The Italian dementia with Lewy bodies study group (DLB-SINdem): toward a standardization of clinical procedures and multicenter cohort studies design.

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.

Clinical and biomarker profiling of prodromal Alzheimer's disease in workpackage 5 of the Innovative Medicines Initiative PharmaCog project: a 'European ADNI study'.

BACKGROUND: In the field of Alzheimer's disease (AD), the validation of biomarkers for early AD diagnosis and for use as a surrogate outcome in AD clinical trials is of considerable research interest. OBJECTIVE: To characterize the clinical profile and genetic, neuroimaging and neurophysiological biomarkers of prodromal AD in amnestic mild cognitive impairment (aMCI) patients enrolled in the IMI WP5 PharmaCog (also referred to as the European ADNI study). METHODS: A total of 147 aMCI patients were enrolled in 13 European memory clinics. Patients underwent clinical and neuropsychological evaluation, magnetic resonance imaging (MRI), electroencephalography (EEG) and lumbar puncture to assess the levels of amyloid ß peptide 1-42 (Aß42), tau and p-tau, and blood samples were collected. Genetic (APOE), neuroimaging (3T morphometry and diffusion MRI) and EEG (with resting-state and auditory oddball event-related potential (AO-ERP) paradigm) biomarkers were evaluated. RESULTS: Prodromal AD was found in 55 aMCI patients defined by low Aß42 in the cerebrospinal fluid (Aß positive). Compared to the aMCI group with high Aß42 levels (Aß negative), Aß positive patients showed poorer visual (P = 0.001), spatial recognition (P < 0.0005) and working (P = 0.024) memory, as well as a higher frequency of APOE4 (P < 0.0005), lower hippocampal volume (P = 0.04), reduced thickness of the parietal cortex (P < 0.009) and structural connectivity of the corpus callosum (P < 0.05), higher amplitude of delta rhythms at rest (P = 0.03) and lower amplitude of posterior cingulate sources of AO-ERP (P = 0.03). CONCLUSION: These results suggest that, in aMCI patients, prodromal AD is characterized by a distinctive cognitive profile and genetic, neuroimaging and neurophysiological biomarkers. Longitudinal assessment will help to identify the role of these biomarkers in AD progression.

Evaluation of symptomatic drug effects in Alzheimer's disease: strategies for prediction of efficacy in humans.

In chronic diseases such as Alzheimer's disease (AD), the arsenal of biomarkers available to determine the effectiveness of symptomatic treatment is very limited. Interpretation of the results provided in literature is cumbersome and it becomes difficult to predict their standardization to a larger patient population. Indeed, cognitive assessment alone does not appear to have sufficient predictive value of drug efficacy in early clinical development of AD treatment. In recent years, research has contributed to the emergence of new tools to assess brain activity relying on innovative technologies of imaging and electrophysiology. However, the relevance of the use of these newer markers in treatment response assessment is waiting for validation. This review shows how the early clinical assessment of symptomatic drugs could benefit from the inclusion of suitable pharmacodynamic markers. This review also emphasizes the importance of re-evaluating a step-by-step strategy in drug development.

Early diagnosis of Alzheimer's disease: the role of biomarkers including advanced EEG signal analysis. Report from the IFCN-sponsored panel of experts.

Alzheimer's disease (AD) is the most common neurodegenerative disease among the elderly with a progressive decline in cognitive function significantly affecting quality of life. Both the prevalence and emotional and financial burdens of AD on patients, their families, and society are predicted to grow significantly in the near future, due to a prolongation of the lifespan. Several lines of evidence suggest that modifications of risk-enhancing life styles and initiation of pharmacological and non-pharmacological treatments in the early stage of disease, although not able to modify its course, helps to maintain personal autonomy in daily activities and significantly reduces the total costs of disease management. Moreover, many clinical trials with potentially disease-modifying drugs are devoted to prodromal stages of AD. Thus, the identification of markers of conversion from prodromal form to clinically AD may be crucial for developing strategies of early interventions. The current available markers, including volumetric magnetic resonance imaging (MRI), positron emission tomography (PET), and cerebral spinal fluid (CSF) analysis are expensive, poorly available in community health facilities, and relatively invasive. Taking into account its low cost, widespread availability and non-invasiveness, electroencephalography (EEG) would represent a candidate for tracking the prodromal phases of cognitive decline in routine clinical settings eventually in combination with other markers. In this scenario, the present paper provides an overview of epidemiology, genetic risk factors, neuropsychological, fluid and neuroimaging biomarkers in AD and describes the potential role of EEG in AD investigation, trying in particular to point out whether advanced analysis of EEG rhythms exploring brain function has sufficient specificity/sensitivity/accuracy for the early diagnosis of AD.

Effects of tiredness on visuo-spatial attention processes in elite karate athletes and non-athletes.

"Attentional" adaptations are fundamental effects for sport performance. We tested the hypothesis that tiredness and muscular fatigue poorly affect visuo-spatial attentional processes in elite karate athletes. To this aim, 14 elite karate athletes and 11 non-athletes were involved in an isometric contraction exercise protocol up to muscular fatigue. Blood lactate and attention measurements were taken. Posner's test probed "endogenous" (i.e., internally planned allocation of spatial attention) and "reflexive" (i.e., brisk variation of endogenous spatial attention due to unexpected external stimuli) attention. Lactate and attentional measurements were performed before (Block 1, B1) and after the fatiguing exercise (B2) and at the end of a recovery period (B3). Compared to the non-athletes, the athletes showed a better performance in the fatigue protocol, confirmed by the higher absolute lactate values in B2. The correct responses in the "valid trials" probing "endogenous" attention were 92.4% (B1), 93.9% (B2), and 95.8% (B3) in the non-athletes, and 98.5%, 96.4%, 95.5% in the elite karate athletes. The correct responses in the "invalid trials" probing "reflexive" attention were 95.4%, 89.7%, 93.2% in the non-athletes, and 96.4%, 97.3%, 98.5% in the elite karate athletes. The percentage of correct responses in the "invalid" trials significantly decreased from B1 to B2 in the non-athletes but not in the elite karate athletes. In conclusion, tiredness and muscular fatigue do not affect "reflexive" attentional processes of elite karate athletes, which is crucial to contrast attacks coming from an unexpected spatial region.

Hypothalamus, sexual arousal and psychosexual identity in human males: a functional magnetic resonance imaging study.

In a recent functional magnetic resonance imaging study, a complex neural circuit was shown to be involved in human males during sexual arousal [A. Ferretti et al. (2005) Neuroimage, 26, 1086]. At group level, there was a specific correlation between penile erection and activations in anterior cingulate, insula, amygdala, hypothalamus and secondary somatosensory regions. However, it is well known that there are remarkable inter-individual differences in the psychological view and attitude to sex of human males. Therefore, a crucial issue is the relationship among cerebral responses, sexual arousal and psychosexual identity at individual level. To address this issue, 18 healthy male subjects were recruited. Their deep sexual identity (DSI) was assessed following the construct revalidation by M. Olivetti Belardinelli [(1994) Sci. Contrib. Gen. Psychol., 11, 131] of the Franck drawing completion test, a projective test providing, according to this revalidation, quantitative scores on 'accordance/non-accordance' between self-reported and psychological sexual identity. Cerebral activity was evaluated by means of functional magnetic resonance imaging during hard-core erotic movies and sport movies. Results showed a statistically significant positive correlation between the blood oxygen level-dependent signal in bilateral hypothalamus and the Franck drawing completion test score during erotic movies. The higher the blood oxygen level-dependent activation in bilateral hypothalamus, the higher the male DSI profile. These results suggest that, in male subjects, inter-individual differences in the DSI are strongly correlated with blood flow to the bilateral hypothalamus, a dimorphic brain region deeply implicated in instinctual drives including reproduction.

Prefrontal [correction of Prefontal] cortex in long-term memory: an "interference" approach using magnetic stimulation.

Neuroimaging has consistently shown engagement of the prefrontal cortex during episodic memory tasks, but the functional relevance of this metabolic/hemodynamic activation in memory processing is still to be determined. We used repetitive transcranial magnetic stimulation (rTMS) to transiently interfere with either left or right prefrontal brain activity during the encoding or retrieval of pictures showing complex scenes. We found that the right dorsolateral prefrontal cortex (DLPFC) was crucial for the retrieval of the encoded pictorial information, whereas the left DLPFC was involved in encoding operations. This 'interference' approach allowed us to establish whether a cortical area activated by a memory task actually contributes to behavioral performance.

Homocysteine and electroencephalographic rhythms in Alzheimer disease: a multicentric study.

High plasma concentration of homocysteine is an independent risk factor for Alzheimer's disease (AD), due to microvascular impairment and consequent neural loss [Seshadri S, Beiser A, Selhub J, Jacques PF, Rosenberg IH, D'Agostino RB, Wilson PW, Wolf PA (2002) Plasma homocysteine as a risk factor for dementia and Alzheimer's disease. N Engl J Med 346(7):476-483]. Is high plasma homocysteine level related to slow electroencephalographic (EEG) rhythms in awake resting AD subjects, as a reflection of known relationships between cortical neural loss and these rhythms? To test this hypothesis, we enrolled 34 mild AD patients and 34 subjects with mild cognitive impairment (MCI). Enrolled people were then subdivided into four sub-groups of 17 persons: MCI and AD subjects with low homocysteine level (MCI- and AD-, homocysteine level <11 micromol/l); MCI and AD subjects with high homocysteine level (MCI+ and AD+, homocysteine level >or=11 micromol/l). Resting eyes-closed EEG data were recorded. EEG rhythms of interest were delta (2-4 Hz), theta (4-8 Hz), alpha 1 (8-10.5 Hz), alpha 2 (10.5-13 Hz), beta 1 (13-20 Hz), and beta 2 (20-30 Hz). EEG cortical sources were estimated by low-resolution brain electromagnetic tomography (LORETA). Results showed that delta (frontal and temporal), theta (central, frontal, parietal, occipital, and temporal), alpha 1 (parietal, occipital, and temporal), and alpha 2 (parietal and occipital) sources were stronger in magnitude in AD+ than AD- group. Instead, no difference was found between MCI- and MCI+ groups. In conclusion, high plasma homocysteine level is related to unselective increment of cortical delta, theta, and alpha rhythms in mild AD, thus unveiling possible relationships among that level, microvascular concomitants of advanced neurodegenerative processes, and synchronization mechanisms generating EEG rhythms.

Conversion from mild cognitive impairment to Alzheimer's disease is predicted by sources and coherence of brain electroencephalography rhythms.

Objective. Can quantitative electroencephalography (EEG) predict the conversion from mild cognitive impairment (MCI) to Alzheimer's disease (AD)? Methods. Sixty-nine subjects fulfilling criteria for MCI were enrolled; cortical connectivity (spectral coherence) and (low resolution brain electromagnetic tomography) sources of EEG rhythms (delta=2-4 Hz; theta=4-8 Hz; alpha 1=8-10.5 Hz; alpha 2=10.5-13 Hz: beta 1=13-20 Hz; beta 2=20-30 Hz; and gamma=30-40) were evaluated at baseline (time of MCI diagnosis) and follow up (about 14 months later). At follow-up, 45 subjects were still MCI (MCI Stable) and 24 subjects were converted to AD (MCI Converted). Results. At baseline, fronto-parietal midline coherence as well as delta (temporal), theta (parietal, occipital and temporal), and alpha 1 (central, parietal, occipital, temporal, limbic) sources were stronger in MCI Converted than stable subjects (P<0.05). Cox regression modeling showed low midline coherence and weak temporal source associated with 10% annual rate AD conversion, while this rate increased up to 40% and 60% when strong temporal delta source and high midline gamma coherence were observed respectively. Interpretation. Low-cost and diffuse computerized EEG techniques are able to statistically predict MCI to AD conversion.

Decrease of functional coupling between left and right auditory cortices during dichotic listening: an electroencephalography study.

The present study focused on functional coupling between human bilateral auditory cortices and on possible influence of right over left auditory cortex during dichotic listening of complex non-verbal tones having near (competing) compared with distant non-competing fundamental frequencies. It was hypothesized that dichotic stimulation with competing tones would induce a decline of functional coupling between the two auditory cortices, as revealed by a decrease of electroencephalography coherence and an increase of directed transfer function from right (specialized for the present stimulus material) to left auditory cortex. Electroencephalograph was recorded from T3 and T4 scalp sites, overlying respectively left and right auditory cortices, and from Cz scalp site (vertex) for control purposes. Event-related coherence between T3 and T4 scalp sites was significantly lower for all electroencephalography bands of interest during dichotic listening of competing than non-competing tone pairs. This was a specific effect, since event-related coherence did not differ in a monotic control condition. Furthermore, event-related coherence between T3 and Cz and between T4 and Cz scalp sites showed no significant effects. Conversely, the directed transfer function results showed negligible influence at group level of right over left auditory cortex during dichotic listening. These results suggest a decrease of functional coupling between bilateral auditory cortices during competing dichotic stimuli as a possible neural substrate for the lateralization of auditory stimuli during dichotic listening.

Assessing cortical functional connectivity by linear inverse estimation and directed transfer function: simulations and application to real data.

OBJECTIVE: To test a technique called Directed Transfer Function (DTF) for the estimation of human cortical connectivity, by means of simulation study and human study, using high resolution EEG recordings related to finger movements. METHODS: The method of the Directed Transfer Function (DTF) is a frequency-domain approach, based on a multivariate autoregressive modeling of time series and on the concept of Granger causality. Since the spreading of the potential from the cortex to the sensors makes it difficult to infer the relation between the spatial patterns on the sensor space and those on the cortical sites, we propose the use of the DTF method on cortical signals estimated from high resolution EEG recordings, which exhibit a higher spatial resolution than conventional cerebral electromagnetic measures. The simulation study was followed by an analysis of variance (ANOVA) of the results obtained for different levels of Signal to Noise Ratio (SNR) and temporal length, as they have been systematically imposed on simulated signals. The whole methodology was then applied to high resolution EEG data recorded during a visually paced finger movement. RESULTS: The statistical analysis performed returns that during simulations, DTF is able to estimate correctly the imposed connectivity patterns under reasonable operative conditions, i.e. when data exhibit a SNR of at least 3 and a length of at least 75 s of non-consecutive recordings at 64 Hz of sampling rate, equivalent, more generally, to 4800 data samples. CONCLUSIONS: Functional connectivity patterns of cortical activity can be effectively estimated under general conditions met in any practical EEG recordings, by combining high resolution EEG techniques, linear inverse estimation and the DTF method. SIGNIFICANCE: The estimation of cortical connectivity can be performed not only with hemodynamic measurements, by using functional MRI recordings, but also with modern EEG recordings treated with advanced computational techniques.

Coupling between "hand" primary sensorimotor cortex and lower limb muscles after ulnar nerve surgical transfer in paraplegia.

Previous neuroimaging evidence revealed an "invasion" of "hand" over "lower limb" primary sensorimotor cortex in paraplegic subjects, with the exception of a rare patient who received a surgical motor reinnervation of hip-thigh muscles by the ulnar nerve. Here, the authors show that a functional reorganization of cortico-muscular and cortico-cortical oscillatory coupling was related to the recovery of the rare patient, as a paradigmatic case of long-term plasticity in human sensorimotor cortex after motor reinnervation of paraplegic muscles. This conclusion was based on electroencephalographic and electromyographic data collected while the patient and normal control subjects performed isometric muscle contraction of the left hand or lower limb. Cortico-muscular and cortico-cortical coupling was estimated by electroencephalographic-electromyographic coherence and directed transfer function of a multivariate autoregressive model.

Human cortical activity related to unilateral movements. A high resolution EEG study.

In the present study a modern high resolution electroencephalography (EEG) technique was used to investigate the dynamic functional topography of human cortical activity related to simple unilateral internally triggered finger movements. The sensorimotor area (M1-S1) contralateral to the movement as well as the supplementary motor area (SMA) and to a lesser extent the ipsilateral M1-S1 were active during the preparation and execution of these movements. These findings suggest that both hemispheres may cooperate in both planning and production of simple unilateral volitional acts.

Human short latency cortical responses to somatosensory stimulation. A high resolution EEG study.

Human short-latency cortical responses to median nerve stimulation were investigated with a new high resolution electroencephalography technology that markedly enhanced spatial details of somatosensory-evoked potentials (SEPs). Maximum amplitude potentials were estimated over contralateral and/or frontal-mesial scalp regions about 20, 22, 24, 26, 30, 32 and 45 ms following the stimulation. Frontal-lateral P20-N24-N30-P45 and parietal-lateral N20-P24-P30-N45 showed dipolar patterns, whereas frontal-mesial N24-N30-P45 and central-lateral P22-N26-N32-P45 presented no clearcut dipole counterpart. Plausibly, the spatially enhanced frontal-parietal SEP components were generated (tangential dipoles) within the lateral central sulcus cortex, and anticipated the central-lateral and frontal-mesial components generated (radial dipoles) from the crown of the pre- and/or post-central gyri and the supplementary motor area, respectively.

Topography of spatially enhanced human short-latency somatosensory evoked potentials.

In the present study modern high resolution electroencephalography (EEG) was used to spatially enhance human median nerve short-latency somatosensory evoked potentials (SEPs). It was shown that the spatially enhanced N30 consisted of two frontal subcomponents, one located in the frontal-lateral area of the scalp, the other located in the frontal-mesial area. Both of these subcomponents were most reduced in amplitude (or disappeared) during concomitant hand movement ipsilateral to the stimulus, but were differentially influenced by executed contralateral movement and imagined ipsilateral movement. These results support the hypothesis of an involvement of the frontal-mesial cortex (including the supplementary motor area) in the generation of the frontal N30.

"Gating" of human short-latency somatosensory evoked cortical responses during execution of movement. A high resolution electroencephalography study.

The present study aimed at investigating gating of median nerve somatosensory evoked cortical responses (SECRs), estimated during executed continuous complex ipsilateral and contralateral sequential finger movements. SECRs were modeled with an advanced high resolution electroencephalography technology that dramatically improved spatial details of the scalp recorded somatosensory evoked potentials. Integration with magnetic resonance brain images allowed us to localize different SECRs within cortical areas. The working hypothesis was that the gating effects were time varying and could differently influence SECRs. Maximum statistically significant (p<0. 01) time-varying gating (magnitude reduction) of the short-latency SECRs modeled in the contralateral primary motor and somatosensory and supplementary motor areas was computed during the executed ipsilateral movement. The gating effects were stronger on the modeled SECRs peaking 30-45 ms (N30-P30, N32, P45-N45) than 20-26 ms (P20-N20, P22, N26) post-stimulus. Furthermore, the modeled SECRs peaking 30 ms post-stimulus (N30-P30) were significantly increased in magnitude during the executed contralateral movement. These results may delineate a distributed cortical sensorimotor system responsible for the gating effects on SECRs. This system would be able to modulate activity of SECR generators, based on the integration of afferent somatosensory inputs from the stimulated nerve with outputs related to the movement execution.

Bilateral neuromagnetic activation of human primary sensorimotor cortex in preparation and execution of unilateral voluntary finger movements.

Extracranial magnetoencephalographic activity was separately recorded (25 channels) from bilateral primary sensorimotor cortex (M1-S1) of normal right-handers during unilateral finger movements. Standard dipole analysis indicated only a contralateral M1-S1 source for first movement-evoked field (MEF1) peaking at about 115 ms after electromyographic onset. However, the subtraction of the magnetic field generated by this source from the recorded magnetic field disclosed a low-amplitude ipsilateral central-parietal MEF1 that was explained by an ipsilateral M1-S1 source.

Statistical analysis of topographic maps of short-latency somatosensory evoked potentials in normal and parkinsonian subjects.

This work had the following objectives: i) to integrate temporal analysis (N30 peak) with power-spectrum topographic mapping of short-latency somatosensory evoked potentials (SEP's) recorded in parkinsonian and normal control subjects; and ii) to analyze with a new statistical approach the between-group topographical differences in both the time and frequency domains. The principal aim was to better determine the topography of the scalp frontal areas where the amplitude of the N30 wave was previously found to be significantly reduced in parkinsonians. The statistical procedure was based on the combined use of descriptive data analysis (DDA) and multivariate analysis. In the context of DDA, an improved version of significance probability mapping (SPM) was used by which it is possible to evaluate homo- and nonhomoscedastic data with parametric tests. The statistical evaluation of between-group differences was performed with the multivariate Hotelling's T2 test and the associated post hoc test. With this statistical procedure, it was possible to determine that the between-group statistical differences in both the temporal and power spectrum distributions were localized only in midline and contiguous contralateral frontal areas of the scalp.

Computerized processing of EEG-EOG-EMG artifacts for multi-centric studies in EEG oscillations and event-related potentials.

The aim of this study is to present a package including standard software for the electroencephalographic (EEG), electro-oculographic (EOG) and electromyographic (EMG) preliminary data analysis, which may be suitable to standardize the results of many EEG research centers studies (i.e. multi-centric studies) especially focused on event-related potentials. In particular, our software package includes (semi)automatic procedures for (i) EOG artifact detection and correction, (ii) EMG analysis, (iii) EEG artifact analysis, (iv) optimization of the ratio between artifact-free EEG channels and trials to be rejected. The performances of the software package on EOG-EEG-EMG data related to cognitive-motor tasks were evaluated with respect to the preliminary data analysis performed by two expert electroencephalographists (gold standard). Due to its extreme importance for multi-centric EEG studies, we compared the performances of two representative "regression" methods for the EOG correction in time and frequency domains. The aim was the selection of the most suitable method in the perspective of a multi-centric EEG study. The results showed an acceptable agreement of approximately 95% between the human and software behaviors, for the detection of vertical and horizontal EOG artifacts, the measurement of hand EMG responses for a cognitive-motor paradigm, the detection of involuntary mirror movements, and the detection of EEG artifacts. Furthermore, our results indicated a particular reliability of a 'regression' EOG correction method operating in time domain (i.e. ordinary least squares). These results suggest that such a software package could be used for multi-centric EEG studies.

Integration of high resolution EEG and functional magnetic resonance in the study of human movement-related potentials.

Cortical sources of human movement-related potentials (i.e. unilateral finger extension) were modeled using functional magnetic resonance imaging (fMR) data as a constraint of a linear inverse source estimation from highly sampled (128 channels) EEG data. Remarkably, this estimation was performed within realistic subject's MR-constructed head models by boundary element techniques. An appropriate figure of merit served to set the optimal amount of fMR constraints. With respect to standard linear inverse source estimates, fMR-constrained ones presented increased spatial detail and provided a more reliable timing of activation in bilateral sensorimotor cortical regions of interest.