Intrathecal IgM production is a strong risk factor for early conversion to multiple sclerosis.

OBJECTIVES: To evaluate intrathecal immunoglobulin M (IgM) production, as compared to previously established risk factors, as risk factor for conversion from clinically isolated syndrome (CIS) to multiple sclerosis (MS) and to explore the association of intrathecal IgM production with onset age and radiologic and CSF findings in CIS/early MS. METHODS: Comprehensive CSF data, including oligoclonal immunoglobulin G (IgG) bands (OCB) and calculated intrathecal IgM and IgG production, were collected in a prospective study of 150 patients with CIS/early MS with regular clinical and MRI assessments. RESULTS: Intrathecal IgM production >0% occurred in 23.2% (33/142) of patients, who were on average 5 years younger at disease onset (p = 0.013) and more frequently had infratentorial lesions (18/32, 56.3%) than patients without intrathecal IgM production (33/104, 31.7%, p = 0.021). In multivariable Cox regression analyses, intrathecal IgM production in patients with a CIS (n = 93, median clinical and MRI follow-up 24 and 21 months) was strongly associated with conversion to MS according to the McDonald 2010 criteria (hazard ratio [95% confidence interval] 3.05 [1.45-6.44], p = 0.003) after adjustment for age (0.96 [0.93-1.00], p = 0.059), OCB (0.92 [0.33-2.61], p = 0.879), intrathecal IgG production (0.98 [0.48-1.99], p = 0.947), and radiologic evidence of dissemination in space (2.63 [1.11-6.22], p = 0.028). CONCLUSION: Intrathecal IgM production is a strong independent risk factor for early conversion to MS and may thus represent a clinically meaningful marker for predicting future disease activity in patients with a CIS.

Non-enhancing relapse of a primary CNS lymphoma with multiple diffusion-restricted lesions.

Primary CNS lymphoma (PCNSL) and its variant primary intraocular lymphoma (PIOL) are rare forms of extranodal non-Hodgkin's lymphoma confined to the CNS including the retina and the optical nerve; histologically, most cases are diffuse large B cell lymphomas. PCNSL in immunocompetent patients display typical radiological features on MRI, i.e. intensely and homogeneously enhancing lesions with moderate edema. Here, we report a 52-year-old male with a history of a PIOL and two consecutive intracerebral relapses who presented with dysarthria, dysphagia, and gait ataxia. Gadolinium-enhanced T1 scans were unremarkable but multiple lesions with restricted water diffusivity were seen on diffusion-weighted imaging. Relapse of his PCNSL was secured histologically only on autopsy. The possible etiology of the diffusion-restricted lesions is discussed.

Seizure or syncope? A channelopathy with cardiac and cerebral manifestation.

A 24-year-old woman was diagnosed with long QT syndrome (LQTS) because of recurring losses of consciousness. She was implanted with a cardioverter-defibrillator, but losses of consciousness reoccurred. Genetic analysis proved LQTS. An electroencephalogram showed spontaneous generalised spikes and polyspike waves with a 3-4/s frequency. Losses of consciousness ceased only after antiepileptic treatment. We conclude that it may by worthwhile scrutinising patients with LQTS for subtle epileptic activity to find evidence for a cerebral manifestation of a disease thought to be confined to the heart.

Proprioceptive head posture-related processing in human polysensory cortical areas.

Besides visual input and vestibular afferents, proprioceptive input from muscle spindle receptors of the neck region contributes to the perception of egocentric space. Using fMRI we performed a neck muscle vibration paradigm in humans in order to detect brain areas involved in processing changes of the head position in relation to the rest of the body. We identified a network of primary and secondary cortical areas: (I) regions that presumably receive direct proprioceptive thalamic input such as areas 3a, 2, S2 and the parieto-insular vestibular cortex (PIVC), (II) foci in the intraparietal sulcus, motor and premotor areas, and the frontal eye field (FEF). Activation of the former reflect early stages of proprioceptive processing, nevertheless these areas contain polysensory subdivisions such as area 3aNv, which also receives vestibular afferents. Together with area PIVC and the vestibular field in area 2 (2v), area 3aNv constitutes the inner vestibular circuit, an interconnected cortical triangle of polysensory areas that project to the posterior parietal cortex (PPC), which is known to be involved in polysensory integration. With respect to possible analogies in the monkey, we speculate that the activation we observed in the PPC is closely related to the LIP and VIP regions of the macaque.

What happens in between? Human oscillatory brain activity related to crossmodal spatial cueing.

Previous studies investigated the effects of crossmodal spatial attention by comparing the responses to validly versus invalidly cued target stimuli. Dynamics of cortical rhythms in the time interval between cue and target might contribute to cue effects on performance. Here, we studied the influence of spatial attention on ongoing oscillatory brain activity in the interval between cue and target onset. In a first experiment, subjects underwent periods of tactile stimulation (cue) followed by visual stimulation (target) in a spatial cueing task as well as tactile stimulation as a control. In a second experiment, cue validity was modified to be 50%, 75%, or else 25%, to separate effects of exogenous shifts of attention caused by tactile stimuli from that of endogenous shifts. Tactile stimuli produced: 1) a stronger lateralization of the sensorimotor beta-rhythm rebound (15-22 Hz) after tactile stimuli serving as cues versus not serving as cues; 2) a suppression of the occipital alpha-rhythm (7-13 Hz) appearing only in the cueing task (this suppression was stronger contralateral to the endogenously attended side and was predictive of behavioral success); 3) an increase of prefrontal gamma-activity (25-35 Hz) specifically in the cueing task. We measured cue-related modulations of cortical rhythms which may accompany crossmodal spatial attention, expectation or decision, and therefore contribute to cue validity effects. The clearly lateralized alpha suppression after tactile cues in our data indicates its dependence on endogenous rather than exogenous shifts of visuo-spatial attention following a cue independent of its modality.

Human cortical areas involved in sustaining perceptual stability during smooth pursuit eye movements.

Because both, eye movements and object movements induce an image motion on the retina, eye movements must be compensated to allow a coherent and stable perception of our surroundings. The inferential theory of perception postulates that retinal image motion is compared with an internal reference signal related to eye movements. This mechanism allows to distinguish between the potential sources producing retinal image motion. Referring to this theory, we investigated referential calculation during smooth pursuit eye movements (SPEM) in humans using event-related functional magnetic resonance imaging (fMRI). The blood oxygenation level dependent (BOLD) response related to SPEM in front of a stable background was measured for different parametric steps of preceding motion stimuli and therefore assumed for different states of the referential system. To achieve optimally accurate anatomy and more detectable fMRI signal changes in group analysis, we applied cortex-based statistics both to all brain volumes and to defined regions of interest. Our analysis revealed that the activity in a temporal region as well as the posterior parietal cortex (PPC) depended on the velocity of the preceding stimuli. Previous single-cell recordings in monkeys demonstrated that the visual posterior sylvian area (VPS) is relevant for perceptual stability. The activation apparent in our study thus may represent a human analogue of this area. The PPC is known as being strongly related to goal-directed eye movements. In conclusion, temporal and parietal cortical areas may be involved in referential calculation and thereby in sustaining visual perceptual stability during eye movements.

Increased serotonin transporter availability in the brainstem of migraineurs.

For decades, serotonin has been speculated to play a major role in migraine pathophysiology. The central serotonergic system is located in the raphe nuclei and the adjacent reticular formation in the brainstem. Recently, radioligands targeting the brain serotonin transport protein (SERT) have been developed. We used the highly specific SERT-radioligand (123)I-ADAM [2-((2-((dimethylamino) methyl)phenyl)thio)-5-iodophenylamine] to test the hypothesis of the mesopontine serotonergic system being involved in the pathophysiology of migraine. Nineteen migraine patients and 10 healthy, age- and sex-matched controls were enrolled. The neuroimaging study was performed interictally during the pain-free interval. Single Photon Emission Computed Tomography (SPECT)-images were coregistered with MRI-scans. Region of interest (ROI)-analysis revealed a highly significant increase of (123)I-ADAM uptake in the mesopontine brainstem of migraineurs (p < 0.001). In contrast, (123)IADAM uptake in the thalamus did not differ significantly between migraineurs and controls. Our study demonstrates for the first time a significant increase of brainstem SERT-availability in migraineurs, suggesting a dysregulation of the brainstem serotonergic system. It remains to be elucidated whether the altered SERT-availability is causally related to migraine pathophysiology or whether it reflects secondary pathophysiological mechanisms.

Cytochrome-c-oxidase redox changes during visual stimulation measured by near-infrared spectroscopy cannot be explained by a mere cross talk artefact.

The detection of redox changes in cytochrome-c-oxidase ([Cyt-ox]) in response to cerebral activation by non-invasive NIRS is hampered by methodological spectroscopic issues related to the modification of the Beer-Lambert law. Also, the question whether a change in the enzyme's redox-state is elicited by functional stimulation is unresolved. In a previous study, we found physiological evidence in favour of an activation-induced increase in oxidation of the enzyme [J. Cereb. Blood Flow Metab. 19 (1999) 592], while in a second study on spectroscopic cross talk, we found that the [Cyt-ox] changes to potentially be an artefact of the spectroscopic approach [J. Biomed. Opt. 7 (2002) 51]. Here, we use two different stimuli which differentially activate areas either rich or poor in [Cyt-ox] content (blob/interblob in visual cortex V1 and pale/thin stripes in V2) to further clarify this apparent discrepancy. In a first experiment, two stimuli were presented in an alternating fashion for 20 s and all stimulation periods were separated by resting periods of 40 s. We observed similar changes in [Cyt-ox] for both stimuli. To become more sensitive to the potentially very small optical changes related to changes in [Cyt-ox], we tried to minimise global haemodynamic and metabolic effects in a second experiment by omitting the resting periods. Our hypothesis was that [Cyt-ox] changes could be fully explained by cross talk as it is predicted from our last study [J. Biomed. Opt. 7 (2002) 51]. However, in more than half of the experiments, we were not able to model the changes in Cyt-ox calculated from measured attenuation spectra as a cross talk artefact. We interpret this finding as an argument in favour of the existence of [Cyt-ox] changes in response to functional stimulation. This finding, however, does not lessen the liability of the [Cyt-ox] changes to cross talk and calls for great caution when [Cyt-ox] changes are derived from NIRS measurements based on the modified Beer-Lambert approach. Further (invasive) validation studies are required.

Are VEP correlated fast optical signals detectable in the human adult by non-invasive nearinfrared spectroscopy (NIRS)?

The potential of near infrared spectroscopy (NIRS) to detect vascular changes in cerebral cortical tissue elicited by functional stimulation has been established (1). The vascular response is considered the result of neuronal activity in the investigated area and forms the basis of imaging techniques such as BOLD-contrast fMRI and PET. In the animal optical methods have been shown to detect optical changes in the illuminated tissue which exactly follow the time course of electrical potential changes, thus optical techniques can potentially assess both the 'fast' neuronal and the 'slow' vascular response. Lately a group of investigators has reported data showing that the 'fast optical signal' is detectable in the adult human in response to a visual stimulus ("optical VEP" termed EROS, i.e. event related optical signal). We failed to reproduce these results, with an almost identical instrumentation and experimental protocol. The negative result is reported in this paper. To check the expected magnitude of such changes we performed a simulation based on data reported in the animal and a human head model of optical properties. The result indicates that changes in optical properties to be expected in a non-invasive approach in the human adult are about three orders of magnitude smaller than those reported previously by the group of Gratton and co-workers (2). Also they are so small that they are below the noise level of the presently available NIRS monitors.

Habituation of the visually evoked potential and its vascular response: implications for neurovascular coupling in the healthy adult.

In the human, visually evoked potentials (VEP) and cerebral oxygenation changes, as measured by near-infrared spectroscopy (NIRS), are assessed to elucidate the relation between electrophysiological and vascular responses to a checkerboard stimulus reversing at 3 Hz. Habituation of either response is analysed on two time scales. Within the 1-min stimulation period we find a decrease in P100N135-component amplitude, closely coupled to a decrease in the amplitude of the oxygenation parameters (concentration changes in oxygenated and deoxygenated haemoglobin, [oxy-Hb] and [deoxy-Hb]). The N75P100-component amplitude exhibits a different behaviour along the 1-min stimulation period. An initial increase is overridden by an overall decrease, the latter not reaching statistical significance. The analysis across the 13 successive stimulation blocks separated by resting periods of equal duration yields a trend for an decrease in the VEP-components' amplitude, not reflected in the vascular response. When calculating a ratio between the amplitude of the P100N135-component and the concentration changes in the haemoglobins a "coupling index" of a 0.2 microM decrease in [deoxy-Hb] and an increase of 0.6 microM in [oxy-Hb] is found per 1 microV increase in VEP-component amplitude. The ratio is the same irrespective of its assessment from the difference stimulation/ rest or from the habituation effect, i.e., the difference between the amplitudes at the beginning and towards the end of the stimulation period. Although supporting the notion that the coupling between neuronal activation and the vascular response exhibits linear aspects, our findings cannot be taken as a proof of such a linearity across all brain regions and activation types. On the contrary, tentatively calculating a coupling index for the data assessed in the visual system, we intend to stress the necessity to assess both neuronal and vascular response to allow for a comparison between different systems and conditions in whom neurovascular coupling is expected to be altered (Miller et al, 2001; Mechelli et al, 2001).

Human vestibular cortex as identified with caloric stimulation in functional magnetic resonance imaging.

Anatomic and electrophysiological studies in monkeys have yielded a detailed map of cortex areas receiving vestibular afferents. In contrast, comparatively little is known about the cortical representation of the human vestibular system. In this study we applied caloric stimulation and fMRI to further characterize human cortical vestibular areas and to test for hemispheric dominance of vestibular information processing. For caloric vestibular stimulation we used cold nitrogen to avoid susceptibility artifacts induced by water calorics. Right and left side vestibular stimulation was repetitively performed inducing a nystagmus for at least 90 s after the end of the stimulation in all subjects. Only the first 60 s of this nystagmus period was included for statistical analysis and compared with the baseline condition. Activation maps revealed a cortical network with right hemispheric dominance, which in all subjects comprised the temporoparietal junction extending into the posterior insula and, furthermore, the anterior insula, pre- and postcentral gyrus, areas in the parietal lobe, the ventrolateral portion of the occipital lobe, and the inferior frontal gyrus extending into the inferior part of the precentral sulcus. In conclusion, caloric stimulation in fMRI reveals a widespread cortical network involved in vestibular signal processing corresponding to the findings from animal experiments and previous functional imaging studies in humans. Furthermore, this study demonstrates a strong right hemispheric dominance of vestibular cortex areas regardless of the stimulated side, consistent with the current view of a rightward asymmetrical cortical network for spatial orientation.