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Objective: Midbrain dopamine function plays a key role in translational models of substance use disorders. Whether midbrain dopamine function is associated with substance use frequency and severity or reward function in 20-24 year-olds remains a critical gap in knowledge. The authors collected neuromelanin-sensitive magnetic resonance imaging (NM-MRI), a validated index of lifetime dopamine function in the substantia nigra/ventral tegmentum area (SN-VTA) complex, to characterize altered dopamine function., Method: Midbrain NM-MRI contrast-to-noise ratio (CNR) was acquired in 135 20-24 year-olds (105 women and 30 men). A composite measure of cumulative substance use was derived from factor analysis of lifetime alcohol intoxications, lifetime cannabis use, use of nicotine in heaviest month, number of classes of drugs used, and ever meeting DSM-5 criteria for a SUD. Trait reward function was assessed by self-report., Results: Cumulative substance use was significantly positively associated with NM-MRI CNR in a large area of the bilateral SN-VTA complex, an effect which was driven by women (who comprised most of the sample) and by voxels with greater NM-MRI CNR, including the ventral tegmentum area. NM-MRI CNR was not associated with individual differences in trait reward function., Conclusions: History of substance use is associated with greater NM signal in NM-rich areas of the midbrain, especially in women. Future longitudinal studies with repeated NM-MRI assessments, especially in younger cohorts and while including more men, are warranted to evaluate whether aberrant dopamine function predates, follows, or is modulated by substance use., Competing Interests: Dr. Abi-Dargham serves on the Scientific Advisory Board for Neurocrine, Sunovion, and Abbvie; on the Data Safety Monitoring Board for Merck; and as the Deputy Editor of Biological Psychiatry; holds stock options in Herophilus and Terran Life Sciences; and has received consulting fees/honoraria from Boehringer Ingelheim, Merck, Neurocrine, Otsuka, Roche, and Sunovion. Dr Horga reports an investigator-initiated sponsored research agreement from Terran Biosciences outside the submitted work and having filed patents for the analysis and use of neuromelanin-sensitive magnetic resonance imaging in central nervous system disorders licensed to Terran Biosciences with no royalties received (WO2021034770A1, WO2022192728A3, AU2021377338A1, AU2019359377A1). Dr Wengler reports having filed patents for the analysis and use of neuromelanin-sensitive magnetic resonance imaging in central nervous system disorders licensed to Terran Biosciences with no royalties received (WO2021034770A1, WO2022192728A3, AU2021377338A1). The remaining authors report no financial relationships with commercial interests.

Neuromelanin-sensitive MRI is a burgeoning non-invasive neuroimaging method with an increasing number of applications in psychiatric research. This MRI modality is sensitive to the concentration of neuromelanin, which is synthesized from intracellular catecholamines and accumulates in catecholaminergic nuclei including the dopaminergic substantia nigra and the noradrenergic locus coeruleus. Emerging data suggest the utility of neuromelanin-sensitive MRI as a proxy measure for variability in catecholamine metabolism and function, even in the absence of catecholaminergic cell loss. Given the importance of catecholamine function to several psychiatric disorders and their treatments, neuromelanin-sensitive MRI is ideally positioned as an informative and easy-to-acquire catecholaminergic index. In this review paper, we examine basic aspects of neuromelanin and neuromelanin-sensitive MRI and focus on its psychiatric applications in the contexts of mechanistic research and biomarker development. We discuss ongoing debates and state-of-the-art research into the mechanisms of the neuromelanin-sensitive MRI contrast, standardized protocols and optimized analytic approaches, and application of cutting-edge methods such as machine learning and artificial intelligence to enhance the feasibility and predictive power of neuromelanin-sensitive-MRI-based tools. We finally lay out important future directions to allow neuromelanin-sensitive-MRI to fulfill its potential as a key component of the research, and ultimately clinical, toolbox in psychiatry., (© 2024. The Author(s), under exclusive licence to American College of Neuropsychopharmacology.)

Background: Despite longstanding interest in the central cholinergic system in schizophrenia (SCZ), cholinergic imaging studies with patients have been limited to receptors. Here, we conducted a proof-of-concept positron emission tomography study using [ 18 F]-VAT, a new radiotracer that targets the vesicular acetylcholine transporter as a proxy measure of acetylcholine transmission capacity, in patients with SCZ and explored relationships of vesicular acetylcholine transporter with clinical symptoms and cognition., Methods: A total of 18 adult patients with SCZ or schizoaffective disorder (the SCZ group) and 14 healthy control participants underwent a positron emission tomography scan with [ 18 F]-VAT. Distribution volume (V T ) for [ 18 F]-VAT was derived for each region of interest, and group differences in V T were assessed with 2-sample t tests. Functional significance was explored through correlations between V T and scores on the Positive and Negative Syndrome Scale and a computerized neurocognitive battery (PennCNB)., Results: No group differences in [ 18 F]-VAT V T were observed. However, within the SCZ group, psychosis symptom severity was positively associated with V T in multiple regions of interest, with the strongest effects in the hippocampus, thalamus, midbrain, cerebellum, and cortex. In addition, in the SCZ group, working memory performance was negatively associated with V T in the substantia innominata and several cortical regions of interest including the dorsolateral prefrontal cortex., Conclusions: In this initial study, the severity of 2 important features of SCZ-psychosis and working memory deficit-was strongly associated with [ 18 F]-VAT V T in several cortical and subcortical regions. These correlations provide preliminary evidence of cholinergic activity involvement in SCZ and, if replicated in larger samples, could lead to a more complete mechanistic understanding of psychosis and cognitive deficits in SCZ and the development of therapeutic targets., (Copyright © 2024 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Alzheimer's disease (AD) is a devastating neurodegenerative disease that affects millions of seniors in the United States. Resting-state functional magnetic resonance imaging (rs-fMRI) is widely used to study neurophysiology in AD and its prodromal condition, mild cognitive impairment (MCI). The intrinsic neural timescale (INT), which can be estimated through the magnitude of the autocorrelation of neural signals from rs-fMRI, is thought to quantify the duration that neural information is stored in a local circuit. Such heterogeneity of the timescales forms a basis of the brain functional hierarchy and captures an aspect of circuit dynamics relevant to excitation/inhibition balance, which is broadly relevant for cognitive functions. Given that, we applied rs-fMRI to test whether distinct changes of INT at different hierarchies are present in people with MCI, those progressing to AD (called Converter), and AD patients of both sexes. Linear mixed-effect model was implemented to detect altered hierarchical gradients across populations followed by pairwise comparisons to identify regional differences. High similarities between AD and Converter were observed. Specifically, the inferior temporal, caudate, and pallidum areas exhibit significant alterations in both AD and Converter. Distinct INT-related pathological changes in MCI and AD were found. For AD/Converter, neural information is stored for a longer time in lower hierarchical areas, while higher levels of hierarchy seem to be preferentially impaired in MCI leading to a less pronounced hierarchical gradient. These results inform that the INT holds great potential as an additional measure for AD prediction, even a stable biomarker for clinical diagnosis., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 the authors.)

Objective: Markers for treatment resistance in schizophrenia are needed to reduce delays in effective treatment. Nigrostriatal hyperdopaminergic function plays a critical role in the pathology of schizophrenia, yet antipsychotic nonresponders do not show increased dopamine function. Neuromelanin-sensitive MRI (NM-MRI), which indirectly measures dopamine function in the substantia nigra, has potential as a noninvasive marker for nonresponders. Increased NM-MRI signal has been shown in psychosis, but has not yet been assessed in nonresponders. In this study, the authors investigated whether nonresponders show lower NM-MRI signal than responders., Methods: NM-MRI scans were acquired in 79 patients with first-episode psychosis and 20 matched healthy control subjects. Treatment response was assessed at a 6-month follow-up. An a priori voxel-wise analysis within the substantia nigra tested the relation between NM-MRI signal and treatment response in patients., Results: Fifteen patients were classified as nonresponders and 47 patients as responders. Seventeen patients were excluded, primarily because of medication nonadherence or change in diagnosis. Voxel-wise analysis revealed 297 significant voxels in the ventral tier of the substantia nigra that were negatively associated with treatment response. Nonresponders and healthy control subjects had significantly lower NM-MRI signal than responders. Receiver operating characteristic curve analysis showed that NM-MRI signal separated nonresponders with areas under the curve between 0.62 and 0.85. In addition, NM-MRI signal in patients did not change over 6 months., Conclusions: These findings provide further evidence for dopaminergic differences between medication responders and nonresponders and support the potential of NM-MRI as a clinically applicable marker for treatment resistance in schizophrenia., Competing Interests: Drs. Wengler, Cassidy, and Horga are inventors on patents for analysis and use of NM-MRI, licensed to Terran Biosciences, but have received no royalties. Drs. Cassidy and Horga have an investigator-initiated sponsored research agreement and a licensing agreement with Terran Biosciences. The other authors report no financial relationships with commercial interests.

Importance: The link between psychosis and dopaminergic dysfunction is established, but no generalizable biomarkers with clear potential for clinical adoption exist., Objective: To replicate previous findings relating neuromelanin-sensitive magnetic resonance imaging (NM-MRI), a proxy measure of dopamine function, to psychosis severity in antipsychotic-free individuals in the psychosis spectrum and to evaluate the out-of-sample predictive ability of NM-MRI for psychosis severity., Design, Setting, and Participants: This cross-sectional study recruited participants from 2019 to 2023 in the New York City area (main samples) and Mexico City area (external validation sample). The main samples consisted of 42 antipsychotic-free patients with schizophrenia, 53 antipsychotic-free individuals at clinical high risk for psychosis (CHR), and 52 matched healthy controls. An external validation sample consisted of 16 antipsychotic-naive patients with schizophrenia., Main Outcomes and Measures: NM-MRI contrast within a subregion of the substantia nigra previously linked to psychosis severity (a priori psychosis region of interest [ROI]) and psychosis severity measured using the Positive and Negative Syndrome Scale (PANSS) in schizophrenia and the Structured Interview for Psychosis-Risk Syndromes (SIPS) in CHR. The cross-validated performance of linear support vector regression to predict psychosis severity across schizophrenia and CHR was assessed, and a final trained model was tested on the external validation sample., Results: Of the 163 included participants, 76 (46.6%) were female, and the mean (SD) age was 29.2 (10.4) years. In the schizophrenia sample, higher PANSS positive total scores correlated with higher mean NM-MRI contrast in the psychosis ROI (t37 = 2.24, P = .03; partial r = 0.35; 95% CI, 0.05 to 0.55). In the CHR sample, no significant association was found between higher SIPS positive total score and NM-MRI contrast in the psychosis ROI (t48 = -0.55, P = .68; partial r = -0.08; 95% CI, -0.36 to 0.23). The 10-fold cross-validated prediction accuracy of psychosis severity was above chance in held-out test data (mean r = 0.305, P = .01; mean root-mean-square error [RMSE] = 1.001, P = .005). External validation prediction accuracy was also above chance (r = 0.422, P = .046; RMSE = 0.882, P = .047)., Conclusions and Relevance: This study provided a direct ROI-based replication of the in-sample association between NM-MRI contrast and psychosis severity in antipsychotic-free patients with schizophrenia. In turn, it failed to replicate such association in CHR individuals. Most critically, cross-validated machine-learning analyses provided a proof-of-concept demonstration that NM-MRI patterns can be used to predict psychosis severity in new data, suggesting potential for developing clinically useful tools.

Alzheimer's disease (AD) is a devastating neurodegenerative disease that affects millions of older adults in the US and worldwide. Resting-state functional magnetic resonance imaging (rs-fMRI) has become a widely used neuroimaging tool to study neurophysiology in AD and its prodromal condition, mild cognitive impairment (MCI). The intrinsic neural timescale (INT), which can be estimated through the magnitude of the autocorrelation of intrinsic neural signals using rs-fMRI, is thought to quantify the duration that neural information is stored in a local cortical circuit. The heterogeneity of the timescales is considered to be a basis of the functional hierarchy in the brain. In addition, INT captures an aspect of circuit dynamics relevant to excitation/inhibition (E/I) balance, which is thought to be broadly relevant for cognitive functions. Here we examined its relevance to AD. We used rs-fMRI data of 904 individuals from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. The subjects were divided into 4 groups based on their baseline and end-visit clinical status, which were cognitively normal (CN), stable MCI, Converter, and AD groups. Linear mixed effect model and pairwise comparison were implemented to investigate the large-scale hierarchical organization and local differences. We observed high similarities between AD and Converter groups. Specifically, among the eight identified ROIs with distinct INT alterations in AD, three ROIs (inferior temporal, caudate, pallidum areas) exhibit stable and significant alteration in AD converter. In addition, distinct INT related pathological changes in stable MCI and AD/Converter were found. For AD and Converter groups, neural information is stored for a longer time in lower hierarchical order areas, while higher levels of hierarchy seem to be preferentially impaired in stable MCI leading to a less pronounced hierarchical gradient effect. These results inform that the INT holds great potential as an additional measure for AD prediction, a stable biomarker for clinical diagnosis and an important therapeutic target in AD.

Obsessive-compulsive disorder (OCD) is an impairing psychiatric condition, which often onsets in childhood. Growing research highlights dopaminergic alterations in adult OCD, yet pediatric studies are limited by methodological constraints. This is the first study to utilize neuromelanin-sensitive MRI as a proxy for dopaminergic function among children with OCD. N = 135 youth (6-14-year-olds) completed high-resolution neuromelanin-sensitive MRI across two sites; n = 64 had an OCD diagnosis. N = 47 children with OCD completed a second scan after cognitive-behavioral therapy. Voxel-wise analyses identified that neuromelanin-MRI signal was higher among children with OCD compared to those without (483 voxels, permutation-corrected p = 0.018). Effects were significant within both the substania nigra pars compacta (p = 0.004, Cohen's d = 0.51) and ventral tegmental area (p = 0.006, d = 0.50). Follow-up analyses indicated that more severe lifetime symptoms (t = -2.72, p = 0.009) and longer illness duration (t = -2.22, p = 0.03) related to lower neuromelanin-MRI signal. Despite significant symptom reduction with therapy (p < 0.001, d = 1.44), neither baseline nor change in neuromelanin-MRI signal associated with symptom improvement. Current results provide the first demonstration of the utility of neuromelanin-MRI in pediatric psychiatry, specifically highlighting in vivo evidence for midbrain dopamine alterations in treatment-seeking youth with OCD. Neuromelanin-MRI likely indexes accumulating alterations over time, herein, implicating dopamine hyperactivity in OCD. Given evidence of increased neuromelanin signal in pediatric OCD but negative association with symptom severity, additional work is needed to parse potential longitudinal or compensatory mechanisms. Future studies should explore the utility of neuromelanin-MRI biomarkers to identify early risk prior to onset, parse OCD subtypes or symptom heterogeneity, and explore prediction of pharmacotherapy response., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Introduction: Pretreatment positron emission tomography (PET) with 2-deoxy-2-[ 18 F]fluoro-D-glucose (FDG) and magnetic resonance spectroscopy (MRS) may identify biomarkers for predicting remission (absence of depression). Yet, no such image-based biomarkers have achieved clinical validity. The purpose of this study was to identify biomarkers of remission using machine learning (ML) with pretreatment FDG-PET/MRS neuroimaging, to reduce patient suffering and economic burden from ineffective trials., Methods: This study used simultaneous PET/MRS neuroimaging from a double-blind, placebo-controlled, randomized antidepressant trial on 60 participants with major depressive disorder (MDD) before initiating treatment. After eight weeks of treatment, those with ≤ 7 on 17-item Hamilton Depression Rating Scale were designated a priori as remitters (free of depression, 37%). Metabolic rate of glucose uptake (metabolism) from 22 brain regions were acquired from PET. Concentrations (mM) of glutamine and glutamate and gamma-aminobutyric acid (GABA) in anterior cingulate cortex were quantified from MRS. The data were randomly split into 67% train and cross-validation ( n = 40), and 33% test ( n = 20) sets. The imaging features, along with age, sex, handedness, and treatment assignment (selective serotonin reuptake inhibitor or SSRI vs. placebo) were entered into the eXtreme Gradient Boosting (XGBoost) classifier for training., Results: In test data, the model showed 62% sensitivity, 92% specificity, and 77% weighted accuracy. Pretreatment metabolism of left hippocampus from PET was the most predictive of remission., Conclusions: The pretreatment neuroimaging takes around 60 minutes but has potential to prevent weeks of failed treatment trials. This study effectively addresses common issues for neuroimaging analysis, such as small sample size, high dimensionality, and class imbalance., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial or personal relationships that could be viewed as influencing the work reported in this paper.

Previous proton magnetic resonance spectroscopy ( 1 H-MRS) studies suggest a perturbation in glutamate and/or GABA in Major Depressive Disorder (MDD). However, no studies examine the ratio of glutamate and glutamine (Glx) to GABA (Glx/GABA) as it relates to depressive symptoms, which may be more sensitive than either single metabolite. Using a within-subject design, we hypothesized that reduction in depressive symptoms correlates with reduction in Glx/GABA in the anterior cingulate cortex (ACC). The present trial is a randomized clinical trial that utilized 1 H-MRS to examine Glx/GABA before and after 8 weeks of escitalopram or placebo. Participants completed the 17-item Hamilton Depression Rating Scale (HDRS 17 ) and underwent magnetic resonance spectroscopy before and after treatment. Two GABA-edited MEGA-PRESS acquisitions were interleaved with a water unsuppressed reference scan. GABA and Glx were quantified from the average difference spectrum, with preprocessing using Gannet and spectral fitting using TARQUIN. Linear mixed models were utilized to evaluate relationships between change in HDRS 17 and change in Glx/GABA using a univariate linear regression model, multiple linear regression incorporating treatment type as a covariate, and Bayes Factor (BF) hypothesis testing to examine strength of evidence. No significant relationship was detected between percent change in Glx, GABA, or Glx/GABA and percent change in HDRS 17 , regardless of treatment type. Further, MDD severity before/after treatment did not correlate with ACC Glx/GABA. In light of variable findings in the literature and lack of association in our investigation, future directions should include evaluating glutamate and glutamine individually to shed light on the underpinnings of MDD severity. Advancing Personalized Antidepressant Treatment Using PET/MRI, ClinicalTrials.gov, NCT02623205., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Patients with schizophrenia have a high prevalence of cigarette smoking and respond poorly to conventional treatments, highlighting the need for new therapies. We conducted a mechanistic, proof-of-concept study using bilateral deep repetitive transcranial magnetic stimulation (dTMS) of insular and prefrontal cortices at high frequency, using the specialized H4 coil. Feasibility of dTMS was tested for disruption of tobacco self-administration, insula target engagement, and insula circuit modulation, all of which were a priori outcomes of interest. Twenty patients completed the study, consisting of weekday dTMS sessions (randomization to active dTMS or sham; double-blind; 10 patients per group), a laboratory tobacco self-administration paradigm (pre/post assessments), and multimodal imaging (three MRI total sessions). Results showed that participants assigned to active dTMS were slower to initiate smoking their first cigarette compared with sham, consistent with smoking disruption. The imaging analyses did not reveal significant Time × Group interactions, but effects were in the anticipated directions. In arterial spin labeling analyses testing for target engagement, an overall decrease in insula blood flow, measured during a post-treatment MRI versus baseline, was numerically more pronounced in the active dTMS group than sham. In fMRI analyses, resting-state connectivity between the insula and default mode network showed a numerically greater change from baseline in the active dTMS group than sham, consistent with a functional change to insula circuits. Exploratory analyses further suggested a therapeutic effect of dTMS on symptoms of psychosis. These initial observations pave the way for future confirmatory studies of dTMS in smoking patients with schizophrenia., (© 2022. The Author(s).)

Loneliness is defined as the subjective feeling that one's social needs are not satisfied by both quantity and quality of one's social relationships. Loneliness has been linked to a broad range of adverse physical and mental health consequences. There is an interest in identifying the neural and molecular processes by which loneliness adversely affects health. Prior imaging studies reported divergent networks involved in cognitive, emotional, and social processes associated with loneliness. Although loneliness is common among both younger and older adults, it is experienced differently across the lifespan and has different antecedents and consequences. The current study measured regional cerebral blood flow (CBF) using pulsed arterial spin labeling imaging. Forty-five older ( M age  = 63.4) and forty-four younger adults ( M age  = 20.9) with comparable degrees of loneliness were included. Whole-brain voxel-wise analysis revealed a main effect of age (in superior temporal and supramarginal gyri), but no main effect of loneliness. Furthermore, the age effect was only observed among people who reported higher level of loneliness. These regions have previously been implicated in social- and attention-related functions. The moderation of loneliness on age and regional CBF suggests that younger and older individuals present differential neural manifestations in response to loneliness, even with comparable levels of loneliness.

Background: Neuromelanin-sensitive magnetic resonance imaging (NM-MRI) is a validated measure of neuromelanin concentration in the substantia nigra-ventral tegmental area (SN-VTA) complex and is a proxy measure of dopaminergic function with potential as a noninvasive biomarker. The development of generalizable biomarkers requires large-scale samples necessitating harmonization approaches to combine data collected across sites., Purpose: To develop a method to harmonize NM-MRI across scanners and sites., Study Type: Prospective., Population: A total of 128 healthy subjects (18-73 years old; 45% female) from three sites and five MRI scanners., Field Strength/sequence: 3.0 T; NM-MRI two-dimensional gradient-recalled echo with magnetization-transfer pulse and three-dimensional T1-weighted images., Assessment: NM-MRI contrast (contrast-to-noise ratio [CNR]) maps were calculated and CNR values within the SN-VTA (defined previously by manual tracing on a standardized NM-MRI template) were determined before harmonization (raw CNR) and after ComBat harmonization (harmonized CNR). Scanner differences were assessed by calculating the classification accuracy of a support vector machine (SVM). To assess the effect of harmonization on biological variability, support vector regression (SVR) was used to predict age and the difference in goodness-of-fit (Δr) was calculated as the correlation (between actual and predicted ages) for the harmonized CNR minus the correlation for the raw CNR., Statistical Tests: Permutation tests were used to determine if SVM classification accuracy was above chance level and if SVR Δr was significant. A P-value <0.05 was considered significant., Results: In the raw CNR, SVM MRI scanner classification was above chance level (accuracy = 86.5%). In the harmonized CNR, the accuracy of the SVM was at chance level (accuracy = 29.5%; P = 0.8542). There was no significant difference in age prediction using the raw or harmonized CNR (Δr = -0.06; P = 0.7304)., Data Conclusion: ComBat harmonization removes differences in SN-VTA CNR across scanners while preserving biologically meaningful variability associated with age., Level of Evidence: 2 TECHNICAL EFFICACY: 1., (© 2021 International Society for Magnetic Resonance in Medicine.)

The dopaminergic system plays a crucial role in healthy cognition (e.g., reward learning and uncertainty) and neuropsychiatric disorders (e.g., Parkinson's disease and schizophrenia). Neuromelanin is a byproduct of dopamine synthesis that accumulates in dopaminergic neurons of the substantia nigra. Neuromelanin-sensitive magnetic resonance imaging (NM-MRI) is a noninvasive method for measuring neuromelanin in those dopaminergic neurons, providing a direct measure of dopaminergic cell loss in the substantia nigra and a proxy measure of dopamine function. Although NM-MRI has been shown to be useful for studying various neuropsychiatric disorders, it is challenged by a limited field-of-view in the inferior-superior direction resulting in the potential loss of data from the accidental exclusion of part of the substantia nigra. In addition, the field is lacking a standardized protocol for the acquisition of NM-MRI data, a critical step in facilitating large-scale multisite studies and translation into the clinic. This protocol describes a step-by-step NM-MRI volume placement procedure and online quality control checks to ensure the acquisition of good-quality data covering the entire substantia nigra.

Late-life depression (LLD) is a prevalent and disabling condition in older adults that is often accompanied by slowed processing and gait speed. These symptoms are related to impaired dopamine function and sometimes remedied by levodopa (L-DOPA). In this study, we recruited 33 older adults with LLD to determine the association between a proxy measure of dopamine function-neuromelanin-sensitive magnetic resonance imaging (NM-MRI)-and baseline slowing measured by the Digit Symbol test and a gait speed paradigm. In secondary analyses, we also assessed the ability of NM-MRI to predict L-DOPA treatment response in a subset of these patients (N = 15) who received 3 weeks of L-DOPA. We scanned a further subset of these patients (N = 6) with NM-MRI at baseline and after treatment to preliminarily evaluate the effects of L-DOPA treatment on the NM-MRI signal. We found that lower baseline NM-MRI correlated with slower baseline gait speed (346 of 1807 substantia nigra-ventral tegmental area (SN-VTA) voxels, P corrected  = 0.038), particularly in the more medial, anterior, and dorsal SN-VTA. Secondary analyses failed to show an association between baseline NM-MRI and treatment-related changes in gait speed, processing speed, or depression severity (all P corrected  > 0.361); we however found preliminary evidence of increases in the NM-MRI signal 3 weeks post-treatment with L-DOPA compared to baseline (200 of 1807 SN-VTA voxels; P corrected  = 0.046), although the small sample size of these preliminary analyses warrants caution in their interpretation and future replications. Overall, our findings indicate that NM-MRI is sensitive to variability in gait speed in patients with LLD, suggesting this non-invasive MRI measure may provide a promising marker for dopamine-related psychomotor slowing in geriatric neuropsychiatry.

Hierarchical perceptual-inference models of psychosis may provide a holistic framework for understanding psychosis in schizophrenia including heterogeneity in clinical presentations. Particularly, hypothesized alterations at distinct levels of the perceptual-inference hierarchy may explain why hallucinations and delusions tend to cluster together yet sometimes manifest in isolation. To test this, we used a recently developed resting-state fMRI measure of intrinsic neural timescale (INT), which reflects the time window of neural integration and captures hierarchical brain gradients. In analyses examining extended sensory hierarchies that we first validated, we found distinct hierarchical INT alterations for hallucinations versus delusions in the auditory and somatosensory systems, thus providing support for hierarchical perceptual-inference models of psychosis. Simulations using a large-scale biophysical model suggested local elevations of excitation-inhibition ratio at different hierarchical levels as a potential mechanism. More generally, our work highlights the robustness and utility of INT for studying hierarchical processes relevant to basic and clinical neuroscience., Competing Interests: KW, AG, GC, GH No competing interests declared, (© 2020, Wengler et al.)

Relapsing-remitting multiple sclerosis (RRMS) is associated with persistent blood-brain barrier (BBB) dysfunction. The impact of this persistent dysfunction in both active and chronic MS lesions has yet to be investigated due to technological challenges associated with invasive assessment of BBB water transportation (e.g. 15 O-PET). The purpose of this study was to test if persistent BBB dysfunction in RRMS manifests as lower BBB water exchange in chronic lesions using a recently developed noninvasive MRI paradigm. Patients with relapsing-remitting MS and healthy subjects were recruited for this prospective study. The novel Intrinsic Diffusivity Encoding of Arterial Labeled Spins (IDEALS) MRI method was used to map BBB water extraction fraction (E w ) and water permeability surface area product (PS w ), as well as cerebral blood flow (CBF). Regional differences in BBB water exchange were evaluated between MS patients (normal appearing white matter [NAWM] and normal appearing gray matter [NAGM]) and healthy subjects (white matter [WM] and gray matter [GM]) and within MS subjects in non gadolinium-based contrast-agent (GBCA) enhancing chronic lesions, perilesional areas, and NAWM. Significantly lower PS w and E w were observed in NAWM compared to WM (ΔPS w : -11.9 mL/100 g/min, p < .05; ΔE w : -4.3%, p < .01). Significantly lower E w was observed in NAGM compared to GM (ΔE w : -12.1%, p < .01). Significantly lower PS w and CBF were observed in non-GBCA contrast enhancing lesions compared to NAWM (ΔPS w  = -11.5 mL/100 g/min, p < .05; ΔCBF = -8.1 mL/100 g/min, p < .05). E w was significantly higher in non-GBCA enhancing chronic MS lesions compared to NAWM (ΔE w  = 1.6%, p < .05). The lower BBB water exchange in chronic MS lesions is consistent with previously reported observations and may demonstrate metabolic changes associated with MS., Competing Interests: Declaration of Competing Interest The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Patellar tendon (PT) microstructure integrity and microcirculation status play a crucial role in the progression of tendinopathy and tendon repair., Purpose: To assess the feasibility and robustness of stimulated-echo based diffusion-weighted MRI with readout-segmented echo-planar imaging (ste-RS-EPI) for noninvasive assessment of microstructure and microcirculation of human PT., Study Type: Prospective., Subjects: Fifteen healthy volunteers., Field Strength/sequence: PT diffusion tensor imaging (DTI) and intravoxel incoherent motion (IVIM) were acquired with an ste-RS-EPI protocol on a 3T MRI scanner., Assessment: Subjects were positioned with their PT at the magic angle. DTI-derived parameters including axial diffusivity (AD), radial diffusivity (RD), mean diffusivity (MD), and fractional anisotropy (FA) were estimated with b-values of 0 and 800 s/mm 2 and 12 diffusion directions. IVIM-derived parameters, f p , D* × f p , V b , and D* × V b were assessed in the central-third and the outer-two thirds of the PT with b-values of 0, 20, 30, 60, 80, 120, 200, 400, and 600 s/mm 2 in three orthogonal directions., Statistical Tests: Paired t-tests were used to evaluate differences in IVIM parameters between the central-third and outer-two thirds regions of the patellar tendon. Paired t-tests and within-subject coefficient of variation were used to assess the intra- and intersession reproducibility of PT DTI and IVIM parameters., Results: DTI parameters for healthy PT were 1.54 ± 0.09 × 10 -3 mm 2 /s, 1.01 ± 0.05 × 10 -3 mm 2 /s, 1.18 ± 0.06 × 10 -3 mm 2 /s, and 0.30 ± 0.04 for AD, RD, MD, and FA, respectively. Significantly higher (P < 0.05) IVIM parameters f p and D* × f p were observed in the outer-two thirds (6.1% ± 2.4% and 95.2 ± 49.6, respectively) compared with the central-third (3.8% ± 2.3% and 48.6 ± 35.2, respectively) of the PT., Data Conclusion: Diffusion MRI of PT with an ste-RS-EPI protocol is clinically feasible. Both DTI- and IVIM-derived parameters of the PT demonstrated good test-retest reproducibility and interrater reliability., Level of Evidence: 2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2020;51:780-790., (© 2019 International Society for Magnetic Resonance in Medicine.)

Neuromelanin-sensitive MRI (NM-MRI) provides a noninvasive measure of the content of neuromelanin (NM), a product of dopamine metabolism that accumulates with age in dopamine neurons of the substantia nigra (SN). NM-MRI has been validated as a measure of both dopamine neuron loss, with applications in neurodegenerative disease, and dopamine function, with applications in psychiatric disease. Furthermore, a voxelwise-analysis approach has been validated to resolve substructures, such as the ventral tegmental area (VTA), within midbrain dopaminergic nuclei thought to have distinct anatomical targets and functional roles. NM-MRI is thus a promising tool that could have diverse research and clinical applications to noninvasively interrogate in vivo the dopamine system in neuropsychiatric illness. Although a test-retest reliability study by Langley et al. using the standard NM-MRI protocol recently reported high reliability, a systematic and comprehensive investigation of the performance of the method for various acquisition parameters and preprocessing methods has not been conducted. In particular, most previous studies used relatively thick MRI slices (~3 ​mm), compared to the typical in-plane resolution (~0.5 ​mm) and to the height of the SN (~15 ​mm), to overcome technical limitations such as specific absorption rate and signal-to-noise ratio, at the cost of partial-volume effects. Here, we evaluated the effect of various acquisition and preprocessing parameters on the strength and test-retest reliability of the NM-MRI signal to determine optimized protocols for both region-of-interest (including whole SN-VTA complex and atlas-defined dopaminergic nuclei) and voxelwise measures. Namely, we determined a combination of parameters that optimizes the strength and reliability of the NM-MRI signal, including acquisition time, slice-thickness, spatial-normalization software, and degree of spatial smoothing. Using a newly developed, detailed acquisition protocol, across two scans separated by 13 days on average, we obtained intra-class correlation values indicating excellent reliability and high contrast, which could be achieved with a different set of parameters depending on the measures of interest and experimental constraints such as acquisition time. Based on this, we provide detailed guidelines covering acquisition through analysis and recommendations for performing NM-MRI experiments with high quality and reproducibility. This work provides a foundation for the optimization and standardization of NM-MRI, a promising MRI approach with growing applications throughout clinical and basic neuroscience., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Existing ultrashort echo time magnetic resonance imaging (UTE MRI) methods require prohibitively long acquisition times (~ 20-40 min) to quantitatively assess the clinically relevant fast decay T 2 * component in ligaments and tendons. The purpose of this study was to evaluate the feasibility and clinical translatability of a novel abbreviated quantitative UTE MRI paradigm for monitoring graft remodeling after anterior cruciate ligament (ACL) reconstruction., Methods: Eight patients who had Graftlink™ hamstring autograft reconstruction were recruited for this prospective study. A 3D double-echo UTE sequence at 3.0 Tesla was performed at 3- and 6-months post-surgery. An abbreviated UTE MRI paradigm was established based on numerical simulations and in vivo validation from healthy knees. This proposed approach was used to assess the T 2 * for fast decay component ([Formula: see text]) and bound water signal fraction (f bw ) of ACL graft in regions of interest drawn by a radiologist., Results: Compared to the conventional bi-exponential model, the abbreviated UTE MRI paradigm achieved low relative estimation bias for [Formula: see text] and f bw over a range of clinically relevant values for ACL grafts. A decrease in [Formula: see text] of the intra-articular graft was observed in 7 of the 8 ACL reconstruction patients from 3- to 6-months (- 0.11 ± 0.16 ms, P = 0.10). Increases in [Formula: see text] and f bw from 3- to 6-months were observed in the tibial intra-bone graft ([Formula: see text]: 0.19 ± 0.18 ms, P < 0.05; Δf bw : 4% ± 4%, P < 0.05). Lower [Formula: see text] (- 0.09 ± 0.11 ms, P < 0.05) was observed at 3-months when comparing the intra-bone graft to the graft/bone interface in the femoral tunnel. The same comparisons at the 6-months also yielded relatively lower [Formula: see text] (- 0.09 ± 0.12 ms, P < 0.05)., Conclusion: The proposed abbreviated 3D UTE MRI paradigm is capable of assessing the ACL graft remodeling process in a clinically translatable acquisition time. Longitudinal changes in [Formula: see text] and f bw of the ACL graft were observed.

Although radiography continues to play a critical role in osseous tumor assessment, there have been remarkable advances in cross-sectional imaging. MRI has taken a lead in this assessment due to high tissue contrast and spatial resolution, which are well suited for bone lesion assessment. More recently, although somewhat lagging other organ systems, quantitative parameters have shown promising potential as biomarkers for osseous tumors. Among these sequences are chemical shift imaging (CSI), apparent diffusion coefficient (ADC), and intravoxel incoherent motion (IVIM) from diffusion-weighted imaging (DWI), quantitative dynamic contrast enhanced (DCE)-MRI, and magnetic resonance spectroscopy (MRS). In this article, we review the background and recent roles of these quantitative MRI biomarkers for osseous tumors. Level of Evidence: 3 Technical Efficacy Stage: 3 J. MAGN. RESON. IMAGING 2019. J. Magn. Reson. Imaging 2019;50:702-718., (© 2019 International Society for Magnetic Resonance in Medicine.)

Purpose: Abnormalities in hepatic oxygen delivery and oxygen consumption may serve as a significant indicator of hepatic cellular dysfunction and may predict treatment response. However, conventional and oxygen-enhanced hepatic BOLD MRI can only provide semiquantitative assessment of hepatic oxygenation., Methods: A hepatic quantitative BOLD (qBOLD) model was proposed for noninvasive mapping of hepatic venous blood oxygen saturation (Y v ) and deoxygenated blood volume (DBV) in human subjects. The validity and the estimation bias of the proposed model were evaluated by Monte Carlo simulations. Eight healthy subjects were scanned after written consent with institutional review board approval., Results: Monte Carlo simulations demonstrated that the proposed single-compartment hepatic qBOLD model leads to significant deviation of the predicted T 2 * decay profile from the simulated signal due to high hepatic blood volume fraction. Small relative estimation bias for hepatic Y v and significant overestimation for hepatic DBV were observed, which can be corrected by applying the calibration curves established from simulations. After correction, the mean hepatic Y v in human subjects was 56.8 ± 6.8%, and the mean hepatic DBV was 0.190 ± 0.035, consistent with measurements from other invasive approaches. Except in regions with significant vascular contamination, the maps for hepatic Y v and DBV were relatively homogenous., Conclusions: With estimation bias correction, the hepatic qBOLD approach enables noninvasive mapping of hepatic blood volume and oxygenation in human subjects. The established protocol may be used to quantitatively assess hepatic tissue hypoxia in multiple liver diseases., (© 2019 International Society for Magnetic Resonance in Medicine.)

This work proposes a novel MRI method - Intrinsic Diffusivity Encoding of Arterial Labeled Spin (IDEALS) - for the whole-brain mapping of water permeability in the human brain without an exogenous contrast agent. Quantitative separation of the intravascular and extravascular labeled water MRI signal was achieved in arterial spin labeling experiments with segmented 3D-GRASE acquisition by modulating the relative sensitivity between relaxation, true diffusion, and pseudodiffusion. The intrinsic diffusivity encoding in k-space created different broadening of the image-domain point spread functions for intravascular and extravascular labeled spins, from which blood-brain barrier (BBB) water extraction fraction (E w ) and water permeability surface area product (PS w ) were estimated. The feasibility and sensitivity of this method was evaluated in healthy subjects at baseline and after caffeine challenge. The estimated baseline E w and PS w maps showed contrast among gray matter (GM) and white matter (WM). GM E w was significantly lower than that of WM (78.8% ± 3.3% in GM vs. 83.9% ± 4.6% in WM; p < 0.05) and GM PS w was significantly higher than that of WM (131.7 ± 29.5 mL/100  g/min in GM vs. 76.2 ± 18.4 mL/100  g/min in WM; p < 0.05). BBB E w was significantly lower for females than males (74.9% ± 3.7% for females vs. 81.3% ± 3.3% for males in GM; 80.5% ± 4.7% for females vs. 86.1 ± 3.0 for males in WM; p < 0.05 for both), while significant PS w differences were only observed in WM (143.8 ± 34.4 mL/100  g/min for females vs. 123.6 ± 24.4 mL/100  g/min for males in GM; 91.6 ± 15.0 mL/100  g/min for females vs. 65.9 ± 12.5 mL/100  g/min for males in WM; p = 0.20 and p < 0.05 for GM and WM respectively). Significant correlations between E w and CBF (r = -0.32, p < 0.05) and between PS w and CBF (r = 0.89, p < 0.05) were observed, consistent with 15 O-H 2 O PET findings. After caffeine challenge, reduced CBF, E w and PS w were observed, demonstrating the sensitivity of IDEALS approach., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: Healing, regeneration, and remodeling of the injured Achilles tendon are associated with notable changes in tendon architecture. However, assessing Achilles microstructural properties with conventional diffusion tension imaging (DTI) remains a challenge because of very short T 2 / T 2 * values of the tendon. Hence, the objective of this study was to develop a novel Achilles tendon DTI protocol for a non-invasive investigation of the changes of microstructural integrity in tendinopathy., Methods: A novel stimulated echo readout-segmented EPI (ste-RS-EPI) DTI sequence was proposed to achieve a TE of ∼14-20 ms for typical b-values of 400-800 s/mm 2 on clinical 3T MRI scanners. To further boost tendon MR signal, the Achilles was positioned at the magic angle (∼55 °) with respect to the scanner B 0 field. The sensitivity of the developed protocol was evaluated in 19 healthy participants and 6 patients with clinically confirmed tendinopathy., Results: Compared to spin echo RS-EPI DTI protocol, ste-RS-EPI provided an ∼100-200% increase in Achilles MR signal. Tendinopathic Achilles demonstrated a high degree of microstructural disruption based on DTI tractography analysis, with significantly lower (P < 0.05) axial diffusivity (1.20 ± 0.19 vs. 1.39 ± 0.10 × 10 -3 mm 2 /s), radial diffusivity (0.72 ± 0.11 vs. 0.81 ± 0.08 × 10 -3 mm 2 /s), and mean diffusivity (0.87 ± 0.14 vs. 1.00 ± 0.07 × 10 -3 mm 2 /s), but no significant difference in fractional anisotropy (0.38 ± 0.04 vs. 0.38 ± 0.05; P = 0.86)., Conclusion: Achilles tendon ste-RS-EPI DTI can non-invasively detect the tendinopathy-induced changes to microstructural integrity, consistent with the disruption of collagen arrangement and increased cellularity. This study demonstrated the robustness and sensitivity of the proposed protocol in Achilles tendinopathy., (© 2018 International Society for Magnetic Resonance in Medicine.)

Background: Limited microcirculation has been implicated in Achilles tendinopathy and may affect healing and disease progression. Existing invasive and noninvasive approaches to evaluate tendon microcirculation lack sensitivity and spatial coverage., Purpose: To develop a novel Achilles tendon intravoxel incoherent motion (IVIM) MRI protocol to overcome the limitations from low tendon T 2 /T 2 * value and low intratendinous blood volume and blood velocity to evaluate tendon microcirculation., Study Type: Prospective., Subjects: Sixteen healthy male participants (age 31.0 ± 2.1) were recruited., Field Strength/sequence: A stimulated echo readout-segmented echo planar imaging (ste-RS-EPI) IVIM sequence at 3.0T., Assessment: The feasibility of the proposed ste-RS-EPI IVIM protocol combined with Achilles tendon magic angle effect was evaluated. The sensitivity of the protocol was assessed by an exercise-induced intratendinous hemodynamic response in healthy participants. The vascular origin of the observed IVIM signal was validated by varying the diffusion mixing time and echo time., Statistical Tests: Two-tailed t-tests were used to evaluate differences (P < 0.05 was considered significant)., Results: Consistent with known tendon hypovascularity, the midportion Achilles tendon at baseline showed significantly lower IVIM-derived perfusion fraction (f p ) (3.1 ± 0.9%) compared to the proximal and distal Achilles tendon (6.0 ± 1.8% and 6.1 ± 2.0%, respectively; P < 0.01). Similarly, the midportion Achilles tendon exhibited significantly lower baseline blood flow index (D*×f p ) (40.9 ± 19.2, 18.3 ± 5.3, and 32.0 ± 9.4 in proximal, midportion, and distal Achilles tendon, respectively; P < 0.01). Eccentric heel-raise exercise led to ∼2 times increase of Achilles tendon blood flow in healthy participants. Consistent with its vascular origin, the estimated f p demonstrated a high dependency to IVIM protocol parameters, while the T 1 /T 2 -corrected absolute intratendinous microvascular blood volume fraction (V b ) did not vary., Data Conclusion: Achilles tendon ste-RS-EPI IVIM noninvasively assessed baseline values and exercise-induced changes to tendon microcirculation in healthy tendon., Level of Evidence: 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;48:1690-1699., (© 2018 International Society for Magnetic Resonance in Medicine.)

Purpose: To evaluate the role of true diffusion and flow-related pseudodiffusion in cerebral blood flow (CBF) quantification using arterial spin labeling (ASL) with single-shot or segmented 3D gradient and spin echo (GRASE) readouts., Theory: The extended phase graph (EPG) algorithm, originally designed to model the effects of T 1 /T 2 relaxation and true diffusion in MRI acquisitions utilizing multiple refocusing RF pulses, was augmented (aEPG). This augmentation accounted for flow-related pseudodiffusion attenuation of intravascular MRI signal in the k-space domain during 3D-GRASE acquisition, which leads to blur along the partition direction in the image domain. Blurring of ASL signal into neighboring voxels can lead to underestimation of CBF in small, high-flow structures such as cortical gray matter (GM)., Methods: The diffusion sensitivity of 3D-GRASE was evaluated through aEPG simulations and in vivo experiments in 13 healthy subjects. The CBF estimation bias for different postlabeling delays, crusher gradient strengths, and segmentation factors along the partition (PAR) and phase-encoding (PE) directions was numerically assessed by simulations and experimentally validated., Results: In vivo experiments demonstrated systematic underestimation of mean GM CBF measured with segmented 3D-GRASE. The GM CBF underestimation depended on ASL preparation and imaging parameters; it reached up to 25% at low-segmentation schemes (1 PAR  × 2 PE ) but was considerably lower at high-segmentation schemes (4 PAR  × 2 PE or 8 PAR  × 2 PE ). Theoretical predictions showed that conventional T 1 /T 2 relaxation and true diffusion may account for at most ∼25% of GM CBF estimation bias, whereas the pseudodiffusion effect constituted the major fraction in a typical ASL experiment., Conclusion: The pseudodiffusion effect leads to considerable estimation bias in ASL-based CBF quantification using 3D-GRASE readouts. This bias can be substantially reduced by increasing the segmentation factors. Magn Reson Med 80:736-747, 2018. Published 2018. This article is a U.S. Government work and is in the public domain in the USA., (Published 2018. This article is a U.S. Government work and is in the public domain in the USA.)

Many software tools provide facilities for depicting reaction network diagrams in a visual form. Two aspects of such a visual diagram can be distinguished: the layout (i.e.: the positioning and connections) of the elements in the diagram, and the graphical form of the elements (for example, the glyphs used for symbols, the properties of the lines connecting them, and so on). This document describes the SBML Level 3 Render package that complements the SBML Level 3 Layout package and provides a means of capturing the precise rendering of the elements in a diagram. The SBML Level 3 Render package provides a flexible approach to rendering that is independent of both the underlying SBML model and the Layout information. There can be one block of render information that applies to all layouts or an additional block for each layout. Many of the elements used in the current render specification are based on corresponding elements from the SVG specification. This allows us to easily convert a combination of layout information and render information into a SVG drawing.

Purpose: Patients with cancers of oropharynx have a favorable prognosis and are an ideal candidate for adaptive therapy. A replan to improve coverage or escalate/de-escalate dose based on morphological information alone may not be adequate as the grossly involved lymph nodes (LNs) of a subset of these patients tend to become cystic and often do not regress. Functional adaptation may be a better approach when considering replanning for these patients. The purpose of this study was to evaluate the weekly trends in treatment related morphological and physiological changes for these LNs using diffusion-weighted MRI (DW-MRI) and evaluate its implications for adaptive replanning., Methods: Ten patients with histologically proven oropharynx HNSCC undergoing concurrent chemoradiation were analyzed in this study. MR imaging protocol included axial T1w, T2w, and DW-MRI using a 3 T Philips MR scanner. The patients were scanned weekly in radiation treatment planning position using a 16 element phased-array anterior coil and a 44 element posterior coil. A total of 65 DWI and T2w scans were analyzed. DWI was performed using an optimized single-shot echo planar imaging sequence (TR/TE = 5000/65 ms, slice thickness = 5 mm; slices = 28; b values = 0 and 800 s/mm(2)). Quantification of the DW-MRI images was performed by calculating the apparent diffusion coefficient (ADC). T2w and DWI scans were imported into the Eclipse treatment planning system and gross tumor volumes (GTVs) corresponding to grossly involved LNs were contoured on each axial slice by physician experts. An attempt was made to remove any cystic or necrotic components so that the ADC analysis was of viable tumor only. A pixel-by-pixel fit of signal intensities within the GTVs was performed assuming monoexponential behavior. From each GTV histogram mean, median, standard deviation, skewness, and kurtosis were calculated. Absolute and percent change in weekly ADC histogram parameters and percent change in T2w GTV were also calculated., Results: For all nodes, an immediate change in ADC was observed during first 2-3 weeks after which ADC values either continued to increase or plateaued. A few nodal volumes had a slightly decreased ADC value during later weeks. Percent increase in median ADC from weeks 1 to 6 with respect to baseline was 14%, 25%, 41%, 42%, 45%, and 58%. The corresponding change in median T2 volumes was 8%, 10%, 16%, 22%, 40%, and 42%, respectively. The ADC distribution of the viable tumors was initially highly kurtotic; however, the kurtosis decreased as treatment progressed. The ADC distribution also showed a higher degree of skewness in the first 2 weeks, progressively becoming less skewed as treatment progressed so as to slowly approach a more symmetric distribution., Conclusions: Physiological changes in LNs represented by changes in ADC evaluated using DW-MRI are evident sooner than the morphological changes calculated from T2w MRI. The decisions for adaptive replanning may need to be individualized and should be based primarily on tumor functional information. The authors' data also suggest that for many patients, week 3 maybe the optimal time to intervene and replan. Larger studies are needed to confirm their findings.

Many software tools provide facilities for depicting reaction network diagrams in a visual form. Two aspects of such a visual diagram can be distinguished: the layout (i.e.: the positioning and connections) of the elements in the diagram, and the graphical form of the elements (for example, the glyphs used for symbols, the properties of the lines connecting them, and so on). For software tools that also read and write models in SBML (Systems Biology Markup Language) format, a common need is to store the network diagram together with the SBML representation of the model. This in turn raises the question of how to encode the layout and the rendering of these diagrams. The SBML Level 3 Version 1 Core specification does not provide a mechanism for explicitly encoding diagrams, but it does provide a mechanism for SBML packages to extend the Core specification and add additional syntactical constructs. The Layout package for SBML Level 3 adds the necessary features to SBML so that diagram layouts can be encoded in SBML files, and a companion package called SBML Rendering specifies how the graphical rendering of elements can be encoded. The SBML Layout package is based on the principle that reaction network diagrams should be described as representations of entities such as species and reactions (with direct links to the underlying SBML elements), and not as arbitrary drawings or graphs; for this reason, existing languages for the description of vector drawings (such as SVG) or general graphs (such as GraphML) cannot be used.

Aim: To compare the treatment, patient satisfaction, life quality and costs of elective referred patients seen by a geriatric team at home or in a geriatric day hospital., Materials and Methods: Elective patients were randomised to primary contact by home visit (n=175) or to primary contact in the day hospital (n=176), median age 81 and 83 years, median Barthel - index 85 and 85, MMSE 25 and 25. 61% of elective referrals were randomised., Results: There were no differences between the two groups' number of problems regarding referrals, treatment offered, number of blood tests, number of X-rays, number of outpatient contacts, number of admissions to hospital wards or number of diagnosis. The patient had to invest on average 99.5 min together with the geriatric team at the first visit at home and 57.7 min on following visits. The patient had to invest more time if seen in the day hospital: 159.0 min. at the first visit and 120 min. at the following visits. Despite this difference in time-consumption, no differences were found in patient satisfaction or life quality. Of the overall time used by the geriatric team for home visits 20% was used for transportation at the first visit and 30% at the following visits. On average the hospital costs were 3.50 hours/activity at home visits as compared to 1.55 hours/activity in the day hospital., Conclusion: Geriatric home visits are expensive and time-consuming.

Any increase of daily requests for care at a hospital emergency room in Berlin (capital of the GDR) were not reported during the days of extraordinary immission situation (Smog) in January 1982 and 1985. But a special attention is necessary for people over 75 years. The information is based on the analysis of 13,000 acute internal affections from 1981 to 1985 recorded in a hospital emergency room.

A questionnaire investigation was undertaken to register the extent to which 212 insulin-treated diabetic patients undertook home measurements of blood glucose and the consequences which they drew from these measurements. This was compared with the metabolic regulation estimated by HbA1c. The average HbA1c-value was 8.0%. Only 13% had HbA1c-values within the reference range for non-diabetic persons. 85% of the patients undertook self-monitoring of blood glucose. In 47.6% insulin was administered once or twice daily, 42.5% were treated with multiple injections and 9.9% employed insulin pumps. Regardless or the form of treatment, good metabolic control was associated with numerous daily measurements of blood glucose whereas no independent connection was found between the form of treatment and the level of regulation. The best regulated patients altered the dosage of insulin with low blood glucose values and planned reduced activity. No connection was observed between the form of treatment, level of regulation or whether the patients undertook self-monitoring and the number of hospital contacts on account of hypoglycaemia or hyperglycaemia. Metabolic regulation was not satisfactory despite self monitoring of blood glucose and good understanding of the disease.

Fructosamine and various measures of blood glucose were compared to glycosylated hemoglobin as indices of glycaemic control in 148 patients with insulin treated diabetes. Fructosamine correlated fairly well with glycosylated hemoglobin (r = 0.67), but around 40 per cent of the patients with glycosylated hemoglobin below upper reference limit had a fructosamine value over upper reference limit and vice versa. The possibility to predict the level of glycosylated hemoglobin from fasting blood glucose, postprandial blood glucose, and self-measured blood glucose was poor. The difference in self-measured blood glucose from patients with high versus low levels of glycosylated hemoglobin was very modest (0.5-2.0 mmol/l). It is concluded that it is reasonable to measure both glycosylated hemoglobin and fructosamine to evaluate glycaemic control in insulin treated diabetic patients. Fasting blood glucose, postprandial blood glucose, and self-measured blood glucose only seem to reflect glycaemic control to a minor degree.