Non invasive detection and monitoring of substantia nigra degeneration is a long sought aim for neuroscientists, clinicians and pharmaceutical companies with an interest in Parkinson's disease (PD). Functional imaging techniques are established tools to assess the extent of striatal dopaminergic denervation that indirectly reflects nigral degeneration. They allow characterization of the dopaminergic denervation during the premotor phase of PD and have clinical value to establish the diagnosis in parkinsonism, but have proven to be unsatisfactory as surrogate markers in recent treatment trials. There is strong research interest in developing new imaging tests for nigral degeneration using a variety of structural brain imaging techniques. Nigral hyperechogenicity assessed by transcranial sonography emerges as a robust and low cost test to diagnose PD. Additionally, various advanced magnetic resonance imaging contrasts and high field magnetic resonance spectroscopy show promising sensitivity to nigral pathology in PD. Qualification of these emerging imaging tests against defined biomarker criteria is a complex and challenging task ahead. More systematic validation studies analogous to clinical trials are needed to meet the expectations and criteria defined by regulatory bodies before imaging biomarkers can be used as surrogate endpoints for neuroprotective or restorative trials.

The purpose of this work was to assess the reproducibility of diffusion imaging, and in particular the apparent diffusion coefficient (ADC), intra-voxel incoherent motion (IVIM) parameters and diffusion tensor imaging (DTI) parameters, across multiple centres using clinically available protocols with limited harmonization between sequences. An ice-water phantom and nine healthy volunteers were scanned across fives centres on eight scanners (four Siemens 1.5T, four Philips 3T). The mean ADC, IVIM parameters (diffusion coefficient D and perfusion fraction f) and DTI parameters (mean diffusivity MD and fractional anisotropy FA), were measured in grey matter, white matter and specific brain sub-regions. A mixed effect model was used to measure the intra- and inter-scanner coefficient of variation (CV) for each of the five parameters. ADC, D, MD and FA had a good intra- and inter-scanner reproducibility in both grey and white matter, with a CV ranging between 1% and 7.4%; mean 2.6%. Other brain regions also showed high levels of reproducibility except for small structures such as the choroid plexus. The IVIM parameter f had a higher intra-scanner CV of 8.4% and inter-scanner CV of 24.8%. No major difference in the inter-scanner CV for ADC, D, MD and FA was observed when analysing the 1.5T and 3T scanners separately. ADC, D, MD and FA all showed good intra-scanner reproducibility, with the inter-scanner reproducibility being comparable or faring slightly worse, suggesting that using data from multiple scanners does not have an adverse effect compared with using data from the same scanner. The IVIM parameter f had a poorer inter-scanner CV when scanners of different field strengths were combined, and the parameter was also affected by the scan acquisition resolution. This study shows that the majority of diffusion MRI derived parameters are robust across 1.5T and 3T scanners and suitable for use in multi-centre clinical studies and trials.

This study investigates associations between cortical thickness and pain duration, and central sensitization as markers of pain progression in painful knee osteoarthritis.

Functional magnetic resonance imaging (fMRI) was used in 14 healthy subjects to measure brain activation, while response shifting was performed. In the activation phase, subjects were asked to shift their attention between two different types of visually presented stimuli. In the baseline phase, subjects were required to attend to one stimulus type only. Subjects responded by pressing a left or right key according to the side of presentation of the target stimuli. In a verbal task, subjects were required to switch between letters and numbers. In a figural task, subjects reacted to round and square shapes. Stimuli were presented for 750 or 1500 ms. Response shifting revealed significantly increased activation compared to non-switching in the bilateral superior parietal cortex, right occipital cortex, left inferior frontal cortex, left and right striatum, and bilateral dorsolateral prefrontal cortex (DLPFC). Superior parietal and occipital cortex activation may be due to spatial analysis during response shifting. Subvocal rehearsal of the task instructions may have led to activation in the left inferior frontal cortex. Activation in the striatum was related to prefrontal activation and may represent the association between basal ganglia and prefrontal activation during executive control. However, the most important brain region involved in the execution of response shifting was the bilateral DLPFC. Higher task speed increased executive top-down attentional control and, therefore, significantly increased activity in the bilateral DLPFC. Brain activation did not differ significantly between verbal and figural stimulus material. This result suggests that brain activation in the present study illustrates the brain regions involved in the basic cognitive mechanisms of response shifting.

To investigate factors affecting the pattern of motor brain activation reported in people with Parkinson's (PwP), aiming to differentiate disease-specific features from treatment effects.

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.

Improved markers for the progression of Parkinson's disease (PD) are required. Previous work has proven that iron dependent MRI scans can detect the largest Nigrosome (N1) within the substantia nigra (SN) pars compacta and changes in PD. Histopathological studies have shown that N1 is particularly affected in early PD whereas the other nigrosomes (N2-N5) and the surrounding iron-rich SN are affected later. In this study we aimed to determine whether MRI can detect the smaller nigrosomes (N2-N5) and whether graded signal alterations can be detected on T2*-weighted MRI at different disease stages consistent with histopathological changes. An observational prospective study was performed within the research imaging centre at the University of Nottingham, UK. Altogether 26 individuals with confirmed PD (median Hoehn&Yahr stage = 1, Unified PD Rating Scale [UPDRS] = 12.5) and 15 healthy controls participated. High resolution T2*weighted 7T MRI of the brain was performed and visibility of N1-N5 within the SN was qualitatively rated. Normalised T2*weighted signal intensities in manually segmented N1-N5 regions and iron-rich SN were calculated. We performed group comparisons and correlations with severity based on UPDRS. Qualitative measures were a nigrosome visibility score and a confidence score for identification. Quantitative measures were T2*weighted contrast of N1-5 and iron-rich SN relative to white matter. We found that visual assessment of the SN for N1-N5 revealed normal range visibility scores in 14 of 15 controls. N1 was identified with the highest confidence and visibility was in abnormal range in all 26 PD patients. The other nigrosomes were less well visible and less confidently identified. There was a larger PD induced signal reduction in all nigrosomes than in the iron-rich SN (median signal difference N1-5 PD compared to controls: 19.4% [IQR = 24%], iron-rich SN 11% [IQR = 24%, p = 0.017]). The largest PD induced signal reduction was in N1: 37.2% [IQR = 19%] which inversely correlated with UPDRS in PD (R2 = 0.19). All nigrosomes can be detected using 7T MRI, and PD induced T2*weighted signal reduction was greatest in the nigrosomes (especially N1). The graded T2*weighted signal alterations in the nigrosomes match previously described differential histopathological effects of PD. N1 was identified with the highest confidence and T2*weighted signal in N1 correlated with UPDRS confirming N1 as the most promising SN marker of PD pathology.

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).

The maturation of ultra-high-field magnetic resonance imaging (MRI) [≥7 Tesla (7T)] has improved our capability to depict and characterise brain structures efficiently, with better signal-to-noise ratio (SNR) and spatial resolution. We evaluated whether these improvements benefit the clinical detection and management of Parkinson's disease (PD).

Disruption in reciprocal connectivity between the right anterior insula and the left dorsolateral prefrontal cortex is associated with depression and may be a target for neuromodulation. In a five-center, parallel, double-blind, randomized controlled trial we personalized resting-state functional magnetic resonance imaging neuronavigated connectivity-guided intermittent theta burst stimulation (cgiTBS) at a site based on effective connectivity from the right anterior insula to the left dorsolateral prefrontal cortex. We tested its efficacy in reducing the primary outcome depression symptoms measured by the GRID Hamilton Depression Rating Scale 17-item over 8, 16 and 26 weeks, compared with structural magnetic resonance imaging (MRI) neuronavigated repetitive transcranial magnetic stimulation (rTMS) delivered at the standard stimulation site (F3) in patients with 'treatment-resistant depression'. Participants were randomly assigned to 20 sessions over 4-6 weeks of either cgiTBS (n = 128) or rTMS (n = 127) with resting-state functional MRI at baseline and 16 weeks. Persistent decreases in depressive symptoms were seen over 26 weeks, with no differences between arms on the primary outcome GRID Hamilton Depression Rating Scale 17-item score (intention-to-treat adjusted mean, -0.31, 95% confidence interval (CI) -1.87, 1.24, P = 0.689). Two serious adverse events were possibly related to TMS (mania and psychosis). MRI-neuronavigated cgiTBS and rTMS were equally effective in patients with treatment-resistant depression over 26 weeks (trial registration no. ISRCTN19674644).

There is increasing interest in developing a reliable, affordable and accessible disease biomarker of Parkinson's disease (PD) to facilitate disease modifying PD-trials. Imaging biomarkers using magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) can describe parameters such as fractional anisotropy (FA), mean diffusivity (MD) or apparent diffusion coefficient (ADC). These parameters, when measured in the substantia nigra (SN), have not only shown promising but also varying and controversial results. To clarify the potential diagnostic value of nigral DTI in PD and its dependency on selection of region-of-interest, we undertook a high resolution DTI study at 3 T. 59 subjects (32 PD patients, 27 age and sex matched healthy controls) were analysed using manual outlining of SN and substructures, and voxel-based analysis (VBA). We also performed a systematic literature review and meta-analysis to estimate the effect size (DES) of disease related nigral DTI changes. We found a regional increase in nigral mean diffusivity in PD (mean ± SD, PD 0.80 ± 0.10 vs. controls 0.73 ± 0.06 · 10(- 3) mm(2)/s, p = 0.002), but no difference using a voxel based approach. No significant disease effect was seen using meta-analysis of nigral MD changes (10 studies, DES = + 0.26, p = 0.17, I(2) = 30%). None of the nigral regional or voxel based analyses of this study showed altered fractional anisotropy. Meta-analysis of 11 studies on nigral FA changes revealed a significant PD induced FA decrease. There was, however, a very large variation in results (I(2) = 86%) comparing all studies. After exclusion of five studies with unusual high values of nigral FA in the control group, an acceptable heterogeneity was reached, but there was non-significant disease effect (DES = - 0.5, p = 0.22, I(2) = 28%). The small PD related nigral MD changes in conjunction with the negative findings on VBA and meta-analysis limit the usefulness of nigral MD measures as biomarker of Parkinson's disease. The negative results of nigral FA measurements at regional, sub-regional and voxel level in conjunction with the results of the meta-analysis of nigral FA changes question the stability and validity of this measure as a PD biomarker.

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.

This study aims to investigate the role of the mid-anterior cingulate cortex γ-aminobutyric acid levels in chronic nociceptive pain. The molecular mechanisms of pain chronification are not well understood. In fibromyalgia, low mid-anterior cingulate cortex γ-aminobutyric acid was associated with high pain suggesting a role of prefrontal disinhibition. We hypothesize that mid-anterior cingulate cortex GABAergic disinhibition may underpin chronic pain independent of the pain etiology and comorbid negative affect. Proton magnetic resonance spectra were acquired at 3T from the mid-anterior cingulate cortex in 20 patients with chronic painful knee osteoarthritis, and 19 healthy pain-free individuals using a point resolved spectroscopy sequence optimized for detection of γ-aminobutyric acid. Participants underwent questionnaires for negative affect (depression and anxiety) and psychophysical pain phenotyping.

Assessment of treatment response by measuring tumor size is known to be a late and potentially confounded response index. Serial diffusion MRI has shown potential for allowing earlier and possibly more reliable response assessment in adult patients, with limited experience in clinical settings and in pediatric brain cancer. We present a retrospective study of clinical MRI data in children with high-grade brain tumors to assess and compare the values of several diffusion change metrics to predict treatment response.

Several lines of evidence implicate glycogen synthase kinase 3 beta (GSK3beta) in mood disorders. We recently reported associations between GSK3beta polymorphisms and brain structural changes in patients with recurrent major depressive disorder (MDD). Here we provide supporting observations by showing that polymorphisms in additional genes encoding proteins directly related to GSK3beta biological functions are associated with similar regional grey matter (GM) volume changes in MDD patients. We tested specifically for associations with genetic variation in canonical Wnt signaling pathway genes and in genes that encode substrate proteins of GSK3beta. We applied a general linear model with non-stationary cluster-based inference to examine associations between polymorphisms and regional voxel-based morphometry GM volume differences in recurrent MDD patients (n=134) and in age-, gender-, and ethnicity-matched healthy controls (n=144) to test for genotype-by-MDD interactions. We observed associations for polymorphisms in 8/13 canonical Wnt pathway genes and 5/10 GSK3beta substrate genes, predominantly in the temporolateral and medial prefrontal cortices. Similar associations were not found for 100 unrelated polymorphisms tested. This work suggests that identifying SNPs related to genes that encode functionally-interacting proteins that modulate common anatomical regions offers a useful approach to increasing confidence in outcomes from imaging genetics association studies. This is of particular interest when replication datasets are not available. Our observations lend support to the hypothesis that polymorphisms in GSK3beta play a role in MDD susceptibility or expression, in part, by acting via the canonical Wnt signaling pathway and related substrates.

Coordinate based meta-analysis (CBMA) is widely used to find regions of consistent activation across fMRI studies that have been selected for their functional relevance to a given hypothesis. Only reported coordinates (foci), and a model of their spatial uncertainty, are used in the analysis. Results are clusters of foci where multiple studies have reported in the same spatial region, indicating functional relevance. There are several published methods that perform the analysis in a voxel-wise manner, resulting in around 10(5) statistical tests, and considerable emphasis placed on controlling the risk of type 1 statistical error. Here we address this issue by dramatically reducing the number of tests, and by introducing a new false discovery rate control: the false cluster discovery rate (FCDR). FCDR is particularly interpretable and relevant to the results of CBMA, controlling the type 1 error by limiting the proportion of clusters that are expected under the null hypothesis. We also introduce a data diagnostic scheme to help ensure quality of the analysis, and demonstrate its use in the example studies. We show that we control the false clusters better than the widely used ALE method by performing numerical experiments, and that our clustering scheme results in more complete reporting of structures relevant to the functional task.

Maladaptive mechanisms of pain processing in chronic pain conditions (CP) are poorly understood. We used coordinate based meta-analysis of 266 fMRI pain studies to study functional brain reorganisation in CP and experimental models of hyperalgesia. The pattern of nociceptive brain activation was similar in CP, hyperalgesia and normalgesia in controls. However, elevated likelihood of activation was detected in the left putamen, left frontal gyrus and right insula in CP comparing stimuli of the most painful vs. other site. Meta-analysis of contrast maps showed no difference between CP, controls, mood conditions. In contrast, experimental hyperalgesia induced stronger activation in the bilateral insula, left cingulate and right frontal gyrus. Activation likelihood maps support a shared neural pain signature of cutaneous nociception in CP and controls. We also present a double dissociation between neural correlates of transient and persistent pain sensitisation with general increased activation intensity but unchanged pattern in experimental hyperalgesia and, by contrast, focally increased activation likelihood, but unchanged intensity, in CP when stimulated at the most painful body part.

There is a recognized need to improve selection of patients with carotid artery stenosis for carotid endarterectomy (CEA). We assessed the value of magnetic resonance imaging (MRI)-defined carotid plaque hemorrhage (MRIPH) to predict recurrent ipsilateral cerebral ischemic events, and stroke in symptomatic carotid stenosis.

Different emotions are accompanied by different bodily states and it is unclear which brain structures are involved in both, the cerebral representation of the bodily change and the representation of its perception. Structures connecting bodily signals and interoceptive awareness could trigger, in a feedforward manner, behavioral responses appropriate to maintain a desired state of the cardiovascular system. The present functional magnetic resonance imaging study aimed at identifying brain structures that are mutually activated during interoceptive awareness of heartbeats and during cardiovascular arousal. Additionally, we searched for brain regions connecting interoception with feelings. During the interoceptive task (directing attention towards heartbeats in relation to an exteroceptive task) the thalamus, the insula, the medial frontal/dorsal cingulate and the inferior frontal gyrus, as well as the somatomotor cortex were activated. The conjunction of the interoceptive awareness of heartbeats and cardiovascular arousal revealed structures presumably connecting both conditions, i.e. the right thalamus, insula, somatomotor cortex, and the dorsal cingulate as well as medial frontal gyrus. Furthermore, the degree of interoceptive awareness predicted the degree of activation of both the insula and the medial frontal/dorsal cingulate gyrus. Negative feelings correlated with the BOLD response of the interoceptive awareness condition in the dorsal cingulate gyrus extending into the dorsomedial prefrontal cortex. We provide evidence that the insula, the dorsal cingulate gyrus, and the dorsomedial prefrontal cortex are specifically involved in processing cardiac sensations. The dorsal cingulate gyrus and the dorsomedial prefrontal cortex presumably represent the neural substrates of experiencing negative emotions.

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.