Multimodal Fingerprints of Resting State Networks as assessed by Simultaneous Trimodal MR-PET-EEG Imaging.

Simultaneous MR-PET-EEG (magnetic resonance imaging - positron emission tomography - electroencephalography), a new tool for the investigation of neuronal networks in the human brain, is presented here for the first time. It enables the assessment of molecular metabolic information with high spatial and temporal resolution in a given brain simultaneously. Here, we characterize the brain's default mode network (DMN) in healthy male subjects using multimodal fingerprinting by quantifying energy metabolism via 2- [18F]fluoro-2-desoxy-D-glucose PET (FDG-PET), the inhibition - excitation balance of neuronal activation via magnetic resonance spectroscopy (MRS), its functional connectivity via fMRI and its electrophysiological signature via EEG. The trimodal approach reveals a complementary fingerprint. Neuronal activation within the DMN as assessed with fMRI is positively correlated with the mean standard uptake value of FDG. Electrical source localization of EEG signals shows a significant difference between the dorsal DMN and sensorimotor network in the frequency range of δ, θ, α and ß-1, but not with ß-2 and ß-3. In addition to basic neuroscience questions addressing neurovascular-metabolic coupling, this new methodology lays the foundation for individual physiological and pathological fingerprints for a wide research field addressing healthy aging, gender effects, plasticity and different psychiatric and neurological diseases.

Spatiotemporal properties of auditory intensity processing in multisensor MEG.

Loudness dependence of auditory evoked potentials (LDAEP) evaluates loudness processing in the human auditory system and is often altered in patients with psychiatric disorders. Previous research has suggested that this measure may be used as an indicator of the central serotonergic system through the highly serotonergic innervation of the auditory cortex. However, differences among the commonly used analysis approaches (such as source analysis and single electrode estimation) may lead to different results. Putatively due to discrepancies of the underlying structures being measured. Therefore, it is important to learn more about how and where in the brain loudness variation is processed. We conducted a detailed investigation of the LDAEP generators and their temporal dynamics by means of multichannel magnetoencephalography (MEG). Evoked responses to brief tones of five different intensities were recorded from 19 healthy participants. We used magnetic field tomography in order to appropriately localize superficial as well as deep source generators of which we conducted a time series analysis. The results showed that apart from the auditory cortex other cortical sources exhibited activation during the N1/P2 time window. Analysis of time courses in the regions of interest revealed a sequential cortical activation from primary sensory areas, particularly the auditory and somatosensory cortex to posterior cingulate cortex (PCC) and to premotor cortex (PMC). The additional activation within the PCC and PMC has implications on the analysis approaches used in LDAEP research.

The temporal dynamics of the Müller-Lyer illusion.

By attaching arrows to a line's ends, the Müller-Lyer illusion can be used to modulate perceived line length. In the present study, we investigated the dynamics of the brain processes underlying this illusion using magnetoencephalography. Subjects were presented with a horizontal line with arrows attached to its ends. Across trials, the angles formed by the arrows were repeatedly changed such that 2 variants of the Müller-Lyer length illusion were either induced or not. The onset of both variants of the illusion revealed consistent activations in visual areas between 85 and 130 ms after stimulus onset, as well as strong and longer lasting activations along the ventral visual processing stream including inferior occipital, inferior temporal, and fusiform gyrus within the range of 195-220 ms. Subsequent neural activation was observed in the right superior temporal cortex, as well as in the right inferior parietal and the right inferior frontal cortex. The time course and the location of the activations suggest that the mechanisms involved in generating the Müller-Lyer illusion are closely linked to the ones associated with object perception, consistent with theories considering a relevant contribution of higher visual areas to the generation of the Müller-Lyer illusion.

Optimized mismatch negativity paradigm reflects deficits in schizophrenia patients. A combined EEG and MEG study.

Mismatch negativity (MMN) and its neuromagnetic analog (MMNm) are event-related brain responses elicited by changes in a sequence of auditory events and indexes early cognitive processing. It consistently detects neural processing deficits in schizophrenia. So far MMN is assessed with different methods (electroencephalography, EEG; magnetoencephalography, MEG) and with different paradigms: the "traditional" oddball design with rare deviants (20%) or the "optimum" design with 50% deviants varying in one of five parameters each. These MMN measures may not reflect one unitary mechanism which is equally affected in schizophrenia. We compared both designs in 12 patients with schizophrenia and controls using MEG and EEG. Automated, observer-independent data analysis rendered the procedures suitable for clinical applications. The optimum design was fastest to detect MMN and MEG had the best signal-to-noise ratio. In addition MMN was mostly reduced in schizophrenia if measured with MEG in the optimum paradigm. Optimized paradigms improve sensitivity and speed for the detection of schizophrenia endophenotypes. Dysfunctions in this disorder may lie primarily in the fast and automatic encoding of stimulus features at the auditory cortex.

Injection with methylprednisolone in patients with the carpal tunnel syndrome: a randomised double blind trial testing three different doses.

OBJECTIVE: To determine the efficacy of 20, 40 and 60 mg methylprednisolone injections in patients with the carpal tunnel syndrome. METHODS: Included were patients with signs and symptoms of carpal tunnel syndrome of more than 3 months duration confirmed by electrophysiological tests. Patients were in a double blind trial randomised to treatment consisting of injections proximal to the carpal tunnel with 20, 40 or 60 mg methylprednisolone. Primary outcome was improvement of symptoms requiring no further treatment. These patients were followed for one year. RESULTS: There were no significant differences in the treatment response between the three randomised groups at one-year follow-up (log rank analysis 1.51, 2 df, 0.4711). In the 20, 40 and 60 mg treatment groups, 56%, 53% and 73% of the patients respectively were free of important symptoms at six months follow-up. Of the patients treated with one or two injections 22% were finally referred to surgery within one year of the first treatment. No side effects were recorded. CONCLUSION: A single local injection of methylprednisolone 20, 40 or 60 mg results in long lasting improvement in approximately half of the patients. There is a trend in favour of the highest dose. A second injection may further reduce the number of patients requiring surgery.

Synchronization tomography: a method for three-dimensional localization of phase synchronized neuronal populations in the human brain using magnetoencephalography.

We present a noninvasive technique which allows the anatomical localization of phase synchronized neuronal populations in the human brain with magnetoencephalography. We study phase synchronization between the reconstructed current source density (CSD) of different brain areas as well as between the CSD and muscular activity. We asked four subjects to tap their fingers in synchrony with a rhythmic tone, and to continue tapping at the same rate after the tone was switched off. The phase synchronization behavior of brain areas relevant for movement coordination, inner voice, and time estimation changes drastically when the transition to internal pacing occurs, while their averaged amplitudes remain unchanged. Information of this kind cannot be derived with standard neuroimaging techniques like functional magnetic resonance imaging or positron emission tomography.

Disturbed facial affect recognition in patients with schizophrenia associated with hypoactivity in distributed brain regions: a magnetoencephalographic study.

OBJECTIVE: The authors sought to identify brain mechanisms underlying the well-documented facial affect recognition deficit in patients with schizophrenia. Since this deficit is stable over the course of the illness and relatively specific for schizophrenic disorders, it was expected that knowledge about the related brain mechanisms would provide substantial information about the pathophysiology of the illness. METHOD: Fifteen partly remitted schizophrenic inpatients and 12 healthy volunteers categorized facial expressions of emotion and performed two control tasks while magnetoencephalographic recordings were done by means of a 148-channel whole head system, which revealed foci of high cerebral activity and their evolution in time. Anatomical sites were defined through coregistrated magnetic resonance images. RESULTS: The magnetoencephalography data recorded in response to facial expressions of emotion revealed that patients generated weaker activations (primary current density) in inferior prefrontal, temporal, occipital, and inferior parietal areas at circumscribed latencies. Group differences did not occur in basic visual areas during a first sensory-related activation between 60 and 120 msec. Behavioral performance was associated with strength of activation in inferior prefrontal areas, the right posterior fusiform gyrus region, right anterior temporal cortex, and the right inferior parietal cortex. CONCLUSIONS: Disturbed facial affect recognition in schizophrenic patients might be a result of hypoactivity in distributed brain regions, some of them previously related to the pathophysiology of schizophrenic disorders. These regions are probably working within a spatially and temporally defined circuitry.

Using real patients in problem-based learning: students' comments on the value of using real, as opposed to paper cases, in a problem-based learning module in general practice.

OBJECTIVES: To explore the feasibility and value of using real patients as trigger material in problem-based learning (PBL). DESIGN: A questionnaire was given to all students participating in a PBL module including a question about 'the added value of using real, as opposed to paper cases', in problem-based learning. Resources used by students and assessment of feasibility were recorded by the course tutors. SETTING: A 7-week student-selected problem-based module in general practice in the fourth-year undergraduate medical curriculum, University of Newcastle upon Tyne. SUBJECTS: 69 students participating in the module over 2 years. RESULTS: All students valued the use of real patients. A total of 10 categories were identified, all congruent with accepted educational principles for effective adult learning. Real patients stimulated the use of a very wide range of resources and imaginative presentation of what had been learned. CONCLUSION: Real patients are potent trigger stimuli in problem-based learning. The use of real patients in this general practice-based module presented no organizational or ethical difficulties. Their use should be considered more widely.

Real time processing of affective and cognitive stimuli in the human brain extracted from MEG signals.

The magnetoencephalography (MEG) signal was recorded while subjects watched a video containing separate blocks of affective and cognitive advertisements and recalled slides extracted from the video a day later. An earlier behavioural study using the same video material showed that the affective advertisements were better recalled and that administration of propranolol (a beta-adrenergic blocker) abolished this effect. Magnetic field tomography (MFT) was used to extract tomographic estimates of activity millisecond by millisecond from the continuous MEG signal. Statistically significant differences between affective and cognitive blocks were identified in posterior and prefrontal areas. Cognitive blocks produced stronger activity in posterior parietal areas and superior prefrontal cortex in all three subjects. Affective blocks modulated activity in orbitofrontal and retrosplenial cortex, amygdala and brainstem. Individual contributions to the statistical maps were traced in real time from milliseconds to many seconds. Time-locked responses from the recall session were used to compare average and single trial MFT solutions and to combine activations from all subjects into a common anatomical space. The last step produced statistically significant increases in occipital and inferior ventral cortex between 100 and 200 ms compared to a prestimulus baseline.

Neuromagnetic localization of CMV generators using incomplete and full-head biomagnetometer.

Contingent magnetic variation (CMV) data were recorded in three healthy male subjects using a 2 x 37 biomagnetometer system. The experiment was repeated for one of the subjects using a 151 whole-head biomagnetometer; the same auditory GO/NOGO choice reaction time paradigm as in the first experiment was used, extended to include repetitions of identical runs and additional control conditions. Magnetic field tomography was applied to the averaged data of each subject, for each run and condition (e.g., GO/NOGO). An independent estimate of the current density in the brain was obtained every few milliseconds. The slow components were emphasized by integrating the square of the current density vector, pixel by pixel, revealing in each subject activity in the auditory cortex, sensorimotor cortex, inferior prefrontal area, and posterior inferior parietal area. The intersubject variability was large, but looking across subjects the auditory and sensorimotor cortex (which were best covered by the two probes) were consistently identified in each subject as contributing to the generation of the early and late slow CMV components. These findings were confirmed by the whole-head single-subject experiment, in which slow activity was also identified in the supplementary motor area (SMA) and posterior cingulate cortex (PCC), areas very likely missed in the first experiment because of the limited view of the twin system. The PCC and particularly the SMA activations were substantially reduced when identical runs were repeated.

Injection with methylprednisolone proximal to the carpal tunnel: randomised double blind trial.

OBJECTIVE: To assess the effect of a 40 mg methylprednisolone injection proximal to the carpal tunnel in patients with the carpal tunnel syndrome. DESIGN: Randomised double blind placebo controlled trial. SETTING: Outpatient neurology clinic in a district general hospital. PARTICIPANTS: Patients with symptoms of the carpal tunnel syndrome for more than 3 months, confirmed by electrophysiological tests and aged over 18 years. INTERVENTION: Injection with 10 mg lignocaine (lidocaine) or 10 mg lignocaine and 40 mg methylprednisolone. Non-responders who had received lignocaine received 40 mg methylprednisolone and 10 mg lignocaine and were followed in an open study. MAIN OUTCOME MEASURES: Participants were scored as having improved or not improved. Improved was defined as no symptoms or minor symptoms requiring no further treatment. RESULTS: At 1 month 6 (20%) of 30 patients in the control group had improved compared with 23 (77%) of 30 patients the intervention group (difference 57% (95% confidence interval 36% to 77%)). After 1 year, 2 of 6 improved patients in the control group did not need a second treatment, compared with 15 of 23 improved patients in the intervention group (difference 43% (23% to 63%). Of the 28 non-responders in the control group, 24 (86%) improved after methylprednisolone. Of these 24 patients, 12 needed surgical treatment within one year. CONCLUSION: A single injection with steroids close to the carpal tunnel may result in long term improvement and should be considered before surgical decompression.

Neurophysiological correlates of the recognition of facial expressions of emotion as revealed by magnetoencephalography.

MEG correlates of the recognition of facial expressions of emotion were studied in four healthy volunteers. Subjects performed a facial emotion recognition task and a control task involving recognition of complex objects including faces. Facial emotion recognition activated inferior frontal cortex, amygdala and different parts of temporal cortex in a relatively consistent time sequence. The characteristics of these activations were clearly different from those recorded during the control task. Most interesting was the fact that faces evoked different MEG responses as a function of task demands, i.e., the activations recorded during facial emotion recognition were different from those recorded during simple face recognition in the control task. These findings support the assumption that MEG is able to specifically identify the activation pattern of the brain when recognition of the emotional expression of a face is performed.

Magnetic field tomography analysis of continuous speech.

In this article we investigate MEG correlates of syntactic violations in continuous speech. An early left anterior negativity (ELAN) has been reported in previous EEG studies and has been related to syntactic processing. We used Magnetic Field Tomography (MFT) to extract a 3D estimate of the current density distribution J, from MEG data recorded while subjects listened to continuous speech. Separate estimates were obtained from the activity associated with the first word of the sentence, and the last words of the sentence which signified syntactic violation, semantic violation or correct sentences. In each case independent 3D MFT estimates of activity were obtained 2 ms apart. After converting the solutions into a PET-like format we perform a statistical analysis on a voxel-by-voxel basis. Visual inspection of the power of J at the time of the ELAN component and the statistical maps overlaid on the individual anatomical MRI suggests generators in the vicinity of the auditory cortex and in left frontal regions. Directional activation curves are computed to show the variation of activity as a function of time, from well circumscribed areas. The activation curve for the auditory cortex has a characteristic pattern consisting of three peaks, seen in the average time-locked to the onset of the first word, and the critical word of the syntactic violation. The left auditory cortex shows a delay of about 30 ms in the syntactic violation condition compared to the first word condition. No such delay is seen in the right auditory cortex.

Increased visual impairment after exercise (Uhthoff's phenomenon) in multiple sclerosis: therapeutic possibilities.

The Uhthoff symptom, a transient impairment of visual function after exercise, is demonstrated in 2 multiple sclerosis patients. Following exercise, impairment of visual function, as documented most clearly by the testing of contrast sensitivity, was less obvious after body surface cooling and after treatment with orally administered 4-aminopyridine. It is hypothesized that both treatment modalities improve the nerve conduction safety factor and thereby prevent the occurrence of a conduction block, which is believed to be the mechanism underlying the Uhthoff symptom.

Parents' meetings in two neonatal units: a way of increasing support for parents.

For a combined total of three years meetings have been held regularly on two neonatal units for parents with infants requiring neonatal intensive care. These meetings give parents an opportunity to meet each other and members of staff in an informal atmosphere in the hope that mutual support will be gained. Initial assessment shows that the parents gain confidence in their ability to look after such small babies. The staff have gained a greater insight into the parents' anxieties and problems and changes have been made in the procedures on these units. If new insight is to result in changes that benefit the parents their views must be made known and taken into account when policy decisions are made.