Gil Cunha

GABA deficit in the visual cortex of patients with neurofibromatosis type 1: genotype-phenotype correlations and functional impact.

Alterations in the balance between excitatory and inhibitory neurotransmission have been implicated in several neurodevelopmental disorders. Neurofibromatosis type 1 is one of the most common monogenic disorders causing cognitive deficits for which studies on a mouse model (Nfl(+/-)) proposed increased γ-aminobutyric acid-mediated inhibitory neurotransmission as the neural mechanism underlying these deficits. To test whether a similar mechanism translates to the human disorder, we used magnetic resonance spectroscopy to measure γ-aminobutyric acid levels in the visual cortex of children and adolescents with neurofibromatosis type 1 (n = 20) and matched control subjects (n = 26). We found that patients with neurofibromatosis type 1 have significantly lower γ-aminobutyric acid levels than control subjects, and that neurofibromatosis type 1 mutation type significantly predicted cortical γ-aminobutyric acid. Moreover, functional imaging of the visual cortex indicated that blood oxygen level-dependent signal was correlated with γ-aminobutyric acid levels both in patients and control subjects. Our results provide in vivo evidence of γ-aminobutyric acidergic dysfunction in neurofibromatosis type 1 by showing a reduction in γ-aminobutyric acid levels in human patients. This finding is relevant to understand the physiological profile of the disorder and has implications for the identification of targets for therapeutic strategies.

Abnormal Brain Activation in Neurofibromatosis Type 1: A Link between Visual Processing and the Default Mode Network

Neurofibromatosis type 1 (NF1) is one of the most common single gene disorders affecting the human nervous system with a high incidence of cognitive deficits, particularly visuospatial. Nevertheless, neurophysiological alterations in low-level visual processing that could be relevant to explain the cognitive phenotype are poorly understood. Here we used functional magnetic resonance imaging (fMRI) to study early cortical visual pathways in children and adults with NF1. We employed two distinct stimulus types differing in contrast and spatial and temporal frequencies to evoke relatively different activation of the magnocellular (M) and parvocellular (P) pathways. Hemodynamic responses were investigated in retinotopically-defined regions V1, V2 and V3 and then over the acquired cortical volume. Relative to matched control subjects, patients with NF1 showed deficient activation of the low-level visual cortex to both stimulus types. Importantly, this finding was observed for children and adults with NF1, indicating that low-level visual processing deficits do not ameliorate with age. Moreover, only during M-biased stimulation patients with NF1 failed to deactivate or even activated anterior and posterior midline regions of the default mode network. The observation that the magnocellular visual pathway is impaired in NF1 in early visual processing and is specifically associated with a deficient deactivation of the default mode network may provide a neural explanation for high-order cognitive deficits present in NF1, particularly visuospatial and attentional. A link between magnocellular and default mode network processing may generalize to neuropsychiatric disorders where such deficits have been separately identified.

Multivariate pattern analysis reveals subtle brain anomalies relevant to the cognitive phenotype in neurofibromatosis type 1.

Neurofibromatosis Type 1 (NF1) is a common genetic condition associated with cognitive dysfunction. However, the pathophysiology of the NF1 cognitive deficits is not well understood. Abnormal brain structure, including increased total brain volume, white matter (WM) and grey matter (GM) abnormalities have been reported in the NF1 brain. These previous studies employed univariate model‐driven methods preventing detection of subtle and spatially distributed differences in brain anatomy. Multivariate pattern analysis allows the combination of information from multiple spatial locations yielding a discriminative power beyond that of single voxels. Here we investigated for the first time subtle anomalies in the NF1 brain, using a multivariate data‐driven classification approach. We used support vector machines (SVM) to classify whole‐brain GM and WM segments of structural T1‐weighted MRI scans from 39 participants with NF1 and 60 non‐affected individuals, divided in children/adolescents and adults groups. We also employed voxel‐based morphometry (VBM) as a univariate gold standard to study brain structural differences. SVM classifiers correctly classified 94% of cases (sensitivity 92%; specificity 96%) revealing the existence of brain structural anomalies that discriminate NF1 individuals from controls. Accordingly, VBM analysis revealed structural differences in agreement with the SVM weight maps representing the most relevant brain regions for group discrimination. These included the hippocampus, basal ganglia, thalamus, and visual cortex. This multivariate data‐driven analysis thus identified subtle anomalies in brain structure in the absence of visible pathology. Our results provide further insight into the neuroanatomical correlates of known features of the cognitive phenotype of NF1. Hum Brain Mapp 35:89–106, 2014.

Distinct functional properties of the vertical and horizontal saccadic network in Health and Parkinson's disease: An eye-tracking and fMRI study.

Saccadic behaviour ranges from reflexive (e.g., prosaccade) to goal oriented voluntary movements (e.g., antisaccade). Behavioural asymmetries between vertical and horizontal saccades have been described both in normal individuals (greater delay of vertical prosaccades) and in disease states such as Parkinsons disease (PD) (prosaccades are short and antisaccades are delayed, especially in the vertical plane, possibly due to a frontostriatal deficit). Importantly, the cortical mechanisms for the generation of vertical saccades are largely unknown, both in health and disease, when compared with their horizontal counterpart. Moreover, studies exploring saccadic neural correlates and putative compensatory mechanisms at a functional level in PD are scarce. We investigated horizontal and vertical prosaccades and antisaccades in an eye tracking paradigm in 19 PD patients off medication and 22 healthy controls, followed by a block-design functional Magnetic Resonance Imaging (fMRI) study, consisting of two runs (prosaccade, antisaccade) of 6 blocks each (3 vertical, 3 horizontal). While saccade metrics were not significantly different between groups, PD showed left frontal underactivation during horizontal prosaccades and right parietal overactivation during horizontal and vertical prosaccades and horizontal antisaccades. Moreover, controls showed greater deactivation of the default-mode network (DMN) during antisaccades. Vertical prosaccades were associated with greater right frontal and cerebellar activity in controls, and cuneus hypoactivity in PD. Vertical antisaccades were associated with greater DMN deactivation in both groups and left frontal hypoactivity in PD. Putative functional compensatory changes in the right parietal cortex in PD patients may help to keep saccadic behaviour at the same level as the healthy controls. We provide first time evidence showing that functional cortical asymmetries between vertical and horizontal saccades occur distinctively in PD patients and healthy controls.

Parametric fMRI of paced motor responses uncovers novel whole-brain imaging biomarkers in spinocerebellar ataxia type 3.

Machado‐Joseph Disease, inherited type 3 spinocerebellar ataxia (SCA3), is the most common form worldwide. Neuroimaging and neuropathology have consistently demonstrated cerebellar alterations. Here we aimed to discover whole‐brain functional biomarkers, based on parametric performance‐level‐dependent signals. We assessed 13 patients with early SCA3 and 14 healthy participants. We used a combined parametric behavioral/functional neuroimaging design to investigate disease fingerprints, as a function of performance levels, coupled with structural MRI and voxel‐based morphometry. Functional magnetic resonance imaging (fMRI) was designed to parametrically analyze behavior and neural responses to audio‐paced bilateral thumb movements at temporal frequencies of 1, 3, and 5 Hz. Our performance‐level‐based design probing neuronal correlates of motor coordination enabled the discovery that neural activation and behavior show critical loss of parametric modulation specifically in SCA3, associated with frequency‐dependent cortico/subcortical activation/deactivation patterns. Cerebellar/cortical rate‐dependent dissociation patterns could clearly differentiate between groups irrespective of grey matter loss. Our findings suggest functional reorganization of the motor network and indicate a possible role of fMRI as a tool to monitor disease progression in SCA3. Accordingly, fMRI patterns proved to be potential biomarkers in early SCA3, as tested by receiver operating characteristic analysis of both behavior and neural activation at different frequencies. Discrimination analysis based on BOLD signal in response to the applied parametric finger‐tapping task significantly often reached >80% sensitivity and specificity in single regions‐of‐interest.Functional fingerprints based on cerebellar and cortical BOLD performance dependent signal modulation can thus be combined as diagnostic and/or therapeutic targets in hereditary ataxia. Hum Brain Mapp 37:3656–3668, 2016.

Developmental dissociation of visual dorsal stream parvo and magnocellular representations and the functional impact of negative retinotopic BOLD responses

Localized neurodevelopmental defects provide an opportunity to study structure-function correlations in the human nervous system. This unique multimodal case report of epileptogenic dysplasia in the visual cortex allowed exploring visual function across distinct pathways in retinotopic regions and the dorsal stream, in relation to fMRI retinotopic mapping and spike triggered BOLD responses. Pre-surgical EEG/video monitoring, MRI/DTI, EEG/fMRI, PET and SPECT were performed to characterize structure/function correlations in this patient with a very early lesion onset. In addition, we included psychophysical methods (assessing parvo/konio and magnocellular pathways) and retinotopic mapping. We could identify dorsal stream impairment (with extended contrast sensitivity deficits within the input magno system contrasting with more confined parvocellular deficits) with disrupted active visual field input representations in regions neighboring the lesion. Simultaneous EEG/fMRI identified perilesional and retinotopic bilaterally symmetric BOLD deactivation triggered by interictal spikes, which matched the contralateral spread of magnocellular dysfunction revealed in the psychophysical tests. Topographic changes in retinotopic organization further suggested long term functional effects of abnormal electrical discharges during brain development. We conclude that fMRI based visual field cortical mapping shows evidence for retinotopic dissociation between magno and parvocellular function well beyond striate cortex, identifiable in high level dorsal visual representations around visual area V3A which is consistent with the effects of epileptic spike triggered negative BOLD.

Cortical control of vertical and horizontal saccades in progressive supranuclear palsy: An exploratory fMRI study

Progressive supranuclear palsy (PSP) is a neurodegenerative disorder showing predominant brainstem involvement, characterized by marked slowing of rapid eye movements (saccades), particularly along the vertical plane. While the contribution of the brainstem damage for the saccadic disturbance in PSP has been extensively studied, much less is known about its cortical and subcortical pathomechanisms. We measured reflexive (prosaccades) and voluntary (antisaccades) saccades in the vertical and horizontal plane in PSP patients (n=8) and controls (n=10) in an eye tracking study, followed by the measurement of blood oxygenation-level dependent (BOLD) activation (PSP, n=6; controls, n=10) during similar saccade paradigms. Behaviorally, PSP patients evidenced slower and lower amplitude prosaccades (horizontal and vertical) and lower amplitude antisaccades (vertical) than controls. Functionally, patients showed decreased frontostriatal BOLD activation during prosaccades (horizontal and vertical) and antisaccades (vertical), relative to controls. Additionally, PSP patients showed less default mode network (DMN) deactivation than controls for all types of saccades. Within groups, controls showed no BOLD differences between horizontal and vertical prosaccades while PSP patients demonstrated greater DMN deactivation during vertical prosaccades. Both groups evidenced greater DMN deactivation during vertical antisaccades when compared to their horizontal counterpart and patients further showed relative frontostriatal BOLD hypoactivity during vertical antisaccades. We found fMRI evidence of frontostriatal hypoactivity in PSP patients relative to controls, especially during vertical saccades. These new findings highlight the impact of cortical impairment in saccadic disturbance of PSP.

Image analysis in radiology and nuclear medicine

Over the years medical imaging has been developed based on the interaction between two different requirements. The first is the demand from clinicians to increase the accuracy in their medical diagnostic. The second is the relationship between basic, translational, clinical researchers and biomedical engineers committed to research and development of new diagnostic techniques. In this paper we report the application of two analysis techniques to the quantification of [18F]FDG PET imaging and Voxel-based morphometry (VBM) of brain MRI images. Results obtained indicate that this techniques are an important tool to a more detailed analysis of different brain diseases or/and indirect complications of other pathologies.

Multivariate pattern analysis of brain structure: A diagnostic tool for Neurofibromatosis type 1

Neurofibromatosis type 1 (NF1) is a genetic disorder characterized by increased predisposition for tumor development and cognitive deficits. In this work, we used maps of grey matter density obtained from Magnetic Resonance (MR) brain structural scans to distinguish between NF1 patients and healthy controls with a multivariate pattern analysis technique, Support Vector Machines. Up to 83% of all participants were correctly classified (mean sensitivity of 82%; mean specificity of 84%; significance level p < 0.01). This high level of classification accuracy of NF1 patients suggests this technique as a potential diagnostic tool. In addition, we determined the brain regions that the algorithm used to distinguish between NF1 patients and healthy controls. These regions were not identified as abnormal using univariate voxel-by-voxel comparison indicating that multivariate techniques are a useful powerful tool with which to identify potential structural defects in the NF1 brain.