Michela Tosetti

A cortical area that responds specifically to optic flow, revealed by fMRI

The continuously changing optic flow on the retina provides information about direction of heading and about the three-dimensional structure of the environment. Here we use functional magnetic resonance imaging (fMRI) to demonstrate that an area in human cortex responds selectively to components of optic flow, such as circular and radial motion. This area is within the region commonly referrred to as V5/MT complex, but is distinct from the part of this region that responds to translation. The functional properties of these two areas of the V5/MT complex are also different; the response to optic flow was obtained only with changing flow stimuli, whereas response to translation occurred during exposure to continuous motion.

Arginine:Glycine Amidinotransferase Deficiency: The Third Inborn Error of Creatine Metabolism in Humans

Arginine:glycine amidinotransferase (AGAT) catalyzes the first step of creatine synthesis, resulting in the formation of guanidinoacetate, which is a substrate for creatine formation. In two female siblings with mental retardation who had brain creatine deficiency that was reversible by means of oral creatine supplementation and had low urinary guanidinoacetate concentrations, AGAT deficiency was identified as a new genetic defect in creatine metabolism. A homozygous G-A transition at nucleotide position 9297, converting a tryptophan codon (TGG) to a stop codon (TAG) at residue 149 (T149X), resulted in undetectable cDNA, as investigated by reverse-transcription PCR, as well as in undetectable AGAT activity, as investigated radiochemically in cultivated skin fibroblasts and in virus-transformed lymphoblasts of the patients. The parents were heterozygous for the mutant allele, with intermediate residual AGAT activities. Recognition and treatment with oral creatine supplements may prevent neurological sequelae in affected patients.

Age dependence of cerebral perfusion assessed by magnetic resonance continuous arterial spin labeling.

To study the normal dependence of cerebral perfusion changes on age, to measure values of perfusion early in life, and to create a reference dataset.

Spatiotopic selectivity of BOLD responses to visual motion in human area MT

Many neurons in the monkey visual extrastriate cortex have receptive fields that are affected by gaze direction. In humans, psychophysical studies suggest that motion signals may be encoded in a spatiotopic fashion. Here we use functional magnetic resonance imaging to study spatial selectivity in the human middle temporal cortex (area MT or V5), an area that is clearly implicated in motion perception. The results show that the response of MT is modulated by gaze direction, generating a spatial selectivity based on screen rather than retinal coordinates. This area could be the neurophysiological substrate of the spatiotopic representation of motion signals.

Creatine depletion in a new case with AGAT deficiency: clinical and genetic study in a large pedigree

Arginine:glycine amidinotransferase (AGAT, EC 2.1.4.1) deficiency is a recently recognized autosomal recessive inborn error of creatine biosynthesis, characterized by mental retardation and severe language impairment. We extensively investigated a third 5-year-old patient with AGAT deficiency, discovered in the pedigree of the same Italian family as the two index cases. At the age of 2 years he presented with psychomotor and language delay, and autistic-like behavior. Brain MRI was normal, but brain 1H-MRS disclosed brain creatine depletion, which almost completely normalized following creatine monohydrate supplementation. A remarkable clinical improvement paralleled the restoration of brain creatine concentration. AGAT and GAMT (guanidinoacetate:methyltransferase) genes were analyzed in the proband and in 26 relatives, including the two cousins with AGAT deficiency. Sequencing of the probands AGAT gene disclosed the same homozygous mutation at nt position 9093 converting a tryptophan (TGG) to a stop codon (TAG) at residue 149 (W149X), as already described in the two previously reported cases. The probands parents and 10 additional subjects of the pedigree were carriers for this mutation. AGAT deficiency was further confirmed by undetectable AGAT activity in the patients lymphoblasts. Mutation analysis of the GAMT gene revealed a sequence variation in exon 6 (T209M), not in the proband, but in 15 additional subjects from the pedigree. The silent nature of this sequence variation is supported by its homozygosity in one AGAT deficient cousin and in one asymptomatic adult, both with normal GAMT activity.

White matter connectivity in children with Autism spectrum disorders: a tract-based spatial statistics study

BackgroundAutism spectrum disorders (ASD) are associated with widespread alterations in white matter (WM) integrity. However, while a growing body of studies is shedding light on microstructural WM alterations in high-functioning adolescents and adults with ASD, literature is still lacking in information about whole brain structural connectivity in children and low-functioning patients with ASD. This research aims to investigate WM connectivity in ASD children with and without mental retardation compared to typically developing controls (TD).MethodsDiffusion tensor imaging (DTI) was performed in 22 young children with ASD (mean age: 5.54 years) and 10 controls (mean age: 5.25 years). Data were analysed both using the tract-based spatial statistics (TBSS) and the tractography. Correlations were investigated between the WM microstructure in the identified altered regions and the productive language level.ResultsThe TBSS analysis revealed widespread increase of fractional anisotropy (FA) in major WM pathways. The tractographic approach showed an increased fiber length and FA in the cingulum and in the corpus callosum and an increased mean diffusivity in the indirect segments of the right arcuate and the left cingulum. Mean diffusivity was also correlated with expressive language functioning in the left indirect segments of the arcuate fasciculus.ConclusionsOur study confirmed the presence of several structural connectivity abnormalities in young ASD children. In particular, the TBSS profile of increased FA that characterized the ASD patients extends to children a finding previously detected in ASD toddlers only. The WM integrity abnormalities detected may be relevant to the pathophysiology of ASD, since the structures involved participate in some core atypical characteristics of the disorder.

Female children with autism spectrum disorder: an insight from mass-univariate and pattern classification analyses.

Several studies on structural MRI in children with autism spectrum disorders (ASD) have mainly focused on samples prevailingly consisting of males. Sex differences in brain structure are observable since infancy and therefore caution is required in transferring to females the results obtained for males. The neuroanatomical phenotype of female children with ASD (ASDf) represents indeed a neglected area of research. In this study, we investigated for the first time the anatomic brain structures of a sample entirely composed of ASDf (n=38; 2-7 years of age; mean=53 months; SD=18) with respect to 38 female age and non verbal IQ matched controls, using both mass-univariate and pattern classification approaches. The whole brain volumes of each group were compared using voxel-based morphometry (VBM) with diffeomorphic anatomical registration through exponentiated lie algebra (DARTEL) procedure, allowing us to build a study-specific template. Significantly more gray matter (GM) was found in the left superior frontal gyrus (SFG) in ASDf subjects compared to controls. The GM segments obtained in the VBM-DARTEL preprocessing are also classified with a support vector machine (SVM), using the leave-pair-out cross-validation protocol. Then, the recursive feature elimination (SVM-RFE) approach allows for the identification of the most discriminating voxels in the GM segments and these prove extremely consistent with the SFG region identified by the VBM analysis. Furthermore, the SVM-RFE map obtained with the most discriminating set of voxels corresponding to the maximum Area Under the Receiver Operating Characteristic Curve (AUC(max)=0.80) highlighted a more complex circuitry of increased cortical volume in ASDf, involving bilaterally the SFG and the right temporo-parietal junction (TPJ). The SFG and TPJ abnormalities may be relevant to the pathophysiology of ASDf, since these structures participate in some core atypical features of autism.

MR Imaging of the Substantia Nigra at 7 T Enables Diagnosis of Parkinson Disease

PURPOSE To evaluate the anatomy of the substantia nigra (SN) in healthy subjects by performing 7-T magnetic resonance (MR) imaging of the SN, and to prospectively define the accuracy of 7-T MR imaging in distinguishing Parkinson disease (PD) patients from healthy subjects on an individual basis. MATERIALS AND METHODS The 7-T MR imaging protocol was approved by the Italian Ministry of Health and by the local competent ethics committee. SN anatomy was described ex vivo on a gross brain specimen by using highly resolved proton-density (spin-echo proton density) and gradient-recalled-echo (GRE) images, and in vivo in eight healthy subjects (mean age, 40.1 years) by using GRE three-dimensional multiecho susceptibility-weighted images. After training on appearance of SN in eight healthy subjects, the SN anatomy was evaluated twice by two blinded observers in 13 healthy subjects (mean age, 54.7 years) and in 17 PD patients (mean age, 56.9 years). Deviations from normal SN appearance were described and indicated as abnormal, and both diagnostic accuracy and intra- and interobserver agreement for diagnosis of PD with 7-T MR imaging were calculated. RESULTS Three-dimensional multiecho susceptibility-weighted 7-T MR imaging reveals a three-layered organization of the SN allowing readers to distinguish pars compacta ventralis and dorsalis from pars reticulata. The abnormal architecture of the SN allowed a discrimination between PD patients and healthy subjects with sensitivity and specificity of 100% and 96.2% (range, 92.3%-100%), respectively. Intraobserver agreement (κ = 1) and interobserver agreement (κ = 0.932) were excellent. CONCLUSION MR imaging at 7-T allows a precise characterization of the SN and visualization of its inner organization. Three-dimensional multiecho susceptibility-weighted images can be used to accurately differentiate healthy subjects from PD patients, which provides a novel diagnostic opportunity.

Spatiotopic Coding of BOLD Signal in Human Visual Cortex Depends on Spatial Attention

The neural substrate of the phenomenological experience of a stable visual world remains obscure. One possible mechanism would be to construct spatiotopic neural maps where the response is selective to the position of the stimulus in external space, rather than to retinal eccentricities, but evidence for these maps has been inconsistent. Here we show, with fMRI, that when human subjects perform concomitantly a demanding attentive task on stimuli displayed at the fovea, BOLD responses evoked by moving stimuli irrelevant to the task were mostly tuned in retinotopic coordinates. However, under more unconstrained conditions, where subjects could attend easily to the motion stimuli, BOLD responses were tuned not in retinal but in external coordinates (spatiotopic selectivity) in many visual areas, including MT, MST, LO and V6, agreeing with our previous fMRI study. These results indicate that spatial attention may play an important role in mediating spatiotopic selectivity.

Brainstem involvement in Unverricht–Lundborg disease (EPM1): An MRI and 1H MRS study

Abstract—MRI of the brain and proton MRS (1H MRS) of the pons and dentate were obtained in 10 patients with genetically confirmed Unverricht–Lundborg disease (EPM1) and 20 control subjects. Patients with EPM1 showed (p ≤ 0.01) loss of bulk of the basis pontis, medulla, and cerebellar hemispheres. Cerebral atrophy was present in six patients. The N-acetylaspartate/creatine and choline/creatine ratios were reduced in the pons but not in the dentate (p ≤ 0.005). Brainstem involvement could play a role in pathophysiology of EPM1.