From text to interaction: The digital advance directive method for advance directives.

Advance directives allow people to specify individual treatment preferences in case of decision-making incapacity involving decisions of utmost importance. There are many tools that provide information on the topic, digital forms for structured data input, or platforms that support data storage and availability. Yet, there is no tool supporting the innermost process of an advance directive: decision making itself. To address this issue, we developed a visual-interactive, semi-quantitative method for generating digital advance directives (DiADs) that harnesses the potential of digitalization in healthcare. In this article, we describe the DiAD method and its app lined with the exemplary narrative of user Mr S. linking the theory to an exemplary use case. The DiAD method is intended to lower barriers and increase comfort in creating an advance directive by shifting the focus from heavily text-based processes to visual representation and interaction, that is, from text to reflection.

The Advance Care Compass- A New Mechanics for Digitally Transforming Advance Directives.

Advance directives allow people to declare their treatment preferences for a potential future state of incompetency. Covid-19, with its high numbers of quickly deteriorating patients requiring intensive care, has acutely demonstrated how helpful it would be for clinicians to have reliable, readily available, up-to-date information at hand to be able to act in accordance with what the individual patient would have wanted. Yet for the past few decades advance directives have fallen short of their potential, for various reasons. At worst, advance directives are perceived as unwieldy legal documents that put excessive demands on patients without providing useful guidance for better care. Recent efforts such as advance care planning have tried to remedy some of these shortcomings but have so far met with limited success. We suggest a new concept-the Advance Care Compass-that harnesses the potential of digitalization in healthcare to overcome many of difficulties encountered so far.

Exposure to 16 h of normobaric hypoxia induces ionic edema in the healthy brain.

Following prolonged exposure to hypoxic conditions, for example, due to ascent to high altitude, stroke, or traumatic brain injury, cerebral edema can develop. The exact nature and genesis of hypoxia-induced edema in healthy individuals remain unresolved. We examined the effects of prolonged, normobaric hypoxia, induced by 16 h of exposure to simulated high altitude, on healthy brains using proton, dynamic contrast enhanced, and sodium MRI. This dual approach allowed us to directly measure key factors in the development of hypoxia-induced brain edema: (1) Sodium signals as a surrogate of the distribution of electrolytes within the cerebral tissue and (2) Ktrans as a marker of blood-brain-barrier integrity. The measurements point toward an accumulation of sodium ions in extra- but not in intracellular space in combination with an intact endothelium. Both findings in combination are indicative of ionic extracellular edema, a subtype of cerebral edema that was only recently specified as an intermittent, yet distinct stage between cytotoxic and vasogenic edemas. In sum, here a combination of imaging techniques demonstrates the development of ionic edemas following prolonged normobaric hypoxia in agreement with cascadic models of edema formation.

Sodium MRI in Multiple Sclerosis is Compatible with Intracellular Sodium Accumulation and Inflammation-Induced Hyper-Cellularity of Acute Brain Lesions.

The cascade of inflammatory pathogenetic mechanisms in multiple sclerosis (MS) has no specific conventional MRI correlates. Clinicians therefore stipulate improved imaging specificity to define the pathological substrates of MS in vivo including mapping of intracellular sodium accumulation. Based upon preclinical findings and results of previous sodium MRI studies in MS patients we hypothesized that the fluid-attenuated sodium signal differs between acute and chronic lesions. We acquired brain sodium and proton MRI data of N = 29 MS patients; lesion type was defined by the presence or absence of contrast enhancement. N = 302 MS brain lesions were detected, and generalized linear mixed models were applied to predict lesion type based on sodium signals; thereby controlling for varying numbers of lesions among patients and confounding variables such as age and medication. Hierarchical model comparisons revealed that both sodium signals average tissue (χ(2)(1) = 27.89, p < 0.001) and fluid-attenuated (χ(2)(1) = 5.76, p = 0.016) improved lesion type classification. Sodium MRI signals were significantly elevated in acute compared to chronic lesions compatible with intracellular sodium accumulation in acute MS lesions. If confirmed in further studies, sodium MRI could serve as biomarker for diagnostic assessment of MS, and as readout parameter in clinical trials promoting attenuation of chronic inflammation.

MR Angiography at 7T to Visualize Cerebrovascular Territories.

BACKGROUND: There is considerable amount of interindividual variability in the size and location of the vascular territories of the major brain arteries. More data are needed to assess the amount of variability and the possible implications for further research and patient care. Arterial spin labeling (ASL) magnetic resonance imaging has been applied in various forms to facilitate noninvasive imaging of cerebrovascular flow territories, but it requires the definition of the flow territory of interest prior to image acquisition. OBJECTIVE: Assessing the vascular territories of the major brain territories by using ultra-high-field time-of-flight (TOF) magnetic resonance angiography. METHODS: We have developed an alternative method to ASL by simulating cerebrovascular dye injections. Following bias field normalization and segmentation of the vessels from 7 Tesla TOF imaging, a virtual model of the arterial vessel tree was generated and a simulation of dye dispersion into the brain tissue was performed. RESULTS: The results provided by our method are consistent with the data obtained by autoptic dye injection studies in 23 human beings by van der Zwan in 1993. CONCLUSION: Further technical improvements in imaging and segmentation techniques will improve the accuracy of the method and will facilitate the delineation of flow territories after image acquisition on even smaller subtrees of the cerebral vasculature.

Virtual Raters for Reproducible and Objective Assessments in Radiology.

Volumetric measurements in radiologic images are important for monitoring tumor growth and treatment response. To make these more reproducible and objective we introduce the concept of virtual raters (VRs). A virtual rater is obtained by combining knowledge of machine-learning algorithms trained with past annotations of multiple human raters with the instantaneous rating of one human expert. Thus, he is virtually guided by several experts. To evaluate the approach we perform experiments with multi-channel magnetic resonance imaging (MRI) data sets. Next to gross tumor volume (GTV) we also investigate subcategories like edema, contrast-enhancing and non-enhancing tumor. The first data set consists of N = 71 longitudinal follow-up scans of 15 patients suffering from glioblastoma (GB). The second data set comprises N = 30 scans of low- and high-grade gliomas. For comparison we computed Pearson Correlation, Intra-class Correlation Coefficient (ICC) and Dice score. Virtual raters always lead to an improvement w.r.t. inter- and intra-rater agreement. Comparing the 2D Response Assessment in Neuro-Oncology (RANO) measurements to the volumetric measurements of the virtual raters results in one-third of the cases in a deviating rating. Hence, we believe that our approach will have an impact on the evaluation of clinical studies as well as on routine imaging diagnostics.

Deep MRI brain extraction: A 3D convolutional neural network for skull stripping.

Brain extraction from magnetic resonance imaging (MRI) is crucial for many neuroimaging workflows. Current methods demonstrate good results on non-enhanced T1-weighted images, but struggle when confronted with other modalities and pathologically altered tissue. In this paper we present a 3D convolutional deep learning architecture to address these shortcomings. In contrast to existing methods, we are not limited to non-enhanced T1w images. When trained appropriately, our approach handles an arbitrary number of modalities including contrast-enhanced scans. Its applicability to MRI data, comprising four channels: non-enhanced and contrast-enhanced T1w, T2w and FLAIR contrasts, is demonstrated on a challenging clinical data set containing brain tumors (N=53), where our approach significantly outperforms six commonly used tools with a mean Dice score of 95.19. Further, the proposed method at least matches state-of-the-art performance as demonstrated on three publicly available data sets: IBSR, LPBA40 and OASIS, totaling N=135 volumes. For the IBSR (96.32) and LPBA40 (96.96) data set the convolutional neuronal network (CNN) obtains the highest average Dice scores, albeit not being significantly different from the second best performing method. For the OASIS data the second best Dice (95.02) results are achieved, with no statistical difference in comparison to the best performing tool. For all data sets the highest average specificity measures are evaluated, whereas the sensitivity displays about average results. Adjusting the cut-off threshold for generating the binary masks from the CNN's probability output can be used to increase the sensitivity of the method. Of course, this comes at the cost of a decreased specificity and has to be decided application specific. Using an optimized GPU implementation predictions can be achieved in less than one minute. The proposed method may prove useful for large-scale studies and clinical trials.

Evaluation of adaptive combination of 30-channel head receive coil array data in 23Na MR imaging.

PURPOSE: The aim was to optimally combine multichannel coil array data in sodium ((23) Na) MRI. METHODS: (23) Na MRI was conducted on a 3 Tesla MR system using a 30-channel head receive coil array. The parameters used for the adaptive combination (ADC) reconstruction of the low signal-to-noise ratio (SNR) dataset have been optimized by finding the maximum mean SNR. A pseudo multiple-replica approach has been used to obtain SNR maps of the combined images. To prove reproducibility of the combination algorithm, the procedure was repeated for several measurements. RESULTS: For low SNR data, sum-of-squares (SOS) reconstruction leads to high background noise and a signal bias in the imaged object. The ADC reconstruction clearly reduces noise in the image and leads to an increase of the mean SNR in the range of 8% to 50%, compared to weighted SOS depending on the absolute SNR of the image. The evaluation of the effects of different noise scans showed that a small number of projections can be used to estimate noise statistics of the coil array without substantially decreasing the resulting SNR. CONCLUSION: (23) Na MRI can be markedly improved by using a 30-channel receive array and ADC reconstruction. The ADC reconstruction showed robust results for all measurements without the need for sensitivity maps.

Spatial Distortion in MRI-Guided Stereotactic Procedures: Evaluation in 1.5-, 3- and 7-Tesla MRI Scanners.

BACKGROUND: Magnetic resonance imaging (MRI) is replacing computed tomography (CT) as the main imaging modality for stereotactic transformations. MRI is prone to spatial distortion artifacts, which can lead to inaccuracy in stereotactic procedures. OBJECTIVE: Modern MRI systems provide distortion correction algorithms that may ameliorate this problem. This study investigates the different options of distortion correction using standard 1.5-, 3- and 7-tesla MRI scanners. METHODS: A phantom was mounted on a stereotactic frame. One CT scan and three MRI scans were performed. At all three field strengths, two 3-dimensional sequences, volumetric interpolated breath-hold examination (VIBE) and magnetization-prepared rapid acquisition with gradient echo, were acquired, and automatic distortion correction was performed. Global stereotactic transformation of all 13 datasets was performed and two stereotactic planning workflows (MRI only vs. CT/MR image fusion) were subsequently analysed. RESULTS: Distortion correction on the 1.5- and 3-tesla scanners caused a considerable reduction in positional error. The effect was more pronounced when using the VIBE sequences. By using co-registration (CT/MR image fusion), even a lower positional error could be obtained. In ultra-high-field (7 T) MR imaging, distortion correction introduced even higher errors. However, the accuracy of non-corrected 7-tesla sequences was comparable to CT/MR image fusion 3-tesla imaging. CONCLUSION: MRI distortion correction algorithms can reduce positional errors by up to 60%. For stereotactic applications of utmost precision, we recommend a co-registration to an additional CT dataset.

Nuclear-Overhauser-enhanced MR imaging of (31)P-containing metabolites: multipoint-Dixon vs. frequency-selective excitation.

The purpose of this study is to develop nuclear-Overhauser-enhanced (NOE) [(1)H]-(31)P magnetic resonance imaging (MRI) based on 3D fully-balanced steady-state free precession (fbSSFP). Therefore, two implementations of a 3D fbSSFP sequence are compared using frequency-selective excitation (FreqSel) and multipoint-Dixon (MP-Dixon). (31)P-containing model solutions and four healthy volunteers were examined at field strengths of B0=3T and 7T. Maps of the distribution of phosphocreatine (PCr), inorganic phosphate (Pi), and adenosine 5´-triphosphate (ATP) in the human calf were obtained with an isotropic resolution of 1.5cm (1.0cm) in an acquisition time of 5min (10min). NOE-pulses had the highest impact on the PCr acquisitions enhancing the signal up to (82 ± 13) % at 3T and up to (37 ± 9) % at 7T. An estimation of the level of PCr in muscle tissue from [(1)H]-(31)P MRI data yielded a mean value of (33 ± 8) mM. In conclusion, direct [(1)H]-(31)P imaging using FreqSel as well as MP-Dixon is possible in clinically feasible acquisition times. FreqSel should be preferred for measurements where only a single metabolite resonance is considered. MP-Dixon performs better in terms of SNR if a larger spectral width is of interest.

Combined acquisition technique (CAT) for neuroimaging of multiple sclerosis at low specific absorption rates (SAR).

PURPOSE: To compare a novel combined acquisition technique (CAT) of turbo-spin-echo (TSE) and echo-planar-imaging (EPI) with conventional TSE. CAT reduces the electromagnetic energy load transmitted for spin excitation. This radiofrequency (RF) burden is limited by the specific absorption rate (SAR) for patient safety. SAR limits restrict high-field MRI applications, in particular. MATERIAL AND METHODS: The study was approved by the local Medical Ethics Committee. Written informed consent was obtained from all participants. T2- and PD-weighted brain images of n = 40 Multiple Sclerosis (MS) patients were acquired by CAT and TSE at 3 Tesla. Lesions were recorded by two blinded, board-certificated neuroradiologists. Diagnostic equivalence of CAT and TSE to detect MS lesions was evaluated along with their SAR, sound pressure level (SPL) and sensations of acoustic noise, heating, vibration and peripheral nerve stimulation. RESULTS: Every MS lesion revealed on TSE was detected by CAT according to both raters (Cohen's kappa of within-rater/across-CAT/TSE lesion detection κCAT = 1.00, at an inter-rater lesion detection agreement of κLES = 0.82). CAT reduced the SAR burden significantly compared to TSE (p<0.001). Mean SAR differences between TSE and CAT were 29.0 (± 5.7) % for the T2-contrast and 32.7 (± 21.9) % for the PD-contrast (expressed as percentages of the effective SAR limit of 3.2 W/kg for head examinations). Average SPL of CAT was no louder than during TSE. Sensations of CAT- vs. TSE-induced heating, noise and scanning vibrations did not differ. CONCLUSION: T2-/PD-CAT is diagnostically equivalent to TSE for MS lesion detection yet substantially reduces the RF exposure. Such SAR reduction facilitates high-field MRI applications at 3 Tesla or above and corresponding protocol standardizations but CAT can also be used to scan faster, at higher resolution or with more slices. According to our data, CAT is no more uncomfortable than TSE scanning.

Grey matter abnormalities within cortico-limbic-striatal circuits in acute and weight-restored anorexia nervosa patients.

Functional disturbances within cortico-striatal control systems have been implicated in the psychobiology (i.e. impaired cognitive-behavioral flexibility, perfectionist personality) of anorexia nervosa. The aim of the present study was to investigate the morphometry of brain regions within cortico-striatal networks in acute anorexia nervosa (AN) as well as long-term weight-restored anorexia nervosa (AN-WR) patients. A total of 39 participants: 12 AN, 13 AN-WR patients, and 14 healthy controls (HC) underwent high-resolution, T1-weighted magnetic resonance imaging (MRI), a cognitive-behavioral flexibility task, and a psychometric assessment. Group differences in local grey matter volume (GMV) were analyzed using whole brain voxel-based morphometry (VBM) and brain-atlas based automatic volumetry computation (IBASPM). Individual differences in total GMV were considered as a covariate in all analyses. In the regional brain morphometry, AN patients, as compared to HC, showed decreased GMVs (VBM and volumetry) in the anterior cingulate cortex (ACC), the supplementary motor area (SMA), and in subcortical regions (amygdala, putamen: VBM only). AN-WR compared to HC showed decreased GMV (VBM and volumetry) in the ACC and SMA, whereas GMV of the subcortical region showed no differences. The findings of the study suggest that structural abnormalities of the ACC and SMA were independent of the disease stage, whereas subcortical limbic-striatal changes were state dependent.

The potential of relaxation-weighted sodium magnetic resonance imaging as demonstrated on brain tumors.

OBJECTIVES: : Total tissue sodium (Na) content is associated with the viability of cells and can be assessed by Na magnetic resonance imaging. However, the resulting total sodium signal (NaT) represents a volume-weighted average of different sodium compartments assigned to the intra- and extracellular space. In addition to the spin-density weighted contrast of NaT imaging, relaxation-weighted (NaR) sequences were applied. The aim of this study was to evaluate the potential of NaR imaging for tissue characterization and putative additional benefits to NaT imaging. MATERIALS AND METHODS: : For NaT and NaR imaging, novel magnetic resonance imaging sequences were established and applied in 16 patients suffering from brain tumors (14 WHO grade I-IV and 2 metastases). All Na sequences were based on density-adapted three-dimensional radial projection reconstruction to obtain short echo times and high signal-to-noise ratio efficiency. RESULTS: : NaT imaging revealed increased signal intensities in 15 of 16 brain tumors before therapy. In addition, NaR imaging enabled further differentiation of these lesions; all glioblastomas demonstrated higher NaR signal intensities as compared with WHO grade I-III tumors. Thus, NaR imaging allowed for correct separation between WHO grade I-III and WHO grade IV gliomas. In contrast to the NaT signal, the NaR signal correlated with the MIB-1 proliferation rate of tumor cells. CONCLUSIONS: : These results serve as a proof of concept that NaR imaging reveals important physiological tissue characteristics different from NaT imaging. Furthermore, they indicate that the combined use of NaT and NaR imaging might add valuable information for the functional in vivo characterization of brain tissue.

An unusual case of optic neuritis.

Optic neuritis is a frequent disease with well established tests and therapeutic strategies. However, possible differential diagnoses cover a broad spectrum. Therefore, clinical work-up can be challenging and routine testing and therapies may not be sufficient. In this case, a 26 year old female is described who presented with clinical features of optic neuritis, yet failed to respond to common therapeutic strategies and lost vision on the affected eye. Diagnostic nerve transection was performed, histopathology suggested inflammation. As the second nerve became affected, immunosuppressive therapy with cyclophosphamide was started and stopped further deterioration. Although additional molecular work-up of the transected nerve revealed clonal rearrangement of the B-cell-receptor-locus IgH, overall histopathologic features and the absence of systemic disease suggested an aggressive inflammatory process rather than lymphoma. Additional B-cell depletion with rituximab prompted significant and sustained visual improvement. This case emphasizes the necessity to consider rare differential diagnoses of optic neuritis, when uncommon features arise during the course of disease. Aggressive immunosuppression might be required to achieve stable improvement of vision.

Functional role of ipsilateral motor areas in multiple sclerosis.

BACKGROUND: In patients with multiple sclerosis (MS), motor tasks are associated with increased activation of ipsilateral motor cortical areas. The authors examined the role of two ipsilateral motor areas during performance of a simple motor task in MS patients in relation to their motor impairment and CNS injury. METHODS: Single pulses of transcranial magnetic stimulation (TMS) were used to interfere transiently with neuronal processing in the contralateral (M1(CONTRA)) or ipsilateral (M1(IPSI)) primary motor cortex or ipsilateral dorsal premotor cortex (PMd(IPSI)) during a simple reaction time (RT) task in 26 right-handed patients with moderately severe stable MS and matched healthy controls. Subjects responded to an auditorily presented Go signal as quickly as possible by performing isometric right-thumb abductions. TMS was applied 100 ms after the Go signal. Motor impairment was evaluated by hand function tests. CNS injury was assessed by magnetic resonance spectroscopy (normalised N-acetyl-aspartate spectra, NAA/Cr), by the total cerebral T2-weighted MRI hyperintense lesion load, and by corticomuscular latency (CML) to the abductor pollicis brevis muscle. RESULTS: TMS applied to M1(CONTRA) slowed RT in patients and controls. In contrast, stimulation of M1(IPSI) or PMd(IPSI) increased RT only in MS patients. In patients, the relative RT changes following TMS over M1(IPSI) or PMd(IPSI) did not correlate with any of the motor function tests or with NAA/Cr or total cerebral lesion load. However, RT changes following TMS over M1(IPSI) correlated inversely with CML. CONCLUSIONS: Recruitment of ipsilateral motor areas may be a functionally relevant, yet limited adaptive response to chronic brain injury in MS patients.

Neural correlates of reward processing in schizophrenia--relationship to apathy and depression.

The present study employs a new framework to categorise the heterogeneous findings on the relationship between impaired reward processing and negative and affective symptoms of schizophrenia. Based on previous behavioural and neuroimaging studies we postulate that "wanting" (i.e. anticipation) of a reward is specifically related to apathy, whereas "liking" (i.e. hedonic impact) is related to anhedonia and depression--symptoms commonly observed in schizophrenia. Fifteen patients with schizophrenia or schizoaffective disorder treated with atypical antipsychotic drugs and fifteen healthy controls performed a probabilistic monetary incentive delay task while undergoing functional magnetic resonance imaging. At the group level we found no significant differences between patients and controls in neural activation during anticipation or receipt of a reward. However, in patients with schizophrenia specific relationships between ventral-striatal activation and symptoms were observed. Ventral-striatal activation during reward anticipation was negatively correlated with apathy, while activation during receipt of reward was negatively correlated with severity of depressive symptoms. These results suggest that the link between negative symptoms and reward anticipation might specifically relate to apathy, i.e. a lack of motivation and drive. Impaired hedonic reward processing might contribute to the development of depressive symptoms in patients with schizophrenia, but it is not directly associated with self-rated anhedonia. These results indicate the necessity of more specifically differentiating negative and affective symptoms in schizophrenia in order to understand the role of the reward system in their pathogenesis.

The effect of ethanol on human brain metabolites longitudinally characterized by proton MR spectroscopy.

The effect ethanol exerts on the human brain has not yet been addressed by longitudinal magnetic resonance (MR) spectroscopic experiments. Therefore, we longitudinally characterized cerebral metabolite changes in 15 healthy individuals by proton magnetic resonance spectroscopy ((1)H-MRS) subsequent to the ingestion of a standard beverage (mean peak blood alcohol concentration (BAC): 51.43 +/- 10.27 mg/dL). Each participant was examined before, over 93.71 +/- 11.17 mins immediately after and 726.36 +/- 94.96 mins (12.11 +/ -1.58 h) past per os alcohol exposure. Fronto-mesial and cerebellar ethanol concentrations over time were similar as determined by the LCModel analysis of spectral data. Alcohol-induced changes of fronto-mesial creatine, choline, glucose, inositol and aspartate levels at 5.79 +/- 2.94 [corrected] mins upon ingestion as well as cerebellar choline and inositol levels at 8.64 +/- 2.98 [corrected] mins past exposure. Closely associated with ethanol concentrations, supratentorial creatine, choline, inositol and aspartate levels decreased after ethanol administration, whereas glucose levels increased. Similarly, infratentorial choline and inositol concentrations were negatively correlated with ethanol levels over time. There were no changes in N-acetyl-aspartate levels upon alcohol exposure. Furthermore, no influence of ethanol on brain water integrals was detected. Ethanol consumption may directly increase oxidative stress and the neuronal vulnerability to it. In addition, our results are compatible with ethanol-induced cell membrane modifications and alternative energy substrate usage upon alcohol exposure.

Scanning for the scanner: FMRI of audition by read-out omissions from echo-planar imaging.

Echo-planar imaging (EPI) generates considerable acoustic noise by rapidly oscillating gradients. In functional magnetic resonance imaging (FMRI), unshielded EPI sounds activate the auditory system inasmuch as it is responsive. Instead of attenuating EPI noise, our goal was to utilize it for auditory FMRI by omitting read-outs from the pulse sequence's gradient train. Read-out gradient pulses are the primary noise determinant of EPI introducing its peak sound level and fundamental frequency peak which inversely relates to twice the echo spacing. Using model-driven analyses, we demonstrate that withholding read-outs from EPI is suited to reliably evoke hemodynamic blood oxygenation level-dependent (BOLD) signal modulations bilaterally in the auditory cortex of normal hearing subjects (n=60). To investigate the utility of EPI read-out omissions for auditory FMRI at an individual subject's level, we compare traditional Family-Wise-Error-Rate (FWER)-corrected maximum height thresholding to spatial mixture modeling (SMM). With the latter, appropriate bilateral auditory activations were confirmed in 95% of the individuals, whereas FWER-based voxel thresholding detected such activations in up to 72%. We illustrate the applicability of this novel EPI modification for clinical diagnostic purposes and report on a patient with bilateral large vestibular aqueducts (LVAs) and severe binaural sensorineural hearing loss (SNHL). In this particular case, read-out omissions from EPI were used to assert residual audition prior to cochlear implantation (CI). Requiring no specific task compliance or sophisticated stimulation equipment other than the scanner on its own, FMRI by read-out omissions lends itself to auditory investigations and to quickly probe audition.