"Back to Braak": Role of Nucleus Reuniens and Subcortical Pathways in Alzheimer's Disease Progression.

BACKGROUND: Patients with Alzheimer's Disease (AD) exhibit structural alterations of the thalamus that correlate with clinical symptoms. However, given the anatomical complexity of this brain structure, it is still unclear whether atrophy affects specific thalamic nuclei and modulates the clinical progression from a prodromal stage, known as Mild Cognitive Impairment (MCI), to full-fledged AD. OBJECTIVES: To characterize the structural integrity of distinct thalamic nuclei across the AD spectrum, testing whether MCI patients who convert to AD (c-MCI) show a distinctive pattern of thalamic structural alterations compared to patients who remain stable (s-MCI). DESIGN: Investigating between-group differences in the volumetric features of distinct thalamic nuclei across the AD spectrum. SETTING: Prodromal and clinical stages of AD. PARTICIPANTS: We analyzed data from 84 healthy control subjects (HC), 58 individuals with MCI, and 102 AD patients. The dataset was obtained from the AD Neuroimaging Initiative (ADNI-3) database. The MCI group was further divided into two subgroups depending on whether patients remained stable (s-MCI, n=22) or progressed to AD (s-MCI, n=36) in the 48 months following the diagnosis. MEASUREMENTS: A multivariate analysis of variance (MANOVA) assessed group differences in the volumetric features of distinct thalamic nuclei obtained from magnetic resonance (MR) images. A stepwise discriminant function analysis identified which feature most effectively predicted the conversion to AD. The corresponding predictive performance was evaluated through a Receiver Operating Characteristic approach. RESULTS: AD and c-MCI patients showed generalized atrophy of thalamic nuclei compared to HC. In contrast, no significant structural differences were observed between s-MCI and HC subjects. Compared to s-MCI, c-MCI individuals displayed significant atrophy of the nucleus reuniens and a trend toward significant atrophy in the anteroventral and laterodorsal nuclei. The discriminant function analysis confirmed the nucleus reuniens as a significant predictor of AD conversion, with a sensitivity of 0.73 and a specificity of 0.69. CONCLUSIONS: In line with the pathophysiological relevance of the nucleus reuniens proposed by seminal post-mortem studies on patients with AD, we confirm the pivotal role of this nucleus as a critical hub in the clinical progression to AD. We also propose a theoretical model to explain the evolving dysfunction of subcortical brain networks in the disease process.

Multimodal assessment of hemispheric lateralization for language and its relevance for behavior.

Although different MRI-based techniques have been proposed to assess the hemispheric lateralization for language (HLL), the agreement across methods, and its relationship with language abilities, are still a matter of debate. In the present study we obtained measures of HLL using both task-evoked activity during the execution of three different protocols and task-free methods of functional [resting state functional connectivity (rs-FC)] and anatomical [diffusion tensor imaging (DTI) tractography] connectivity. Regional analyses focusing on the perisylvian language network were conducted to assess the consistency of HLL across techniques. In addition, following a multimodal approach, we identified macro-factors of lateralization and examined their relationship with language performance. Our findings indicate the existence of a negative relationship between the structural asymmetry of the direct segment of the arcuate fasciculus (AF) and the inter-hemispheric rs-FC of key nodes of the perisylvian network. Instead, despite all the language tasks exhibited a leftward pattern of asymmetry, measures of HLL derived from task-evoked activity did not show a direct relationship with those obtained with the two task-free methods. Furthermore, a robust brain-behavioral relationship was observed only with a specific macro-factor that combined HLL measures derived from all MRI techniques. In particular, general language performance was positively related to more symmetrical structural organization, stronger inter-hemispheric communication at rest but more lateralized activation of Wernicke's territory during production tasks. Our findings, while not supporting the existence of a direct relationship between indices of hemispheric lateralization for language derived from different MRI techniques, indicate that general language performance can be indexed using combined MRI measures. The same approach might prove successful for likewise complex human behaviours.

Reorganization of functional connectivity of the language network in patients with brain gliomas.

BACKGROUND AND PURPOSE: fcMRI measures spontaneous and synchronous fluctuations of BOLD signal between spatially remote brain regions. The present study investigated potential LN fcMRI modifications induced by left hemisphere brain gliomas. MATERIALS AND METHODS: We retrospectively evaluated fcMRI in 39 right-handed patients with a left hemisphere brain glioma and 13 healthy controls. Patients and controls performed a verb-generation task to identify individual BOLD activity in the left IFG (Broca area); the active region was used as seed to create whole-brain background connectivity maps and to identify the LN (including bilateral regions of the IFG, STS, and TPJ) following regression of task-evoked activity. We assessed differences between patients and controls in the pattern of functional connectivity of the LN, as well as potential effects of tumor position, histopathology, and volume. RESULTS: Global fcMRI of the LN was significantly reduced in patients with tumor compared with controls. Specifically, fcMRI was significantly reduced within seed regions of the affected hemisphere (left intrahemispheric fcMRI) and between the TPJ of the 2 hemispheres. In patients, the left TPJ node showed the greatest decrease of functional connectivity within the LN. CONCLUSIONS: The presence of a brain tumor in the left hemisphere significantly reduced the degree of fcMRI between language-related brain regions. The pattern of fcMRI was influenced by tumor position but was not restricted to the area immediately surrounding the tumor because the connectivity between remote and contralateral areas was also affected.

Comparison of hypothesis- and a novel hybrid data/hypothesis-driven method of functional MR imaging analysis in patients with brain gliomas.

BACKGROUND AND PURPOSE: An alternative technique, which is less influenced by tumor- and patient-related factors, is required to overcome the limits of GLM analysis of fMRI data in patients. The aim of this study was to statistically assess differences in the identification of language regions and hemispheric lateralization of language function between controls and patients as estimated by both the GLM and a novel combined ICA-GLM procedure. MATERIALS AND METHODS: We retrospectively evaluated 42 patients with pathologically confirmed brain gliomas of the left frontal and/or temporoparietal lobes and a control group of 14 age-matched healthy volunteers who underwent BOLD fMRI to lateralize language functions in the cerebral hemispheres. Data were processed by using a classic GLM and ICA-GLM. RESULTS: ICA-GLM demonstrated a higher sensitivity in detecting language activation, specifically in the left TPJ of patients. There were no significant differences between the GLM and ICA-GLM in controls; however, statistically significant differences were observed by using ICA-GLM for the LI in patients. For the computation of the LI, ICA-GLM was less influenced by the chosen statistical threshold compared with the GLM. CONCLUSIONS: We suggest the use of the ICA-GLM as a valid alternative to the classic GLM method for presurgical mapping in patients with brain tumors and to replicate the present results in a broader sample of patients.

Functional connectivity MR imaging of the language network in patients with drug-resistant epilepsy.

BACKGROUND AND PURPOSE: Subtle linguistic dysfunction and reorganization of the language network were described in patients with epilepsy, suggesting the occurrence of plasticity changes. We used resting state FC-MRI to investigate the effects induced by chronic epilepsy on the connectivity of the language-related brain regions and correlated it with language performance. MATERIALS AND METHODS: FC-MRI was evaluated in 22 right-handed patients with drug-resistant epilepsy (11 with LE and 11 with RE) and in 12 healthy volunteers. Neuropsychological assessment of verbal IQ was performed. Patients and controls underwent BOLD fMRI with a verb-generation task, and language function was lateralized by an LI. Intrinsic activity fluctuations for FC analysis were extracted from data collected during the task. Six seeding cortical regions for speech in both hemispheres were selected to obtain a measure of the connectivity pattern among the language networks. RESULTS: Patients with LE presented atypical language lateralization and an overall reduced connectivity of the language network with respect to controls. In patients with both LE and RE, the mean FC was significantly reduced within the left (dominant) hemisphere and between the 2 hemispheres. In patients with LE, there was a positive correlation between verbal IQ scores and the left intrahemispheric FC. CONCLUSIONS: In patients with intractable epilepsy, FC-MRI revealed an overall reduction and reorganization of the connectivity pattern within the language network. FC was reduced in the left hemisphere regardless of the epileptogenic focus side and was positively correlated with linguistic performance only in patients with LE.

An fMRI investigation on image generation in different sensory modalities: the influence of vividness.

In the present fMRI study the issue of the specific cortices activation during imagery generation in different sensory modalities is addressed. In particular, we tested whether the vividness variability of imagery was reflected in the BOLD signal within specific sensory cortices. Subjects were asked to generate a mental image for each auditory presented sentence. Each imagery modality was contrasted with an abstract sentence condition. In addition, subjects were asked to fill the Italian version of the Questionnaire Upon Mental Imagery (QMI) prior to each neuroimaging session. In general, greater involvement of sensory specific cortices in high-vivid versus low-vivid subjects was found for visual (occipital), gustatory (anterior insula), kinaesthetic (pre-motor), and tactile and for somatic (post-central parietal) imagery modalities. These results support the hypothesis that vividness is related to image format: high-vivid subjects would create more analogical representations relying on the same specific neural substrates active during perception with respect to low-vivid subjects. Results are also discussed according to the simulation perspective.

Independence of anticipatory signals for spatial attention from number of nontarget stimuli in the visual field.

Covertly attending to a location modulates the activity of visual areas even in the absence of visual stimulation. These effects are widespread, being found in the cortical representations of both attended and unattended portions of the visual field. It is not clear, however, whether preparatory modulations depend on subjects' expectation regarding the presence of additional nontarget stimuli in the visual field. Here, we asked subjects to endogenously direct attention to a peripheral location in the upper visual field, to identify the orientation of a low-contrast target stimulus, and we manipulated the number and behavioral relevance of other low-contrast nontarget stimuli in the visual field. Anticipatory (i.e., prestimulus) blood oxygenation level-dependent (BOLD) signal increments in visual cortex were strongest at the contralateral attended location, whereas signal decrements were strongest at the unattended mirror-opposite ipsilateral location/region of visual cortex. Importantly, these strong anticipatory decrements were not related to the presence/absence of nontarget low-contrast stimuli and did not correlate with either weaker target-evoked responses or worse performance. Second, the presence of other low-contrast stimuli in the visual field, even when potential targets, did not modify the anticipatory signal modulation either at target or nontarget locations. We conclude that the topography of spatial attention-related anticipatory BOLD signal modulation across visual cortex, specifically decrements at unattended locations, is mainly determined by processes at the cued location and not by the number or behavioral relevance of distant low-contrast nontarget stimuli elsewhere in the visual field.

Brain network for passive word listening as evaluated with ICA and Granger causality.

Brain network modeling is probably the biggest challenge in fMRI data analysis. Higher cognitive processes in fact, rely on complex dynamics of temporally and spatially segregated brain activities. A number of different techniques, mostly derived from paradigmatic hypothesis-driven methods, have been successfully applied for such purpose. This paper instead, presents a new data-driven analysis approach that applies both independent components analysis (ICA) and the Granger causality (GC). The method includes two steps: (1) ICA is used to extract the independent functional activities; (2) the GC is applied to the independent component (IC) most correlated with the stimuli, to indicate its functional relation with other ICs. This new method is applied to the analysis of fMRI study of listening to high-frequency trisyllabic words, non-words and reversed words. As expected, activity was found in the primary and secondary auditory cortices. Additionally, a parieto-frontal network of activations, supported by temporal and causality relationships, was found. This network is modulated by experimental conditions in agreement with the most recent models presented for word perception. The results have confirmed the validity of the proposed method, and seem promising for the detection of cognitive causal relationships in neuroimaging data.

"What" versus "where" in the audiovisual domain: an fMRI study.

Similar "what/where" functional segregations have been proposed for both visual and auditory cortical processing. In this fMRI study, we investigated if the same segregation exists in the crossmodal domain, when visual and auditory stimuli have to be matched in order to perform either a recognition or a localization task. Recent neuroimaging research highlighted the contribution of different heteromodal cortical regions during various forms of crossmodal binding. Interestingly, crossmodal effects during audiovisual speech and object recognition have been found in the superior temporal sulcus, while crossmodal effects during the execution of spatial tasks have been found over the intraparietal sulcus, suggesting an underlying "what/where" segregation. In order to directly compare the specific involvement of these two heteromodal regions, we scanned ten male right-handed subjects during the execution of two crossmodal matching tasks. Participants were simultaneously presented with a picture and an environmental sound, coming from either the same or the opposite hemifield and representing either the same or a different object. The two tasks required a manual YES/NO response respectively about location or semantic matching of the presented stimuli. Both group and individual subject analysis were performed. Task-related differences in BOLD response were observed in the right intraparietal sulcus and in the left superior temporal sulcus, providing a direct confirmation of the "what-where" functional segregation in the crossmodal audiovisual domain.