Search

ObjectiveQuantitative magnetic resonance imaging was used to determine partition coefficients and characteristic time constants for diffusion of MRI contrast agents in disc tissue.Materials and methodsTwenty-two excised equine intervertebral discs were exposed to a range of contrast agents: six to manganese chloride, eight to Magnevist (gadopentetate dimeglumine) and eight to Gadovist (gadobutrol), and uptake into the disc was quantified inT1-weighted images.ResultsDiffusion for all contrast agents was approximately 25% faster in the nucleus than in the outer annulus; disc-average time constants ranged from (2.28 ± 0.23) × 104 s for Gadovist (uncharged, molecular mass 605 g/mol) to (5.07 ± 0.75) × 104 s for the manganese cation (charge + 2). Disc-average partition coefficients ranged from 0.77 ± 0.04 for the anion in Magnevist (charge − 2, molecular mass 548 g/mol) to 5.14 ± 0.43 for the manganese cation.ConclusionThe MRI technique provides high-quality quantitative data which correspond well to theoretical predictions, allowing values for partition coefficient and time constant to be readily determined. These measurements provide information to underpin similar studies in vivo and may be used as a model for the transport of nutrients and pharmaceutical agents in the disc.

Previous neuroimaging studies of scenarios such as the prisoner’s dilemma and ultimatum game show how brain systems which evolved to process rewarding and aversive stimuli are activated differentially during adherence to and breaches of norms. One theory of how shared social norms evolve is that they arise from mutually rewarding conventions which, through repeated execution, acquire a normative value that sustains social cohesion even when individual self-interest is not served. The authors report an fMRI study of a 2-player coordination game in which players must coordinate on an arbitrary convention (a left or right button press) to obtain monetary rewards. Once this convention has been established, one of the participants is incentivized to deviate from the equilibrium with the offer of extra reward. During the period prior to decisions to violate the convention, activity was observed in regions associated with reward processing, such as the midbrain, caudate, and orbitofrontal cortex. Activations in advance of decisions to continue coordinating included the amygdala and anterior insula–inferior frontal gyrus. The data are discussed in the light of theories which propose the existence of multiple interacting value-based decision-making systems in the human brain.

We report a functional magnetic resonance imaging (fMRI) study which investigated whether brain areas involved in updating task rules within the frontal lobe of the cerebral cortex show activity related to the modality of motor response used in the task. Participants performed a rule switching task using different effector modalities. In some blocks participants responded with left/right button presses, whilst in other blocks left/right saccades were required. The color of a Cue event instructed a left or right response based upon a rule, followed by a Feedback which indicated whether the rule was to stay the same or "Flip" on the next trial. The findings revealed variation in the locus of activity within the ventrolateral frontal cortex dependent upon effector modality. Other frontal areas showed no significant difference in activity between response epochs but changed their pattern of connectivity with posterior cortical areas dependent upon response. Multivariate analysis revealed that the pattern of activity evoked by Flip rule Feedbacks within an apparently supra modal frontal region (dorsolateral frontal cortex) discriminated between response epochs. The results are consistent with the existence of multi-modal representations of stimulus-response (SR) rules within the frontal cerebral cortex.

This paper describes an evaluation of a simple electronic simulation of sensorineural hearing loss intended to raise the awareness of mainstream trainee teachers during role play as both teacher and hearing-impaired pupil. In the wake of the continuing commitment to integration, it is hoped that such a device can improve the preparation of mainstream trainee teachers for their role as teachers of the hearing impaired. Twenty-four trainee teachers experienced both roles during the simulation, and their comments were scored by an expert panel for their importance. It was found that participants achieved a significant increase in awareness during their two five-minute simulated experiences of being a hearing pupil and teaching a hearing-impaired pupil. The experience of learning as a pupil with a simulated impairment was demonstrated to be as valuable as teaching a pupil with a simulated impairment, although there were differences with respect to the types of issues highlighted.

Cardiac arrest is a major cause of unexpected sudden death in adults. In the majority of cases an arrhythmia is the primary cause. A multitude of agents have been used in the treatment of ventricular fibrillation and asystole during cardiac arrest. At present there is no evidence to indicate that any of these agents ultimately improve the final outcome in humans. Prevention, competent basic life support and rapid defibrillation for patients in ventricular fibrillation remain the mainstays of treatment for cardiac arrest.

The design of a radiofrequency coil of U-shaped geometry, specifically intended to image individual knuckle joints of the hand, has been investigated. The coil geometry is that of a "split and opened" birdcage coil. The optimum leg positions for such a U-shaped coil have been theoretically predicted using a novel technique that considers both the signal-to-noise ratio and the homogeneity of the field-of-view. Two particular coils of this type have been constructed, each optimum for a different size of image space and assuming a different source of image noise (sample-dominated or coil-dominated). The experimentally determined radiofrequency fields produced by the coils correspond well to theory. Either coil can be used to obtain good-quality, high-resolution (130 microns x 130 microns in-plane) images in vivo of the first, second, or fifth metacarpophalangeal joints of the hand, sites of particular interest in the study of arthritis.

To the Editor: Functional MRI (fMRI) using a blood oxygen level dependent (BOLD) sequence provides a tool to measure the effects of alterations in blood glucose on the patterns and magnitudes of neuronal activation in the human brain [1]. Previous experiments using a glucose load have suggested that it is possible in humans to identify changes in the BOLD signal from areas within the hypothalamus [2–6]; however, the results have been contradictory. This study involved seven healthy participants aged 27– 38 years (three female, four male; mean±SD BMI 23.6± 1.3 kg/m), who gave informed consent. The study was approved by the local research ethics committee. Each participant attended for two studies in random order: one involving ingestion of a glucose load and the other water. After anatomical scans and a 5 min baseline period of fMRI acquisition, participants were either given 75 g glucose diluted with 200 ml water or the same volume of water only. fMRI acquisition continued for a further 25 min after the start of drinking. Blood samples for measurement of plasma glucose were taken 5 min before the start of drinking and 25 min after the start of drinking. There was no difference in mean glucose levels between conditions at baseline, but significantly higher values in the glucose arm at the end of the study (4.41±0.31 mmol/l for the water arm vs 5.36± 0.28 mmol/l for the glucose arm, p00.001). With the use of a six-channel head coil at 1.5 T, fMRI variables were: repetition time04 s (three-shot echo planar imaging, volume acquisition in 12 s); echo time045 ms; 50 sagittal slices; 2 mm slice thickness; 0.2 mm interslice gap; 2×2 mm in-plane resolution. The 30 min fMRI measurement produced a sequence of 150 volume acquisitions, which were aligned to the 80th volume using SPM5 software (Wellcome Trust Centre for Neuroimaging, London, UK). The position of the hypothalamus was identified on a near-midline sagittal slice of the 80th fMRI volume acquisition on the basis of landmarks: the anterior commissure (AC), the optic chiasm (OC) and the mammillary body (MM). The MarsBaR toolbox for SPM5 (available from http://marsbar.sourceforge.net/) was used to specify the overall region of interest (ROI)—a parallelogram with three D. E. Flanagan (*) :B. Krishnan :A. Watt Department of Endocrinology, Level 9, Derriford Hospital, Plymouth PL6 8DH, UK e-mail: danielflanagan@nhs.net

Using a 100-element tactile stimulator on the fingertip during functional-magnetic-resonance imaging, brain areas were identified that were selectively activated by a moving vibrotactile stimulus (the sensation of a moving line being dragged over the fingertip). Activation patterns elicited by tactile motion, contrasted to an equivalent stationary stimulus, were compared in six human subjects with those generated by a moving visual stimulus, contrasted to an equivalent stationary stimulus. Results provide further evidence for a neuroanatomical convergence of tactile-motion processing and visual-motion processing in humans. The sites of this convergence are found to lie in the middle temporal complex (hMT+V5), an area with known specialization for visual-motion processing, and in the intraparietal area of the posterior parietal cortex. In an advance on previous studies, the present study includes separate delineation of activations for moving tactile stimuli and activations for moving visual stimuli. Results suggest that the two sets of activations are not entirely collocated. Compared to the visual-motion activations, the tactile-motion activations are found to lie nearer the midline of the brain and further superior.

This study investigates the discrimination of small changes of interval size in short sequences of musical tones. Major, minor and neutral thirds were varied in increments of 15 cents. The nine subjects had varying degrees of amateur musical experience-their level of musical training was lower than that of professional musicians. In some experiments the stimuli were presented purely melodically and in others they were presented together with a sustained tone at a higher pitch. Some subjects were able to make use of the additional cues from beats in the latter case. Category widths for identification were measured at around 70 cents and just-noticeable differences in frequency were measured at around 10 cents. Little significant variation of inter-stimulus sensitivity index d' was observed across the stimulus sets, i.e., there was little evidence for "anchors" or "landmarks" within the range of tunings employed. However, for major thirds, discrimination of the 15 cent increment between 400 and 415 cents was reduced compared to discrimination of other 15 cent increments within the stimulus sets.

Many complex tasks require us to flexibly switch between behavioral rules, associations, and strategies. The prefrontal cerebral cortex is thought to be critical to the performance of such behaviors, although the relative contribution of different components of this structure and associated subcortical regions are not fully understood. We used functional magnetic resonance imaging to measure brain activity during a simple task which required repeated reversals of a rule linking a colored cue and a left/right motor response. Each trial comprised three discrete events separated by variable delay periods. A colored cue instructed which response was to be executed, followed by a go signal which told the subject to execute the response and a feedback instruction which indicated whether to “hold” or “flip” the rule linking the colored cue and response. The design allowed us to determine which brain regions were recruited by the specific demands of preparing a rule contingent motor response, executing such a response, evaluating the significance of the feedback, and reconfiguring stimulus-response (SR) associations. The results indicate that an increase in neural activity occurs within the anterior cingulate gyrus under conditions in which SR associations are labile. In contrast, lateral frontal regions are activated by unlikely/unexpected perceptual events regardless of their significance for behavior. A network of subcortical structures, including the mediodorsal nucleus of the thalamus and striatum were the only regions showing activity that was exclusively correlated with the neurocognitive demands of reversing SR associations. We conclude that lateral frontal regions act to evaluate the behavioral significance of perceptual events, whereas medial frontal-thalamic circuits are involved in monitoring and reconfiguring SR associations when necessary.

Two experiments on the discrimination of time-varying tactile stimuli were performed, with comparison of stimulus delivery to the distal pad of the right index finger and to the right wrist (palmar surface). Subjects were required to perceive differences in short sequences of computer-generated stimulus elements (experiment 1) or differences in short tactile stimuli derived from a speech signal (experiment 2). The pulse-train stimuli were distinguished by differences in frequency (i.e., pulse repetition rate) and amplitude, and by the presence/absence of gaps (approximately 100-ms duration). Stimulation levels were 10 dB higher at the wrist than at the fingertip, to compensate for the lower vibration sensitivity at the wrist. Results indicate similar gap detection at wrist and fingertip and similar perception of frequency differences. However, perception of amplitude differences was found to be better at the wrist than at the fingertip. Maximum information transfer rates for the stimuli in experiment 1 were estimated at 7 bits s(-1) at the wrist and 5 bits s(-1) at the fingertip.

This study investigates the relation between objective and subjective parameters which relate to the quality of magnetic-resonance images, with a view to developing procedures for minimizing imaging time. The investigation uses high-resolution images of the thumb as example. Detection thresholds for an artificial lesion and ratings of image quality were obtained for a variety of images, with several experienced observers. In addition, the information content was calculated for each image, using the method developed by Fuderer (1988 IEEE Tralns. Med. Imaging 7 368-80). Results suggest that information content can be used as a predictor of either detection threshold or quality rating, with a critical information content beyond which there is no significant improvement in either of these aspects of image quality. Since it is possible to estimate the effect of imaging variables on information content, it is possible to predict the effect of time-saving imaging strategies on image quality. A procedure is suggested for determining the combination of imaging variables which gives the shortest possible imaging time whilst retaining image quality.

Knowledge of the state of tissue hydration in patients suffering from peripheral vascular disease and neuropathy as a result of diabetes is important in their treatment. Further, because magnetic resonance imaging (MRI) is uniquely able to generate information about soft tissues and their water content, it is ideal for studying disorders of this kind. The feet and hands, often affected in diabetes, are ideal for studying fundamental aspects of the disease state and the response of patients to treatment. In this preliminary study, two related areas are reported: the measurement of diffusion coefficients in the finger and the visualization of the distribution of edema and muscle atrophy in the feet of people suffering from diabetes. Diffusion coefficients of water have been measured in the normal finger as a baseline study for a current patient study. It was found that the measured diffusion coefficient increased with subject age; this is not consistent with a direct-hydration model and it is conjectured that this could be linked to structural changes in proteins. Linked to this study, we have also imaged the feet of patients suffering from diabetes. Magnetization transfer has clearly demonstrated changes in muscle tissue with atrophy caused by motor neuropathy—in general, the amount of tissue water is increased as muscle volume decreases. Further, it is evident that these changes can be related to changes in cross-linking of protein and collagen molecules as muscle fibers become thinned, thus relating these studies to the diffusion coefficient measurements. The studies of the feet have also revealed artifacts in the images, consistent with the deposition of ferrous material in tissues. It is surmised that this is caused by hemosiderin deposits at ulcer sites associated with progress of the disease. MRI could be a useful tool for monitoring the distribution of ulcers below the skin surface and provide a means of determining the response of patients to treatment.

Arthritis is intimately associated with the destruction of cartilage. High-resolution (100–200-μm)in vivo images of the finger joints have been obtained using a targeted magnetic resonance imaging (MRI) system. The study of asymptomatic subjects has enabled the normal anatomical zones of cartilage as visualised by MRI to be identified. In patients with advanced osteoarthritis features such as osteophytes and loss of cartilage are clearly demonstrated. An obvious question is whether MRI can be used to measure cartilage thickness and then whether this parameter can be utilized to quantify cartilage loss during the evolution of disease processes or response to therapy. However, there are a number of difficulties with this measurement which are discussed. It is possible that more valuable insights may be gained by careful choice of specific arthropathies to be studied—for example, acromegaly, which can lead to osteoarthritis—offers a way of observing subtle early changes that occur in the cartilage and subchondral bone.

To report the development of high-resolution targeted magnetic-resonance imaging (MRI) techniques (not using injections of contrast media) to investigate and monitor rheumatoid arthritis (RA) in the metacarpophalangeal (MCP) joints.A total of 25 RA patients (age range 30-68 years) with varying degrees of disease severity ranging from early onset through active disease to the burnt-out stage, were imaged. (One patient subsequently underwent surgery and histological data was obtained.) A series of 10 control subjects were also studied--two for each 10-year age range. All the RA subjects were assessed for disease activity using standard clinical criteria and radiography as part of normal procedures. MRI was carried out using a targeted system and novel radiofrequency coil. Images of the MCP were performed at very high resolution with 1.5 mm slice thickness and in-plane resolution 130 microns. Standard gradient-echo (GE) sequences were used for anatomical imaging, multiple-echo GE sequences used to produce effective spin-spin relaxation time (T2*) maps and optimised binomialpulse presaturation used in conjunction with a GE sequence to generate magnetization-transfer (MT) ratio maps.High-quality high-resolution images of the MCP joints were obtained which highlighted normal anatomy and key features characterising the disease state (e.g. pannus, bone erosions, vascularity). Accurate measurements of T2* and MT with variations of +/- 4% and +/- 2% respectively were achieved. In active disease, variations in T2* and MT could be determined throughout areas of pannus, clearly demonstrating the heterogeneity of this erosive tissue. Pannus in MCP joints with active destruction was found to have high values of T2* varying from 25 ms to 40 ms with pockets up to 100 ms, whereas pannus present in chronic destruction, or burnt-out disease, had T2* values ranging from 21 to 29 ms. MT-active tissue was uniformly distributed in burnt-out disease, which was confirmed histologically in one case, compared with a more heterogeneous distribution in active disease.The MRI sequences and targeted system developed allow high-resolution studies of RA disease progression and activity. The data confirm the variable pattern of the disease and, in particular, heterogeneity of pannus.

Abstract The therapy of brain cancers such as Glioblastoma multiforme (GBM) is often hampered by the blood-brain-barrier, which limits the access of drugs to the brain. High blood concentrations of a drug can increase transport into the brain but in the case of cytotoxic drugs often lead to dose-limiting peripheral toxicity, typically myelosuppression. In the current study we explore the potential of Nanomerics’ Molecular Envelope Technology (MET) nanoparticles to enhance transport of the cytotoxic drug lomustine to the brain while avoiding dose-limiting peripheral bone marrow toxicity. We have previously shown that these particles increase the brain activity of drugs such as the intravenous anaesthetic propofol by a factor of ten. MET nanoparticles were prepared from a self-assembling amphiphilic chitosan based polymer - quaternary ammonium palmitoyl glycol chitosan. Lomustine, a poorly water soluble alkylating nitrosourea (CCNU), was encapsulated within these particles at a concentration of 2mg mL−1, 20x higher than what is achievable with conventional ethanolic- polysorbate 80 formulations. In order to determine the therapeutic efficacy of the formulations, orthotopic intracranial human glioblastomas (U87- MG cells) were studied in female CD-1 nude mice. Established tumours were treated at the maximal achievable lomustine concentrations using MET lomustine (13 mg kg−1/day) and the conventional formulation (1.2 mg kg−1/day) for 10 days. The mean survival time for animals that received the MET formulation was significantly (p Animal white blood cell and femoral cell counts were not affected by any of the lomustine formulations, however both treated groups of animals showed a transient drop in the platelet count on Day 7 with recovery by day 22. The MET lomustine particulate formulation thus enabled the administration of a more than ten times higher dose of lomustine which dramatically improved therapeutic outcome with little evidence of any additional toxicity or dose limiting toxic effects. The results of this study suggest that MET nanoparticles may provide a safe means to improve therapeutic outcomes in brain cancer using current cytotoxic drugs. Citation Format: Funmilola A. Fisusi, Ahmed Alzharani, Ian Summers, Julian Morger, Omotunde Okubanjo, Kar wai Chooi, Andreas G. Schätzlein, Ijeoma F. Uchegbu. Lomustine nanoparticles are effective brain cancer treatments. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4519. doi:10.1158/1538-7445.AM2013-4519

To establish the best strategy for transmitting speech-derived information via a single tactile channel, measurements were made on the perception of frequency- and/or amplitude-modulated pulse-train stimuli, with a comparison of the electrotactile and vibrotactile modalities. In one experiment, vibrotactile perception of 2-oct step changes in stimulus frequency was found to be significantly better than electrotactile on a time-scale appropriate for the transmission of speech features (e.g., with practiced subjects, information transfer of 69% with 200-ms vibrotactile stimuli, 32% with 200-ms electrotactile stimuli). Perception of step changes in stimulus amplitude was similar in the two modalities when changes in amplitude were tailored to match the different dynamic ranges available. In a second experiment, vibrotactile-perception of voice fundamental frequency with various codings was investigated. Both experiments showed information transfer for vibrotactile stimuli to be greater when frequency and amplitude modulation were used together rather than with one or the other in isolation (sentence-stress identification scores: 66% for FM stimuli, 69% for AM stimuli, 80% for FM/AM stimuli). It is concluded that frequency- and amplitude-modulated vibratory stimulation is a good choice in a practical device for the profoundly hearing impaired.

Diffusion coefficients of water have been measured in the fingers of humans by magnetic resonance imaging. It was found that the measured diffusion coefficients increased with subject age in certain regions of the finger but that these regions differed between males and females. The observation of an increased diffusion coefficient with age appears to be inconsistent with a direct-hydration model and possible explanations are given using other models. It is conjectured that the measured diffusion coefficient of water increases with age as a result of structural changes to proteins.

Measurements have been made on the ability of normally hearing subjects to identify the stressed word in simple sentences, using only tactile information. Vibrotactile stimuli were presented to the distal pad of the second finger via a single vibrator. A range of coding strategies was investigated, voice pitch or speech amplitude being represented as stimulus frequency and/or intensity. Test results show that, even without specific training, subjects can be quite successful in identifying stress patterns. The most effective coding strategies were (i) voice frequency presented as continuously variable stimulus frequency over the range 40-220 Hz, with a correlated modulation of stimulus amplitude, (ii) speech amplitude presented as two discrete levels of stimulus amplitude.

Profoundly deaf subjects were given information about sound level in their environment by means of a body-worn unit coupled to a small vibrator worn on the finger. Results of trials on 19 adults are discussed. The Tactile Acoustic Monitor was found to be useful for identifying domestic sounds by means of their distinctive timing patterns. No significant overall improvement in subject's control of voice level was observed, although some subjects found that having a voice level monitor gave them greater confidence to join conversations. Various design improvements were suggested by the trials. Modifications which have been incorporated into an improved unit are described.