Singlet-Contrast Magnetic Resonance Imaging: Unlocking Hyperpolarization with Metabolism*.

Hyperpolarization-enhanced magnetic resonance imaging can be used to study biomolecular processes in the body, but typically requires nuclei such as 13 C, 15 N, or 129 Xe due to their long spin-polarization lifetimes and the absence of a proton-background signal from water and fat in the images. Here we present a novel type of 1 H imaging, in which hyperpolarized spin order is locked in a nonmagnetic long-lived correlated (singlet) state, and is only liberated for imaging by a specific biochemical reaction. In this work we produce hyperpolarized fumarate via chemical reaction of a precursor molecule with para-enriched hydrogen gas, and the proton singlet order in fumarate is released as antiphase NMR signals by enzymatic conversion to malate in D2 O. Using this model system we show two pulse sequences to rephase the NMR signals for imaging and suppress the background signals from water. The hyperpolarization-enhanced 1 H-imaging modality presented here can allow for hyperpolarized imaging without the need for low-abundance, low-sensitivity heteronuclei.

Paroxysmal atrial fibrillation with high vs. low arrhythmia burden: atrial remodelling and ablation outcome.

AIMS: The relation between atrial tachyarrhythmia (ATA) burden in paroxysmal atrial fibrillation (AF), atrial remodelling, and efficacy of catheter ablation (CA) is unknown. We investigated whether high vs. low-burden paroxysmal AF patients have distinct clinical characteristics or electro-mechanical properties of the left atrium (LA) and whether burden impacts outcome of CA. METHODS AND RESULTS: Atrial tachyarrhythmia burden, defined as the percentage of time spent in ATA, was assessed by insertable cardiac monitors in 105 patients before and after CA. Clinical characteristics and electro-mechanical properties of LA were compared between patients with high vs. low ATA burden. Catheter ablation efficacy was assessed by reduction in ATA burden and 1-year freedom from any ATA. Median ATA burden was 2.7% (highest tertile 9.3%). Clinical characteristics and electrical properties of LA (refractoriness, conduction velocity, low voltage) did not differ between high (≥9.3%) vs. low ATA burden (<9.3%) patients. High ATA burden patients had larger LA diameter (46.5 ± 6 vs. 42.5 ± 6mm, P < 0.01), volume (93.8 ± 22 vs. 80.4 ± 21mL, P = 0.01), and lower LA reservoir and contractile strain (19.7 ± 6 vs. 24.7 ± 6%, P < 0.01; 10.3 ± 3 vs. 12.8 ± 4%, P = 0.01). Catheter ablation reduced ATA burden by 100% (100-100) in both groups (P = 1.0). Freedom from ATA after CA was equally high (83% vs. 89%, P = 0.38). CONCLUSION: Paroxysmal AF patients with high ATA burden have altered LA mechanical properties, reflected by larger size and impaired function. Despite mechanical remodelling of the atria, they are excellent responders to CA. Most likely the lack of fibrosis and/or advanced electrical remodelling explain why pulmonary veins remain the dominant trigger for AF in this patient cohort.

[Second look: practical diagnostic and therapeutic checks in neurorehabilitation]. / Der zweite Blick: praktische diagnostische und therapeutische Checks in der rehabilitativen Neurologie.

Post-acute inpatient neurorehabilitation facilities are increasingly treating patients who are not only severely ill and multimorbid but who are also referred from non-neurological departments. These patients are still often medically unstable so that the previous diagnostics and treatment must be reevaluated and when necessary adapted or supplemented. Certain interdisciplinary diagnostic and therapeutic problems, such as antithrombotic therapy, regularly reoccur. This article presents these problems in a checklist fashion, which should provide indications in individual cases when previously carried out measures need to be questioned and adapted.

Caloric restriction improves memory in elderly humans.

Animal studies suggest that diets low in calories and rich in unsaturated fatty acids (UFA) are beneficial for cognitive function in age. Here, we tested in a prospective interventional design whether the same effects can be induced in humans. Fifty healthy, normal- to overweight elderly subjects (29 females, mean age 60.5 years, mean body mass index 28 kg/m(2)) were stratified into 3 groups: (i) caloric restriction (30% reduction), (ii) relative increased intake of UFAs (20% increase, unchanged total fat), and (iii) control. Before and after 3 months of intervention, memory performance was assessed under standardized conditions. We found a significant increase in verbal memory scores after caloric restriction (mean increase 20%; P < 0.001), which was correlated with decreases in fasting plasma levels of insulin and high sensitive C-reactive protein, most pronounced in subjects with best adherence to the diet (all r values < -0.8; all P values <0.05). Levels of brain-derived neurotrophic factor remained unchanged. No significant memory changes were observed in the other 2 groups. This interventional trial demonstrates beneficial effects of caloric restriction on memory performance in healthy elderly subjects. Mechanisms underlying this improvement might include higher synaptic plasticity and stimulation of neurofacilitatory pathways in the brain because of improved insulin sensitivity and reduced inflammatory activity. Our study may help to generate novel prevention strategies to maintain cognitive functions into old age.

Zero field splitting of the chalcogen diatomics using relativistic correlated wave-function methods.

The spectrum arising from the (π*)(2) configuration of the chalcogen dimers, namely, the X(2)1, a2, and b0(+) states, is calculated using wave-function theory based methods. Two-component (2c) and four-component (4c) multireference configuration interaction (MRCI) and Fock-space coupled cluster (FSCC) methods are used as well as two-step methods spin-orbit complete active space perturbation theory at 2nd order (SO-CASPT2) and spin-orbit difference dedicated configuration interaction (SO-DDCI). The energy of the X(2)1 state corresponds to the zero-field splitting of the ground state spin triplet. It is described with high accuracy by the 2- and 4-component methods in comparison with experiment, whereas the two-step methods give about 80% of the experimental values. The b0(+) state is well described by 4c-MRCI, SO-CASPT2, and SO-DDCI, but FSCC fails to describe this state and an intermediate Hamiltonian FSCC ansatz is required. The results are readily rationalized by a two-parameter model; Δε, the π* spinor splitting by spin-orbit coupling and K, the exchange integral between the π(1)* and the π(-1)* spinors with, respectively, angular momenta 1 and -1. This model holds for all systems under study with the exception of Po(2).

Bilateral occipital lobe infarct neglect deficit (BLIND) syndrome.

Cortical blindness is characterized by loss of vision due to dysfunction of the visual cortices, most commonly secondary to bilateral ischemic infarcts of the occipital lobe. Other causes include surgery such as aortic valve replacement, laryngeal surgery, craniotomy, cerebral angiography, head trauma, and partial seizures. Visual anosognosia is a distinct feature of cortical blindness, wherein patients claim they can see and confabulate visual perceptions, despite loss of sight. We herewith present a rare phenomenon known as Anton Syndrome, an eponym named after the Austrian neurologist and psychiatrist, Gabriel Anton (1858-1933). There are a limited number of cases of Anton's Syndrome in the literature, with only 28 case reports published from 1965-2016. Although he was bestowed a neurologic eponym, Anton was an advocate of eugenics and racial hygiene. He publicly advocated for 'superior breeding' and 'selection' in order to 'build a brave and noble race.' We therefore propose replacing the eponym with Bilateral Occipital Lobe Infarct Neglect Deficit (BLIND) Syndrome, with intention of raising awareness of this unique presentation as well as of the widespread interest in eugenics in the early 1900s amongst physicians, notably Gabriel Anton.

Physical activity and memory functions: are neurotrophins and cerebral gray matter volume the missing link?

Epidemiological studies reveal better cognitive function in physically active individuals. Possible mediators for this effect are neurotrophins, which are up-regulated through physical exercise and induce neuronal growth and synaptogenesis in the animal model. Here we cross-sectionally assessed 75 healthy older individuals for levels of physical activity, aerobic fitness, and memory encoding, as well as neurotrophin levels and cerebral gray matter volume. We found that physical activity, but not cardiovascular fitness, was associated with better memory encoding after controlling for age, sex, education, depression, alcohol consumption, and smoking. Higher levels of physical activity were associated with higher levels of the neurotrophin granulocyte colony stimulating factor (G-CSF) and increased cerebral gray matter volume in prefrontal and cingulate cortex as assessed by magnetic resonance voxel-based morphometry. While mediating factors will need to be further elucidated, these findings indicate that even low-level physical activity exerts beneficial effects on memory functions in older individuals.

Pattern and progression of white-matter changes in a case of posterior cortical atrophy using diffusion tensor imaging.

BACKGROUND: The progression of white-matter changes in a case of posterior cortical atrophy (PCA) was examined over a period of 15 months using diffusion tensor imaging (DTI) and the association with neuropsychological variables was studied. PATIENT AND METHODS: A PCA patient was observed over a period of 15 months. DTI and volumetric magnetic resonance imaging were obtained at visit 1 and 15 months later. Fractional anisotropy (FA) and volumetric changes were compared with findings in a typical case of Alzheimer disease (AD) and in 65 healthy volunteers, and the association of neuropsychological deficits with these changes was studied. RESULTS: Reduction in FA was focused on the occipital lobe in the early stages of PCA. During the 15-month period, the FA values of the PCA patient tended to align with the FA ratios of the AD patient, with a more pronounced FA reduction in the parietal lobes, as opposed to a stable FA level in the occipital lobe. In addition to the DTI changes, clinical and neuropsychological symptoms deteriorated further. Brain volumes (grey matter, white matter and total normalised brain volume) of the PCA patient were substantially decreased compared with the control group, but loss of tissue volumes showed only marginal progression between visit 1 and 2. CONCLUSIONS: The findings suggest that PCA starts as distinct clinical syndrome but in its later course might turn into a final pathway shared with AD. DTI might be helpful in detecting changes in cerebral white matter during disease progression in PCA patients.

[Intense language training for aphasia. Contribution of cognitive factors]. / Intensives Sprachtraining bei Aphasie. Einfluss kognitiver Faktoren.

The best predictor of successful language therapy after stroke is a high intensity of treatment (with 5-10 h training per week). However, the necessity of several hours of language exercises each day draws considerably on attentional and cognitive resources of the patients. Thus, not all aphasic patients may be equally suited for intense training approaches. In the present review non-verbal cognitive deficits that often accompany a stroke-induced aphasia are described. Furthermore, initial empirical data on cognitive functions, which predict the success of therapy (intense) after stroke, are summarized. Patients in the acute stage benefit most from intense aphasia treatment, when long-term memory consolidation is relatively preserved. For the chronic stage, indirect evidence suggests that premorbid intelligence as well as attentional functions have positive effects on the success of intense therapy. An empirically based allocation of patients to intense aphasia treatment awaits the results of multicenter trials with sufficiently large sample sizes.

Degree of language lateralization determines susceptibility to unilateral brain lesions.

Language is considered a function of either the left or, in exceptional cases, the right side of the brain. Functional imaging studies show, however, that in the general population a graded continuum from left hemispheric to right hemispheric language lateralization exists. To determine the functional relevance of lateralization differences, we suppressed language regions using transcranial magnetic stimulation (TMS) in healthy human subjects who differed in lateralization of language-related brain activation. Language disruption correlated with both the degree and side of lateralization. Subjects with weak lateralization (more bilaterality) were less affected by either left- or right-side TMS than were subjects with strong lateralization to one hemisphere. Thus in some people, language processing seems to be distributed evenly between the hemispheres, allowing for ready compensation after a unilateral lesion.

Efficacy of advanced pace-mapping technology for idiopathic premature ventricular complexes ablation.

PURPOSE: Catheter ablation is an effective treatment for premature ventricular complexes (PVCs). Activation mapping is accurate but requires PVCs at the time of the ablation. Pace-mapping correlation (PMC) is a supplemental tool recently developed as an integrated module for an electro-anatomical mapping platform. Our study sought to investigate whether pace-mapping technology provides similar ablation results in patients with low versus high idiopathic PVC burden at the time of ablation and the relationship between sites with the highest PMC and the earliest local activation time (LAT). METHODS: A total of 59 consecutive patients undergoing catheter ablation for idiopathic PVCs were enrolled. Twelve out of 59 patients (20%) were classified in the low PVC burden group (defined as < 2 PVCs/min) and 47/59 (80%) in the high PVC burden group. RESULTS: The most common origin of PVCs was the right ventricular outflow tract (RVOT) followed by aortic cusps, coronary sinus, parahisian region, and aorto-mitral continuity. Procedural and 1-month success rate were 95 and 87% respectively. PVC burden at the time of ablation did not influence the success rate. The median distance between the earliest LAT points and the highest PMC points was 6.4 (4.9-10.6) mm. CONCLUSIONS: Pace-mapping correlation is useful and accurate in localizing the origin of idiopathic PVCs irrespective of the initial PVC burden. It provides optimal ablation results when combined with LAT. Success rate at mid-term follow-up is higher when the origin of PVCs is located in the RVOT as compared to other locations.

Molecular characterization of a novel, widespread nuclear protein that colocalizes with spliceosome components.

We report the identification and molecular characterization of a novel type of constitutive nuclear protein that is present in diverse vertebrate species, from Xenopus laevis to human. The cDNA-deduced amino acid sequence of the Xenopus protein defines a polypeptide of a calculated mass of 146.2 kDa and a isoelectric point of 6.8, with a conspicuous domain enriched in the dipeptide TP (threonine-proline) near its amino terminus. Immunolocalization studies in cultured cells and tissues sections of different origin revealed an exclusive nuclear localization of the protein. The protein is diffusely distributed in the nucleoplasm but concentrated in nuclear speckles, which represent a subnuclear compartment enriched in small nuclear ribonucleoprotein particles and other splicing factors, as confirmed by colocalization with certain splicing factors and Sm proteins. During mitosis, when transcription and splicing are downregulated, the protein is released from the nuclear speckles and transiently dispersed throughout the cytoplasm. Biochemical experiments have shown that the protein is recovered in a approximately 12S complex, and gel filtration studies confirm that the protein is part of a large particle. Immunoprecipitation and Western blot analysis of chromatographic fractions enriched in human U2 small nuclear ribonucleoprotein particles of distinct sizes (12S, 15S, and 17S), reflecting their variable association with splicing factors SF3a and SF3b, strongly suggests that the 146-kDa protein reported here is a constituent of the SF3b complex.

Liquid-state carbon-13 hyperpolarization generated in an MRI system for fast imaging.

Hyperpolarized (HP) tracers dramatically increase the sensitivity of magnetic resonance imaging (MRI) to monitor metabolism non-invasively and in vivo. Their production, however, requires an extra polarizing device (polarizer) whose complexity, operation and cost can exceed that of an MRI system itself. Furthermore, the lifetime of HP tracers is short and some of the enhancement is lost during transfer to the application site. Here, we present the production of HP tracers in water without an external polarizer: by Synthesis Amid the Magnet Bore, A Dramatically Enhanced Nuclear Alignment (SAMBADENA) is achieved within seconds, corresponding to a hyperpolarization of ∼20%. As transfer of the tracer is no longer required, SAMBADENA may permit a higher polarization at the time of detection at a fraction of the cost and complexity of external polarizers. This development is particularly promising in light of the recently extended portfolio of biomedically relevant para-hydrogen-tracers and may lead to new diagnostic applications.

A benefit-cost framework of motivation for a specific activity.

How can an individual be motivated to perform a target exercise or activity? This question arises in training, therapeutic, and education settings alike, yet despite-or even because of-the large range of extant motivation theories, finding a clear answer to this question can be challenging. Here we propose an application-friendly framework of motivation for a specific activity or exercise that incorporates core concepts from several well-regarded psychological and economic theories of motivation. The key assumption of this framework is that motivation for performing a given activity is determined by the expected benefits and the expected costs of (performance of) the activity. Benefits comprise positive feelings, gains, and rewards experienced during performance of the activity (intrinsic benefits) or achieved through the activity (extrinsic benefits). Costs entail effort requirements, time demands, and other expenditure (intrinsic costs) as well as unwanted associated outcomes and missing out on alternative activities (extrinsic costs). The expected benefits and costs of a given exercise are subjective and state dependent. We discuss convergence of the proposed framework with a selection of extant motivation theories and briefly outline neurobiological correlates of its main components and assumptions. One particular strength of our framework is that it allows to specify five pathways to increasing motivation for a target exercise, which we illustrate and discuss with reference to previous empirical data.

Changing health behavior motivation from I-must to I-want.

In the past, medicine was dominated by acute diseases. Since treatments were unknown to patients they followed their medical doctors´ directives-at least for the duration of the disease. Behavior was thus largely motivated by avoiding expected costs associated with alternative behaviors (I-must). The health challenges prevailing today are chronic conditions resulting from the way we chose to live. Traditional directive communication has not been successful in eliciting and maintaining appropriate lifestyle changes. An approach successful in other fields is to motivate behavior by increasing expected rewards (I-want). Drawing on neuroeconomic and marketing research, we outline strategies including simplification, repeated exposure, default framing, social comparisons, and consumer friendliness to foster sustained changes in preference. We further show how these measures could be integrated into the health care system.

Motivation: What have we learned and what is still missing?

This final chapter deliberates three overarching topics and conclusions of the research presented in this volume: the endurance of the concept of extrinsic vs intrinsic motivation, the importance of considering subjective costs of activities when aiming to understand and enhance motivation, and current knowledge of the neurobiological underpinnings of motivation. Furthermore, three topics for future motivation research are outlined, namely the assessment and determinants of intrinsic benefits, the reconciliation of activity-specific motivation models with generalized motivation impairments in clinical populations, and the motivational dynamics of groups.

Increasing self-directed training in neurorehabilitation patients through competition.

This proof-of-concept study aimed to test whether competition could be a useful tool to increase intensity and amount of self-directed training in neurorehabilitation. Stroke patients undergoing inpatient neurorehabilitation (n=93) conducted self-directed endurance training on a (wheelchair-compatible) bicycle trainer under three experimental conditions: a "Competition" condition and two noncompetition control conditions (repeated randomized within-subject design). Training performance and perceived exertion were recorded and statistically analyzed. Three motivational effects of competition were found. First, competition led to an increase in self-directed training. Patients exercised significantly more intensively under competition than in the two noncompetition control conditions. Second, (winning a) competition had a positive influence on performance in the subsequent training session. Third, training performance was particularly high during rematch competitions; that is to say, during second encounter competitions against an opponent that the patient had just beaten. No systematic effect of competition upon perceived exertion (controlled for training performance) was found. Together, our results demonstrate that competition is a potent motivational tool to increase self-directed training in neurorehabilitation.

Hemispheric lateralization of spatial attention in right- and left-hemispheric language dominance.

Hemispheric lateralization of the neural systems supporting language and spatial attention most commonly dissociate in healthy individuals. However, the reverse pattern with association of language and attention within the right hemispheres has also been observed. We investigated in 75 healthy volunteers (37 right-handed, 38 left-handed) if language and spatial attention may associate not only in individuals with an atypical pattern of language lateralization, but also in subjects showing the standard, i.e. left-hemispheric dominance for language. Hemispheric lateralization of cerebral perfusion was determined with functional transcranial Doppler ultrasonography during a visuospatial attention, and a word generation task. We found that language and visuospatial attention associated within the left hemisphere in five subjects and within the right hemisphere in eight subjects. We conclude that all combinations of cerebral lateralization for language and attention may exist in the healthy brain.