New tissue priors for improved automated classification of subcortical brain structures on MRI.

Despite the constant improvement of algorithms for automated brain tissue classification, the accurate delineation of subcortical structures using magnetic resonance images (MRI) data remains challenging. The main difficulties arise from the low gray-white matter contrast of iron rich areas in T1-weighted (T1w) MRI data and from the lack of adequate priors for basal ganglia and thalamus. The most recent attempts to obtain such priors were based on cohorts with limited size that included subjects in a narrow age range, failing to account for age-related gray-white matter contrast changes. Aiming to improve the anatomical plausibility of automated brain tissue classification from T1w data, we have created new tissue probability maps for subcortical gray matter regions. Supported by atlas-derived spatial information, raters manually labeled subcortical structures in a cohort of healthy subjects using magnetization transfer saturation and R2* MRI maps, which feature optimal gray-white matter contrast in these areas. After assessment of inter-rater variability, the new tissue priors were tested on T1w data within the framework of voxel-based morphometry. The automated detection of gray matter in subcortical areas with our new probability maps was more anatomically plausible compared to the one derived with currently available priors. We provide evidence that the improved delineation compensates age-related bias in the segmentation of iron rich subcortical regions. The new tissue priors, allowing robust detection of basal ganglia and thalamus, have the potential to enhance the sensitivity of voxel-based morphometry in both healthy and diseased brains.

Disentangling in vivo the effects of iron content and atrophy on the ageing human brain.

Evidence from magnetic resonance imaging (MRI) studies shows that healthy aging is associated with profound changes in cortical and subcortical brain structures. The reliable delineation of cortex and basal ganglia using automated computational anatomy methods based on T1-weighted images remains challenging, which results in controversies in the literature. In this study we use quantitative MRI (qMRI) to gain an insight into the microstructural mechanisms underlying tissue ageing and look for potential interactions between ageing and brain tissue properties to assess their impact on automated tissue classification. To this end we acquired maps of longitudinal relaxation rate R1, effective transverse relaxation rate R2* and magnetization transfer - MT, from healthy subjects (n=96, aged 21-88 years) using a well-established multi-parameter mapping qMRI protocol. Within the framework of voxel-based quantification we find higher grey matter volume in basal ganglia, cerebellar dentate and prefrontal cortex when tissue classification is based on MT maps compared with T1 maps. These discrepancies between grey matter volume estimates can be attributed to R2* - a surrogate marker of iron concentration, and further modulation by an interaction between R2* and age, both in cortical and subcortical areas. We interpret our findings as direct evidence for the impact of ageing-related brain tissue property changes on automated tissue classification of brain structures using SPM12. Computational anatomy studies of ageing and neurodegeneration should acknowledge these effects, particularly when inferring about underlying pathophysiology from regional cortex and basal ganglia volume changes.

Regional specificity of MRI contrast parameter changes in normal ageing revealed by voxel-based quantification (VBQ).

Normal ageing is associated with characteristic changes in brain microstructure. Although in vivo neuroimaging captures spatial and temporal patterns of age-related changes of anatomy at the macroscopic scale, our knowledge of the underlying (patho)physiological processes at cellular and molecular levels is still limited. The aim of this study is to explore brain tissue properties in normal ageing using quantitative magnetic resonance imaging (MRI) alongside conventional morphological assessment. Using a whole-brain approach in a cohort of 26 adults, aged 18-85years, we performed voxel-based morphometric (VBM) analysis and voxel-based quantification (VBQ) of diffusion tensor, magnetization transfer (MT), R1, and R2* relaxation parameters. We found age-related reductions in cortical and subcortical grey matter volume paralleled by changes in fractional anisotropy (FA), mean diffusivity (MD), MT and R2*. The latter were regionally specific depending on their differential sensitivity to microscopic tissue properties. VBQ of white matter revealed distinct anatomical patterns of age-related change in microstructure. Widespread and profound reduction in MT contrasted with local FA decreases paralleled by MD increases. R1 reductions and R2* increases were observed to a smaller extent in overlapping occipito-parietal white matter regions. We interpret our findings, based on current biophysical models, as a fingerprint of age-dependent brain atrophy and underlying microstructural changes in myelin, iron deposits and water. The VBQ approach we present allows for systematic unbiased exploration of the interaction between imaging parameters and extends current methods for detection of neurodegenerative processes in the brain. The demonstrated parameter-specific distribution patterns offer insights into age-related brain structure changes in vivo and provide essential baseline data for studying disease against a background of healthy ageing.

Correlation between structural and functional changes in brain in an idiopathic headache syndrome.

Fundamental to the concept of idiopathic or primary headache, including migraine, tension-type headache and cluster headache, is the currently accepted view that these conditions are due to abnormal brain function with completely normal brain structure. Cluster headache is one such idiopathic headache with many similarities to migraine, including normal brain structure on magnetic resonance imaging and abnormal function in the hypothalamic grey matter by positron emission tomography. Given the consistency of the positron emission tomography findings with the clinical presentation, we sought to assess whether the brains of such patients were structurally normal. We used voxel-based morphometry, an objective and automated method of analyzing changes in brain structure, to study the structure of the brains of patients with cluster headache. We found a co-localization of structural changes and changes in local brain activity with positron emission tomography in the same area of the brain in the same patients. The results indicate that the current view of the neurobiology of cluster headache requires complete revision and that this periodic headache is associated with a hitherto unrecognized brain abnormality in the hypothalamic region. We believe that voxel-based morphometry has the potential to change in the most fundamental way our concept of primary headache disorders, requiring a radical reappraisal of the tenet of structural normality.

[Early neurorehabilitation in an acute university hospital: from dream to reality]. / Neurorééducation précoce au Centre hospitalier universitaire vaudois: du rêve à la réalité.

The need for an early neurorehabilitation pathway was identified in an acute university hospital. A team was formed to draw up and implement it. A neuro-sensorial, interdisciplinary and coordinated therapy program was developed, focused on tracheostomised patients as soon as they were admitted to the intermediate care in neurology and neurosurgery. The impact of this care plan was evaluated by comparing the results obtained with that pertaining to patients treated previously in the same services. The comparison showed a reduction of 48% of the mean duration of tracheostomy, of 39% in the time to inscription in a neurorehabilitation centre and of 20% in the length of stay in the intermediate care. An early neurorehabilitation care program, with an interdisciplinary and coordinated team, reduces complications and lengths of stay.

Genotype-phenotype interactions in primary dystonias revealed by differential changes in brain structure.

Our understanding of how genotype determines phenotype in primary dystonia is limited. Familial young-onset primary dystonia is commonly due to the DYT1 gene mutation. A critical question, given the 30% penetrance of clinical symptoms in DYT1 mutation carriers, is why the same genotype leads to differential clinical expression and whether non-DYT1 adult-onset primary dystonia, with and without family history share pathophysiological mechanisms with DYT1 dystonia. This study examines the relationship between dystonic phenotype and the DYT1 gene mutation by monitoring whole-brain structure using voxel-based morphometry. We acquired magnetic resonance imaging data of symptomatic and asymptomatic DYT1 mutation carriers, of non-DYT1 primary dystonia patients, with and without family history and control subjects with normal DYT1 alleles. By crossing the factors genotype and phenotype we demonstrate a significant interaction in terms of brain anatomy confined to the basal ganglia bilaterally. The explanation for this effect differs according to both gene and dystonia status: non-DYT1 adult-onset dystonia patients and asymptomatic DYT1 carriers have significantly larger basal ganglia compared to healthy subjects and symptomatic DYT1 mutation carriers. There is a significant negative correlation between severity of dystonia and basal ganglia size in DYT1 mutation carriers. We propose that differential pathophysiological and compensatory mechanisms lead to brain structure changes in non-DYT1 primary adult-onset dystonias and DYT1 gene carriers. Given the range of age of onset, there may be differential genetic modulation of brain development that in turn determines clinical expression. Alternatively, a DYT1 gene dependent primary defect of motor circuit development may lead to stress-induced remodelling of the basal ganglia and hence dystonia.

Two modulatory effects of attention that mediate object categorization in human cortex.

Attentional modulation of cortical activity was examined by varying the rate of visual stimuli in object categorization tasks according to single and conjoined features. Activation of dorsolateral frontal cortex was independent of the stimulus presentation rate and elicited by the participant's attention to conjoined compared with single features. Several cortical regions showed attentionally modulated activity. In inferior temporal cortex, modulation was due to an additional bias signal underlying normal rate-correlated activity. In two other regions (premotor cortex and cerebellum), attention modified the correlation of activity and the stimulus presentation rate. Attentional effects in the human cortex are expressed by at least two physiologically distinct mechanisms acting on spatially distributed areas.

The prefrontal cortex: response selection or maintenance within working memory?

It is controversial whether the dorsolateral prefrontal cortex is involved in the maintenance of items in working memory or in the selection of responses. We used event-related functional magnetic resonance imaging to study the performance of a spatial working memory task by humans. We distinguished the maintenance of spatial items from the selection of an item from memory to guide a response. Selection, but not maintenance, was associated with activation of prefrontal area 46 of the dorsal lateral prefrontal cortex. In contrast, maintenance was associated with activation of prefrontal area 8 and the intraparietal cortex. The results support a role for the dorsal prefrontal cortex in the selection of representations. This accounts for the fact that this area is activated both when subjects select between items on working memory tasks and when they freely select between movements on tasks of willed action.

Knowing where and getting there: a human navigation network.

The neural basis of navigation by humans was investigated with functional neuroimaging of brain activity during navigation in a familiar, yet complex virtual reality town. Activation of the right hippocampus was strongly associated with knowing accurately where places were located and navigating accurately between them. Getting to those places quickly was strongly associated with activation of the right caudate nucleus. These two right-side brain structures function in the context of associated activity in right inferior parietal and bilateral medial parietal regions that support egocentric movement through the virtual town, and activity in other left-side regions (hippocampus, frontal cortex) probably involved in nonspatial aspects of navigation. These findings outline a network of brain areas that support navigation in humans and link the functions of these regions to physiological observations in other mammals.

Grafts of fetal dopamine neurons survive and improve motor function in Parkinson's disease.

Neural transplantation can restore striatal dopaminergic neurotransmission in animal models of Parkinson's disease. It has now been shown that mesencephalic dopamine neurons, obtained from human fetuses of 8 to 9 weeks gestational age, can survive in the human brain and produce marked and sustained symptomatic relief in a patient severely affected with idiopathic Parkinson's disease. The grafts, which were implanted unilaterally into the putamen by stereotactic surgery, restored dopamine synthesis and storage in the grafted area, as assessed by positron emission tomography with 6-L-[18F]fluorodopa. This neurochemical change was accompanied by a therapeutically significant reduction in the patient's severe rigidity and bradykinesia and a marked diminuation of the fluctuations in the patient's condition during optimum medication (the "on-off" phenomenon). The clinical improvement was most marked on the side contralateral to the transplant.

Cross-modal plasticity underpins language recovery after cochlear implantation.

Postlingually deaf subjects learn the meaning of sounds after cochlear implantation by forming new associations between sounds and their sources. Implants generate coarse frequency responses, preventing place-coding fine enough to discriminate sounds with similar temporal characteristics, e.g., buck/duck. This limitation imposes a dependency on visual cues, e.g., lipreading. We hypothesized that cross-modal facilitation results from engagement of the visual cortex by purely auditory tasks. In four functional neuroimaging experiments, we show recruitment of early visual cortex (V1/V2) when cochlear implant users listen to sounds with eyes closed. Activity in visual cortex evolved in a stimulus-specific manner as a function of time from implantation reflecting experience-dependent adaptations in the postimplant phase.

Anti-basal ganglia antibodies and Tourette's syndrome: a voxel-based morphometry and diffusion tensor imaging study in an adult population.

Anti-basal ganglia antibodies (ABGAs) have been suggested to be a hallmark of autoimmunity in Gilles de la Tourette's syndrome (GTS), possibly related to prior exposure to streptococcal infection. In order to detect whether the presence of ABGAs was associated with subtle structural changes in GTS, whole-brain analysis using independent sets of T(1) and diffusion tensor imaging MRI-based methods were performed on 22 adults with GTS with (n = 9) and without (n = 13) detectable ABGAs in the serum. Voxel-based morphometry analysis failed to detect any significant difference in grey matter density between ABGA-positive and ABGA-negative groups in caudate nuclei, putamina, thalami and frontal lobes. These results suggest that ABGA synthesis is not related to structural changes in grey and white matter (detectable with these methods) within frontostriatal circuits.

Analysis of temporal structure in sound by the human brain.

For over a century, models of pitch perception have been based on the frequency composition of the sound. Pitch phenomena can also be explained, however, in terms of the time structure, or temporal regularity, of sounds. To locate the mechanism for the detection of temporal regularity in humans, we used functional imaging and a 'delay-and-add' noise, which activates all frequency regions uniformly, like noise, but which nevertheless produces strong pitch perceptions and tuneful melodies. This stimulus has temporal regularity that can be systematically altered. We found that the activity of primary auditory cortex increased with the regularity of the sound. Moreover, a melody composed of delay-and-add 'notes' produced a distinct pattern of activation in two areas of the temporal lobe distinct from primary auditory cortex. These results suggest a hierarchical analysis of time structure in the human brain.

Right parietal cortex is involved in the perception of sound movement in humans.

Changes in the delay (phase) and amplitude of sound at the ears are cues for the analysis of sound movement. The detection of these cues depends on the convergence of the inputs to each ear, a process that first occurs in the brainstem. The conscious perception of these cues is likely to involve higher centers. Using novel stimuli that produce different perceptions of movement in the presence of identical phase and amplitude modulation components, we have demonstrated human brain areas that are active specifically during the perception of sound movement. Both functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) demonstrated the involvement of the right parietal cortex in sound movement perception with these stimuli.

Human cortical areas selectively activated by apparent sound movement.

BACKGROUND: Positron emission tomography (PET) measures cerebral blood flow, an indicator of neural activity. PET has been used successfully to identify visual association areas in the human brain, which are involved in the analysis of different aspects of visual stimuli. However, comparable studies have not yet been carried out for the human auditory system. RESULTS: We have attempted to identify human cortical areas that are selectively activated during sound movement analysis. Using PET, we have identified cortical areas that appeared to be selectively activated while human subjects attended to the position of a moving sound image compared to when they attended to a stationary sound image. The areas are in the right insula, adjacent to the right posterior cingulate, and in the cerebellum. CONCLUSIONS: We suggest that the insula may be acting as an auditory association cortex involved in sound movement analysis, analogous to area V5 in the visual system.

Functional mapping of verbal memory and language.

Francis O. Schmitt wrote in his introduction to The Mindful Brain that 'Many theories of higher brain function (learning, memory, perception, self-awareness, consciousness) have been proposed; but in general these lack cogency with respect to the established anatomical and physiological facts and are without biophysical and biochemical plausibility'. A central aim of functional mapping studies of the human brain is a physiological and anatomical description of the brain regions that participate in different brain functions. Language and memory have become, with the advent of modern imaging technologies, the subject of a comparatively large number of mapping studies in recent years. The quality of the data and of the experimental design continue to evolve so that sophisticated questions are being addressed, and convergent findings are now being reported. This article will critically review mapping studies of language and memory and assess how they advance our knowledge of the functional organization of these human faculties.

The impact of brain imaging technology on our understanding of motor function and dysfunction.

Brain imaging techniques have demonstrated functional specialisation of multiple areas within the motor system. They have also defined the patterns of interactions between these regions during normal motor function and in motor disorders. Functional imaging makes visible the changes in cortical activity that take place over time during motor functions, from the activations a fraction of a second before voluntary action to cortical neuronal plasticity several weeks after injury. Recently, the functional abnormalities underlying various acquired and developmental motor disorders have been described, as well as the effects of therapeutic intervention.

A PET study exploring the laterality of brainstem activation in migraine using glyceryl trinitrate.

Migraine is a common disabling condition likely to be associated with dysfunction of brain pathways involved in pain and other sensory modalities. A cardinal, indeed signature, feature of the disorder that led to its name is that the pain may be lateralized. H(2)15O-labelled PET was used to study 24 migraineurs and eight healthy controls. The migraineurs were divided into three groups according to the site of their headache: right, left or bilateral. In each group, a migraine was induced using a glyceryl trinitrate (GTN) infusion. The subjects were scanned at predefined points: pre-infusion, during GTN, during migraine and post-migraine. SPM99 software was used to analyse the data. Significant brainstem activation was seen in the dorsal lateral pons (P < 0.05 after small volume correction) during the migraine state versus the pain-free state when comparing migraineurs with controls. When each group was analysed separately, to investigate laterality, it was found that the dorsal pontine activation was ipsilateral in the right-sided and left-sided groups and bilateral in the bilateral headache group with a left-sided preponderance. Consistent with previous work, the activation persisted after pain was controlled by sumatriptan. These results suggest that lateralization of pain in migraine is due to lateralized brain dysfunction.

Positron emission tomography of the brain: new possibilities for the investigation of human cerebral pathophysiology.

In the foregoing an overview of positron emission tomography has been presented. Its theoretical, technical, and methodological implications, as well as its clinical applications have been outlined. The emphasis has been on the quantitative aspects of the method and its usefulness is investigating normal and pathological functions of brain tissue. Although the potential of this new research technique is obvious, many theoretical and practical difficulties still need to be solved. Nevertheless it provides an opportunity to bridge the gap between basic experimental research and clinical medicine.

Polymeric nanocapsules with up-converting nanocrystals cargo make ideal fluorescent bioprobes.

An innovative approach for up-converting nanoparticles adaptation for bio-related and theranostic applications is presented. We have successfully encapsulated multiple, ~8 nm in size NaYF4 nanoparticles inside the polymeric nanocarriers with average size of ~150 nm. The initial coating of nanoparticles surfaces was preserved due to the hydrophobic environment inside the nanocapsules, and thus no single nanoparticle surface functionalization was necessary. The selection of biodegradable and sugar-based polyelectrolyte shells ensured biocompatibility of the nanostructures, while the choice of Tm(3+) and Yb(3+) NaYF4 nanoparticles co-doping allowed for near-infrared to near-infrared bioimaging of healthy and cancerous cell lines. The protective role of organic shell resulted in not only preserved high up-converted emission intensity and long luminescence lifetimes, without quenching from water environment, but also ensured low cytotoxicity and high cellular uptake of the engineered nanocapsules. The multifunctionality of the proposed nanocarriers is a consequence of both the organic exterior part that is accessible for conjugation with biologically important molecules, and the hydrophobic interior, which in future application may be used as a container for co-encapsulation of inorganic nanoparticles and anticancer drug cargo.