Eleonora Fornari

Distinct Pathways Involved in Sound Recognition and Localization: A Human fMRI Study

Evidence from psychophysical studies in normal and brain-damaged subjects suggests that auditory information relevant to recognition and localization are processed by distinct neuronal populations. We report here on anatomical segregation of these populations. Brain activation associated with performance in sound identification and localization was investigated in 18 normal subjects using fMRI. Three conditions were used: (i) comparison of spatial stimuli simulated with interaural time differences; (ii) identification of environmental sounds; and (iii) rest. Conditions (i) and (ii) required acknowledgment of predefined targets by pressing a button. After coregistering, images were normalized and smoothed. Activation patterns were analyzed using SPM99 for individual subjects and for the whole group. Sound recognition and localization activated, as compared to rest, inferior colliculus, medial geniculate body, Heschl gyrus, and parts of the temporal, parietal, and frontal convexity bilaterally. The activation pattern on the fronto-temporo-parietal convexity differed in the two conditions. Middle temporal gyrus and precuneus bilaterally and the posterior part of left inferior frontal gyrus were more activated by recognition than by localization. Lower part of inferior parietal lobule and posterior parts of middle and inferior frontal gyri were more activated, bilaterally, by localization than by recognition. Regions selectively activated by sound recognition, but not those selectively activated by localization, were significantly larger in women. Passive listening paradigm revealed segregated pathways on superior temporal gyrus and inferior parietal lobule. Thus, anatomically distinct networks are involved in sound recognition and sound localization.

Multisensory Mechanisms in Temporo-Parietal Cortex Support Self-Location and First-Person Perspective

Self-consciousness has mostly been approached by philosophical enquiry and not by empirical neuroscientific study, leading to an overabundance of diverging theories and an absence of data-driven theories. Using robotic technology, we achieved specific bodily conflicts and induced predictable changes in a fundamental aspect of self-consciousness by altering where healthy subjects experienced themselves to be (self-location). Functional magnetic resonance imaging revealed that temporo-parietal junction (TPJ) activity reflected experimental changes in self-location that also depended on the first-person perspective due to visuo-tactile and visuo-vestibular conflicts. Moreover, in a large lesion analysis study of neurological patients with a well-defined state of abnormal self-location, brain damage was also localized at TPJ, providing causal evidence that TPJ encodes self-location. Our findings reveal that multisensory integration at the TPJ reflects one of the most fundamental subjective feelings of humans: the feeling of being an entity localized at a position in space and perceiving the world from this position and perspective.

Glutathione Precursor, N-Acetyl-Cysteine, Improves Mismatch Negativity in Schizophrenia Patients

In schizophrenia patients, glutathione dysregulation at the gene, protein and functional levels, leads to N-methyl-D-aspartate (NMDA) receptor hypofunction. These patients also exhibit deficits in auditory sensory processing that manifests as impaired mismatch negativity (MMN), which is an auditory evoked potential (AEP) component related to NMDA receptor function. N-acetyl-cysteine (NAC), a glutathione precursor, was administered to patients to determine whether increased levels of brain glutathione would improve MMN and by extension NMDA function. A randomized, double-blind, cross-over protocol was conducted, entailing the administration of NAC (2g/day) for 60 days and then placebo for another 60 days (or vice versa). 128-channel AEPs were recorded during a frequency oddball discrimination task at protocol onset, at the point of cross-over, and at the end of the study. At the onset of the protocol, the MMN of patients was significantly impaired compared to sex- and age- matched healthy controls (p=0.003), without any evidence of concomitant P300 component deficits. Treatment with NAC significantly improved MMN generation compared with placebo (p=0.025) without any measurable effects on the P300 component. MMN improvement was observed in the absence of robust changes in assessments of clinical severity, though the latter was observed in a larger and more prolonged clinical study. This pattern suggests that MMN enhancement may precede changes to indices of clinical severity, highlighting the possible utility AEPs as a biomarker of treatment efficacy. The improvement of this functional marker may indicate an important pathway towards new therapeutic strategies that target glutathione dysregulation in schizophrenia.

Long-term effects of cannabis on brain structure.

The dose-dependent toxicity of the main psychoactive component of cannabis in brain regions rich in cannabinoid CB1 receptors is well known in animal studies. However, research in humans does not show common findings across studies regarding the brain regions that are affected after long-term exposure to cannabis. In the present study, we investigate (using Voxel-based Morphometry) gray matter changes in a group of regular cannabis smokers in comparison with a group of occasional smokers matched by the years of cannabis use. We provide evidence that regular cannabis use is associated with gray matter volume reduction in the medial temporal cortex, temporal pole, parahippocampal gyrus, insula, and orbitofrontal cortex; these regions are rich in cannabinoid CB1 receptors and functionally associated with motivational, emotional, and affective processing. Furthermore, these changes correlate with the frequency of cannabis use in the 3 months before inclusion in the study. The age of onset of drug use also influences the magnitude of these changes. Significant gray matter volume reduction could result either from heavy consumption unrelated to the age of onset or instead from recreational cannabis use initiated at an adolescent age. In contrast, the larger gray matter volume detected in the cerebellum of regular smokers without any correlation with the monthly consumption of cannabis may be related to developmental (ontogenic) processes that occur in adolescence.

Topography of EEG multivariate phase synchronization in early Alzheimer's disease

Alzheimers disease (AD) is likely to disrupt the synchronization of the bioelectrical processes in the distributed cortical networks underlying cognition. We analyze the surface topography of the multivariate phase synchronization (MPS) of multichannel EEG in 17 patients (Clinical Dementia Rating (CDR) Scale: 0.5-1; Functional Assessment Staging (FAST): 3-4) compared to 17 controls by applying a combination of global and regional MPS measures to the resting EEG. In early AD, whole-head mapping reveals a specific landscape of synchronization characterized by a decrease in MPS over the fronto-temporal region and an increase over the temporo-parieto-occipital region predominantly of the left hemisphere. These features manifest themselves through the EEG delta-beta bands and discriminate patients from controls with an accuracy of up to 94%. Moreover, the abnormal MPS in both anterior and posterior clusters correlates with the Mini Mental State Examination score, binding regional EEG synchronization to cognitive decline in AD patients. The MPS technique reveals that the EEG phenotype of early AD is relevant to the clinical picture and may ultimately become its sensitive and specific biomarker.

Subjective mental time: the functional architecture of projecting the self to past and future

Human experience takes place in the line of mental time (MT) created through ‘self‐projection’ of oneself to different time‐points in the past or future. Here we manipulated self‐projection in MT not only with respect to one’s life events but also with respect to one’s faces from different past and future time‐points. Behavioural and event‐related functional magnetic resonance imaging activity showed three independent effects characterized by (i) similarity between past recollection and future imagination, (ii) facilitation of judgements related to the future as compared with the past, and (iii) facilitation of judgements related to time‐points distant from the present. These effects were found with respect to faces and events, and also suggest that brain mechanisms of MT are independent of whether actual life episodes have to be re‐experienced or pre‐experienced, recruiting a common cerebral network including the anteromedial temporal, posterior parietal, inferior frontal, temporo‐parietal and insular cortices. These behavioural and neural data suggest that self‐projection in time is a fundamental aspect of MT, relying on neural structures encoding memory, mental imagery and self.

Sound recognition and localization in man: specialized cortical networks and effects of acute circumscribed lesions

Functional imaging studies have shown that information relevant to sound recognition and sound localization are processed in anatomically distinct cortical networks. We have investigated the functional organization of these specialized networks by evaluating acute effects of circumscribed hemispheric lesions. Thirty patients with a primary unilateral hemispheric lesion, 15 with right-hemispheric damage (RHD) and 15 with left-hemispheric damage (LHD), were evaluated for their capacity to recognise environmental sounds, to localize sounds in space and to perceive sound motion. One patient with RHD and 2 with LHD had a selective deficit in sound recognition; 3 with RHD a selective deficit in sound localization; 2 with LHD a selective deficit in sound motion perception; 4 with RHD and 3 with LHD a combined deficit of sound localization and motion perception; 2 with RHD and 1 with LHD a combined deficit of sound recognition and motion perception; and 1 with LHD a combined deficit of sound recognition, localization and motion perception. Five patients with RHD and 6 with LHD had normal performance in all three domains. Deficient performance in sound recognition, sound localization and/or sound motion perception was always associated with a lesion that involved the shared auditory structures and the specialized What and/or Where networks, while normal performance was associated with lesions within or outside these territories. Thus, damage to regions known to be involved in auditory processing in normal subjects is necessary, but not sufficient for a deficit to occur. Lesions of a specialized network was not always associated with the corresponding deficit. Conversely, specific deficits tended not be associated predominantly with lesions of the corresponding network; e.g. deficits in auditory spatial tasks were observed in patients whose lesions involved to a larger extent the shared auditory structures and the specialized What network than the specialized Where network, and deficits in sound recognition in patients whose lesions involved mostly the shared auditory structures and to a varying degree the specialized What network. The human auditory cortex consists of functionally defined auditory areas, whose intrinsic organization is currently not understood. In particular, areas involved in the What and Where pathways can be conceived as: (1) specialized regions, in which lesions cause dysfunction limited to the damaged part; observed deficits should be then related to the specialization of the damaged region and their magnitude to the extent of the damage; or (2) specialized networks, in which lesions cause dysfunction that may spread over the two specialized networks; observed deficits may then not be related to the damaged region and their magnitude not proportional to the extent of the damage. Our results support strongly the network hypothesis.

Demyelination of superficial white matter in early Alzheimer's disease: a magnetization transfer imaging study

Assuming selective vulnerability of short association U-fibers in early Alzheimers disease (AD), we quantified demyelination of the surface white matter (dSWM) with magnetization transfer ratio (MTR) in 15 patients (Clinical Dementia Rating Scale [CDR] 0.5-1; Functional Assessment Staging [FAST]: 3-4) compared with 15 controls. MTRs were computed for 39 areas in each hemisphere. We found a bilateral MTR decrease in the temporal, cingulate, parietal, and prefrontal areas. With linear discriminant analysis, we successfully classified all the participants with 3 variates including the cuneus, parahippocampal, and superior temporal regions of the left hemisphere. The pattern of dSWM changed with the age of AD onset. In early onset patients, we found bilateral posterior demyelination spreading to the temporal areas in the left hemisphere. The late onset patients showed a distributed bilateral pattern with the temporal and cingulate areas strongly affected. A correlation with Mini Mental State Examination (MMSE), Lexis, and memory tests revealed the dSWM impact on cognition. A specific landscape of dSWM in early AD shows the potential of MTR imaging as an in vivo biomarker superior to currently used techniques.

Imaging of a synchronous neuronal assembly in the human visual brain.

Perception, motion, and cognition involve the formation of cooperative neuronal assemblies distributed over the cerebral cortex. It remains to explore what characterizes the assemblies, their location, and the structural substrate of assembly formation. In this EEG/fMRI study, we describe the response of the visual areas of the two hemispheres in subjects who viewed bilateral iso-oriented (IG) or orthogonally-oriented (OG) moving gratings projected in the two hemifields. The IG stimulus synchronized activity across the hemispheres, as shown by an increased EEG coherence. The increase was restricted to the occipital electrodes and to the beta band. Compared with OG, IG increased the BOLD signal in a restricted territory corresponding to area VP/V4. Within this territory, a linear relation was found between the increased interhemispheric EEG coherence and BOLD. Thus, the increased BOLD localized a trans-hemispheric, synchronous neuronal assembly probably achieved by a callosal cortico-cortical connection. This assembly might reflect an early stage of perceptual grouping since the IG stimulus conforms to Gestalt psychology principles of collinearity and common fate.

Brain structure in asymptomatic FMR1 premutation carriers at risk for fragile X-associated tremor/ataxia syndrome.

Fragile X-associated tremor/ataxia syndrome (FXTAS), a late-onset movement disorder affecting FMR1 premutation carriers, is associated with cerebral and cerebellar lesions. The aim of this study was to test whether computational anatomy can detect similar patterns in asymptomatic FMR1 premutation carriers (mean age 46.7 years) with qualitatively normal -appearing grey and white matter on brain MRI. We used a multimodal imaging protocol to characterize brain anatomy by automated assessment of gray matter volume and white matter properties. Structural changes in the hippocampus and in the cerebellar motor network with decreased gray matter volume in lobule VI and white matter alterations of the corresponding afferent projections through the middle cerebellar peduncles are demonstrated. Diffuse subcortical white matter changes in both hemispheres, without corresponding gray matter alterations, are only identified through age × group interactions. We interpret the hippocampal fimbria and cerebellar changes as early alterations with a possible neurodevelopmental origin. In contrast, progression of the diffuse cerebral hemispheric white matter changes suggests a neurodegenerative process, leading to late-onset lesions, which may mark the imminent onset of FXTAS.