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Dementia with Lewy bodies (DLB) causes elevated outlays for the National Health Systems due to high institutionalization rate and patients' reduced quality of life and high mortality. Furthermore, DLB is often misdiagnosed as Alzheimer's disease. These data motivate harmonized multicenter longitudinal cohort studies to improve clinical management and therapy monitoring. The Italian DLB study group of the Italian Neurological Society for dementia (SINdem) developed and emailed a semi-structured questionnaire to 572 national dementia centers (from primary to tertiary) to prepare an Italian large longitudinal cohort. The questionnaire surveyed: (1) prevalence and incidence of DLB; (2) clinical assessment; (3) relevance and availability of diagnostic tools; (4) pharmacological management of cognitive, motor, and behavioural disturbances; (5) causes of hospitalization, with specific focus on delirium and its treatment. Overall, 135 centers (23.6 %) contributed to the survey. Overall, 5624 patients with DLB are currently followed by the 135 centers in a year (2042 of them are new patients). The percentage of DLB patients was lower (27 ± 8 %) than that of Alzheimer's disease and frontotemporal dementia (56 ± 27 %) patients. The majority of the centers (91 %) considered the clinical and neuropsychological assessments as the most relevant procedure for a DLB diagnosis. Nonetheless, most of the centers has availability of magnetic resonance imaging (MRI; 95 %), electroencephalography (EEG; 93 %), and FP-CIT single photon emission-computerized tomography (SPECT; 75 %) scan for clinical applications. It will be, therefore, possible to recruit a large harmonized Italian cohort of DLB patients for future cross-sectional and longitudinal multicenter studies.

Different aspects of episodic long-term, short-term and implicit long-term memory were investigated in subjects who strictly fulfilled the criteria for the amnestic form of Mild Cognitive Impairment (a-MCI). Results showed normal short-term memory abilities in these subjects, while each of the episodic long-term memory indices explored showed poorer results in a-MCI subjects with respect to normal controls. Although some episodic memory functions were relatively well preserved, others appeared to have deteriorated to a level comparable to that of mild AD patients. The finding of an extensive impairment of all memory functions depending on hippocampal structures in a population with a high risk of developing dementia is strongly supportive of the hypothesis that a pure amnesic syndrome characterizes the preclinical phase of AD. Copyright © Taylor & Francis Ltd.

We used fMRI to explore the extent of the anatomical overlap of three neural systems that the literature on developmental dyslexia associates with reading: the auditory phonological, the visual magnocellular, and the motor/cerebellar systems. Twenty‐eight normal subjects performed four tasks during fMRI scans: word and pseudoword reading, auditory rhyming for letter names, visual motion perception, and a motor sequence learning task. We found that the left occipitotemporal cortex (OTC), which previous studies reported to be dysfunctional in dyslexia, can be fractionated into different functional areas: an anterior and lateral area that was activated by both reading and auditory rhyming tasks; a posterior area that was commonly activated by both the reading and the motion perception task and a medial/intermediate area, including the so‐called Visual Word Form Area, which was specifically activated by the reading task. These results show that the left OTC is an area of segregated convergence of different functional systems. We compared our results with the hypoactivation pattern reported for reading in a previous cross‐cultural PET study on 36 dyslexic subjects from three countries. The region of decreased activation in dyslexia overlapped with regions that are specific for reading and those activated during both the auditory rhyming task and the single word and pseudoword reading task described in the present fMRI study. No overlap was found with the activation patterns for the visual motion perception task or for the motor sequence learning task. These observations challenge current theories of dyslexia. Hum Brain Mapp 34:2669–2687, 2013. © 2012 Wiley Periodicals, Inc.

The early differentiation of Alzheimer’s disease (AD) from frontotemporal dementia (FTD) may be difficult. The Tower of London (ToL), thought to assess executive functions such as planning and visuo-spatial working memory, could help in this purpose. Twentytwo Dementia Centers consecutively recruited patients with early FTD or AD. ToL performances of these groups were analyzed using both the conventional statistical approaches and the Artificial Neural Networks (ANNs) modelling. Ninety-four non aphasic FTD and 160 AD patients were recruited. ToL Accuracy Score (AS) significantly (p < 0.05) The use of hidden information contained in the different items of ToL and the non linear processing of the data through ANNs allows a high discrimination between FTD and AD in individual patients. However, the discriminant validity of AS checked by ROC curve analysis, yielded no significant results in terms of sensitivity and specificity (AUC 0.63). The performances of the 12 Success Subscores (SS) together with age, gender and schooling years were entered into advanced ANNs developed by Semeion Institute. The best ANNs were selected and submitted to ROC curves. The nonlinear model was able to discriminate FTD from AD with an average AUC for 7 independent trials of 0.82. The use of hidden information contained in the different items of ToL and the non linear processing of the data through ANNs allows a high discrimination between FTD and AD in individual patients.

Background: Postmarketing surveillance studies (PMS) are an important tool for evaluating a drug’s effectiveness and safety in clinical practice. To our knowledge, no PMS on memantine monotherapy for moderately-severe-to-severe Alzheimer’s disease (AD) according to National Institute of Neurological and Communicative Disorders and Stroke — Alzheimer’s Disease and Related Disorders Association criteria has been conducted to date. Objective: The Lombardy Health Office, Italy, promoted this PMS to evaluate the effectiveness and safety of memantine in the treatment of moderately-severe-to-severe AD in clinical practice. Methods: A total of 451 patients with moderately-severe-to-severe AD (mean age 77 ± 7 years; 72% female), free of cholinergic medication, received memantine (standard titration to 10 mg twice daily). After 6 months of therapy, treatment effectiveness was evaluated according to two definitions of response (‘no deterioration’ and ‘improvement’), as measured by changes in baseline scores on the Clinical Global Impression of Change, Mini-Mental State Examination, Neuropsychiatric Inventory and Activities of Daily Living scales. The safety measure was the frequency of adverse events (AEs). Results: At 6-month assessment, 26.8% of subjects showed no deterioration and 3.8% showed improvement. In those showing no deterioration, response to treatment at the 3-month assessment was associated with a greater probability of a response at 6 months (adjusted odds ratio = 8.54; 95% CI 4.54, 16.05). Seventy patients (15.5%) experienced at least one AE and 39 (8.6%) discontinued treatment prematurely because of an AE. Of those who experienced an AE, 27 (38.6%) manifested behavioural and psychological symptoms of dementia. Conclusion: The proportion of responders to memantine treatment in this PMS was similar to that reported in a previous randomized clinical trial (26.8% vs 29%, respectively). The proportion of patients who discontinued treatment prematurely because of an AE (8.6%) was similar to that reported in two previous randomized clinical trials (10% and 12.4%). This PMS provides additional evidence that both the effectiveness and the tolerability of memantine may be transferred into real world medicine, where AD patients receiving treatment are not selected according to strict criteria.

BACKGROUND/OBJECTIVES: Subjects affected by mild cognitive impairment (MCI) may improve during the observation period. This is the first study investigating qualitative features of memory deficits in subjects affected by reversible MCI [reversible cognitive impairment (RCI)]. METHODS: Baseline cognitive and memory performances of 18 subjects affected by amnestic MCI who had normalized cognitive performances at follow-ups were compared with those of 76 amnestic MCI subjects who still showed impaired cognitive performances at the 24-month follow-up (MCI) and with those of a group of 87 matched control subjects (normal controls). RESULTS: Compared with normal controls the memory deficit in the MCI group affected all aspects of explicit long-term memory functioning; in the RCI group, instead, the memory deficit only affected the free recall of verbal material, particularly when the encoding could be improved by the use of semantic strategies. CONCLUSIONS: These results are consistent with the view that the memory deficit in the MCI group is due to a very early degenerative pathology; in the RCI group, instead, a transitory reduction of processing resources, resulting a poor encoding of incoming material, is likely at the origin of the reversible memory disorder.

Background: Different rates and cognitive predictors of conversion to dementia have been reported in subjects with different kinds of mild cognitive impairment (MCI). Methods: A prospective, 24-month follow-up study, involving 269 subjects who strictly fulfilled criteria for the amnestic MCI. Results: Conversion rate to dementia was 21.4% per year. Seventy-nine out of the 83 individuals who developed dementia were affected by probable Alzheimer’s disease (AD). Among others, at the 24-month follow-up 24.1% were still affected by amnestic MCI, 13.3% had changed their neuropsychological profile of impairment and 17.2% were cognitively normalised. Compared to subjects who did not convert to AD, those who did convert showed poorer immediate and delayed recall and recognition of verbal and visual material at baseline as well as reduced executive abilities. A combination of age, Clinical Dementia Rating boxes and scores on delayed recall and recognition of verbal and visual material accurately identified 86% of the subjects who developed AD. Conclusions: Elderly subjects affected by an isolated memory disorder have a high probability of developing AD. The ability of verbal and visual measures to predict incipient dementia of memory impairment may be increased by the simultaneous assessment of individual features, such as age or rate of functional impairment.

The effects of adaptation to prisms displacing rightwards the field of vision on omission errors, and on perseveration and other graphic productions in a line cancellation task, were assessed in nine right-brain-damaged patients with left unilateral spatial neglect. Prism adaptation improved both neglect, as indexed by omission errors, and perseveration behaviour, up to a delay of 60 min. No correlation was found between omission and perseveration errors in all assessments. The suggestion is made that perseveration and other complex graphic productions made by right brain-damaged-patients with left spatial unilateral neglect is due to a defective monitoring of complex motor behaviour, frequently associated to cerebral damage involving the right frontal lobe. Interpretations of perseveration behaviour in terms of allochiria and directional hypokinesia are considered, and their limits discussed.

Patients with Alzheimer’s disease after an initial response to cholinesterase inhibitors may complain a later lack of efficacy. This, in association with incident neuropsychiatric symptoms, may worsen patient quality of life. Thus, the switch to another cholinesterase inhibitor could represent a valid therapeutic strategy. The aim of this study was to investigate the effectiveness of the switch from one to another cholinesterase inhibitor on cognitive and affective symptoms in mild to moderate Alzheimer disease patients. Four hundred twenty-three subjects were included from the EVOLUTION study, an observational, longitudinal, multicentre study conducted on Alzheimer disease patients who switched to different cholinesterase inhibitor due either to lack/loss of efficacy or response, reduced tolerability or poor compliance. All patients underwent cognitive and neuropsychiatric assessments, carried out before the switch (baseline), and at 3 and 6-month follow-up. A significant effect of the different switch types was found on Mini-Mental State Examination score during time, with best effectiveness on mild Alzheimer’s disease patients switching from oral cholinesterase inhibitors to rivastigmine patch. Depressive symptoms, when measured using continuous Neuropsychiatric Inventory values, decreased significantly, while apathy symptoms remained stable over the 6 months after the switch. However, frequency of both depression and apathy, when measured categorically using Neuropsychiatric Inventory cut-off scores, did not change significantly during time. In mild to moderate Alzheimer disease patients with loss of efficacy and tolerability during cholinesterase inhibitor treatment, the switch to another cholinesterase inhibitor may represent an important option for slowing cognitive deterioration. The evidence of apathy stabilization and the positive tendency of depressive symptom improvement should definitively be confirmed in double-blind controlled studies.

The aim of this study is to evaluate memantine effectiveness on behavioural and psychological symptoms of dementia (BPSD) in clinical practice and to identify variables that may predict the therapy effects. The effects of memantine on behaviour were analysed in the database of a post-marketing surveillance study promoted by the Lombardy Region Health Office and involving 43 Alzheimer's disease (AD) Units. From July to December 2005, 399 moderately severe-to-severe AD patients free of cholinergic medications were enrolled, treated with memantine and followed-up for 6 months. BPSD were assessed in a subgroup of 297 patients [mean age 77 ± 8 years; 73% females; mean neuropsychiatric inventory (NPI) score 28 ± 24] for whom the 12-item NPI subscores at baseline, and at 3 and 6 months were available. The 12 BPSD were clustered as follows: affect, physical behaviour, psychosis and hypomania. The main outcome measure was the proportion of individual cluster responders at 6 months of therapy. The proportion of individual cluster responders was 30% affect, 24% physical behaviour, 29% psychosis, 27% hypomania. Patients taking 20 mg memantine daily during the study period had a statistically significant higher probability to experience behavioural improvement than those who discontinued treatment or did not complete memantine titration (affect OR 9.0; 95% CI 3.8-21.6; physical behaviour OR 17.8; 95% CI 5.9-53.6; psychosis OR 23.6; 95% CI 5.1-110.8). The logistic regression analysis was not applicable to the hypomania subsyndrome because of the low cluster prevalence. The standard 20 mg daily memantine treatment regimen was found to be associated with a modest 6-month behavioural improvement in the affect, physical behaviour and psychosis domains in 24-30% of patients.

Regional cerebral perfusion was evaluated by single photon emission computed tomography (SPECT) using technetium-99m hexamethylpropyleneamine oxime ([99mTc]HM-PAO) in sixteen patients with Alzheimer's disease (AD) in early clinical phase and in 16 healthy elderly controls. In all patients transmission computed tomography (TCT) and/or magnetic resonance imaging (MRI) did not show focal brain abnormalities. Relative to normal subjects, AD patients showed significant reductions in cortical/cerebellar activity ratio: cortical perfusion was globally depressed with the largest reductions in frontal and posterior temporo-parietal cortices. Asymmetries of relative perfusion between cerebral hemispheres were also demonstrated when language was affected or visuospatial functions were unevenly impaired. In patients with early AD, SPECT provides functional information to be compared with clinical and psychometric data.

The International League against Epilepsy (ILAE) proposed a diagnostic scheme for psychogenic non-epileptic seizure (PNES). The debate on ethical aspects of the diagnostic procedures is ongoing, the treatment is not standardized and management might differ according to age group. The objective was to reach an expert and stakeholder consensus on PNES management. A board comprising adult and child neurologists, neuropsychologists, psychiatrists, pharmacologists, experts in forensic medicine and bioethics as well as patients’ representatives was formed. The board chose five main topics regarding PNES: diagnosis; ethical issues; psychiatric comorbidities; psychological treatment; and pharmacological treatment. After a systematic review of the literature, the board met in a consensus conference in Catanzaro (Italy). Further consultations using a model of Delphi panel were held. The global level of evidence for all topics was low. Even though most questions were formulated separately for children/adolescents and adults, no major age-related differences emerged. The board established that the approach to PNES diagnosis should comply with ILAE recommendations. Seizure induction was considered ethical, preferring the least invasive techniques. The board recommended looking carefully for mood disturbances, personality disorders and psychic trauma in persons with PNES and considering cognitive-behavioural therapy as a first-line psychological approach and pharmacological treatment to manage comorbid conditions, namely anxiety and depression. Psychogenic non-epileptic seizure management should be multidisciplinary. High-quality long-term studies are needed to standardize PNES management.

The logopenic variant of primary progressive aphasia (lvPPA) is the most recent variant of primary progressive aphasia (PPA) to be identified; thus far, it has been poorly investigated. Despite being typically associated with Alzheimer disease (AD), lvPPA has recently been linked to frontotemporal lobe degeneration (FTLD), with distinctive cognitive and neural features that are worthy of further investigation. Here, we describe the neuropsychological and linguistic profile, as well as cerebral abnormalities, of an individual exhibiting PPA and carrying a pathogenetic variant in the GRN gene, from a 3-year longitudinal perspective. The individual's initial profile resembled lvPPA because it was characterized by word-finding difficulties and phonological errors in spontaneous speech in addition to sentence repetition and phonological short-term memory impairments. The individual's structural and metabolic imaging data demonstrated left temporal and bilateral frontal atrophy and hypometabolism, respectively. On follow-up, as the pathology progressed, dysprosody, stereotypical speech patterns, agrammatism, and orofacial apraxia appeared, suggesting an overlap with the nonfluent variant of PPA (nfvPPA). Severe sentence comprehension impairment also became evident. Our longitudinal and multidisciplinary diagnostic approach allowed us to better characterize the progression of a GRN-positive lvPPA profile, providing neuropsychological and imaging indicators that might be helpful to improve classification between different PPA variants and to address a nosological issue. Finally, we discuss the importance of early diagnosis of PPA given the possible overlap between different PPA variants during the progression of the pathology.

Background: The standardization of outcome measures is needed for comparing studies and using common measures in clinical practice. We aimed to identify cognitive and patient-reported outcomes and timing of assessment for glioma, meningioma, and vascular surgery. Method: A consensus study was conducted. Participants selected cognitive and patient-reported measures among a list of instruments identified through a literature search. Results: Seventeen cognitive tests for the glioma and meningioma’s evaluation, 8 for the vascular diseases, and one questionnaire on quality of life and one on emotional distress were identified. The timing of outcome assessment selected was before surgery, at discharge, and after 3 and 12 months for glioma; before surgery and after 3 months for meningioma; before surgery, at discharge, and after 6 months for vascular diseases. Conclusion: The identification of common outcome measures is the first step toward a shared data collection improving the quality and comparability of future studies.

Creative production (related to art-making) and aesthetic appreciation (related to art-viewing) are inherently linked in visual arts, but their relationship has never been explored explicitly in cognitive neuroscience, nor the nature of such connection. The available literature suggests two cognitive processes as possible foundations of these two experiences: motor simulation or inhibitory control. In a meta-analysis of fMRI studies, we addressed this issue: we investigated whether there are shared neurofunctional underpinnings behind aesthetic and creative experiences in the visual domain; further, we examined whether any shared brain activation may reflect either motor simulation or inhibitory processes. A conjunction analysis revealed a common involvement of the pre-SMA in both classes of studies, a brain region, if anything, more concerned with top-down inhibitory motor and volitional cognitive control rather than bottom-up motor simulation. In the art-viewing domain, this finding was primarily driven by figurative rather than abstract art. The methodological limitations in the available literature are discussed together with possible new ways to expand the existing findings.

“Body integrity dysphoria" (BID) is a severe condition affecting non-psychotic individuals. In the amputation variant of BID a limb may be experienced as not being part of the body, despite normal anatomical development and intact sensorimotor functions. We previously demonstrated altered brain structural (gray matter) and functional connectivity in 16 men with BID with a long-lasting and exclusive desire for left leg amputation. Here we aimed to identify, in the same sample, altered patterns of white matter structural connectivity. Fractional anisotropy (FA), derived from Diffusion Tensor Imaging data, was considered as a measure of structural connectivity. Results showed reduced structural connectivity of: i) the right superior parietal lobule (rSPL) with the right cuneus, with the superior occipital and with the posterior cingulate gyri ii) the pars orbitalis of the right middle frontal gyrus (rMFGOrb) with the putamen, and iii) the left middle temporal gyrus (lMTG) with the pars triangularis of the left inferior frontal gyrus. Increased connectivity was found between the right paracentral lobule (rPLC) and the right caudate nucleus. By using a complementary method of investigation, we confirmed and extended previous results from the same sample of individuals with BID, showing structural alterations between areas tuned to the processing of the sensorimotor representations of the affected leg (rPCL), and to higher-order components of bodily representation such as the body image (rSPL) and visual processing areas. Alongside this network for bodily awareness, other networks such as the limbic (rMFGOrb) and the mirror (lMTG) systems showed alterations in structural connectivity. These findings consolidate current understanding of the neural correlates of the amputation variant of BID, which might in turn guide diagnostics and rehabilitative treatments. published

Background Patients suffering from stroke in the acute/post-acute phases often present with depressive mood — which negatively impacts on patients’ prognosis. However, psychometric evaluation of mood in acute stroke patients may be challenging due to cognitive deficits. Tools investigating emotional states via a vertical analogue line may overcome language/visuo-spatial disorders. This study thus aimed at (a) investigating the clinical usability of a Visual Analogue Mood Scale (VAMS) in acute stroke patients and (b) investigating the interplay between mood and cognition in this population. Methods Forty-one acute stroke patients were compared to 41 age-, education- and sex-matched healthy participants (HPs) on the VAMS and on cognitive measures (mental performance in acute stroke, MEPS). A control line bisection (LB) task was administered to control for potential visuo-spatial deficits in patients. Results Patients reported higher depression levels than HPs (lower VAMS scores); this between-group difference stayed significant when covarying for LB scores. MEPS scores discriminated patients from HPs; among cognitive measures, only the Clock drawing test (CDT) was positively associated with VAMS scores. Lesion side did not affect patients’ mood state; however, disease duration was inversely related to VAMS scores. Discussion The VAMS proved to be a suitable tool for assessing mood in acute stroke patients, as being independent from post-stroke cognitive sequelae. The CDT might represent an adequate measure of depression-induced, post-stroke cognitive efficiency decrease. Mood disorders might occur and thus should be adequately addressed also in post-acute phases — likely due to longer hospitalization times and regression of anosognosic features.

Freezing of gait (FoG) is a paroxysmal and sporadic gait impairment that severely affects PD patients' quality of life. This review summarizes current neuroimaging investigations that characterize the neural underpinnings of FoG in PD. The review presents and discusses the latest advances across multiple methodological domains that shed light on structural correlates, connectivity changes, and activation patterns associated with the different pathophysiological models of FoG in PD. Resting-state fMRI studies mainly report cortico-striatal decoupling and disruptions in connectivity along the dorsal stream of visuomotor processing, thus supporting the 'interference' and the 'perceptual dysfunction' models of FoG. Task-based MRI studies employing virtual reality and motor imagery paradigms reveal a disruption in functional connectivity between cortical and subcortical regions and an increased recruitment of parieto-occipital regions, thus corroborating the 'interference' and 'perceptual dysfunction' models of FoG. The main findings of fNIRS studies of actual gait primarily reveal increased recruitment of frontal areas during gait, supporting the 'executive dysfunction' model of FoG. Finally, we discuss how identifying the neural substrates of FoG may open new avenues to develop efficient treatment strategies.

Background Working memory (WM) abilities are frequently impaired in neurological disorders affecting fronto-parietal cortical/sub-cortical structures. WM deficits negatively influence interventional outcomes and everyday functioning. This study thus aimed at the following: (a) developing and standardizing an ecologically valid task for WM assessment ( Ice Cream Test, ICT); (b) validating and norming a novel WM test (Digit Ordering Test, DOT), as well as providing updated norms for digit span (DS) tasks, in an Italian population sample; (c) introducing a novel scoring procedure for measuring WM. Methods One-hundred and sixty-eight Italian healthy participants—73 male, 95 females; age: 48.4 ± 19.1 (18–86); education: 12.1 ± 4.8 (4–21)—underwent a thorough WM assessment—DOT, ICT, and both forward and backward DS tasks (FDS, BDS). The ICT requires participants to act as waiters who have to keep track of customers’ orders. For each task, WM and total (T) outcomes were computed, i.e., the number of elements in the longest sequence and that of recalled sequences, respectively. Norms were derived via the equivalent score (ES) method. Results DS ratios (DSRs) were computed for both WM/S and T outcomes on raw DS measures (BDS divided by FDS). Age and education significantly predicted all WM tasks; sex affected FDS and DSR-T scores (males > females). WM measures were highly internally related. Discussion The present work provides Italian practitioners with a normatively updated, multi-component, adaptive battery for WM assessment (WoMAB) as well as with novel outcomes which capture different WM facets—WM capacity and attentive monitoring abilities.

Both visuo-spatial neglect and visual extinction may occur following right-brain damage. So far, studies on brain-damaged patients have not provided definite evidence about which lesion patterns may lead to the association or dissociation of these deficits. This study was set out to address this issue using Intracranial Electrical Stimulation (IES) in a group of nine patients affected by refractory epilepsy. Cerebral regions associated with visuo-spatial neglect and visual extinction were stimulated, including the right frontal, temporal, and posterior parietal areas. During IES, patients with intracranial implantation involving at least one of these cortical regions were administered with a manual line bisection task (N = 9) to assess visuo-spatial neglect, and a computerized task (N = 8) assessing visual extinction. Results showed that parietal IES induced a rightward bias at the manual bisection task, together with a general improvement in reaction times at bilateral and unilateral visual stimuli detection at the extinction task. The occurrence of visual extinction did not vary across stimulations. By adopting a complementary approach to anatomo-clinical correlation studies, our work corroborates the notion that lesions to the right inferior parietal lobule play a pivotal role in the pathogenesis of visuo-spatial neglect. Importantly, our results also suggest that temporarily interfering with the activity of this region is not sufficient per se to generate visual extinction, which instead may involve a broader and/or different network, possibly extending beyond the cerebral regions considered here, posing important theoretical and clinical implications.

In healthy subjects, the transient perturbation of body part ownership is accompanied by regional skin temperature decrease. This observation leaves an open question about a possible body part-specific thermoregulatory response in pathological conditions, in which the sense of ownership over that body part is altered. For instance, Body Integrity Dysphoria (BID), a poorly understood neuropsychiatric disorder, is characterised by the non-acceptance of one or more of one's extremities. This unsettling feeling pervasively captures the individuals' attention towards the unwanted limb. Previous studies characterised BID in terms of absent ownership feeling with preserved ownership judgment. We explored for the first time whether this altered feeling is also associated with a specific thermoregulatory response. We recorded thermal image sequences of circumscribed regions of the limbs' skin in seven individuals with BID desiring to remove one leg while they were invited to focus their attention toward one particular limb (arm or leg). Their event-related thermoregulatory pattern was compared to a group of healthy matched controls. In individuals with BID but not in control persons, we found a bilateral decrease in leg temperature when focusing their attention on either the unwanted or accepted leg. The event-related thermoregulatory response for both upper limbs was similar between individuals with BID and healthy controls. Our results suggest that the alteration of the sense of body ownership in neuropsychiatric conditions such as BID may critically rest on specific event-related thermoregulatory patterns in response to modulation of attention to body parts.

There are few things as irrefutable as the evidence that our limbs belong to us. However, persons with body integrity dysphoria (BID) [1] deny the ownership of one of their fully functional limbs and seek its amputation [2]. We tapped into the brain mechanisms of BID, examining sixteen men desiring the removal of the left healthy leg. The primary sensorimotor area of the to-be-removed leg and the core area of the conscious representation of body size and shape (the right superior parietal lobule [rSPL]) [3, 4] were less functionally connected to the rest of the brain. Furthermore, the left premotor cortex, reportedly involved in the multisensory integration of limb information [5-7], and the rSPL were atrophic. The more atrophic the rSPL, the stronger the desire for amputation, and the more an individual pretended to be an amputee by using wheelchairs or crutches to solve the mismatch between the desired and actual body. Our findings illustrate the pivotal role of the connectivity of the primary sensorimotor limb area in the mediation of the feeling of body ownership. They also delineate the morphometric and functional alterations in areas of higher-order body representation possibly responsible for the dissatisfaction with a standard body configuration. The neural correlates of BID may foster the understanding of other neuropsychiatric disorders involving the bodily self. Ultimately, they may help us understand what most of us take for granted, i.e., the experience of body and self as a seamless unity.

Dyslexia can have different manifestations: this has motivated different theories on its nature, on its underlying brain bases and enduring controversies on how to best treat it. The relative weight of the different manifestations has never been evaluated using both behavioural and fMRI measures, a challenge taken here to assess the major systems called into play in dyslexia by different theories. We found that adult well-compensated dyslexics were systematically impaired only in reading and in visuo-phonological tasks, while deficits for other systems (e.g., motor/cerebellar, visual magnocellular/motion perception) were only very occasional. In line with these findings, fMRI showed a reliable hypoactivation only for the task of reading, in the left occipito-temporal cortex (l-OTC). The l-OTC, normally a crossroad between the reading system and other systems, did not show the same level of intersection in dyslexics; yet, it was not totally silent because it responded, in segregated parts, during auditory phonological and visual motion perception tasks. This minimal behavioural and functional anatomical comorbidity demonstrates that a specific deficit of reading is the best description for developmental dyslexia, at least for adult well-compensated cases, with clear implications for rehabilitation strategies. The reduced intersection of multiple systems in the l-OTC suggests that dyslexics suffer from a coarser connectivity, leading to disconnection between the multiple domains that normally interact during reading.

Highlights • Acute DOC patients with favourable outcome show preserved event-related electrodermal response. • Acute DOC patients showed reduced fALFF in the posterior cingulate cortex. • Event-related electrodermal activity correlated with the fALFFs in the PCC in the acute phase., An accurate prognosis on the outcome of brain-injured patients with disorders of consciousness (DOC) remains a significant challenge, especially in the acute stage. In this study, we applied a multiple-technique approach to provide accurate predictions on functional outcome after 6 months in 15 acute DOC patients. Electrophysiological correlates of implicit cognitive processing of verbal stimuli and data-driven voxel-wise resting-state fMRI signals, such as the fractional amplitude of low-frequency fluctuations (fALFF), were employed. Event-related electrodermal activity, an index of autonomic activation, was recorded in response to emotional words and pseudo-words at baseline (T0). On the same day, patients also underwent a resting-state fMRI scan. Six months later (T1), patients were classified as outcome-negative and outcome-positive using a standard functional outcome scale. We then revisited the baseline measures to test their predictive power for the functional outcome measured at T1. We found that only outcome-positive patients had an earlier, higher autonomic response for words compared to pseudo-words, a pattern similar to that of healthy awake controls. Furthermore, DOC patients showed reduced fALFF in the posterior cingulate cortex (PCC), a brain region that contributes to autonomic regulation and awareness. The event-related electrodermal marker of residual cognitive functioning was found to have a significant correlation with residual local neuronal activity in the PCC. We propose that a residual autonomic response to cognitively salient stimuli, together with a preserved resting-state activity in the PCC, can provide a useful prognostic index in acute DOC.

Exteroceptive and interoceptive signals shape and sustain the bodily self‐awareness. The existence of a set of brain areas, supporting the integration of information coming from the inside and the outside of the body in building the sense of bodily self‐awareness has been postulated, yet the evidence remains limited, a matter of discussion never assessed quantitatively. With the aim of unrevealing where in the brain interoceptive and exteroceptive signals may converge, we performed a meta‐analysis on imaging studies of the sense of body ownership, modulated by external visuotactile stimulation, and studies on interoception, which involves the self‐awareness for internal bodily sensations. Using a multilevel kernel density analysis, we found that processing of stimuli of the two domains converges primarily in the supramarginal gyrus bilaterally. Furthermore, we found a right‐lateralized set of areas, including the precentral and postcentral, and superior temporal gyri. We discuss these results and propose this set of areas as ideal candidates to match multiple body‐related signals contributing to the creation of a multidimensional representation of the bodily self.

Background and purpose: The number of people suffering from stroke is strongly increasing, giving rise to multiple cognitive deficits which frequently prevent a full recovery. The identification of both spared and impaired cognitive domains has a key role to plan adequate interventions. However, the existing standard tests are either too expensive in terms of time and efforts for patients in acute stage or they derived from instruments addressing different pathologies such as dementia. Methods: We developed a brief neuropsychological battery (mental performance in acute stroke, MEPS) to assess different cognitive domains (language, memory, praxis, visual perception) in acute stroke patients. MEPS was validated by enrolling a sample of 204 patients suffering from stroke in acute stage, and 263 healthy controls participants. Results: The results indicated an adequate construct validity and a high ability in discriminating patients from healthy controls. Conclusions: MEPS can be considered a simple and highly valuable bedside battery, easy to administer, with values of sensitivity and specificity suitable to be proposed as a screening tool for patients with acute stroke.

Visual exposure to extreme-sized bodies elicits explicit self-body image variations. Several features of such modulation remain to be clarified. In this study we explored whether this effect: (i) acts on implicit mechanisms in modifying one’s body-size perception, (ii) is body-exposure-specific also at the implicit level, and (iii) is modulated by interoceptive sensibility. We assigned a covert attention task to 100 women, exposing them to extreme-sized bodies (thin and fat) or extreme-sized objects (thin and fat bottles). Before and after the attentional exposure, we tested the association between the “self/others” and “thin/fat” concepts using an Implicit Association Test. We also collected a measure of interoceptive sensibility by means of a self-report questionnaire. Results showed that participants exposed to fat bodies implicitly presented a stronger association between the “self” and “thin” concepts. This association was significantly weaker in the group exposed to thin bodies. This effect was absent after exposure to thin and fat bottles. Notably, participants with a higher tolerance of negative bodily interoceptive signals were less susceptible to the malleability of body image exerted by the exposure attentional task. Our findings shed new light on the relationship between the perception of internal (e.g., visceral) and external (e.g., visual) signals in the representation of our body.

Right brain damaged patients sometimes deny that their left arm is paralysed or even claim to have just moved it. This condition is known as anosognosia for hemiplegia (AHP). Here, we used fMRI to study patients with and without AHP during the execution of a motor task. We found that the delusional belief of having moved was preceded by brain activation of the cortical regions that are implicated in motor control in the left intact hemisphere and in the spared motor regions of the right hemisphere; patients without anosognosia did not present with the same degree of activation. We conclude that the false belief of movement is associated with a combination of strategically placed brain lesions and the preceding residual neural activity of the fronto-parietal motor network. These findings provide evidence that the activity of motor cortices contributes to our beliefs about the state of our motor system.

We describe the clinical manifestations and the lesion patterns of five patients with somatoparaphrenia, the denial of ownership for a paralyzed limb, who showed the rare dissociation from anosognosia for hemiplegia. Similar cases have been only occasionally cited in the literature with scanty descriptions of their symptoms and no detailed anatomical assessment. All patients had extrapersonal and at least mild personal neglect. The lesions pattern was mainly subcortical, with a significant involvement of the right thalamus, the basal ganglia and the internal capsule. A formal comparison between the anatomical pattern previously associated with anosognosia in a study performed in 2005 by Berti and colleagues, and the lesion distribution of each patient clearly shows that our pure somatoparaphrenic patients had a sparing of most of the regions associated with anosognosia for hemiplegia. The behavioral dissociation between SP and anosognosia for hemiplegia, together with this new anatomical evidence, suggests that motor awareness is not sufficient to build up a sense of ownership and therefore these two cognitive abilities are at least in part functionally independent and qualitatively different.

According to recent theories, drug addicted patients suffer of an impaired response inhibition and salience attribution (I-RISA) together with a perturbed connectivity between the nuclei accumbens (NAcs) and the orbito-prefrontal (oPFC) and dorsal prefrontal (dPFC) cortices, brain regions associated with motivation and cognitive control. To empirically test these assumptions, we evaluated the (neuro)psychological trait and the functional organization of the resting state brain networks associated with the NAcs in 18 former cocaine abusers (FCAs), while being in drug abstinence since 5 months. The psychological data were grouped into three empirical variables related with emotion regulation, emotion awareness and strategic and controlled behaviour. Comparison of the resting state patterns between the entire sample of FCAs and 19 controls revealed a reduction of functional connectivity between the NAcs and the dPFC and enhanced connectivity between the NAcs and the dorsal-striatum. In the 8 FCAs who relapsed into cocaine use after 3 months, the level of functional connectivity between the NAcs and dPFC was lower than the functional connectivity estimated in the group of patients that did not relapsed. Finally, in the entire sample of FCAs, the higher the connectivity between the NAc and the oPFC the lower was the level of strategic and controlled behaviour. Taken together, these results are compatible with models of the interactions between the NAcs, the dorsal striatum and frontal cortices in the I-RISA syndrome, showing that such interactions are particularly perturbed in patients at greater risk of relapse into cocaine abuse.

Somatoparaphrenia is a delusional belief whereby a patient feels that a paralyzed limb does not belong to his body; the symptom is typically associated with unilateral neglect and most frequently with anosognosia for hemiplegia. This association of symptoms makes anatomical inference based on single case studies not sufficiently specific. On the other hand, the only three anatomical group studies on somatoparaphrenia are contradictory: the right posterior insula, the supramarginal gyrus and the posterior corona radiata, or the right medial or orbito-frontal regions were all proposed as specific lesional correlates.We compared 11 patients with and 11 without somatoparaphrenia matched for the presence and severity of other associated symptoms (neglect, motor deficits and anosognosia). To take into account the frequent association of SP and neglect and hemiplegia, patients with and without somatoparaphrenia were also compared with a group of fifteen right brain damage patients without neglect and hemiplegia. We found a lesion pattern involving a fronto-temporo-parietal network typically associated with spatial neglect, hemiplegia and anosognosia. Somatoparaphrenic patients showed an additional lesion pattern primarily involving white matter and subcortical grey structures (thalamus, basal ganglia and amygdala). Further cortical damage was present in the middle and inferior frontal gyrus, postcentral gyrus and hippocampus.We propose that somatoparaphrenia occurs providing that a distributed cortical lesion pattern is present together with a subcortical lesion load that prevents most sensory input from being processed in neocortical structures; involvement of deep cortical and subcortical grey structures of the temporal lobe may contribute to reduce the sense of familiarity experienced by somatoparaphrenic patients for their paralyzed limb. © 2011 Elsevier Srl.

Individuals with the peculiar disturbance of '. overcompleteness' experience an intense desire to amputate one of their healthy limbs, describing a sense of disownership for it (Body Integrity Identity Disorder - BIID). This condition is similar to somatoparaphrenia, the acquired delusion that one's own limb belongs to someone else. In ten individuals with BIID, we measured skin conductance response to noxious stimuli, delivered to the accepted and non-accepted limb, touching the body part or simulating the contact (stimuli approach the body without contacting it), hypothesizing that these individuals have responses like somatoparaphrenic patients, who previously showed reduced pain anticipation, when the threat was directed to the disowned limb. We found reduced anticipatory response to stimuli approaching, but not contacting, the unwanted limb. Conversely, stimuli contacting the non-accepted body-part, induced stronger SCR than those contacting the healthy parts, suggesting that feeling of ownership is critically related to a proper processing of incoming threats.

Three cognitive components may play a crucial role in both memory awareness and in anosognosia for memory deficit (AMD): (1) a personal data base (PDB), i.e., a memory store that contains "semantic" representations about the self, (2) monitoring processes (MPs) and (3) an explicit evaluation system (EES), or comparator, that assesses and binds the representations stored in the PDB with information obtained from the environment. We compared both the behavior and the functional connectivity (as assessed by resting-state fMRI) of AMD patients with aware patients and healthy controls. We found that AMD is associated with an impoverished PDB, while MPs are necessary to successfully update the PDB. AMD was associated with reduced functional connectivity within both the default-mode network and in a network that includes the left lateral temporal cortex, the hippocampus and the insula. The reduced connectivity between the hippocampus and the insular cortex was correlated with AMD severity.

Body integrity identity disorder (BIID) is characterized by the overwhelming desire to amputate one or more healthy limbs or to be paraplegic. Recently, a neurological explanation of this condition has been proposed, in part on the basis of findings that the insular cortex might present structural anomalies in these individuals. While these studies focused on body representation, much less is known about emotional processing. Importantly, emotional impairments have been found in psychiatric disorders, and a psychiatric etiology is still a valid alternative to purely neurological accounts of BIID. In this study, we explored, by means of a computerized experiment, facial emotion recognition and emotional responses to disgusting images in seven individuals with BIID, taking into account their clinical features and investigating in detail disgust processing, strongly linked to insular functioning. We demonstrate that BIID is not characterized by a general emotional impairment; rather, there is a selectively reduced disgust response to violations of the body envelope. Taken together, our results support the need to explore this condition under an interdisciplinary perspective, taking into account also emotional connotations and the social modulation of body representation.

Disruption of motor control in the alien hand syndrome might result from a dissociation between intentions and sensory information. We hypothesized that voluntary motor control in this condition could improve by restoring the congruency between motor intentions and visual feedback. The present study shows that, in one patient with right alien hand syndrome, the use of a mirror box paradigm improved motor speed. We speculate that the visual feedback provided by the mirror increases the sense of congruence between intention and sensory feedback, leading to motor improvement.

A complex brain representation of our body allows us to monitor incoming sensory stimuli and plan actions towards the external world. A critical element of such a complex representation is the sense of ownership towards our own body parts. Brain damage may disrupt this representation, leading to the striking neuropsychological condition called somatoparaphrenia, that is, the delusion that one's own limbs belong to someone else. The clinical features characterizing somatoparaphrenia are well known, however, physiological clues of the level at which this condition may disrupt sensory functions are unknown. In the present study we investigated this issue by measuring the anticipatory skin conductance response to noxious stimuli approaching either the affected or the intact body side in a group of patients with somatoparaphrenia (n = 5; three females, age range = 66-84), and in a group of patients with anosognosia for sensory deficits, i.e. preserved ownership but decreased awareness of somatosensory deficit, (n = 5; one female, age range = 62-81 years) and in a group of purely hemiplegic patients (n = 5; two females, age range = 63-74 years) with no deficits of ownership or sensory awareness. Results show that anticipatory skin conductance responses to noxious stimuli directed to the contralesional hand are significantly reduced as compared to noxious stimuli directed to the ipsilesional hand in patients with somatoparaphrenia. By contrast a non-reduced anticipatory skin conductance response was observed in control participants as well as in patients affected by anosognosia for the somatosensory deficit and in patients affected by pure motor deficits. Furthermore, a pain anticipation response was always measured when the stimuli were directed towards the ipsilesional, unaffected hand in all groups. Our results show for the first time that the delusions shown by somatoparaphrenic patients are associated with an altered physiological index of perceptual analysis. The reduced response to sensory threats approaching the body suggests a deep detachment of the affected body part from the patient's body representation. Conversely, normal reactions to incoming threats are found in the presence of impaired sensory awareness but intact body ownership, supporting the notion that representation of the body may be affected at different levels following brain damage. © 2013 The Author.

Neglect patients' performance during cancellation tasks is characterized by left sided omissions and, in many cases, by the production of inappropriate material of various kinds in the ipsilesional space, e.g. additional marks over already cancelled targets, marks drawn away from targets, scribbles, irrelevant drawings. It is unclear whether these behaviours, which have collectively been called perseverative, are functionally and anatomically connected and whether they correlate with the severity of neglect. Here we report a retrospective study on 33 right brain damaged patients with neglect after right hemisphere lesions in whom we measured the intensity of perseveration of the three following kinds: (1) 'additional marks' (AM) perseveration where patients cancelled a target with two or more well separated marks; (2) 'scribble' perseveration, where patients, instead of cancelling the target with a single pen stroke as required by the task, performed multiple pen strokes without breaking the pen-to-paper contact, with the final product being a scribble; (3) 'flying marks' (FM) perseveration where patients produced cancellation marks well away from the targets. We found that AM and FM perseveration correlated with neglect severity, while 'scribble' perseveration did not. The lesion-symptom mapping showed three separate anatomical areas in the right hemisphere: 'scribble' perseveration was associated with lesions of the orbitofrontal cortex and caudate nucleus; AM perseveration was associated with damage to the rolandic operculum, superior temporal gyrus and inferior frontal gyrus; FM perseveration was associated with damage to the dorsal premotor cortex and the temporal pole. Neglect severity followed damage to a region which grossly corresponds to the sum of the regions associated with AM and FM perseveration respectively. This complex behavioural and anatomical pattern is interpreted in terms of a three-factor model, in which AM perseveration is caused by a deficit of disengagement of attention from the right side (also causing omissions), FM perseveration is caused by directional hypokinesia (also causing left-side omissions), and 'scribble' perseveration is the consequence of a failure to inhibit an initiated motor act, which is completely separate (both anatomically and functionally) from the disorder inducing omissions. © 2013 Elsevier Ltd.

Background and Purpose: The mirror box (MB) was developed in the early 1990 s to relieve phantom limb sensations and chronic pain. Although its efficacy has been shown in several clinical populations, the mechanisms underpinning effects still have to be fully understood. Methods: 48 healthy subjects participated in 4 behavioral experiments where kinesthetic sensitivity of the hand inside the MB was tested during the observation of mirror-reflected finger movements, executed with the hand outside the MB. Results: We identified two effects on the hand hidden inside the MB: diminished kinesthetic sensitivity for passive movements, and the occurrence of unconscious, involuntary movements with the finger inside the box, suggesting reduced motor awareness. Such sensory-motor effects were somatotopically specific to the finger moved, were influenced by the contextual presence of the whole hand in the mirror, and occurred for both active and passive movements of the hand outside the MB. Conclusions: The present results suggest that the MB induce a somatotopically and contextually specific overriding of kinesthetic control by vision, compatible with a process of embodiment of the mirror-reflected hand image and provide novel clues to the understanding of the mechanisms underlying MB effects. © 2013 - IOS Press and the authors. All rights reserved.

As neuroinflammation is an early event in the pathogenesis of Alzheimer' s disease, new selective antiinflammatory drugs could lead to promising preventive strategies. We evaluated the safety, tolerability, pharmacokinetics and pharmacodynamics of CHF5074, a new microglial modulator, in a 12-week, double-blind, placebo-controlled, parallel groups, ascending dose study involving 96 MCI patients. Subjects were allocated into three successive study cohorts to receive ascending, titrated doses of CHF5074 (200, 400 or 600 mg/day) or placebo. Vital signs, cardiac safety, neuropsychological performance and safety clinical laboratory parameters were assessed on all subjects. Plasma samples were collected throughout the study for measuring drug concentrations, soluble CD40 ligand (sCD40L) and TNF-α. At the end of treatment, cerebrospinal fluid (CSF) samples were optionally collected after the last dose to measure drug levels, β- amyloid1-42 (Aβ42), tau, phospho-tau181, sCD40L and TNF-α. Ten patients did not complete the study: one in the placebo group (consent withdrawn), two in the 200-mg/day treatment group (consent withdrawn and unable to comply) and seven in the 400-mg/day treatment group (five AEs, one consent withdrawn and one unable to comply). The most frequent treatment-emergent adverse events were diarrhea, dizziness and back pain. There were no clinically significant treatmentrelated clinical laboratory, vital sign or ECG abnormalities. CHF5074 total body clearance depended by gender, age and glomerular filtration rate. CHF5074 CSF concentrations increased in a dose-dependent manner. At the end of treatment, mean sCD40L and TNF-α levels in CSF were found to be inversely related to the CHF5074 dose (p=0.037 and p=0.001, respectively). Plasma levels of sCD40L in the 600-mg/day group were significantly lower than those measured in the placebo group (p=0.010). No significant differences between treatment groups were found in neuropsychological tests but a positive dose-response trend was found on executive function in APOE4 carriers. This study shows that CHF5074 is well tolerated in MCI patients after a 12-week titrated treatment up to 600 mg/day and dose-dependently affects central nervous system biomarkers of neuroinflammation.

The HAROLD (hemispheric asymmetry reduction in older adults) model, proposed by Cabeza in 2002, suggests that age-related neurofunctional changes are characterised by a significant reduction in the functional hemispheric lateralisation in the prefrontal cortex (PFC). The supporting evidence, however, has been derived from qualitative explorations of the data rather than from explicit statistical assessments of functional lateralisation. In contrast, the CRUNCH (compensation-related utilisation of neural circuits hypothesis) model posits that elderly subjects recruit additional brain regions that do not necessarily belong to the contralateral hemisphere as much as they rely on additional strategies to solve cognitive problems. To better assess the validity and generalisability of the HAROLD model, we analysed the fMRI patterns of twenty-four young subjects (age range: 18–30 years) and twenty-four healthy elderly subjects (age range: 50–80 years) collected during the performance of two linguistic/semantic tasks (a picture-naming task and a sentence judgment task) and two episodic long-term memory (eLTM) recognition tasks for the same materials. The functional hemispheric lateralisation in each group and the ensuing between-group differences were quantitatively assessed using statistical lateralisation maps (SLMs). The number of clusters showing a genuine HAROLD effect was proportional to the level of task demand. In addition, when quantitatively significant, these effects were not restricted to the PFC. We conclude that, in its original version, the HAROLD model captures only some of the age-related brain patterns observed in graceful ageing. The results observed in our study are compatible with the more general CRUNCH model, suggesting that the former patterns can be considered a special manifestation of age-related compensatory processes.

We explored the neuropsychological and neuromorphometrical differences between probable Alzheimer's disease patients showing a good or a bad response to nine months treatment with donepezil. Before treatment, the neuropsychological profile of the two patient groups was perfectly matched. By the ninth month after treatment, theBAD-respondersshowed a decline of the MMSE score together with a progressive impairment of executive functions. A voxel-based morphometry investigation (VBM), at the time of the second neuropsychological assessment, showed that theBAD-respondershad larger grey and white matter atrophies involving the substantia innominata of Meynert bilaterally, the ventral part of caudate nuclei and the left uncinate fasciculus, brain areas belonging to the cholinergic pathways. A more widespread degeneration of the central cholinergic pathways may explain the lack of donepezil efficacy in those patients not responding to a treatment that operates on the grounds that some degree of endogeneous release of acetylcholine is still available.

We studied the linguistic profile and neurolinguistic organization of a 14-year-old adolescent (EB) who underwent a left hemispherectomy at the age of 2.5 years. After initial aphasia, his language skills recovered within 2 years, with the exception of some word finding problems. Over the years, the neuropsychological assessments showed that EB's language was near-to-normal, with the exception of lexical competence, which lagged slightly behind for both auditory and written language. Moreover, EB's accuracy and speed in both reading and writing words and non-words were within the normal range, whereas difficulties emerged in reading loan words and in tasks with homophones. EB's functional magnetic resonance imaging (fMRI) patterns for several linguistic and metalinguistic tasks were similar to those observed in the dominant hemisphere of controls, suggesting that his language network conforms to a left-like linguistic neural blueprint. However, a stronger frontal recruitment suggests that linguistic tasks are more demanding for him. Finally, no specific reading activation was found in EB's occipitotemporal region, a finding consistent with the surface dyslexia-like behavioral pattern of the patient. While a lone right hemisphere may not be sufficient to guarantee full blown linguistic competences after early hemispherectomy, EB's behavioral and fMRI patterns suggest that his lone right hemisphere followed a left-like blueprint of the linguistic network.

Motor imagery (M.I.) is a mental state in which real movements are evoked without overt actions. There is some behavioural evidence that M.I. declines with ageing. The neurofunctional correlates of these changes have been investigated only in two studies, but none of the these studies has measured explicit correlations between behavioural variables and the brain response, nor the correlation of M.I. and motor execution (M.E.) of the same acts in ageing. In this paper, we report a behavioural and functional magnetic resonance imaging (fMRI) experiment that aimed to address this issue. Twenty-four young subjects (27 ± 5.6 years) and twenty-four elderly subjects (60 ± 4.6 years) performed two block-design fMRI tasks requiring actual movement (M.E.) or the mental rehearsal (M.I.) of finger movements. Participants also underwent a behavioural mental chronometry test in which the temporal correlations between M.I. and M.E. were measured. We found significant neurofunctional and behavioural differences between the elderly subjects and the young subjects during the M.E. and the M.I. tasks: for the M.E. task, the elderly subjects showed increased activation in frontal and prefrontal (pre-SMA) cortices as if M.E. had become more cognitively demanding; during the M.I. task, the elderly over-recruited occipito-temporo-parietal areas, suggesting that they may also use a visual imagery strategy. We also found between-group behavioural differences in the mental chronometry task: M.I. and M.E. were highly correlated in the young participants but not in the elderly participants. The temporal discrepancy between M.I. and M.E. in the elderly subjects correlated with the brain regions that showed increased activation in the occipital lobe in the fMRI. The same index was correlated with the premotor regions in the younger subjects. These observations show that healthy elderly individuals have decreased or qualitatively different M.I. compared to younger subjects.

Graceful aging has been associated with frontal hyperactivations in working- and episodic long-term memory tasks, a compensatory process, according to some, that allows the best normal elders to perform these tasks at a juvenile level, in spite of natural cortical impoverishment. In this study, 24 young and 24 healthy elderly participants were compared. Graceful aging was explored by investigating domains where most healthy elders perform like youngers (e.g. lexical-semantic knowledge) and tasks that are typically more challenging, like episodic long-term recognition memory tasks. With voxel-based morphometry, we also studied to what extent changes of fMRI activation were consistent with the pattern of brain atrophy. We found that hyperactivations and hypoactivations of the elders were not restricted to the frontal lobes, rather they presented with task-dependent patterns. Only hypoactivations and normal levels of activation systematically overlapped with regional atrophy. We conclude that compensatory processes associated with graceful aging may not necessarily be a sign of early saturation of executive resources, if this was to be represented by a systematic frontal hyperactivation, but rather they may represent the ability of recruiting new cognitive strategies. We discuss two possible approaches to further test this hypothesis.

BackgroundWorry is considered a key feature of generalized anxiety disorder (GAD), whose neural correlates are poorly understood. It is not known whether the brain regions involved in pathological worry are similar to those involved in worry-like mental activity in normal subjects or whether brain areas associated with worry are the same for different triggers such as verbal stimuli or faces. This study was designed to clarify these issues.MethodEight subjects with GAD and 12 normal controls underwent functional magnetic resonance imaging (fMRI) mood induction paradigms based on spoken sentences or faces. Sentences were either neutral or designed to induce worry. Faces conveyed a sad or a neutral mood and subjects were instructed to empathize with those moods.ResultsWe found that the anterior cingulate and dorsal medial prefrontal cortex [Brodmann area (BA) 32/23 and BA 10/11] were associated with worry triggered by sentences in both subjects with GAD and normal controls. However, GAD subjects showed a persistent activation of these areas even during resting state scans that followed the worrying phase, activation that correlated with scores on the Penn State Worry Questionnaire (PSWQ). This region was activated during the empathy experiment for sad faces.ConclusionsThe results show that worry in normal subjects and in subjects with GAD is based on activation of the medial prefrontal and anterior cingulate regions, known to be involved in mentalization and introspective thinking. A dysregulation of the activity of this region and its circuitry may underpin the inability of GAD patients to stop worrying.

Background: Left caloric vestibular stimulation (CVS) transiently reduces impairments of right-brain-damaged patients with left unilateral neglect, including left hemianesthesia, contralateral to the side of the lesion (contralesional). Conversely, no effect on right contralesional hemianesthesia in left-brain-damaged patients is seen with right CVS. This discrepancy is unexplained. Methods: The authors explored the effect of CVS on right- and left-brain-damaged patients with hemianesthesia. One left-brain-damaged patient had an fMRI study during tactile stimulation before and after left CVS. The same fMRI touch study, without CVS, was performed in neurologically unimpaired subjects. Results: A transient remission of right hemianesthesia associated with left brain damage was observed, provided that cold CVS was administered to the left ear. In the left-brain-damaged patient studied with fMRI, left CVS modulated the neural response to right hand tactile stimuli of a portion of the secondary somatosensory area (SII) of the right hemisphere. In neurologically unimpaired subjects, fMRI scans showed that the same part of area SII in the right hemisphere was activated by ipsilateral right-sided touches and to a larger extent than area SII in the left hemisphere by left-sided touches. Conclusions: Left caloric vestibular stimulation is effective on both left and right hemianesthesia because it modulates the hemisphere that has a more complete representation of, or is capable to attend to, the whole somatosensory surface of the body. These results suggest a hardwired hemispheric asymmetry in hand representation, starting from a somatotopically organized brain region such as area SII.

In everyday life, the successful monitoring of behavior requires continuous updating of the effectiveness of motor acts; one crucial step is becoming aware of the movements one is performing. We studied the anatomical distribution of lesions in right-brain–damaged hemiplegic patients, who obstinately denied their motor impairment, claiming that they could move their paralyzed limbs. Denial was associated with lesions in areas related to the programming of motor acts, particularly Brodmann's premotor areas 6 and 44, motor area 4, and the somatosensory cortex. This association suggests that monitoring systems may be implemented within the same cortical network that is responsible for the primary function that has to be monitored.