Striatal and cerebellar vesicular acetylcholine transporter expression is disrupted in human DYT1 dystonia.

Early-onset torsion dystonia (TOR1A/DYT1) is a devastating hereditary motor disorder whose pathophysiology remains unclear. Studies in transgenic mice suggested abnormal cholinergic transmission in the putamen, but this has not yet been demonstrated in humans. The role of the cerebellum in the pathophysiology of the disease has also been highlighted but the involvement of the intrinsic cerebellar cholinergic system is unknown. In this study, cholinergic neurons were imaged using PET with 18F-fluoroethoxybenzovesamicol, a radioligand of the vesicular acetylcholine transporter (VAChT). Here, we found an age-related decrease in VAChT expression in the posterior putamen and caudate nucleus of DYT1 patients versus matched controls, with low expression in young but not in older patients. In the cerebellar vermis, VAChT expression was also significantly decreased in patients versus controls, but independently of age. Functional connectivity within the motor network studied in MRI and the interregional correlation of VAChT expression studied in PET were also altered in patients. These results show that the cholinergic system is disrupted in the brain of DYT1 patients and is modulated over time through plasticity or compensatory mechanisms.

Free water: A marker of age-related modifications of the cingulum white matter and its association with cognitive decline.

Diffusion MRI is extensively used to investigate changes in white matter microstructure. However, diffusion measures within white matter tissue can be affected by partial volume effects due to cerebrospinal fluid and white matter hyperintensities, especially in the aging brain. In previous aging studies, the cingulum bundle that plays a central role in the architecture of the brain networks supporting cognitive functions has been associated with cognitive deficits. However, most of these studies did not consider the partial volume effects on diffusion measures. The aim of this study was to evaluate the effect of free water elimination on diffusion measures of the cingulum in a group of 68 healthy elderly individuals. We first determined the effect of free water elimination on conventional DTI measures and then examined the effect of free water elimination on verbal fluency performance over 12 years. The cingulum bundle was reconstructed with a tractography pipeline including a white matter hyperintensities mask to limit the negative impact of hyperintensities on fiber tracking algorithms. We observed that free water elimination increased the ability of conventional DTI measures to detect associations between tissue diffusion measures of the cingulum and changes in verbal fluency in older individuals. Moreover, free water content and mean diffusivity measured along the cingulum were independently associated with changes in verbal fluency. This suggests that both tissue modifications and an increase in interstitial isotropic water would contribute to cognitive decline. These observations reinforce the importance of using free water elimination when studying brain aging and indicate that free water itself could be a relevant marker for age-related cingulum white matter modifications and cognitive decline.

Changes Over Time of Diffusion MRI in the White Matter of Aging Brain, a Good Predictor of Verbal Recall.

Objective: Extensive research using water-diffusion MRI reported age-related modifications of cerebral White Matter (WM). Moreover, water-diffusion parameter modifications have been frequently associated with cognitive performances in the elderly sample, reinforcing the idea of aging inducing microstructural disconnection of the brain which in turn impacts cognition. However, only few studies really assessed over-time modifications of these parameters and their relationship with episodic memory outcome of elderly. Materials and Methods: One-hundred and thirty elderly subjects without dementia (74.1 ± 4.1 years; 47% female) were included in this study. Diffusion tensor imaging (DTI) was performed at two-time points (3.49 ± 0.68 years apart), allowing the assessment of changes in water-diffusion parameters over time using a specific longitudinal pipeline. White matter hyperintensity (WMH) burden and gray matter (GM) atrophy were also measured on FLAIR and T1-weighted sequences collected during these two MRI sessions. Free and cued verbal recall scores assessed at the last follow-up of the cohort were used as episodic memory outcome. Changes in water-diffusion parameters over time were included in serial linear regression models to predict retrieval or storage ability of elderly. Results: GM atrophy and an increase in mean diffusivity (MD) and WMH load between the two-time points were observed. The increase in MD was significantly correlated with WMH load and the different memory scores. In models accounting for the baseline cognitive score, GM atrophy, or WMH load, MD changes still significantly predict free verbal recall, and not total verbal recall, suggesting the specific association with the retrieval deficit in healthy aging. Conclusion: In elderly, microstructural WM changes are good predictors of lower free verbal recall performances. Moreover, this contribution is not only driven by WMH load increase. This last observation is in line with studies reporting early water-diffusion modification in WM tissue during aging, resulting lately in the appearance of WMH on conventional MRI.

Age-related change in episodic memory: role of functional and structural connectivity between the ventral posterior cingulate and the parietal cortex.

While the neural correlates of age-related episodic memory decline have been extensively studied, the precise involvement of the Posterior Cingulate Cortex (PCC) and posterior parietal cortex (the precuneus and the angular gyrus), remains unclear. The present study examined functional and structural neural correlates of age-related episodic memory change assessed over 12 years in 120 older adults (range 76-90 years). Episodic memory performance was measured using the Free and Cued Selective Reminding Test (FCSRT); functional connectivity metrics were computed from resting-state fMRI images and structural connectivity metrics were assessed through microstructural properties of reconstructed tract using a native space pipeline. We found that FCSRT change was significantly associated with the functional connectivity between the ventral PCC and three parietal regions, the ventral superior, the inferior part of the precuneus, and the rostro dorsal part of the angular gyrus. This association was independent of hippocampal volume. In addition, we found the that change in FCSRT scores was associated with fractional anisotropy of the tract connecting the ventral PCC and the ventral superior part of the precuneus. Change in episodic memory in aging was therefore related to a combination of high functional connectivity and low structural connectivity between the ventral PCC and the ventral superior part of the precuneus.

Resting Heart Rate Predicts Depression and Cognition Early after Ischemic Stroke: A Pilot Study.

BACKGROUND: Early detection of poststroke depression (PSD) and cognitive impairment (PSCI) remains challenging. It is well documented that the function of autonomic nervous system is associated with depression and cognition. However, their relationship has never been investigated in the early poststroke phase. This pilot study aimed at determining whether resting heart rate (HR) parameters measured in early poststroke phase (1) are associated with early-phase measures of depression and cognition and (2) could be used as new tools for early objective prediction of PSD or PSCI, which could be applicable to patients unable to answer usual questionnaires. METHODS: Fifty-four patients with first-ever ischemic stroke, without cardiac arrhythmia, were assessed for resting HR and heart rate variability (HRV) within the first week after stroke and for depression and cognition during the first week and at 3 months after stroke. RESULTS: Multiple regression analyses controlled for age, gender, and stroke severity revealed that higher HR, lower HRV, and higher sympathovagal balance (low-frequency/high-frequency ratio of HRV) were associated with higher severity of depressive symptoms within the first week after stroke. Furthermore, higher sympathovagal balance in early phase predicted higher severity of depressive symptoms at the 3-month follow-up, whereas higher HR and lower HRV in early phase predicted lower global cognitive functioning at the 3-month follow-up. CONCLUSIONS: Resting HR measurements obtained in early poststroke phase could serve as an objective tool, applicable to patients unable to complete questionnaires, to help in the early prediction of PSD and PSCI.

Vascular Cerebral Damage in Frail Older Adults: The AMImage Study.

BACKGROUND: Frailty has been associated with increased risk of adverse-health related outcomes including cognitive impairment. However, little is know about the pathogenesis relating frailty to cognitive decline. Therefore, the main objective of this study was to investigate the association between vascular cerebral damage and frailty. METHODS: Cross-sectional study involving 176 community-dwelling participants aged 67-86 years, participating in the AMImage Study, an ancillary neuro-imaging project of the AMI cohort, a French prospective cohort including older farmers living in rural areas. Frailty was defined as proposed by Fried. 3T magnetic resonance imaging (MRI) examination was performed with anatomical, diffusion, and fluid-attenuated inversion recovery sequences. The evaluation included the assessment of white matter hyperintensities (WMH) volumes and of microstructural white matter integrity through exploration of diffusion tensor imaging (DTI) parameters. RESULTS: The analyses showed that WMH volumes were higher in frail persons compared with nonfrail subgroup. Frail participants presented DTI modifications in extensive areas of white matter. In comparison with nonfrail subgroup, frail participants showed a strong association between WMH volumes and DTI changes. CONCLUSION: These results show that subclinical cerebrovascular damage is present in the frail older person, which could support the hypothesis that frailty is a prodromal state of central nervous system vascular injury.

Patterns of brain atrophy associated with episodic memory and semantic fluency decline in aging.

The cerebral substratum of age-related cognitive decline was evaluated in an elderly-cohort followed for 12 years (n=306). Participants, free of dementia, received neuropsychological assessments every two years and an MRI exam at baseline and four years later. Cognitive decline was evaluated on two broadly used tests to detect dementia: the Free and Cued Selective Reminding Test (FCSRT), a verbal episodic memory task, and the Isaacs Set Test (IST), a semantic fluency task. Using voxel-based approach, the relationship between cognitive decline with 1/ baseline grey matter volumes and 2/ grey matter volume loss between the two scans was explored. Baseline volumes analysis revealed that FCSRT and IST declines were both associated with lower volumes of the medial temporal region. Volumes loss analysis confirmed that both declines are related to medial temporal lobe atrophy and revealed that FCSRT decline was specifically associated with atrophy of the posterior cingulate cortex whereas IST decline was specifically related to temporal pole atrophy. These results suggest that cognitive decline across aging is firstly related to structural modifications of the medial temporal lobe, followed by an atrophy in the posterior midline structures for episodic memory and an atrophy of the temporal pole for semantic fluency.

123I-Iodobenzovesamicol SPECT Imaging of Cholinergic Systems in Dementia with Lewy Bodies.

Cholinergic alterations in dementia with Lewy bodies (DLB) have been widely documented in postmortem studies, whereas in vivo studies are sparse, particularly at the subcortical level. We used 123I-iodobenzovesamicol, a SPECT radiotracer of the vesicular acetylcholine transporter, to evaluate in vivo in DLB the integrity of the 3 main cholinergic pathways-the Ch1 (septohippocampal), the Ch4 (innominatocortical), and the Ch5 (pontothalamic) cholinergic pathways-as well as the striatal cholinergic interneurons. In addition, we assessed the involvement of the cholinergic system in cognitive and neuropsychiatric disorders in DLB patients. METHODS: Twelve healthy volunteers (median age, 72 y; interquartile range, 6.25 y) and 11 DLB patients (median age, 76 y; interquartile range, 10.50 y) underwent a dynamic 123I-iodobenzovesamicol SPECT scan and an MRI scan. MR images were automatically segmented, providing the volumes of several regions of interest, including the striatum and cholinergic terminals in Ch1 (hippocampus), Ch4 (cortical lobes), and Ch5 (thalamus). For each region of interest and each subject, pharmacokinetic modeling allowed calculation of the nondisplaceable binding potential (BPND) values for the binding of 123I-iodobenzovesamicol to the vesicular acetylcholine transporter. A neuropsychological evaluation of participants was performed with the Mini-Mental State Examination and the Grober-Buschke, Set, visual discrimination, Benton, and Wechsler tests, and cognitive fluctuations and apathy were also assessed. RESULTS: Compared with BPND values for healthy subjects, BPND values for DLB patients were significantly lower in the Ch4 terminal regions of the anterior cingulate cortex and the superior and inferior parietal cortices (P = 0.0006, 0.0015, and 0.0023, respectively), in the Ch5 terminal region of the thalamus (P = 0.0003), and in the striatum (P = 0.0042). All of the neuropsychological test scores were significantly lower in DLB patients than in healthy subjects. Four DLB patients with apathy and 4 DLB patients without apathy were identified. For the anterior cingulate cortex, compared with BPND values in healthy subjects, BPND values were significantly lower in patients with apathy (P = 0.004) and were unchanged in patients without apathy. CONCLUSION: Our results confirm the existence in DLB of cholinergic alterations, reaching both cortical and subcortical levels, including the Ch5 pathway and the striatum. Alterations in cholinergic transmission in the anterior cingulate cortex could be closely associated with the development of apathy.

Feasibility and validity of mobile cognitive testing in the investigation of age-related cognitive decline.

Mobile cognitive testing may be used to help characterize subtle deficits at the earliest stages of cognitive decline. Despite growing interest in this approach, comprehensive information concerning its feasibility and validity has been lacking in elderly samples. Over a one-week period, this study applied mobile cognitive tests of semantic memory, episodic memory and executive functioning in a cohort of 114 elderly non-demented community residents. While the study acceptance rate was moderate (66%), the majority of recruited individuals met minimal compliance thresholds and responded to an average of 82% of the repeated daily assessments. Missing data did not increase over the course of the study, but practice effects were observed for several test scores. However, even when controlling for practice effects, traditional neuropsychological tests were significantly associated with mobile cognitive test scores. In particular, the Isaacs Set Test was associated with mobile assessments of semantic memory (γ = 0.084, t = 5.598, p < 0.001), the Grober and Buschke with mobile assessments of episodic memory (γ = 0.069, t = 3.156, p < 0.01, and the Weschler symbol coding with mobile assessments of executive functioning (γ = 0.168, t = 4.562, p < 0.001). Mobile cognitive testing in the elderly may provide complementary and potentially more sensitive data relative to traditional neuropsychological assessment. Copyright © 2016 John Wiley & Sons, Ltd.

Cerebral changes and cognitive impairment after an ischemic heart disease: a multimodal MRI study.

Three to 6 months after an acute coronary syndrome (ACS), cognitive impairment is observed in more than 30 % of the patients, mainly in executive functioning. The aim of this study was to investigate, using multimodal MRI, cerebral anatomo-functional substratum of executive dysfunction. Thirty-three patients were recruited 4 ± 1 months after a first ACS. Executive functions were evaluated with the Trail-Making-Test-B (TMTB) at baseline (ie 4 ± 1 months after ACS) and 6 months later (ie 10 ± 1 months after ACS). Using both time-points, we identified 3 groups of patients according to normative data based on age, gender and education level: 15 'cognitively normal' patients without impairment at each follow-up, 10 'transient impaired' patients with an impairment only at baseline and 8 'impairing' patients with an impairment only at follow-up. We explored, in the whole-brain, the structural integrity using Voxel-Based Morphometry and Tract-Based Spatial Statistics and the resting-state functional connectivity using Network-Based Statistics. No structural difference was observed between impaired and cognitively normal patients. At the functional level, compared to the 'cognitively normal' group, the 'transient impaired' patients presented an increased functional connectivity in a network centered on middle-orbito-frontal regions, whereas the 'impairing' patients presented only a non-significant decrease of functional connectivity. Executive dysfunction in ACS patients is associated to functional but no structural characteristics, particularly to an increased functional connectivity in cognitive networks in transient impaired patients. Further studies with larger sample size are needed to confirm these results and to determine if these patients could be at higher risk for developing permanent cognitive disorders.

Detection of Alzheimer's disease signature in MR images seven years before conversion to dementia: Toward an early individual prognosis.

Finding very early biomarkers of Alzheimer's Disease (AD) to aid in individual prognosis is of major interest to accelerate the development of new therapies. Among the potential biomarkers, neurodegeneration measurements from MRI are considered as good candidates but have so far not been effective at the early stages of the pathology. Our objective is to investigate the efficiency of a new MR-based hippocampal grading score to detect incident dementia in cognitively intact patients. This new score is based on a pattern recognition strategy, providing a grading measure that reflects the similarity of the anatomical patterns of the subject under study with dataset composed of healthy subjects and patients with AD. Hippocampal grading was evaluated on subjects from the Three-City cohort, with a followup period of 12 years. Experiments demonstrate that hippocampal grading yields prediction accuracy up to 72.5% (P < 0.0001) 7 years before conversion to AD, better than both hippocampal volume (58.1%, P = 0.04) and MMSE score (56.9%, P = 0.08). The area under the ROC curve (AUC) supports the efficiency of imaging biomarkers with a gain of 8.4 percentage points for hippocampal grade (73.0%) over hippocampal volume (64.6%). Adaptation of the proposed framework to clinical score estimation is also presented. Compared with previous studies investigating new biomarkers for AD prediction over much shorter periods, the very long followup of the Three-City cohort demonstrates the important clinical potential of the proposed imaging biomarker. The high accuracy obtained with this new imaging biomarker paves the way for computer-based prognostic aides to help the clinician identify cognitively intact subjects that are at high risk to develop AD.

PCC characteristics at rest in 10-year memory decliners.

The present research sought to characterize the intrinsic functional networks associated with a 10-year episodic memory decline in elderly using data from a longitudinal population-based cohort (Bordeaux-3City). Complementary measures of whole-brain resting-state functional magnetic resonance imaging investigations were combined to compare functional architecture of brain networks both at connectional and topological levels in 22 decliners to 22 nondecliners; episodic memory decline being assessed through a multiple time point Free and Cued Selective Reminding Test. The decliners presented differences in functional architecture centered on the posterior cingulate cortex, characterized by a significant decrease of connectivity intensity, a significant increased centrality. In accordance, a decrease of the functional connectivity inside the default mode network was observed in the decliners. Our results highlight the central role of the posterior cingulate cortex in a slow but reliable memory decline in elderly. Because functional alterations of this region are currently described in Alzheimer's disease, this functional signature could constitute a risk for Alzheimer's disease.

Mediterranean diet and preserved brain structural connectivity in older subjects.

INTRODUCTION: The Mediterranean diet (MeDi) has been related to a lower risk of Alzheimer's disease; yet, the underlying mechanisms are unknown. We hypothesized that protection against neurodegeneration would translate into higher gray matter volumes, whereas a specific association with preserved white matter microstructure would suggest alternative mechanisms (e.g., vascular pathways). METHODS: We included 146 participants from the Bordeaux Three-City study nondemented when they completed a dietary questionnaire and who underwent a 3-T magnetic resonance imaging at an average of 9 years later, including diffusion tensor imaging. RESULTS: In multivariate voxel-by-voxel analyses, adherence to the MeDi was significantly associated with preserved white matter microstructure in extensive areas, a gain in structural connectivity that was related to strong cognitive benefits. In contrast, we found no relation with gray matter volumes. DISCUSSION: The MeDi appears to benefit brain health through preservation of structural connectivity. Potential mediation by a favorable impact on brain vasculature deserves further research.

Alzheimer's disease diagnosis on structural MR images using circular harmonic functions descriptors on hippocampus and posterior cingulate cortex.

Recently, several pattern recognition methods have been proposed to automatically discriminate between patients with and without Alzheimer's disease using different imaging modalities: sMRI, fMRI, PET and SPECT. Classical approaches in visual information retrieval have been successfully used for analysis of structural MRI brain images. In this paper, we use the visual indexing framework and pattern recognition analysis based on structural MRI data to discriminate three classes of subjects: normal controls (NC), mild cognitive impairment (MCI) and Alzheimer's disease (AD). The approach uses the circular harmonic functions (CHFs) to extract local features from the most involved areas in the disease: hippocampus and posterior cingulate cortex (PCC) in each slice in all three brain projections. The features are quantized using the Bag-of-Visual-Words approach to build one signature by brain (subject). This yields a transformation of a full 3D image of brain ROIs into a 1D signature, a histogram of quantized features. To reduce the dimensionality of the signature, we use the PCA technique. Support vector machines classifiers are then applied to classify groups. The experiments were conducted on a subset of ADNI dataset and applied to the "Bordeaux-3City" dataset. The results showed that our approach achieves respectively for ADNI dataset and "Bordeaux-3City" dataset; for AD vs NC classification, an accuracy of 83.77% and 78%, a specificity of 88.2% and 80.4% and a sensitivity of 79.09% and 74.7%. For NC vs MCI classification we achieved for the ADNI datasets an accuracy of 69.45%, a specificity of 74.8% and a sensitivity of 62.52%. For the most challenging classification task (AD vs MCI), we reached an accuracy of 62.07%, a specificity of 75.15% and a sensitivity of 49.02%. The use of PCC visual features description improves classification results by more than 5% compared to the use of hippocampus features only. Our approach is automatic, less time-consuming and does not require the intervention of the clinician during the disease diagnosis.

Gray matter characteristics associated with trait anxiety in older adults are moderated by depression.

BACKGROUND: Structural gray matter characteristics of anxiety remain unclear. The aim of this study was to assess the influence of current depressive symptoms and history of depression on the gray matter characteristics of trait anxiety. METHODS: Structural magnetic resonance imaging (MRI) data from 393 individuals aged 65 years or older were used. Regions of interest (ROIs) included the amygdala, anterior cingulate cortex (ACC), insula, orbitofrontal cortex (OFC), and temporal cortex. Trait anxiety was measured by the State-Trait Anxiety Inventory (STAI). Depression and depressive symptoms were measured using DSM-IV criteria and the Center for Epidemiological Studies Depression Scale (CESD). RESULTS: After adjustments for sociodemographics and health-related variables, anxiety had a significant influence on the gray matter characteristics in all cortical ROIs. First, in participants without depression antecedents, higher trait anxiety was associated with a larger cortical thickness in all cortical ROIs. Second, in participants with a previous history of depression, higher trait anxiety was associated with a smaller cortical thickness in all cortical ROIs. CONCLUSIONS: These results suggest that anxiety is related to cortical thickness differently in healthy older adults and in older adults with psychiatric antecedents. Anxiety associated with thinner cortical areas could reflect symptoms of a specific type of depression or a vulnerability to develop depression.

Simplified Quantification Method for In Vivo SPECT Imaging of the Vesicular Acetylcholine Transporter with 123I-Iodobenzovesamicol.

UNLABELLED: (123)I-iodobenzovesamicol is a SPECT radioligand selective for the vesicular acetylcholine transporter (VAChT) and used to assess the integrity of cholinergic pathways in various neurologic disorders. The current noninvasive method for quantitative analysis of (123)I-iodobenzovesamicol, based on multilinear reference tissue model 2 (MRTM2), requires repeated scans for several hours, limiting its application in clinical trials. Our objective was to validate a simplified acquisition method based on a single (123)I-iodobenzovesamicol static scan preserving the quantification accuracy. Three acquisition times were tested comparatively to a kinetic analysis using MRTM2. METHODS: Six healthy volunteers underwent a dynamic SPECT acquisition comprising 14 frames over 28 h and an MR imaging scan. MR images were automatically segmented, providing the volumes of 19 regions of interest (ROIs). SPECT datasets were coregistered with MR images, and regional time-activity curves were derived. For each ROI, a complete MRTM2 pharmacokinetic analysis, using the cerebellar hemispheres as the reference region, led to the calculation of a (123)I-iodobenzovesamicol-to-VAChT binding parameter, the nondisplaceable binding potential (BP(ND-MRTM2)). A simplified analysis was also performed at 5, 8, and 28 h after injection, providing a simplified BP(ND), given as BP(ND-t) = C(ROI) - C(cerebellar hemispheres)/C(cerebellar hemispheres), with C being the averaged radioactive concentration. RESULTS: No significant difference was found among BP(ND-5 h), BP(ND-8 h), and BP(ND-MRTM2) in any of the extrastriatal regions explored. BP(ND-28 h) was significantly higher than BP(ND-5 h), BP(ND-8 h), and BP(ND-MRTM2) in 9 of the 17 regions explored (P < 0.05). BP(ND-5 h), BP(ND-8 h), and BP(ND-28 h) correlated significantly with BP(ND-MRTM2) (P < 0.05; ρ = 0.99, 0.98, and 0.92, respectively). In the striatum, BP(ND-28 h) was significantly higher than BP(ND-5 h) and BP(ND-8 h). BP(ND-5 h) differed significantly from BP(ND-MRTM2) (P < 0.05), with BP(ND-5 h) being 43.6% lower. CONCLUSION: In the extrastriatal regions, a single acquisition at 5 or 8 h after injection provides quantitative results similar to a pharmacokinetic analysis. However, with the highest correlation and accuracy, 5 h is the most suitable time to perform an accurate (123)I-iodobenzovesamicol quantification. In the striatum, none of the 3 times has led to an accurate quantification.

Semantic retrieval over time in the aging brain: Structural evidence of hippocampal contribution.

This study investigates relationship between regional cerebral volumes and performances over time of a categorical fluency task, in a sample of older adults (n = 316). Using voxel-wise technique, the relationship between local grey matter volume and Isaacs Set Test (IST) scores at its early (first 15 sec) and late (last 15 sec) phase production was analyzed with a linear regression model adjusting for age, sex, educational level, ApoEɛ4 allele, handedness and Grey Matter atrophy. Lower early IST scores were associated with smaller volumes in bilateral inferior frontal gyri and in right thalamus, whereas lower late IST scores were associated to smaller left inferior parietal gyrus and left anterior hippocampus. An analysis based on automatic segmentation of hippocampus confirmed the latest relationship which cannot be attributed to the correlation of each variable with global cognitive impairment because it remained when MMSE was accounted for. We observed a switch from frontal to temporo-parietal regions as words retrieval become more difficult over time. Automatic speech production of the early phase of the category fluency task is dependent on executive networks integrity whereas controlled speech production of the late phase is dependent on memory networks integrity, including left hippocampus. These results are concordant with recent imaging studies expanding the implication of hippocampus to semantic memory performances and they underlie the need to consider verbal fluency task over time.

fMRI identifies the right inferior frontal cortex as the brain region where time interval processing is altered by negative emotional arousal.

The reason why human beings are inclined to overestimate the duration of highly arousing negative events remains enigmatic. The issue about what neurocognitive mechanisms and neural structures support the connection between time perception and emotion was addressed here by an event-related neuroimaging study involving a localizer task, followed by the main experiment. The localizer task, in which participants had to categorize either the duration or the average color of visual stimuli aimed at identifying the neural structures constitutive of a duration-specific network. The aim of the main experiment, in which participants had to categorize the presentation time of either neutral or emotionally negative visual stimuli, was to unmask which parts of the previously identified duration-specific network are sensitive to emotionally negative arousal. The duration-specific network that we uncovered from the localizer task comprised the cerebellum bilaterally as well as the orbitofrontal, the anterior cingulate, the anterior insular, and the inferior frontal cortices in the right hemisphere. Strikingly, the imaging data from the main experiment underscored that the right inferior frontal cortex (IFC) was the only region within the duration-specific network whose activity was increased in the face of emotionally negative pictures compared to neutral ones. Remarkably too, the extent of neural activation induced by emotionally negative pictures (compared to neutral ones) in this region correlated with a behavioral index reflecting the extent to which emotionally negative pictures were overestimated compared to neutral ones. The results are discussed in relation to recent models and studies suggesting that the right anterior insular cortex/IFC is of central importance in time perception.