Evidence for hypothalamic ketone body sensing: impact on food intake and peripheral metabolic responses in mice.

Monocarboxylates have been implicated in the control of energy homeostasis. Among them, the putative role of ketone bodies produced notably during high-fat diet (HFD) has not been thoroughly explored. In this study, we aimed to determine the impact of a specific rise in cerebral ketone bodies on food intake and energy homeostasis regulation. A carotid infusion of ketone bodies was performed on mice to stimulate sensitive brain areas for 6 or 12 h. At each time point, food intake and different markers of energy homeostasis were analyzed to reveal the consequences of cerebral increase in ketone body level detection. First, an increase in food intake appeared over a 12-h period of brain ketone body perfusion. This stimulated food intake was associated with an increased expression of the hypothalamic neuropeptides NPY and AgRP as well as phosphorylated AMPK and is due to ketone bodies sensed by the brain, as blood ketone body levels did not change at that time. In parallel, gluconeogenesis and insulin sensitivity were transiently altered. Indeed, a dysregulation of glucose production and insulin secretion was observed after 6 h of ketone body perfusion, which reversed to normal at 12 h of perfusion. Altogether, these results suggest that an increase in brain ketone body concentration leads to hyperphagia and a transient perturbation of peripheral metabolic homeostasis.

Setting boundaries: brain dynamics of modal and amodal illusory shape completion in humans.

Normal visual perception requires differentiating foreground from background objects. Differences in physical attributes sometimes determine this relationship. Often such differences must instead be inferred, as when two objects or their parts have the same luminance. Modal completion refers to such perceptual "filling-in" of object borders that are accompanied by concurrent brightness enhancement, in turn termed illusory contours (ICs). Amodal completion is filling-in without concurrent brightness enhancement. Presently there are controversies regarding whether both completion processes use a common neural mechanism and whether perceptual filling-in is a bottom-up, feedforward process initiating at the lowest levels of the cortical visual pathway or commences at higher-tier regions. We previously examined modal completion (Murray et al., 2002) and provided evidence that the earliest modal IC sensitivity occurs within higher-tier object recognition areas of the lateral occipital complex (LOC). We further proposed that previous observations of IC sensitivity in lower-tier regions likely reflect feedback modulation from the LOC. The present study tested these proposals, examining the commonality between modal and amodal completion mechanisms with high-density electrical mapping, spatiotemporal topographic analyses, and the local autoregressive average distributed linear inverse source estimation. A common initial mechanism for both types of completion processes (140 msec) that manifested as a modulation in response strength within higher-tier visual areas, including the LOC and parietal structures, is demonstrated, whereas differential mechanisms were evident only at a subsequent time period (240 msec), with amodal completion relying on continued strong responses in these structures.

Stem cell transplantation in brain tumors: a new field for molecular imaging?

Neural stem cells have been proposed as a new and promising treatment modality in various pathologies of the central nervous system, including malignant brain tumors. However, the underlying mechanism by which neural stem cells target tumor areas remains elusive. Monitoring of these cells is currently done by use of various modes of molecular imaging, such as optical imaging, magnetic resonance imaging and positron emission tomography, which is a novel technology for visualizing metabolism and signal transduction to gene expression. In this new context, the microenvironment of (malignant) brain tumors and the blood-brain barrier gains increased interest. The authors of this review give a unique overview of the current molecular-imaging techniques used in different therapeutic experimental brain tumor models in relation to neural stem cells. Such methods for molecular imaging of gene-engineered neural stem/progenitor cells are currently used to trace the location and temporal level of expression of therapeutic and endogenous genes in malignant brain tumors, closing the gap between in vitro and in vivo integrative biology of disease in neural stem cell transplantation.

Brain-derived neurotrophic factor enhances the hippocampal expression of key postsynaptic proteins in vivo including the monocarboxylate transporter MCT2.

Brain-derived neurotrophic factor (BDNF) promotes synaptic plasticity via an enhancement in expression of specific synaptic proteins. Recent results suggest that the neuronal monocarboxylate transporter MCT2 is a postsynaptic protein critically involved in synaptic plasticity and long-term memory. To investigate in vivo whether BDNF can modulate the expression of MCT2 as well as other proteins involved in synaptic plasticity, acute injection of BDNF was performed in mouse dorsal hippocampal CA1 area. Using immunohistochemistry, it was found that MCT2 expression was enhanced in part of the CA1 area and in the dentate gyrus 6 h after a single intrahippocampal injection of BDNF. Similarly, expression of the immediate early genes Arc and Zif268 was enhanced in the same hippocampal areas, in accordance with their role in synaptic plasticity. Immunoblot analysis confirmed the significant enhancement in MCT2 protein expression. In contrast, no changes were observed for the glial monocarboxylate transporters MCT1 and MCT4. When other synaptic proteins were investigated, it was found that postsynaptic density 95 (PSD95) and glutamate receptor 2 (GluR2) protein levels were significantly enhanced while no effect could be detected for synaptophysin, synaptosomal-associated protein 25 (SNAP25), αCaMKII and GluR1. These results demonstrate that MCT2 expression can be upregulated together with other key postsynaptic proteins in vivo under conditions related to synaptic plasticity, further suggesting the importance of energetics for memory formation.

Clinicopathologic correlates in the oldest-old: Commentary on "No disease in the brain of a 115-year-old woman".

den Dunnen et al. [den Dunnen, W.F.A., Brouwer, W.H., Bijlard, E., Kamphuis, J., van Linschoten, K., Eggens-Meijer, E., Holstege, G., 2008. No disease in the brain of a 115-year-old woman. Neurobiol. Aging] had the opportunity to follow up the cognitive functioning of one of the world's oldest woman during the last 3 years of her life. They performed two neuropsychological evaluations at age 112 and 115 that revealed a striking preservation of immediate recall abilities and orientation. In contrast, working memory, retrieval from semantic memory and mental arithmetic performances declined after age 112. Overall, only a one-point decrease of MMSE score occurred (from 27 to 26) reflecting the remarkable preservation of cognitive abilities. The neuropathological assessment showed few neurofibrillary tangles (NFT) in the hippocampal formation compatible with Braak staging II, absence of amyloid deposits and other types of neurodegenerative lesions as well as preservation of neuron numbers in locus coeruleus. This finding was related to a striking paucity of Alzheimer disease (AD)-related lesions in the hippocampal formation. The present report parallels the early descriptions of rare "supernormal" centenarians supporting the dissociation between brain aging and AD processes. In conjunction with recent stereological analyses in cases aged from 90 to 102 years, it also points to the marked resistance of the hippocampal formation to the degenerative process in this age group and possible dissociation between the occurrence of slight cognitive deficits and development of AD-related pathologic changes in neocortical areas. This work is discussed in the context of current efforts to identify the biological and genetic parameters of human longevity.

Severe traumatic brain injury in Switzerland - feasibility and first results of a cohort study.

BACKGROUND: We aimed to study the incidence and outcome of severe traumatic brain injury (TBI) in Switzerland and to test the feasibility of a large cohort study with case identification in the first 24 hours and 6-month follow-up. METHODS: From January to June 2005, we consecutively enrolled and followed up all persons with severe TBI (Abbreviated Injury Score of the head region >3 and Glasgow Coma Scale <9) in the catchment areas of 3 Swiss medical centres with neurosurgical facilities. The primary outcome was the Extended Glasgow Outcome Scale (GOSE) after 6 months. Secondary outcomes included survival, Functional Independence Mea - sure (FIM), and health-related quality of life (SF-12) at defined time-points up to 6 months after injury. RESULTS: We recruited 101 participants from a source population of about 2.47 million (ie, about 33% of Swiss population). The incidence of severe TBI was 8.2 per 100,000 person-years. The overall case fatality was 70%: 41 of 101 persons (41%) died at the scene of the accident. 23 of 60 hospitalised participants (38%) died within 48 hours, and 31 (53%) within 6 months. In all hospitalised patients, the median GOSE was 1 (range 1-8) after 6 months, and was 6 (2-8) in 6-month survivors. The median total FIM score was 125 (range 18-126); median-SF-12 component mea - sures were 44 (25-55) for the physical scale and 52 (32-65) for the mental scale. CONCLUSIONS: Severe TBI was associated with high case fatality and considerable morbidity in survivors. We demonstrated the feasibility of a multicentre cohort study in Switzerland with the aim of identifying modifiable determinants of outcome and improving current trauma care.

Central and Cortical Gray Mater Segmentation of Magnetic Resonance Images of the Fetal Brain

Motivation. The study of human brain development in itsearly stage is today possible thanks to in vivo fetalmagnetic resonance imaging (MRI) techniques. Aquantitative analysis of fetal cortical surfacerepresents a new approach which can be used as a markerof the cerebral maturation (as gyration) and also forstudying central nervous system pathologies [1]. However,this quantitative approach is a major challenge forseveral reasons. First, movement of the fetus inside theamniotic cavity requires very fast MRI sequences tominimize motion artifacts, resulting in a poor spatialresolution and/or lower SNR. Second, due to the ongoingmyelination and cortical maturation, the appearance ofthe developing brain differs very much from thehomogenous tissue types found in adults. Third, due tolow resolution, fetal MR images considerably suffer ofpartial volume (PV) effect, sometimes in large areas.Today extensive efforts are made to deal with thereconstruction of high resolution 3D fetal volumes[2,3,4] to cope with intra-volume motion and low SNR.However, few studies exist related to the automatedsegmentation of MR fetal imaging. [5] and [6] work on thesegmentation of specific areas of the fetal brain such asposterior fossa, brainstem or germinal matrix. Firstattempt for automated brain tissue segmentation has beenpresented in [7] and in our previous work [8]. Bothmethods apply the Expectation-Maximization Markov RandomField (EM-MRF) framework but contrary to [7] we do notneed from any anatomical atlas prior. Data set &Methods. Prenatal MR imaging was performed with a 1-Tsystem (GE Medical Systems, Milwaukee) using single shotfast spin echo (ssFSE) sequences (TR 7000 ms, TE 180 ms,FOV 40 x 40 cm, slice thickness 5.4mm, in plane spatialresolution 1.09mm). Each fetus has 6 axial volumes(around 15 slices per volume), each of them acquired inabout 1 min. Each volume is shifted by 1 mm with respectto the previous one. Gestational age (GA) ranges from 29to 32 weeks. Mother is under sedation. Each volume ismanually segmented to extract fetal brain fromsurrounding maternal tissues. Then, in-homogeneityintensity correction is performed using [9] and linearintensity normalization is performed to have intensityvalues that range from 0 to 255. Note that due tointra-tissue variability of developing brain someintensity variability still remains. For each fetus, ahigh spatial resolution image of isotropic voxel size of1.09 mm is created applying [2] and using B-splines forthe scattered data interpolation [10] (see Fig. 1). Then,basal ganglia (BS) segmentation is performed on thissuper reconstructed volume. Active contour framework witha Level Set (LS) implementation is used. Our LS follows aslightly different formulation from well-known Chan-Vese[11] formulation. In our case, the LS evolves forcing themean of the inside of the curve to be the mean intensityof basal ganglia. Moreover, we add local spatial priorthrough a probabilistic map created by fitting anellipsoid onto the basal ganglia region. Some userinteraction is needed to set the mean intensity of BG(green dots in Fig. 2) and the initial fitting points forthe probabilistic prior map (blue points in Fig. 2). Oncebasal ganglia are removed from the image, brain tissuesegmentation is performed as described in [8]. Results.The case study presented here has 29 weeks of GA. Thehigh resolution reconstructed volume is presented in Fig.1. The steps of BG segmentation are shown in Fig. 2.Overlap in comparison with manual segmentation isquantified by the Dice similarity index (DSI) equal to0.829 (values above 0.7 are considered a very goodagreement). Such BG segmentation has been applied on 3other subjects ranging for 29 to 32 GA and the DSI hasbeen of 0.856, 0.794 and 0.785. Our segmentation of theinner (red and blue contours) and outer cortical surface(green contour) is presented in Fig. 3. Finally, torefine the results we include our WM segmentation in theFreesurfer software [12] and some manual corrections toobtain Fig.4. Discussion. Precise cortical surfaceextraction of fetal brain is needed for quantitativestudies of early human brain development. Our workcombines the well known statistical classificationframework with the active contour segmentation forcentral gray mater extraction. A main advantage of thepresented procedure for fetal brain surface extraction isthat we do not include any spatial prior coming fromanatomical atlases. The results presented here arepreliminary but promising. Our efforts are now in testingsuch approach on a wider range of gestational ages thatwe will include in the final version of this work andstudying as well its generalization to different scannersand different type of MRI sequences. References. [1]Guibaud, Prenatal Diagnosis 29(4) (2009). [2] Rousseau,Acad. Rad. 13(9), 2006, [3] Jiang, IEEE TMI 2007. [4]Warfield IADB, MICCAI 2009. [5] Claude, IEEE Trans. Bio.Eng. 51(4) (2004). [6] Habas, MICCAI (Pt. 1) 2008. [7]Bertelsen, ISMRM 2009 [8] Bach Cuadra, IADB, MICCAI 2009.[9] Styner, IEEE TMI 19(39 (2000). [10] Lee, IEEE Trans.Visual. And Comp. Graph. 3(3), 1997, [11] Chan, IEEETrans. Img. Proc, 10(2), 2001 [12] Freesurfer,http://surfer.nmr.mgh.harvard.edu.

Revue critique d'instruments pour evaluer la douleur chez les personnes cérébrolésées non communicantes aux soins intensifs [Critical review of instruments to assess pain in the non communicative brain injured persons in intensive care].

The purpose of this review is to critically appraise the pain assessment tools for non communicative persons in intensive care available in the literature and to determine their relevance for those with brain injury. Nursing and medical electronic databases were searched to identify pain tools, with a description of psychometric proprieties, in English and French. Seven of the ten tools were considered relevant and systematically evaluated according to the criteria and the indicators in the following five areas: conceptualisation, target population, feasibility and clinical utility, reliability and validity. Results indicate a number of well designed pain tools, but additional work is necessary to establish their accuracy and adequacy for the brain injured non communicative person in intensive care. Recommendations are made to choose the best tool for clinical practice and for research.

How local excitation-inhibition ratio impacts the whole brain dynamics.

The spontaneous activity of the brain shows different features at different scales. On one hand, neuroimaging studies show that long-range correlations are highly structured in spatiotemporal patterns, known as resting-state networks, on the other hand, neurophysiological reports show that short-range correlations between neighboring neurons are low, despite a large amount of shared presynaptic inputs. Different dynamical mechanisms of local decorrelation have been proposed, among which is feedback inhibition. Here, we investigated the effect of locally regulating the feedback inhibition on the global dynamics of a large-scale brain model, in which the long-range connections are given by diffusion imaging data of human subjects. We used simulations and analytical methods to show that locally constraining the feedback inhibition to compensate for the excess of long-range excitatory connectivity, to preserve the asynchronous state, crucially changes the characteristics of the emergent resting and evoked activity. First, it significantly improves the model's prediction of the empirical human functional connectivity. Second, relaxing this constraint leads to an unrealistic network evoked activity, with systematic coactivation of cortical areas which are components of the default-mode network, whereas regulation of feedback inhibition prevents this. Finally, information theoretic analysis shows that regulation of the local feedback inhibition increases both the entropy and the Fisher information of the network evoked responses. Hence, it enhances the information capacity and the discrimination accuracy of the global network. In conclusion, the local excitation-inhibition ratio impacts the structure of the spontaneous activity and the information transmission at the large-scale brain level.

Brain aging in the oldest-old.

Nonagenarians and centenarians represent a quickly growing age group worldwide. In parallel, the prevalence of dementia increases substantially, but how to define dementia in this oldest-old age segment remains unclear. Although the idea that the risk of Alzheimer's disease (AD) decreases after age 90 has now been questioned, the oldest-old still represent a population relatively resistant to degenerative brain processes. Brain aging is characterised by the formation of neurofibrillary tangles (NFTs) and senile plaques (SPs) as well as neuronal and synaptic loss in both cognitively intact individuals and patients with AD. In nondemented cases NFTs are usually restricted to the hippocampal formation, whereas the progressive involvement of the association areas in the temporal neocortex parallels the development of overt clinical signs of dementia. In contrast, there is little correlation between the quantitative distribution of SP and AD severity. The pattern of lesion distribution and neuronal loss changes in extreme aging relative to the younger-old. In contrast to younger cases where dementia is mainly related to severe NFT formation within adjacent components of the medial and inferior aspects of the temporal cortex, oldest-old individuals display a preferential involvement of the anterior part of the CA1 field of the hippocampus whereas the inferior temporal and frontal association areas are relatively spared. This pattern suggests that both the extent of NFT development in the hippocampus as well as a displacement of subregional NFT distribution within the Cornu ammonis (CA) fields may be key determinants of dementia in the very old. Cortical association areas are relatively preserved. The progression of NFT formation across increasing cognitive impairment was significantly slower in nonagenarians and centenarians compared to younger cases in the CA1 field and entorhinal cortex. The total amount of amyloid and the neuronal loss in these regions were also significantly lower than those reported in younger AD cases. Overall, there is evidence that pathological substrates of cognitive deterioration in the oldest-old are different from those observed in the younger-old. Microvascular parameters such as mean capillary diameters may be key factors to consider for the prediction of cognitive decline in the oldest-old. Neuropathological particularities of the oldest-old may be related to "longevity-enabling" genes although little or nothing is known in this promising field of future research.

Electrical neuroimaging reveals intensity-dependent activation of human cortical gustatory and somatosensory areas by electric taste.

To analyze the neural basis of electric taste we performed electrical neuroimaging analyses of event-related potentials (ERPs) recorded while participants received electrical pulses to the tongue. Pulses were presented at individual taste threshold to excite gustatory fibers selectively without concomitant excitation of trigeminal fibers and at high intensity evoking a prickling and, thus, activating trigeminal fibers. Sour, salty and metallic tastes were reported at both intensities while clear prickling was reported at high intensity only. ERPs exhibited augmented amplitudes and shorter latencies for high intensity. First activations of gustatory areas (bilateral anterior insula, medial orbitofrontal cortex) were observed at 70-80ms. Common somatosensory regions were more strongly, but not exclusively, activated at high intensity. Our data provide a comprehensive view on the dynamics of cortical processing of the gustatory and trigeminal portions of electric taste and suggest that gustatory and trigeminal afferents project to overlapping cortical areas.

Inter- and intrahemispheric dissociations in ideomotor apraxia: a large-scale lesion-symptom mapping study in subacute brain-damaged patients.

Pantomimes of object use require accurate representations of movements and a selection of the most task-relevant gestures. Prominent models of praxis, corroborated by functional neuroimaging studies, predict a critical role for left parietal cortices in pantomime and advance that these areas store representations of tool use. In contrast, lesion data points to the involvement of left inferior frontal areas, suggesting that defective selection of movement features is the cause of pantomime errors. We conducted a large-scale voxel-based lesion-symptom mapping analyses with configural/spatial (CS) and body-part-as-object (BPO) pantomime errors of 150 left and right brain-damaged patients. Our results confirm the left hemisphere dominance in pantomime. Both types of error were associated with damage to left inferior frontal regions in tumor and stroke patients. While CS pantomime errors were associated with left temporoparietal lesions in both stroke and tumor patients, these errors appeared less associated with parietal areas in stroke than in tumor patients and less associated with temporal in tumor than stroke patients. BPO errors were associated with left inferior frontal lesions in both tumor and stroke patients. Collectively, our results reveal a left intrahemispheric dissociation for various aspects of pantomime, but with an unspecific role for inferior frontal regions.

Clinicopathologic correlates in the oldest-old: Commentary on "No disease in the brain of a 115-year-old woman".

den Dunnen et al. [den Dunnen, W.F.A., Brouwer, W.H., Bijlard, E., Kamphuis, J., van Linschoten, K., Eggens-Meijer, E., Holstege, G., 2008. No disease in the brain of a 115-year-old woman. Neurobiol. Aging] had the opportunity to follow up the cognitive functioning of one of the world's oldest woman during the last 3 years of her life. They performed two neuropsychological evaluations at age 112 and 115 that revealed a striking preservation of immediate recall abilities and orientation. In contrast, working memory, retrieval from semantic memory and mental arithmetic performances declined after age 112. Overall, only a one-point decrease of MMSE score occurred (from 27 to 26) reflecting the remarkable preservation of cognitive abilities. The neuropathological assessment showed few neurofibrillary tangles (NFT) in the hippocampal formation compatible with Braak staging II, absence of amyloid deposits and other types of neurodegenerative lesions as well as preservation of neuron numbers in locus coeruleus. This finding was related to a striking paucity of Alzheimer disease (AD)-related lesions in the hippocampal formation. The present report parallels the early descriptions of rare "supernormal" centenarians supporting the dissociation between brain aging and AD processes. In conjunction with recent stereological analyses in cases aged from 90 to 102 years, it also points to the marked resistance of the hippocampal formation to the degenerative process in this age group and possible dissociation between the occurrence of slight cognitive deficits and development of AD-related pathologic changes in neocortical areas. This work is discussed in the context of current efforts to identify the biological and genetic parameters of human longevity.

Brain energetics (thought needs food).

PURPOSE OF REVIEW: Almost 15 years after its initial proposal, the astrocyte-neuron lactate shuttle hypothesis still occupies the center stage in research on brain energetics. Recent developments have provided further evidence for its validity and have extended its application to different areas of neuroscience. RECENT FINDINGS: Description of cell-specific metabolic characteristics have reinforced the view that a prominent conversion of glucose into lactate takes place in astrocytes, whereas neurons preferentially take up and oxidize lactate over glucose-derived pyruvate. Indeed, specific mechanisms are activated by glutamatergic activity to favor such a net lactate transfer between the two cell types. Moreover, demonstration in vivo of the existence and implication of the astrocyte-neuron lactate shuttle hypothesis for particular neurophysiological processes is beginning to appear. SUMMARY: Brain energetics has undertaken its revolution. A new concept based on metabolic compartmentalization between astrocytes and neurons is establishing itself as the leading paradigm that opens new perspectives in areas such as functional brain imaging and regulation of energy homeostasis.

Spontaneous pre-stimulus fluctuations in the activity of right fronto-parietal areas influence inhibitory control performance.

Inhibitory control refers to the ability to suppress planned or ongoing cognitive or motor processes. Electrophysiological indices of inhibitory control failure have been found to manifest even before the presentation of the stimuli triggering the inhibition, suggesting that pre-stimulus brain-states modulate inhibition performance. However, previous electrophysiological investigations on the state-dependency of inhibitory control were based on averaged event-related potentials (ERPs), a method eliminating the variability in the ongoing brain activity not time-locked to the event of interest. These studies thus left unresolved whether spontaneous variations in the brain-state immediately preceding unpredictable inhibition-triggering stimuli also influence inhibitory control performance. To address this question, we applied single-trial EEG topographic analyses on the time interval immediately preceding NoGo stimuli in conditions where the responses to NoGo trials were correctly inhibited [correct rejection (CR)] vs. committed [false alarms (FAs)] during an auditory spatial Go/NoGo task. We found a specific configuration of the EEG voltage field manifesting more frequently before correctly inhibited responses to NoGo stimuli than before FAs. There was no evidence for an EEG topography occurring more frequently before FAs than before CR. The visualization of distributed electrical source estimations of the EEG topography preceding successful response inhibition suggested that it resulted from the activity of a right fronto-parietal brain network. Our results suggest that the fluctuations in the ongoing brain activity immediately preceding stimulus presentation contribute to the behavioral outcomes during an inhibitory control task. Our results further suggest that the state-dependency of sensory-cognitive processing might not only concern perceptual processes, but also high-order, top-down inhibitory control mechanisms.