = 36) completed magnetic resonance imaging scans and questionnaires. Seed-based MDThal functional connectivity (FC) was compared between groups. Within CKP group, we assessed the interdependence of MDThal FC with negative affect. Finally, post hoc moderation analysis explored whether burden of pain influences affect-related MDThal FC. The CKP group showed altered MDThal FC to hippocampus, ventromedial prefrontal cortex and subgenual anterior cingulate. Furthermore, in CKP group, MDThal connectivity correlated significantly with negative affect in several brain regions, most notably the medial prefrontal cortex, and this association was stronger with increasing pain burden and absent in pain-free controls. In conclusion, we demonstrate mediodorsal thalamo-cortical dysconnectivity in chronic pain with areas linked to mood disorders and associations of MDThal FC with negative affect. Moreover, burden of pain seems to enhance affect sensitivity of MDThal FC. These findings suggest mediodorsal thalamic network changes as possible drivers of the detrimental interplay between chronic pain and negative affect.

Deuterium brain imaging at 7T during D2 O dosing.

PURPOSE: To characterize the (2 H) deuterium MR signal measured from human brain at 7T in participants loading with D2 O to ˜1.5% enrichment over a six-week period. METHODS: 2 H spectroscopy and imaging measurements were used to track the time-course of 2 H enrichment within the brain during the initial eight-hour loading period in two participants. Multi-echo gradient echo (MEGE) images were acquired at a range of TR values from four participants during the steady-state loading period and used for mapping 2 H T1 and T2 * relaxation times. Co-registration to higher resolution 1 H images allowed T1 and T2 * relaxation times of deuterium in HDO in cerebrospinal fluid (CSF), gray matter (GM), and white matter (WM) to be estimated. RESULTS: 2 H concentrations measured during the eight-hour loading were consistent with values estimated from cumulative D2 O dose and body mass. Signal changes measured from three different regions of the brain during loading showed similar time-courses. After summing over echoes, gradient echo brain images acquired in 7.5 minutes with a voxel volume of 0.36 ml showed an SNR of ˜16 in subjects loaded to 1.5%. T1 -values for deuterium in HDO were significantly shorter than corresponding values for 1 H in H2 O, while T2 * values were similar. 2 H relaxation times in CSF were significantly longer than in GM or WM. CONCLUSION: Deuterium MR Measurements at 7T were used to track the increase in concentration of 2 H in brain during heavy water loading. 2 H T1 and T2 * relaxation times from water in GM, WM, and CSF are reported.

Theta Burst Stimulation of the Human Motor Cortex Modulates Secondary Hyperalgesia to Punctate Mechanical Stimuli.

OBJECTIVES: Many chronic pain conditions show evidence of dysregulated synaptic plasticity, including the development and maintenance of central sensitization. This provides a strong rationale for neuromodulation therapies for the relief of chronic pain. However, variability in responses and low fidelity across studies remain an issue for both clinical trials and pain management, demonstrating insufficient mechanistic understanding of effective treatment protocols. MATERIALS AND METHODS: In a randomized counterbalanced crossover designed study, we evaluated two forms of patterned repetitive transcranial magnetic stimulation, known as continuous theta burst stimulation (TBS) and intermittent TBS, during normal and central sensitization states. Secondary hyperalgesia (a form of use-dependent central sensitization) was induced using a well-established injury-free pain model and assessed by standardized quantitative sensory testing involving light touch and pinprick pain thresholds in addition to stimulus-response functions. RESULTS: We found that continuous TBS of the human motor cortex has a facilitatory (pronociceptive) effect on the magnitude of perceived pain to secondary hyperalgesia, which may rely on induction and expression of neural plasticity through heterosynaptic long-term potentiation-like mechanisms. CONCLUSIONS: By defining the underlying mechanisms of TBS-driven synaptic plasticity in the nociceptive system, we offer new insight into disease mechanisms and provide targets for promoting functional recovery and repair in chronic pain. For clinical applications, this knowledge is critical for development of more efficacious and mechanisms-based neuromodulation protocols, which are urgently needed to address the chronic pain and opioid epidemics.

Neuromelanin-MRI to Quantify and Track Nigral Depigmentation in Parkinson's Disease: A Multicenter Longitudinal Study Using Template-Based Standardized Analysis.

BACKGROUND: Clinical diagnosis and monitoring of Parkinson's disease (PD) remain challenging because of the lack of an established biomarker. Neuromelanin-magnetic resonance imaging (NM-MRI) is an emerging biomarker of nigral depigmentation indexing the loss of melanized neurons but has unknown prospective diagnostic and tracking performance in multicenter settings. OBJECTIVES: The aim was to investigate the diagnostic accuracy of NM-MRI in early PD in a multiprotocol setting and to determine and compare serial NM-MRI changes in PD and controls. METHODS: In this longitudinal case-control 3 T MRI study, 148 patients and 97 controls were included from six UK clinical centers, of whom 140 underwent a second scan after 1.5 to 3 years. An automated template-based analysis was applied for subregional substantia nigra NM-MRI contrast and volume assessment. A point estimate of the period of prediagnostic depigmentation was computed. RESULTS: All NM metrics performed well to discriminate patients from controls, with receiver operating characteristic showing 85% accuracy for ventral NM contrast and 83% for volume. Generalizability using a priori volume cutoff was good (79% accuracy). Serial MRI demonstrated accelerated NM loss in patients compared to controls. Ventral NM contrast loss was point estimated to start 5 to 6 years before clinical diagnosis. Ventral nigral depigmentation was greater in the most affected side, more severe cases, and nigral NM volume change correlated with change in motor severity. CONCLUSIONS: We demonstrate that NM-MRI provides clinically useful diagnostic information in early PD across protocols, platforms, and sites. It provides methods and estimated depigmentation rates that highlight the potential to detect preclinical PD and track progression for biomarker-enabled clinical trials. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Meta-Analysis of Apparent Diffusion Coefficient in Pediatric Medulloblastoma, Ependymoma, and Pilocytic Astrocytoma.

BACKGROUND: Medulloblastoma, ependymoma, and pilocytic astrocytoma are common pediatric posterior fossa tumors. These tumors show overlapping characteristics on conventional MRI scans, making diagnosis difficult. PURPOSE: To investigate whether apparent diffusion coefficient (ADC) values differ between tumor types and to identify optimum cut-off values to accurately classify the tumors using different performance metrics. STUDY TYPE: Systematic review and meta-analysis. SUBJECTS: Seven studies reporting ADC in pediatric posterior fossa tumors (115 medulloblastoma, 68 ependymoma, and 86 pilocytic astrocytoma) were included following PubMed and ScienceDirect searches. SEQUENCE AND FIELD STRENGTH: Diffusion weighted imaging (DWI) was performed on 1.5 and 3 T across multiple institution and vendors. ASSESSMENT: The combined mean and standard deviation of ADC were calculated for each tumor type using a random-effects model, and the effect size was calculated using Hedge's g. STATISTICAL TESTS: Sensitivity/specificity, weighted classification accuracy, balanced classification accuracy. A P value < 0.05 was considered statistically significant, and a Hedge's g value of >1.2 was considered to represent a large difference. RESULTS: The mean (± standard deviation) ADCs of medulloblastoma, ependymoma, and pilocytic astrocytoma were 0.76 ± 0.16, 1.10 ± 0.10, and 1.49 ± 0.16 mm2 /sec × 10-3 . To maximize sensitivity and specificity using the mean ADC, the cut-off was found to be 0.96 mm2 /sec × 10-3 for medulloblastoma and ependymoma and 1.26 mm2 /sec × 10-3 for ependymoma and pilocytic astrocytoma. The meta-analysis showed significantly different ADC distributions for the three posterior fossa tumors. The cut-off values changed markedly (up to 7%) based on the performance metric used and the prevalence of the tumor types. DATA CONCLUSION: There were significant differences in ADC between tumor types. However, it should be noted that only summary statistics from each study were analyzed and there were differences in how regions of interest were defined between studies. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 3.

Anticholinergic drugs and forebrain magnetic resonance imaging changes in cognitively normal people and those with mild cognitive impairment.

BACKGROUND AND PURPOSE: Anticholinergic (AC) medication use is associated with cognitive decline and dementia, which may be related to an AC-induced central hypocholinergic state, but the exact mechanisms remain to be understood. We aimed to further elucidate the putative link between AC drug prescription, cognition, and structural and functional impairment of the forebrain cholinergic nucleus basalis of Meynert (NBM). METHODS: Cognitively normal (CN; n = 344) and mildly cognitively impaired (MCI; n = 224) Alzheimer's Disease Neuroimaging Initiative Phase 3 participants with good quality 3-T magnetic resonance imaging were included. Structural (regional gray matter [GM] density) and functional NBM integrity (functional connectivity [FC]) were compared between those on AC medication for > 1 year (AC+ ) and those without (AC- ) in each condition. AC burden was classed as mild, moderate, or severe. RESULTS: MCI AC+ participants (0.55 ± 0.03) showed lower NBM GM density compared to MCI AC- participants (0.56 ± 0.03, p = 0.002), but there was no structural AC effect in CN. NBM FC was lower in CN AC+ versus CN AC- (3.6 ± 0.5 vs. 3.9 ± 0.6, p = 0.001), and in MCI AC+ versus MCI AC- (3.3 ± 0.2 vs. 3.7 ± 0.5, p < 0.001), with larger effect size in MCI. NBM FC partially mediated the association between AC medication burden and cognition. CONCLUSIONS: Our findings provide novel support for a detrimental effect of mild AC medication on the forebrain cholinergic system characterized as functional central hypocholinergic that partially mediated AC-related cognitive impairment. Moreover, structural tissue damage suggests neurodegeneration, and larger effect sizes in MCI point to enhanced susceptibility for AC medication in those at risk of dementia.

Dynamic susceptibility-contrast magnetic resonance imaging with contrast agent leakage correction aids in predicting grade in pediatric brain tumours: a multicenter study.

BACKGROUND: Relative cerebral blood volume (rCBV) measured using dynamic susceptibility-contrast MRI can differentiate between low- and high-grade pediatric brain tumors. Multicenter studies are required for translation into clinical practice. OBJECTIVE: We compared leakage-corrected dynamic susceptibility-contrast MRI perfusion parameters acquired at multiple centers in low- and high-grade pediatric brain tumors. MATERIALS AND METHODS: Eighty-five pediatric patients underwent pre-treatment dynamic susceptibility-contrast MRI scans at four centers. MRI protocols were variable. We analyzed data using the Boxerman leakage-correction method producing pixel-by-pixel estimates of leakage-uncorrected (rCBVuncorr) and corrected (rCBVcorr) relative cerebral blood volume, and the leakage parameter, K2. Histological diagnoses were obtained. Tumors were classified by high-grade tumor. We compared whole-tumor median perfusion parameters between low- and high-grade tumors and across tumor types. RESULTS: Forty tumors were classified as low grade, 45 as high grade. Mean whole-tumor median rCBVuncorr was higher in high-grade tumors than low-grade tumors (mean ± standard deviation [SD] = 2.37±2.61 vs. -0.14±5.55; P<0.01). Average median rCBV increased following leakage correction (2.54±1.63 vs. 1.68±1.36; P=0.010), remaining higher in high-grade tumors than low grade-tumors. Low-grade tumors, particularly pilocytic astrocytomas, showed T1-dominant leakage effects; high-grade tumors showed T2*-dominance (mean K2=0.017±0.049 vs. 0.002±0.017). Parameters varied with tumor type but not center. Median rCBVuncorr was higher (mean = 1.49 vs. 0.49; P=0.015) and K2 lower (mean = 0.005 vs. 0.016; P=0.013) in children who received a pre-bolus of contrast agent compared to those who did not. Leakage correction removed the difference. CONCLUSION: Dynamic susceptibility-contrast MRI acquired at multiple centers helped distinguish between children's brain tumors. Relative cerebral blood volume was significantly higher in high-grade compared to low-grade tumors and differed among common tumor types. Vessel leakage correction is required to provide accurate rCBV, particularly in low-grade enhancing tumors.

Dorsolateral prefrontal circuit effective connectivity mediates the relationship between white matter structure and PASAT-3 performance in multiple sclerosis.

Three decades ago a series of parallel circuits were described involving the frontal cortex and deep grey matter structures, with putative roles in control of motor and oculomotor function, cognition, behaviour and emotion. The circuit comprising the dorsolateral prefrontal cortex, caudate, globus pallidus and thalamus has a putative role in regulating executive functions. The aim of this study is to investigate effective connectivity (EC) of the dorsolateral-prefrontal circuit and its association with PASAT-3 performance in people with multiple sclerosis(MS). We use Granger causality analysis of resting-state functional MRI from 52 people with MS and 36 healthy people to infer that reduced EC in the afferent limb of the dorsolateral prefrontal circuit occurs in the people with MS with cognitive dysfunction (left: p = .006; right: p = .029), with bilateral EC reductions in this circuit resulting in more severe cognitive dysfunction than unilateral reductions alone (p = .002). We show that reduced EC in the afferent limb of the dorsolateral prefrontal circuit mediates the relationship between cognitive performance and macrostrucutral and microstructural alterations of white matter tracts in components of the circuit. Specificity is shown by the absence of any relationship between cognition and EC in the analogous and anatomically proximal motor circuit. We demonstrate good stability of the EC measures in people with MS over an interval averaging 8-months. Key positive and negative results are replicated in an independent cohort of people with MS. Our findings identify the dorsolateral prefrontal circuit as a potential target for therapeutic strategies aimed at improving cognition in people with MS.

Relationship between neuromelanin and dopamine terminals within the Parkinson's nigrostriatal system.

Parkinson's disease is characterized by the progressive loss of pigmented dopaminergic neurons in the substantia nigra and associated striatal deafferentation. Neuromelanin content is thought to reflect the loss of pigmented neurons, but available data characterizing its relationship with striatal dopaminergic integrity are not comprehensive or consistent, and predominantly involve heterogeneous samples. In this cross-sectional study, we used neuromelanin-sensitive MRI and the highly specific dopamine transporter PET radioligand, 11C-PE2I, to assess the association between neuromelanin-containing cell levels in the substantia nigra pars compacta and nigrostriatal terminal density in vivo, in 30 patients with bilateral Parkinson's disease. Fifteen healthy control subjects also underwent neuromelanin-sensitive imaging. We used a novel approach taking into account the anatomical and functional subdivision of substantia nigra into dorsal and ventral tiers and striatal nuclei into pre- and post-commissural subregions, in accordance with previous animal and post-mortem studies, and consider the clinically asymmetric disease presentation. In vivo, Parkinson's disease subjects displayed reduced neuromelanin levels in the ventral (-30 ± 28%) and dorsal tiers (-21 ± 24%) as compared to the control group [F(1,43) = 11.95, P = 0.001]. Within the Parkinson's disease group, nigral pigmentation was lower in the ventral tier as compared to the dorsal tier [F(1,29) = 36.19, P < 0.001] and lower in the clinically-defined most affected side [F(1,29) = 4.85, P = 0.036]. Similarly, lower dopamine transporter density was observed in the ventral tier [F(1,29) = 76.39, P < 0.001] and clinically-defined most affected side [F(1,29) = 4.21, P = 0.049]. Despite similar patterns, regression analysis showed no significant association between nigral pigmentation and nigral dopamine transporter density. However, for the clinically-defined most affected side, significant relationships were observed between pigmentation of the ventral nigral tier with striatal dopamine transporter binding in pre-commissural and post-commissural striatal subregions known to receive nigrostriatal projections from this tier, while the dorsal tier correlated with striatal projection sites in the pre-commissural striatum (P < 0.05, Benjamini-Hochberg corrected). In contrast, there were no statistically significant relationships between these two measures in the clinically-defined least affected side. These findings provide important insights into the topography of nigrostriatal neurodegeneration in Parkinson's disease, indicating that the characteristics of disease progression may fundamentally differ across hemispheres and support post-mortem data showing asynchrony in the loss of neuromelanin-containing versus tyrosine hydroxylase positive nigral cells.

Investigating musculoskeletal health and wellbeing; a cohort study protocol.

BACKGROUND: In an ageing population, pain, frailty and disability frequently coexist across a wide range of musculoskeletal diagnoses, but their associations remain incompletely understood. The Investigating Musculoskeletal Health and Wellbeing (IMH&W) study aims to measure and characterise the development and progression of pain, frailty and disability, and to identify discrete subgroups and their associations. The survey will form a longitudinal context for nested research, permitting targeted recruitment of participants for qualitative, observational and interventional studies; helping to understand recruitment bias in clinical studies; and providing a source cohort for cohort randomised controlled trials. METHODS: IMH&W will comprise a prospective cohort of 10,000 adults recruited through primary and secondary care, and through non-clinical settings. Data collection will be at baseline, and then through annual follow-ups for 4 years. Questionnaires will address demographic characteristics, pain severity (0-10 Numerical Rating Scale), pain distribution (reported on a body Manikin), pain quality (McGill Pain Questionnaire), central aspects of pain (CAP-Knee), frailty and disability (based on Fried criteria and the FRAIL questionnaire), and fracture risk. Baseline characteristics, progression and associations of frailty, pain and disability will be determined. Discrete subgroups and trajectories will be sought by latent class analysis. Recruitment bias will be explored by comparing participants in nested studies with the eligible IMH&W population. DISCUSSION: IMH&W will elucidate associations and progression of pain, frailty and disability. It will enable identification of people at risk of poor musculoskeletal health and wellbeing outcomes who might be suitable for specific interventions, and facilitate generalisation and comparison of research outcomes between target populations. The study will benefit from a large sample size and will recruit from diverse regions across the UK. Purposive recruitment will enrich the cohort with people with MSK problems with high representation of elderly and unwell people. TRIAL REGISTRATION: Clinicaltrials.gov NCT03696134. Date of Registration: 04 October 2018.

Altered Nucleus Basalis Connectivity Predicts Treatment Response in Mild Cognitive Impairment.

Purpose To determine whether functional connectivity (FC) mapping of nucleus basalis of Meynert (NBM) cholinergic network (hereafter, NBM FC) could provide a biomarker of central cholinergic deficits with predictive potential for response to cholinesterase inhibitor (ChEI) treatment. Materials and Methods The Alzheimer's Disease Neuroimaging Initiative (ADNI) was approved by the institutional review boards of all participating sites. All participants and their representatives gave written informed consent prior to data collection. NBM FC was examined in 33 healthy control participants, 102 patients with mild cognitive impairment (MCI), and 33 patients with AD by using resting-state functional MRI data from the ADNI database. NBM FC was compared between groups before and after 6 months of ChEI treatment in MCI. Associations between baseline NBM FC and baseline cognitive performance as well as cognitive outcomes after treatment were investigated. Results Compared with the healthy control group, NBM FC was decreased in patients with untreated MCI and increased in patients with AD treated with ChEI (corrected P ˂ .05). Global cognition (Alzheimer's Disease Assessment Scale-Cognitive subscale score) was associated with NBM FC (r = -0.349; P ˂ .001). NBM FC was higher 6 months after ChEI compared with before ChEI in treated MCI (corrected P ˂ .05), but did not change at 6 months in patients with untreated MCI (corrected P ˂ .05). Baseline NBM FC in MCI strongly predicted cognitive outcomes 6 months after ChEI (R2 = 0.458; P = .001). Conclusion Functional dissociation of the nucleus basalis of Meynert from a cortical network may explain the cognitive deficits in dementia and allow for the selection of individuals who are more likely to respond to cholinesterase inhibitors at early disease stages. © RSNA, 2018 Online supplemental material is available for this article.

Application of pattern recognition techniques for classification of pediatric brain tumors by in vivo 3T 1 H-MR spectroscopy-A multi-center study.

PURPOSE: 3T magnetic resonance scanners have boosted clinical application of 1 H-MR spectroscopy (MRS) by offering an improved signal-to-noise ratio and increased spectral resolution, thereby identifying more metabolites and extending the range of metabolic information. Spectroscopic data from clinical 1.5T MR scanners has been shown to discriminate between pediatric brain tumors by applying machine learning techniques to further aid diagnosis. The purpose of this multi-center study was to investigate the discriminative potential of metabolite profiles obtained from 3T scanners in classifying pediatric brain tumors. METHODS: A total of 41 pediatric patients with brain tumors (17 medulloblastomas, 20 pilocytic astrocytomas, and 4 ependymomas) were scanned across four different hospitals. Raw spectroscopy data were processed using TARQUIN. Borderline synthetic minority oversampling technique was used to correct for the data skewness. Different classifiers were trained using linear discriminative analysis, support vector machine, and random forest techniques. RESULTS: Support vector machine had the highest balanced accuracy for discriminating the three tumor types. The balanced accuracy achieved was higher than the balanced accuracy previously reported for similar multi-center dataset from 1.5T magnets with echo time 20 to 32 ms alone. CONCLUSION: This study showed that 3T MRS can detect key differences in metabolite profiles for the main types of childhood tumors. Magn Reson Med 79:2359-2366, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Radiomics in paediatric neuro-oncology: A multicentre study on MRI texture analysis.

Brain tumours are the most common solid cancers in children in the UK and are the most common cause of cancer deaths in this age group. Despite current advances in MRI, non-invasive diagnosis of paediatric brain tumours has yet to find its way into routine clinical practice. Radiomics, the high-throughput extraction and analysis of quantitative image features (e.g. texture), offers potential solutions for tumour characterization and decision support. In the search for diagnostic oncological markers, the primary aim of this work was to study the application of MRI texture analysis (TA) for the classification of paediatric brain tumours. A multicentre study was carried out, within a supervised classification framework, on clinical MR images, and a support vector machine (SVM) was trained with 3D textural attributes obtained from conventional MRI. To determine the cross-centre transferability of TA, an assessment of how SVM performs on unseen datasets was carried out through rigorous pairwise testing. The study also investigated the nature of features that are most likely to train classifiers that can generalize well with the data. Finally, the issue of class imbalance, which arises due to some tumour types being more common than others, was explored. For each of the tests carried out through pairwise testing, the optimal area under the receiver operating characteristic curve ranged between 76% and 86%, suggesting that the model was able to capture transferable tumour information. Feature selection results suggest that similar aspects of tumour texture are enhanced by MR images obtained at different hospitals. Our results also suggest that the availability of equally represented classes has enabled SVM to better characterize the data points. The findings of the study presented here support the use of 3D TA on conventional MR images to aid diagnostic classification of paediatric brain tumours.

Life span pigmentation changes of the substantia nigra detected by neuromelanin-sensitive MRI.

BACKGROUND: Neuromelanin is a pigment with strong iron-chelating properties preferentially found in dopaminergic neurons of the substantia nigra pars compacta (SNpc). Parkinson's disease is characterized by pronounced, MRI-detectable neuromelanin loss, but the neuroprotective or neurotoxic role of neuromelanin remains debated. Histological studies have demonstrated neuromelanin increases with age, but this has not been confirmed in vivo, and there is uncertainty whether neuromelanin declines, stabilizes, or increases from middle age. METHODS: This study aimed to establish physiological changes of pigmentation of the SNpc using a pooled data set of neuromelanin-sensitive 3T MRI from 134 healthy individuals aged 5-83 years. Neuromelanin-related brightness (regional contrast to ratio) and calibrated hyperintense volumes were analyzed using linear and nonlinear regression models to characterize age effects. Laterality, sex, and subregional effects were also assessed. RESULTS: For brightness, age effects were best described as a quadratic trajectory explaining 81.5% of the observed variance in the SNpc showing a strong increase from childhood to adolescence, with plateauing in middle age and a decline in older age. Similar but less pronounced effects were seen in hyperintense volumes. We also show an anterior-posterior gradient in SNpc contrast, larger normalized neuromelanin-rich volume in women > 47 years old, but no laterality effect. CONCLUSIONS: Using optimized neuromelanin MRI in a life span sample, we demonstrate a strong age effect with inverted U-shaped SNpc pigmentation-related contrast from childhood to old age. This age trajectory of physiological SNpc pigmentation needs to be taken into account for diagnostic applications of depigmentation. The study also paves the way for systematic investigations of the mechanisms of neuromelanin in healthy and pathological brain development and aging. © 2018 International Parkinson and Movement Disorder Society.

Magnetic Resonance Imaging Plaque Hemorrhage for Risk Stratification in Carotid Artery Disease With Moderate Risk Under Current Medical Therapy.

BACKGROUND AND PURPOSE: Magnetic resonance imaging (MRI)-defined carotid plaque hemorrhage (MRIPH) can predict recurrent cerebrovascular ischemic events in severe symptomatic carotid stenosis. It is less clear whether MRIPH can improve risk stratification despite optimized medical secondary prevention in those with moderate risk. METHODS: One-hundred fifty-one symptomatic patients with 30% to 99% carotid artery stenosis (median age: 77, 60.5% men) clinically deemed to not benefit from endarterectomy were prospectively recruited to undergo MRI and clinical follow-up (mean, 22 months). The clinical carotid artery risk score could be evaluated in 88 patients. MRIPH+ve was defined as plaque intensity >150% that of adjacent muscle. Survival analyses were performed with recurrent infarction (stroke or diffusion-positive cerebral ischemia) as the main end point. RESULTS: Fifty-five participants showed MRIPH+ve; 47 had low, 36 intermediate, and 5 high carotid artery risk scores. Cox regression showed MRIPH as a strong predictor of future infarction (hazard ratio, 5.2; 95% confidence interval, 1.64-16.34; P=0.005, corrected for degree of stenosis), also in the subgroup with 50% to 69% stenosis (hazard ratio, 4.1; 95% confidence interval, 1-16.8; P=0.049). The absolute risk of future infarction was 31.7% at 3 years in MRIPH+ve versus 1.8% in patients without (P<0.002). MRIPH increased cumulative risk difference of future infarction by 47.1% at 3 years in those with intermediate carotid artery risk score (P=0.004). CONCLUSIONS: The study confirms MRIPH to be a powerful risk marker in symptomatic carotid stenosis with added value over current risk scores. For patients undergoing current secondary prevention medication with clinically uncertain benefit from recanalization, that is, those with moderate degree stenosis and intermediate carotid artery risk scores, MRIPH offers additional risk stratification.

Targeted transcranial theta-burst stimulation alters fronto-insular network and prefrontal GABA.

Repetitive transcranial magnetic stimulation (rTMS) has been used worldwide to treat depression. However, the exact physiological effects are not well understood. Pathophysiology of depression involves crucial limbic structures (e.g. insula), and it is still not clear if these structures can be modulated through neurostimulation of surface regions (e.g. dorsolateral prefrontal cortex, DLPFC), and whether rTMS-induced excitatory/inhibitory transmission alterations relate to fronto-limbic connectivity changes. Therefore, we sought proof-of-concept for neuromodulation of insula via prefrontal intermittent theta-burst stimulation (iTBS), and how these effects relate to GABAergic and glutamatergic systems. In 27 healthy controls, we employed a single-blind crossover randomised-controlled trial comparing placebo and real iTBS using resting-state functional MRI and magnetic resonance spectroscopy. Granger causal analysis was seeded from right anterior insula (rAI) to locate individualized left DLPFC rTMS targets. Effective connectivity coefficients within rAI and DLPFC were calculated, and levels of GABA/Glx, GABA/Cr and Glx/Cr in DLPFC and anterior cingulate voxels were also measured. ITBS significantly dampened fronto-insular connectivity and reduced GABA/Glx in both voxels. GABA/Glx had a significant mediating effect on iTBS-induced changes in DLPFC-to-rAI connectivity. We demonstrate modulation of the rAI using targeted iTBS through alterations of excitatory/inhibitory interactions, which may underlie therapeutic effects of rTMS, offering promise for rTMS treatment optimization.

Activation induced changes in GABA: Functional MRS at 7T with MEGA-sLASER.

Functional magnetic resonance spectroscopy (fMRS) has been used to assess the dynamic metabolic responses of the brain to a physiological stimulus non-invasively. However, only limited information on the dynamic functional response of γ-aminobutyric acid (GABA), the primary inhibitory neurotransmitter in the brain, is available. We aimed to measure the activation-induced changes in GABA unambiguously using a spectral editing method, instead of the conventional direct detection techniques used in previous fMRS studies. The Mescher-Garwood-semi-localised by adiabatic selective refocusing (MEGA-sLASER) sequence was developed at 7T to obtain the time course of GABA concentration without macromolecular contamination. A significant decrease (-12±5%) in the GABA to total creatine ratio (GABA/tCr) was observed in the motor cortex during a period of 10min of hand-clenching, compared to an initial baseline level (GABA/tCr =0.11±0.02) at rest. An increase in the Glx (glutamate and glutamine) to tCr ratio was also found, which is in agreement with previous findings. In contrast, no significant changes in NAA/tCr and tCr were detected. With consistent and highly efficient editing performance for GABA detection and the advantage of visually identifying GABA resonances in the spectra, MEGA-sLASER is demonstrated to be an effective method for studying of dynamic changes in GABA at 7T.