Magnetic resonance T1w/T2w ratio and voxel-based morphometry in multiple system atrophy.

Diagnosis of multiple system atrophy (MSA) may be improved by using multimodal imaging approaches. We investigated the use of T1-weighted/T2-weighted (T1w/T2w) images ratio combined with voxel-based morphometry to evaluate brain tissue integrity in MSA compared to Parkinson's disease (PD) and healthy controls (HC). Twenty-six patients with MSA, 43 patients with PD and 56 HC were enrolled. Whole brain voxel-based and local regional analyses were performed to evaluate gray and white matter (GM and WM) tissue integrity and mean regional values were used for patients classification using logistic regression. Increased mean regional values of T1w/T2w in bilateral putamen were detected in MSA-P compared to PD and HC. The combined use of regional GM and T1w/T2w values in the right and left putamen showed the highest accuracy in discriminating MSA-P from PD and good accuracy in discriminating MSA from PD and HC. A good accuracy was also found in discriminating MSA from PD and HC by either combining regional GM and T1w/T2w values in the cerebellum or regional WM and T1w/T2w in the cerebellum and brainstem. The T1w/T2w image ratio alone or combined with validated MRI parameters can be further considered as a potential candidate biomarker for differential diagnosis of MSA.

Greater brain response to emotional expressions of their own children in mothers of preterm infants: an fMRI study.

OBJECTIVE: The birth of a preterm infant and Neonatal Intensive Care Unit hospitalization constitute a potentially traumatic experience for mothers. Although behavioral studies investigated the parenting stress in preterm mothers, no study focused on the underlying neural mechanisms. We examined the effect of preterm births in mothers, by comparing brain activation in mothers of preterm and full-term infants. STUDY DESIGN: We used functional magnetic resonance imaging to measure the cerebral response of 10 first-time mothers of preterm infants (gestational age <32 weeks and/or birth weight <1500) and 11 mothers of full-term infants, viewing happy-, neutral- and distress-face images of their own infant, along with a matched unknown infant. RESULTS: While viewing own infant's face preterm mothers showed increased activation in emotional processing area (i.e., inferior frontal gyrus) and social cognition (i.e., supramarginal gyrus) and affiliative behavior (i.e., insula). CONCLUSION: Differential brain activation patterns in mothers appears to be a function of the atypical parenthood transition related to prematurity.

Mastication induces long-term increases in blood perfusion of the trigeminal principal nucleus.

Understanding mechanisms for vessel tone regulation within the trigeminal nuclei is of great interest because some headache syndromes are due to dysregulation of such mechanisms. Previous experiments on animal models suggest that mastication may alter neuron metabolism and blood supply in these nuclei. To investigate this hypothesis in humans, arterial spin-labeling magnetic resonance imaging (MRI) was used to measure blood perfusion within the principal trigeminal nucleus (Vp) and in the dorsolateral-midbrain (DM, including the mesencephalic trigeminal nucleus) in healthy volunteers, before and immediately after a mastication exercise consisting of chewing a gum on one side of the mouth for 1 h at 1 bite/s. The side preference for masticating was evaluated with a chewing test and the volume of the masseter muscle was measured on T1-weighted MRI scans. The results demonstrated that the mastication exercise caused a perfusion increase within the Vp, but not in the DM. This change was correlated to the preference score for the side where the exercise took place. Moreover, the basal Vp perfusion was correlated to the masseter volume. These results indicate that the local vascular tone of the trigeminal nuclei can be constitutively altered by the chewing practice and by strong or sustained chewing.

Brain anatomical substrates of mirror movements in Kallmann syndrome.

Among male patients affected by Kallmann syndrome, a genetically determined disease due to defective neural migration leading to hypogonadropic hypogonadism and hypo/anosmia, about 40% present the peculiar phenomenon of mirror movements, i.e. involuntary movements mirroring contralateral voluntary hand movements. Several pathogenic hypotheses have been proposed, but the ultimate neurological mechanisms are still elusive. The aim of the present study was to investigate brain anatomical substrates of mirror movements in Kallmann syndrome by means of a panel of quantitative MRI analyses. Forty-nine male Kallmann syndrome patients underwent brain MRI. The study protocol included 3D-T1-weighted gradient echo, fluid attenuated inversion recovery and diffusion tensor imaging. Voxel-based morphometry, sulcation, curvature and cortical thickness analyses and tract based spatial statistics were performed using SPM8, Freesurfer and FSL. All patients underwent a complete physical and neurological examination including the evaluation of mirror movements (according to the Woods and Teuber criteria). Kallmann syndrome patients presenting with mirror movements (16/49, 32%) displayed the following brain changes: 1) increased gray matter density in the depth of the left precentral sulcus behind the middle frontal gyrus; 2) decreased cortical thickness in the precentral gyrus bilaterally, in the depth of right precentral sulcus and in the posterior portion of the right superior frontal gyrus; and 3) decreased fractional anisotropy in the left hemisphere involving the temporal lobe and peritrigonal white matter. No differences were shown by cortical curvature and sulcation analyses. The composite array of brain changes observed in Kallmann syndrome patients with mirror movements likely represents the anatomical-structural underpinnings leading to the peculiar derangement of the complex circuitry committed to unilateral hand voluntary movements.

Degeneration and plasticity of the optic pathway in Alström syndrome.

BACKGROUND AND PURPOSE: Alström syndrome is a rare inherited ciliopathy in which early progressive cone-rod dystrophy leads to childhood blindness. We investigated functional and structural changes of the optic pathway in Alström syndrome by using MR imaging to provide insight into the underlying pathogenic mechanisms. MATERIALS AND METHODS: Eleven patients with genetically proved Alström syndrome (mean age, 23 years; range, 6-45 years; 5 females) and 19 age- and sex-matched controls underwent brain MR imaging. The study protocol included conventional sequences, resting-state functional MR imaging, and diffusion tensor imaging. RESULTS: In patients with Alström syndrome, the evaluation of the occipital regions showed the following: 1) diffuse white matter volume decrease while gray matter volume decrease spared the occipital poles (voxel-based morphometry), 2) diffuse fractional anisotropy decrease and radial diffusivity increase while mean and axial diffusivities were normal (tract-based spatial statistics), and 3) reduced connectivity in the medial visual network strikingly sparing the occipital poles (independent component analysis). After we placed seeds in both occipital poles, the seed-based analysis revealed significantly increased connectivity in patients with Alström syndrome toward the left frontal operculum, inferior and middle frontal gyri, and the medial portion of both thalami (left seed) and toward the anterior portion of the left insula (right and left seeds). CONCLUSIONS: The protean occipital brain changes in patients with Alström syndrome likely reflect the coexistence of diffuse primary myelin derangement, anterograde trans-synaptic degeneration, and complex cortical reorganization affecting the anterior and posterior visual cortex to different degrees.

Brain changes in Kallmann syndrome.

BACKGROUND AND PURPOSE: Kallmann syndrome is a rare inherited disorder due to defective intrauterine migration of olfactory axons and gonadotropin-releasing hormone neurons, leading to rhinencephalon hypoplasia and hypogonadotropic hypogonadism. Concomitant brain developmental abnormalities have been described. Our aim was to investigate Kallmann syndrome-related brain changes with conventional and novel quantitative MR imaging analyses. MATERIALS AND METHODS: Forty-five male patients with Kallmann syndrome (mean age, 30.7 years; range, 9-55 years) and 23 age-matched male controls underwent brain MR imaging. The MR imaging study protocol included 3D-T1, FLAIR, and diffusion tensor imaging (32 noncollinear gradient-encoding directions; b-value=800 s/mm2). Voxel-based morphometry, sulcation, curvature, and cortical thickness analyses and tract-based spatial statistics were performed by using Statistical Parametric Mapping 8, FreeSurfer, and the fMRI of the Brain Software Library. RESULTS: Corpus callosum partial agenesis, multiple sclerosis-like white matter abnormalities, and acoustic schwannoma were found in 1 patient each. The total amount of gray and white matter volume and tract-based spatial statistics measures (fractional anisotropy and mean, radial, and axial diffusivity) did not differ between patients with Kallmann syndrome and controls. By specific analyses, patients with Kallmann syndrome presented with symmetric clusters of gray matter volume increase and decrease and white matter volume decrease close to the olfactory sulci; reduced sulcal depth of the olfactory sulci and deeper medial orbital-frontal sulci; lesser curvature of the olfactory sulcus and sharper curvature close to the medial orbital-frontal sulcus; and increased cortical thickness within the olfactory sulcus. CONCLUSIONS: This large MR imaging study on male patients with Kallmann syndrome featured significant morphologic and structural brain changes, likely driven by olfactory bulb hypo-/aplasia, selectively involving the basal forebrain cortex.

Basal forebrain involvement in low-functioning autistic children: a voxel-based morphometry study.

BACKGROUND AND PURPOSE: Imaging studies have revealed brain abnormalities in the regions involved in functions impaired in ASD (social relations, verbal and nonverbal communication, and adaptive behavior). We performed a VBM whole-brain analysis to assess the areas involved in autistic children with DD. MATERIALS AND METHODS: Twenty-one developmentally delayed children with ASD (aged 3-10 years) were compared with 21 controls matched for age, sex, and sociocultural background. All ASD cases had been diagnosed according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria, with the Autism Diagnostic Observation Schedule-Generic, and the Autism Diagnostic Interview-Revised. The VBM data, covaried with intelligence quotient, age, and brain volume, were analyzed. RESULTS: ASD patients showed a pattern of regional GM reduction symmetrically affecting the basal forebrain, accumbens nucleus, cerebellar hemispheres, and perisylvian regions, including insula and putamen. Asymmetric involvement of GM was observed in other brain regions functionally connected to the basal forebrain, ie, an area located close to the medial and ventral surface of the frontal lobe. No regional WM differences were observed between the 2 groups. No significant differences between patients and controls were found regarding total brain volume, GM, and WM. CONCLUSIONS: In children with ASD and DD, the novel finding of our VBM study was the demonstration of reduced GM volume in the basal forebrain and the areas connected with it. This system is involved in social behavior, communication, and cognitive skills. Whether the involvement of the basal forebrain is characteristic of ASD or is related to the DD present in our patients needs further investigation.

Brain morphometry in autism spectrum disorders: a unified approach for structure-specific statistical analysis of neuroimaging data - biomed 2011.

Autism spectrum disorders (ASD) are a neurodevelopmental condition with multiple causes, comorbid conditions, and a wide range in the type and severity of symptoms expressed by different individuals. This makes the neuroanatomy of autism inherently difficult to describe. It has been assumed in the scientific literature that deviations in regional brain size in clinical samples are directly related to maldevelopment or pathogenesis. The performed clinical studies analyzed specific brain structures that are assumed to be correlated to autistic brain behaviors. Examples of performed analyses, based upon manual or semi-automated segmentation from magnetic resonance imaging (MRI) scans, include volumetric measures of specific brain structures, or small groups of structures, as caudate, corpus callosum, putamen, hippocampus, nucleus accumbens, evaluating differences between groups of subjects with autism and control subjects. Nonetheless, the brain regions analyzed that differ between patients and control subjects have not been always consistent over the performed studies. This inconsistency might be due to the fact that the specific single volume differences that have been reported in the literature for the different brain structures under investigation may, instead, be not independent during pathogenesis. Hence, this issue comes into play in logically framing a comprehensive assessment of putative abnormalities in regional brain volumes. To this aim, a whole brain investigation system for a semi-automated morphometric statistical analysis of brain anatomy is presented in this paper and validated on a selected group of patients diagnosed with ASD that completed a 1.5 T magnetic resonance image (MRI) of the brain. The proposed system, which is mainly built basing upon the FreeSurfer and the 3D Slicer software frameworks for the volumetric analysis of brain imaging data, lies its foundations on the higher statistical power of the region of interest (ROI) approach, but equally aims at a higher exploratory power as it doesn’t restrict its focus to a small number of specific regions, thanks to a whole brain unified approach.

Change in regional cerebral function in l'aquila earthquake survivors with post-traumatic stress disorder: preliminary findings.

Subjects with post-traumatic stress disorder (PTSD) present a diminished or blunted emotional response, sometimes called "emotional numbing" (EN), that constitutes one of the central symptoms in PTSD. Symptoms of EN include diminished interest in activities, feeling detached or estranged from others, and restricted range of affect (American Psychiatric Association, 2000). The present work studied the emotional components in individuals with PTSD with the principal aim of investigating subjects' functional alteration in the limbic regions, insula and frontal cortex during an emotional task compared with healthy subjects. Ten subjects with PTSD (survivors of the 6.3 magnitude earthquake of April 6, 2009 in L'Aquila) and ten healthy controls underwent fMRI. PTSD was diagnosed according to DSM-IV-R (APA 2000). All subjects underwent fMRI while viewing content-neutral and emotional stimuli. Data analysis revealed that PTSD subjects had significantly greater cerebral activation in particular in the right anterior insula and in bilateral inferior frontal gyrus. Our data suggest that there is a change in the activation of brain areas responsible for emotional processing in patients with PTSD and are consistent with previous findings demonstrating hyperactivation in frontolimbic structures during emotional tasks. Our study suggests that close personal experience may be critical in engaging the neural mechanisms underlying the emotional modulation of memory. Our findings provide evidence that significant alterations in brain function, similar in many ways to those observed in PTSD, can be seen shortly after major traumatic experiences, highlighting the need for early evaluation and intervention for trauma survivors.

Neuronal basis of haedonic appraisal in early onset schizophrenia: FMRI investigation.

The most important symptoms associated with schizophrenia are affective flattening, decreased expression of emotions, anhedonia and social isolation. The purpose of the present study was to investigate the neural response to disgusting and pleasant visual stimuli in healthy subjects and in patients with first-episode schizophrenia. Twelve subjects in the first episode of schizophrenia (DSM-IV-R, APA, 2000) with a normal IQ and 12 healthy volunteers selected for age and education underwent functional magnetic resonance imaging (fMRI) during observation of pleasant and disgusting visual stimuli. Analysis showed that in healthy subjects, the prefrontal cortex and limbic areas are activated in response to pleasant and disgusting visual stimuli, whereas this does not occur in subjects with schizophrenia since the first episode of illness.

Does the default-mode functional connectivity of the brain correlate with working-memory performances?

The "default-mode" network is an ensemble of cortical regions that are typically deactivated during demanding cognitive tasks in functional magnetic resonance imaging (fMRI) studies. Using functional connectivity analysis, this network can be studied as a "stand-alone" brain system whose functional role is supposed to consist in the dynamic control of intrinsic processing activities like attention focusing and task-unrelated thought generation and suppression. Independent component analysis (ICA) is the method of choice for generating a statistical image of the "default-mode" network (DMN) using a task- and seed-independent distributed model of fMRI functional connectivity without prior specification of node region extent and timing of neural activation. We used a standard graded working-memory task (n-back) to induce fMRI changes in the default-mode regions and ICA to evaluate to DMN functional connectivity in nineteen healthy volunteers. Based on the known spatial variability of the ICA-DMN maps with the task difficulty levels, we hypothesized the ICA-DMN may also correlate with the subject performances. We confirmed that the relative extent of the anterior and posterior midline spots within the DMN were oppositely (resp. positively in the anterior and negatively in the posterior cingulate cortex) correlated with the level of task difficulty and found out that the spatial distribution of DMN also correlates with the individual task performances. We conclude that the working-memory function is related to a spatial re-configuration of the DMN functional connectivity, and that the relative involvement of the cingulate regions within the DMN might function as a novel predictor of the working-memory efficiency.

Head modeling for realistic electrical brain activity mapping identification of a multimodal neuroimaging protocol.

Realistic electrical brain activity mapping implies reconstructing and visualizing sources of electrical brain activity within the specific patient's head. This requires the assumption of a precise and realistic volume conductor model of the specific subject's head, i.e., a 3-D representation of the head's electrical properties in terms of shape and electrical conductivities. Source reconstruction accuracy is influenced by errors committed in head modeling. Clinical images, MRI and CT, are used to identify the head structures to be included in the volume conductor head model. Modeling accuracy mainly relies on the correct image-based identification of head structures, characterized by different electrical conductivities, to be included as separate compartments in the model. This paper analyzes the imaging protocols used in clinical practice to define the most suitable procedures for identification of the various head structures necessary to build an accurate head model also in the presence of morphologic brain pathologies. Furthermore, tissues anisotropy is discussed and identified as well. With this work we have identified a protocol for the acquisition of multimodal patient's imaging data for realistic electrical brain activity mapping purposes, able to account for pathological conditions and for head tissues anisotropy.

3.0-T functional brain imaging: a 5-year experience.

The aim of this paper is to illustrate the technical, methodological and diagnostic features of functional imaging (comprising spectroscopy, diffusion, perfusion and cortical activation techniques) and its principal neuroradiological applications on the basis of the experience gained by the authors in the 5 years since the installation of a high-field magnetic resonance (MR) magnet. These MR techniques are particularly effective at 3.0 Tesla (T) owing to their high signal, resolution and sensitivity, reduced scanning times and overall improved diagnostic ability. In particular, the high-field strength enhances spectroscopic analysis due to a greater signal-to-noise ratio (SNR) and improved spectral, space and time resolution, resulting in the ability to obtain high-resolution spectroscopic studies not only of the more common metabolites, but also--and especially--of those which, due to their smaller concentrations, are difficult to detect using 1.5-T systems. All of these advantages can be obtained with reduced acquisition times. In diffusion studies, the high-field strength results in greater SNR, because 3.0-T magnets enable increased spatial resolution, which enhances accuracy. They also allow exploration in greater detail of more complex phenomena (such as diffusion tensor and tractography), which are not clearly depicted on 1.5-T systems. The most common perfusion study (with intravenous injection of a contrast agent) benefits from the greater SNR and higher magnetic susceptibility by achieving dramatically improved signal changes, and thus greater reliability, using smaller doses of contrast agent. Functional MR imaging (fMRI) is without doubt the modality in which high-field strength has had the greatest impact. Images acquired with the blood-oxygen-level-dependent (BOLD) technique benefit from the greater SNR afforded by 3.0-T magnets and from their stronger magnetic susceptibility effects, providing higher signal and spatial resolution. This enhances reliability of the localisation of brain functions, making it possible to map additional areas, even in the millimetre and submillimetre scale. The data presented and results obtained to date show that 3.0-T morphofunctional imaging can become the standard for high-resolution investigation of brain disease.

Non-Inferential Multi-Subject Study of Functional Connectivity during Visual Stimulation.

Independent component analysis (ICA) is a powerful technique for the multivariate, non-inferential, data-driven analysis of functional magnetic resonance imaging (fMRI) data-sets. The non-inferential nature of ICA makes this a suitable technique for the study of complex mental states whose temporal evolution would be difficult to describe analytically in terms of classical statistical regressors. Taking advantage of this feature, ICA can extract a number of functional connectivity patterns regardless of the task executed by the subject. The technique is so powerful that functional connectivity patterns can be derived even when the subject is just resting in the scanner, opening the opportunity for functional investigation of the human mind at its basal "default" state, which has been proposed to be altered in several brain disorders. However, one major drawback of ICA consists in the difficulty of managing its results, which are not represented by a single functional image as in inferential studies. This produces the need for a classification of ICA results and exacerbates the difficulty of obtaining group "averaged" functional connectivity patterns, while preserving the interpretation of individual differences. Addressing the subject-level variability in the very same framework of "grouping" appears to be a favourable approach towards the clinical evaluation and application of ICA-based methodologies. Here we present a novel strategy for group-level ICA analyses, namely the self-organizing group-level ICA (sog-ICA), which is used on visual activation fMRI data from a block-design experiment repeated on six subjects. We propose the sog-ICA as a multi-subject analysis tool for grouping ICA data while assessing the similarity and variability of the fMRI results of individual subject decompositions.

Subcortical motor plasticity in patients with sporadic ALS: An fMRI study.

OBJECTIVE: To address the potential contribution of subcortical brain regions in the functional reorganization of the motor system in patients with sporadic ALS (sALS) and to investigate whether functional changes in brain activity are different in sALS patients with predominant upper motor neuron (UMN) or lower motor neuron (LMN) dysfunction. METHODS: We studied 16 patients with sALS and 13 healthy controls, using BOLD-fMRI, while they performed a simple visually paced motor task. Seven patients had definite clinical UMN signs while nine patients had prevalent clinical and electrophysiological LMN involvement. fMRI data were analyzed with Brain Voyager QX. RESULTS: Task-related functional changes were identified in motor cortical regions in both patients and healthy controls. Direct group comparisons revealed relatively decreased BOLD fMRI responses in left sensorimotor cortex, lateral premotor area, supplementary motor area and right posterior parietal cortex (p < 0.05 corrected) and relatively increased responses in the left anterior putamen (p < 0.001 uncorrected) in sALS patients. Additional analyses between the two patients subgroups demonstrated significant BOLD fMRI response differences in the anterior cingulate cortex and right caudate nucleus (p < 0.001 uncorrected) with more robust activation of these areas in patients with greater UMN burden. Importantly, there were no significant differences in performance of the motor task between sALS patients and controls as well as between sALS patient subgroups. CONCLUSIONS: Our data demonstrate a different BOLD fMRI pattern between our sALS patients and healthy controls even during simple motor behavior. Furthermore, patients with sALS and greater UMN involvement show a different reorganization of the motor system compared to sALS patients with greater LMN dysfunction.

Sudden re-opening of collapsed transverse sinuses and longstanding clinical remission after a single lumbar puncture in a case of idiopathic intracranial hypertension. Pathogenetic implications.

The aetiopathogenetic role of sinus venous obstructions carried by most idiopathic intracranial hypertension (IIH) patients is controversial. We report the case of a young woman diagnosed with IIH with papilloedema and narrowing of transverse sinuses, in which lowering of intracranial pressure by a single 20 ml cerebrospinal fluid (CSF) resulted in a strong dimensional increase of the transverse sinuses. Changes were followed by clinical remission and normalisation of optical nerve calibre, maintained after a 2-month follow-up. Our findings indicate that, although secondary to CSF hypertension, venous sinuses compression may have an important role in hypertensive status maintenance. Pathogenetic implications of venous sinus compression by hypertensive CSF in IIH are discussed.

Perfusion- and BOLD-based fMRI in the study of a human pathological model for task-related flow reductions.

In the present work, an arteriovenous malformation was taken as a pathological model for studying task-related flow decreases during a motor task. Combined Blood Oxygen Level Dependent (BOLD)-perfusion experiments were applied in order to evaluate the relative sensitivity of these techniques to task-related reductions in cerebral blood flow (CBF). Results shows that, by matching the sensitivity of the methods (which exhibit a different contrast-to-noise ratio) in the primary motor cortex, the spatial extent of the regions of decreased perfusion signal is larger than those of the BOLD signal reduction. The above finding suggests that perfusion imaging, that already represents a gold standard method in the detection of vascular phenomena, may estimate task-related flow decreases in a functional time-series better than BOLD.

High field functional MRI.

Functional magnetic resonance imaging (fMRI) has become the most widely used approach for studying brain functions in humans. The rapid and widespread diffusion of fMRI has been favoured by the properties this technique presents, and particularly by its sensitivity in analysing brain functional phenomena and by the lack of biological invasiveness, resulting in an unprecedented and unparalleled flexibility of use. These properties of fMRI brought the functional examination of the brain within the reach of the whole neuroscience community and have appreciably stimulated the research on the functional processes of the living brain. Among the main features of fMRI, its spatial and temporal resolution represents clear advantages compared with the other methods of functional neuroimaging. In fact, the high spatial resolution of fMRI permits to produce more precise and better localised information, and its temporal resolution provides the potential of a better understanding of neural dynamics at the level of single functional areas and of the neural constituents of functional patterns. A fundamental possibility of improving spatial and temporal resolution without excessively degrading signal-to-noise ratio consists in the use of high magnetic field intensity fMRI units. Besides, high field units make the use of more demanding fMRI paradigms, like single trial event related studies, much more compatible with the need of a solid statistical evaluation. This has notably promoted the diffusion of high field MRI units for human studies throughout the world, with very high field MRI units, up to 8 T, working in a few research centres, and a larger number of MRI units with field intensity ranging between 3 and 5 T.

The aerobic brain: lactate decrease at the onset of neural activity.

The metabolic events of neuronal energetics during functional activity are still partially unexplained. In particular, lactate (and not glucose) was recently proposed as the main substrate for neurons during activity. By means of proton magnetic resonance spectroscopy, lactate was reported to increase during the first minutes of prolonged stimulation, but the studies reported thus far suffered from low temporal resolution. In the present study we used a time-resolved proton magnetic resonance spectroscopy strategy in order to analyse the evolution of lactate during the early seconds following a brief visual stimulation (event-related design). A significant decrease in lactate concentration was observed 5 s after the stimulation, while a recovering of the baseline was observed at 12 s.

Issues concerning the construction of a metabolic model for neuronal activation.

The metabolic events underlying neuronal activity still remain the object of intense debate, in spite of the considerable amount of information provided from different experimental techniques. Indeed, several attempts at linking the cellular metabolic phenomena with the macroscopic physiological changes have not yet attained foolproof conclusions. The difficulties in drawing definitive conclusions are due primarily to the heterogeneity of the experimental procedures used in different laboratories, and also given the impossibility of extrapolating the findings obtained under stationary conditions (prolonged stimulation) to dynamic and transient phenomena. Recently, lactate has received much attention, following its proposal by Pellerin and Magistretti (1994; Proc. Natl. Acad. Sci. USA 91:10625-10629), instead of glucose, as the main substrate for neurons during activity. Several challenging aspects suggest the return to a more conventional view of neuronal metabolism, in which neurons are able to metabolize ambient glucose directly as their major substrate, also during activation.