Evaluation of the Feasibility, Safety and Efficacy of the Use of Intravenous Infusions of Adenosine Triphosphate (ATP) in People Affected by Moderate to Severe Alzheimer's Disease: A Double-Blind Masked Clinical Trial for Dose Finding.

BACKGROUND: There are currently no drug therapies modifying the natural history of patients suffering Alzheimer's disease (AD). Most recent clinical trials in the field include only subjects in early stage of the disease, while patients with advanced AD are usually not represented. OBJECTIVES: To evaluate the feasibility, safety and efficacy of systemic infusions of adenosine triphosphate (ATP) in patients with moderate to severe AD, and to select the minimum effective dose of infusion. DESIGN: A phase IIb, randomized, double-blind, placebo-controlled clinical trial investigates. PARTICIPANTS: A total of 20 subjects with moderate or severe AD were included, 16 in the treatment group and 4 in the placebo group (4:1 randomization) at two dosage regimens, 6-hour or 24-hour infusions. RESULTS: The proof-of-concept study was successfully conducted, with no significant deviations from the study protocol and no serious adverse events reported. Regarding efficacy, only marginal differences were observed between ATP and placebo arms for H-MRS and MMSE variables. CONCLUSIONS: Our study demonstrates that the use of ATP infusion as therapy is feasible and safe. Larger studies are however needed to assess the efficacy of ATP in moderate to severe AD.

Functional Connectivity Hypersynchronization in Relatives of Alzheimer's Disease Patients: An Early E/I Balance Dysfunction?

Alzheimer's disease (AD) studies on animal models, and humans showed a tendency of the brain tissue to become hyperexcitable and hypersynchronized, causing neurodegeneration. However, we know little about either the onset of this phenomenon or its early effects on functional brain networks. We studied functional connectivity (FC) on 127 participants (92 middle-age relatives of AD patients and 35 age-matched nonrelatives) using magnetoencephalography. FC was estimated in the alpha band in areas known both for early amyloid accumulation and disrupted FC in MCI converters to AD. We found a frontoparietal network (anterior cingulate cortex, dorsal frontal, and precuneus) where relatives of AD patients showed hypersynchronization in high alpha (not modulated by APOE-ε4 genotype) in comparison to age-matched nonrelatives. These results represent the first evidence of neurophysiological events causing early network disruption in humans, opening a new perspective for intervention on the excitation/inhibition unbalance.

Spatiotemporal Oscillatory Patterns During Working Memory Maintenance in Mild Cognitive Impairment and Subjective Cognitive Decline.

Working memory (WM) is a crucial cognitive process and its disruption is among the earliest symptoms of Alzheimer's disease. While alterations of the neuronal processes underlying WM have been evidenced in mild cognitive impairment (MCI), scarce literature is available in subjective cognitive decline (SCD). We used magnetoencephalography during a WM task performed by MCI (n = 45), SCD (n = 49) and healthy elders (n = 49) to examine group differences during the maintenance period (0-4000ms). Data were analyzed using time-frequency analysis and significant oscillatory differences were localized at the source level. Our results indicated significant differences between groups, mainly during the early maintenance (250-1250ms) in the theta, alpha and beta bands and in the late maintenance (2750-3750ms) in the theta band. MCI showed lower local synchronization in fronto-temporal cortical regions in the early theta-alpha window relative to controls (p = 2 × 10-03) and SCD (p = 4 × 10-03), and in the late theta window relative to controls (p = 1 × 1003) and SCD (p = 0.01). Early theta-alpha power was significantly correlated with memory scores (rho = 0.24,p = 0.02) and late theta power was correlated with task performance (rho = 0.24,p = 0.03) and functional activity scores (rho = -0.23,p = 0.02). In the early beta window, MCI showed reduced power in temporo-posterior regions relative to controls (p = 3 × 10-03) and SCD (p = 0.02). Our results may suggest that these alterations would reflect that memory-related networks are damaged.

Decreased event-related theta power and phase-synchrony in young binge drinkers during target detection: An anatomically-constrained MEG approach.

BACKGROUND: The prevalence of binge drinking has risen in recent years. It is associated with a range of neurocognitive deficits among adolescents and young emerging adults who are especially vulnerable to alcohol use. Attention is an essential dimension of executive functioning and attentional disturbances may be associated with hazardous drinking. The aim of the study was to examine the oscillatory neural dynamics of attentional control during visual target detection in emerging young adults as a function of binge drinking. METHOD: In total, 51 first-year university students (18 ± 0.6 years) were assigned to light drinking ( n = 26), and binge drinking ( n = 25) groups based on their alcohol consumption patterns. A high-density magnetoencephalography signal was combined with structural magnetic resonance imaging in an anatomically constrained magnetoencephalography model to estimate event-related source power in a theta (4-7 Hz) frequency band. Phase-locked co-oscillations were further estimated between the principally activated regions during task performance. RESULTS: Overall, the greatest event-related theta power was elicited by targets in the right inferior frontal cortex and it correlated with performance accuracy and selective attention scores. Binge drinkers exhibited lower theta power and dysregulated oscillatory synchrony to targets in the right inferior frontal cortex, which correlated with higher levels of alcohol consumption. CONCLUSIONS: These results confirm that a highly interactive network in the right inferior frontal cortex subserves attentional control, revealing the importance of theta oscillations and neural synchrony for attentional capture and contextual maintenance. Attenuation of theta power and synchronous interactions in binge drinkers may indicate early stages of suboptimal integrative processing in young, highly functioning binge drinkers.

A physical model for dementia.

Aging associated brain decline often result in some kind of dementia. Even when this is a complex brain disorder a physical model can be used in order to describe its general behavior. A probabilistic model for the development of dementia is obtained and fitted to some experimental data obtained from the Alzheimer's Disease Neuroimaging Initiative. It is explained how dementia appears as a consequence of aging and why it is irreversible.

Alpha band disruption in the AD-continuum starts in the Subjective Cognitive Decline stage: a MEG study.

The consideration of Subjective Cognitive Decline (SCD) as a preclinical stage of AD remains still a matter of debate. Alpha band alterations represent one of the most significant changes in the electrophysiological profile of AD. In particular, AD patients exhibit reduced alpha relative power and frequency. We used alpha band activity measured with MEG to study whether SCD and MCI elders present these electrophysiological changes characteristic of AD, and to determine the evolution of the observed alterations across AD spectrum. The total sample consisted of 131 participants: 39 elders without SCD, 41 elders with SCD and 51 MCI patients. All of them underwent MEG and MRI scans and neuropsychological assessment. SCD and MCI patients exhibited a similar reduction in alpha band activity compared with the no SCD group. However, only MCI patients showed a slowing in their alpha peak frequency compared with both SCD and no SCD. These changes in alpha band were related to worse cognition. Our results suggest that AD-related alterations may start in the SCD stage, with a reduction in alpha relative power. It is later, in the MCI stage, where the slowing of the spectral profile takes place, giving rise to objective deficits in cognitive functioning.

Functional and structural brain connectivity of young binge drinkers: a follow-up study.

Adolescence is a period of ongoing brain maturation characterized by hierarchical changes in the functional and structural networks. For this reason, the young brain is particularly vulnerable to the toxic effects of alcohol. Nowadays, binge drinking is a pattern of alcohol consumption increasingly prevalent among adolescents. The aim of the present study is to evaluate the evolution of the functional and anatomical connectivity of the Default Mode Network (DMN) in young binge drinkers along two years. Magnetoencephalography signal during eyes closed resting state as well as Diffusion Tensor Imaging (DTI) were acquired twice within a 2-year interval from 39 undergraduate students (22 controls, 17 binge drinkers) with neither personal nor family history of alcoholism. The group comparison showed that, after maintaining a binge drinking pattern along at least two years, binge drinkers displayed an increased brain connectivity of the DMN in comparison with the control group. On the other hand, the structural connectivity did not show significant differences neither between groups nor over the time. These findings point out that a continued pattern of binge drinking leads to functional alterations in the normal brain maturation process, even before anatomical changes can be detected.

Scopolamine effects on functional brain connectivity: a pharmacological model of Alzheimer's disease.

Scopolamine administration may be considered as a psychopharmacological model of Alzheimer's disease (AD). Here, we studied a group of healthy elderly under scopolamine to test whether it elicits similar changes in brain connectivity as those observed in AD, thereby verifying a possible model of AD impairment. We did it by testing healthy elderly subjects in two experimental conditions: glycopyrrolate (placebo) and scopolamine administration. We then analyzed magnetoencephalographic (MEG) data corresponding to both conditions in resting-state with eyes closed. This analysis was performed in source space by combining a nonlinear frequency band-specific measure of functional connectivity (phase locking value, PLV) with network analysis methods. Under scopolamine, functional connectivity between several brain areas was significantly reduced as compared to placebo, in most frequency bands analyzed. Besides, regarding the two complex network indices studied (clustering and shortest path length), clustering significantly decreased in the alpha band while shortest path length significantly increased also in alpha band both after scopolamine administration. Overall our findings indicate that both PLV and graph analysis are suitable tools to measure brain connectivity changes induced by scopolamine, which causes alterations in brain connectivity apparently similar to those reported in AD.

Exploratory Analysis of Power Spectrum and Functional Connectivity During Resting State in Young Binge Drinkers: A MEG Study.

Binge Drinking (BD) is a pattern of intermittent intensive alcohol intake which has spread among young adults over the last decades. Adolescence constitutes a critical neuromaturation period in which the brain is particularly sensitive to the effects of alcohol. However, little is known about how BD affects the brain activity. This study aimed to characterize the brain's functional organization in BD and non-BD young population by means of analyzing functional connectivity (FC) and relative power spectra (PS) profiles measured with magnetoencephalography (MEG) during eyes-closed resting state. Our sample composed 73 first-year university students (35 BDs and 38 controls). Results showed that the BD subjects displayed a decreased alpha FC in frontal-parietal regions, and conversely, an enhanced FC in the delta, theta and beta bands in fronto-temporal networks. Besides the FC differences, the BD group showed a decreased PS within alpha range and an increased PS within theta range in the brain's occipital region. These differences in FC and PS measurements provide new evidence of the neurophysiological alterations related to the alcohol neurotoxicity and could represent an initial sign of an anomalous neural activity caused by a BD pattern of alcohol consumption during youth.

MEG spectral analysis in subtypes of mild cognitive impairment.

Mild cognitive impairment (MCI) has been described as an intermediate stage between normal aging and dementia. Previous studies characterized the alterations of brain oscillatory activity at this stage, but little is known about the differences between single and multidomain amnestic MCI patients. In order to study the patterns of oscillatory magnetic activity in amnestic MCI subtypes, a total of 105 subjects underwent an eyes-closed resting-state magnetoencephalographic recording: 36 healthy controls, 33 amnestic single domain MCIs (a-sd-MCI), and 36 amnestic multidomain MCIs (a-md-MCI). Relative power values were calculated and compared among groups. Subsequently, relative power values were correlated with neuropsychological tests scores and hippocampal volumes. Both MCI groups showed an increase in relative power in lower frequency bands (delta and theta frequency ranges) and a decrease in power values in higher frequency bands (alpha and beta frequency ranges), as compared with the control group. More importantly, clear differences emerged from the comparison between the two amnestic MCI subtypes. The a-md-MCI group showed a significant power increase within delta and theta ranges and reduced relative power within alpha and beta ranges. Such pattern correlated with the neuropsychological performance, indicating that the a-md-MCI subtype is associated not only with a "slowing" of the spectrum but also with a poorer cognitive status. These results suggest that a-md-MCI patients are characterized by a brain activity profile that is closer to that observed in Alzheimer disease. Therefore, it might be hypothesized that the likelihood of conversion to dementia would be higher within this subtype.

Drug polyconsumption is associated with increased synchronization of brain electrical-activity at rest and in a counting task.

Drug abusers typically consume not just one but several types of drugs, starting from alcohol and marijuana consumption, and then dramatically lapsing into addiction to harder drugs, such as cocaine, heroin, or amphetamine. The brain of drug abusers presents various structural and neurophysiological abnormalities, some of which may predate drug consumption onset. However, how these changes translate into modifications in functional brain connectivity is still poorly understood. To characterize functional connectivity patterns, we recorded Electroencephalogram (EEG) activity from 21 detoxified drug abusers and 20 age-matched control subjects performing a simple counting task and at rest activity. To evaluate the cortical brain connectivity network we applied the Synchronization Likelihood algorithm. The results showed that drug abusers had higher synchronization levels at low frequencies, mainly in the θ band (4-8 Hz) between frontal and posterior cortical regions. During the counting task, patients showed increased synchronization in the ß (14-35 Hz), and γ (35-45 Hz) frequency bands, in fronto-posterior and interhemispheric temporal regions. Taken together 'slow-down' at rest and task-related 'over-exertion' could indicate that the brain of drug abusers is suffering from a premature form of ageing. Future studies will clarify whether this condition can be reversed following prolonged periods of abstinence.

Clustering strategies for optimal trial selection in multisensor environments. An eigenvector based approach.

BACKGROUND: Quite often, magnetoencephalography (MEG) measurements are contaminated by a series of artifacts that degrade the quality of the various source localization methods applied to them. In particular, eye blinking, minor head movement and related activities are a constant source of measurement contamination. In order to solve this problem, trial selection and rejection is applied, a task that is usually performed manually. NEW METHOD: The present work shows an automatic trial selection and rejection algorithm based on clustering techniques. These techniques employ a measurement of the dissimilarity of the items belonging to a set. This measure, based on the projection of the eigenvector corresponding to the largest eigenvalue of the covariance matrix, is provided and its rationale is explained. Subsequently, covariance matrices belonging to the selected cluster are averaged and used in the well-known Linearly Constrained Minimum Variance (LCMV) Beamformer. RESULTS: The results show a marked improvement of the specificity of the localization algorithm compared to the application of the LCMV without clustering. COMPARISON WITH EXISTING METHOD(S): The method shows a marked reduction in computational cost compared with other data cleaning procedure widely used: Independent Component Analysis (ICA). CONCLUSIONS: Thus, we propose clustering techniques to be used in brain localization activity algorithms.

Comparison and improvements of LCMV and MUSIC source localization techniques for use in real clinical environments.

The present work shows some improvements realized on practical aspects of the implementation of Singular Value Decomposition (SVD) methods to localize the sources of neural activity by means of magnetoencephalograph (MEG). Two methods have been improved and compared i.e. a spatial filter, the Linearly Constrained Minimum Variance Beamformer (LCMV) method, and a signal subspace method that is an implementation of the MUSIC (Multiple Signal Classification) method due to Mosher et al. (1992). It also shows the performance of both methods comparing three different averaging procedures. The influence of the correct selection of the noise subspace dimension has been analyzed. Using acoustic stimulus for real patient measurements, we discuss the relevant differences of both methods and propose an adequate strategy for future diagnosis based on correct source localization.

Influence of memory strategies on memory test performance: a study in healthy and pathological aging.

The ability to generate memory strategies is a key factor in the performance of episodic memory tasks. Whether the ability to generate memory strategies exerts an influence in the performance of memory tests in the elderly population is still a matter of debate. Here we present results from an experimental memory task (Test of Memory Strategies, TMS), comprised of five lists of words starting from an incidental learning task, and four more lists which progressively gain in their external organization of the material, reducing the necessity of mobilizing complex memory strategies. TMS has been applied to four groups of elderly patients (amnestic Mild Cognitive Impairment - aMCI, multidomain (mMCI), and Vascular Cognitive Impairment - VCI and Depression) and a healthy aging group. In conditions with low organization of the material, the mMCI and VCI groups (both showing a greater executive function impairment) have shown lower performance. However, as the material was progressively organized, they improved their performance. The aMCI group showed similar performance to the control group at the lower level of external organization but did not improve performance in conditions with a high level of external organization. The mMCI and VCI groups showed lower performance on all TMS conditions compared with controls. Discriminant analysis revealed 90% sensitivity and specificity to differentiate between groups based on TMS conditions. These results indicate how executive functions influence performance on memory tasks in elderly subjects with different neuropsychological profiles.

Age-related occipito-temporal hypoactivation during visual search: relationships between mN2pc sources and performance.

Recently, an event-related potential (ERP) study (Lorenzo-López et al., 2008) provided evidence that normal aging significantly delays and attenuates the electrophysiological correlate of the allocation of visuospatial attention (N2pc component) during a feature-detection visual search task. To further explore the effects of normal aging on the N2pc neural sources, neuromagnetic activity during the execution of a visual search task was recorded in healthy young (N=14) and older (N=20) participants by using magnetoencephalography (MEG). The possible relationships between these neural sources and overt performance were explored by assessing the co-variation between the neural N2pc activity and both the task performance and the execution in the Trail Making Test Form A (TMT-A). Results revealed that young participants showed greater activity in occipito-temporal regions than older participants during the mN2pc (magnetic counterpart of the N2pc component) latency range (190-270ms). Moreover, older participants showed reduced relative activation in the right occipito-temporal source of mN2pc. These findings suggest that the previously observed age-related changes in N2pc parameters are associated with a significant hypoactivation of occipito-temporal N2pc sources that is more marked in the right hemisphere.

Biomagnetic profiles of verbal memory success in patients with mesial temporal lobe epilepsy.

The risk of cognitive decline after mesial temporal lobe (MTL) resection in the dominant hemisphere for treatment of epilepsy has been assessed with the intracarotid amytal procedure and functional neuroimaging. In this study we used magnetoencephalography (MEG) to analyze memory profiles in patients with left hippocampal sclerosis (HS). Biomagnetic brain activity related to successful memory was compared in nine patients with left HS and nine age-matched controls. Patients manifested a higher number of activity sources over the right inferior parietal lobe in the late portion of the time window, and higher activity in the right than in the left MTL between 400 and 800 ms. This was reinforced by a -0.46 MTL laterality index, which indicates right MTL dominance. Controls showed a higher number of dipoles in the left anterior ventral prefrontal region, between 400 and 600 ms, and in the left MTL across the whole time window. Three patients who underwent a left temporal lobectomy, were seizure free, and who did not exhibit memory impairment after left temporal lobectomy, showed no activity in the left MTL presurgically. These results could support the ability of MEG to describe the time-modulated brain activity related to memory success in patients with epilepsy with left HS.

Learning orthography in adulthood: a magnetoencephalographic study.

Previous work demonstrated that there were differences between literate and comparable illiterate adult subjects. These differences were found in the performance on several tests and on patterns of activation on PET and fMRI. In the present study subjects that learned to read and to write in adulthood (being previously completely illiterate) were compared to controls, that is subjects that learned at school at the proper age. Magnetoencephalography was done while subjects were reading words. Results showed that, although the reading performance was the same in both groups while performing the task, the pattern of source distribution was different between groups. There were more late sources in right temporo-parietal areas of late literates compared to controls and more late sources in left inferior frontal cortex in control subjects. It is concluded that learning to read in adulthood is a process supported by different brain structures from the ones used when learning occurs at the proper age. This may suggest that the same task can be similarly performed by relying on diverse functional brain anatomic networks.

Efecto de la estimulación auditiva a una frecuencia de 5 Hz en la memoria verbal / Impact of auditory stimulation at a frequency of 5 Hz in verbal memory

Introducción. El objetivo de este estudio es establecer si la estimulación a 5 Hz favorece el recuerdo inmediato de palabras. Método. Veinte participantes recibieron estimulación auditiva a frecuencias de 5 Hz-theta, 13 Hz-beta, ruido blanco (RB) y palabras. Resultados. Los resultados indican diferencias significativas en número de palabras recordadas por día entre las frecuencias. A partir del día 3 hasta el día 5 se observó una asociación significativa entre un mayor número de palabras recordadas con 5 Hz comparadas con las demás frecuencias. Si tenemos en cuenta el número de palabras recordadas durante el registro en la magnetoencefalogrofia, en la segunda medida se encontró diferencias significativas con mayor número de palabras entre 5 Hz y 13 Hz y entre 5 Hz y RB. En la frecuencia mediana sólo se presentaron diferencias significativas en estimulación a una frecuencia de 5 Hz. Conclusión. La estimulación auditiva durante largo tiempo a una frecuencia de 5 Hz genera un acoplamiento de la actividad cerebral a dicho ritmo que aumenta la capacidad de memoria verbal inmediata (AU)

Introduction. The objective of this study was to establish whether stimulation at 5 Hz enables immediate words recall. Method. A total of 20 participants received auditory stimulation at 5 Hz-theta, beta-13 Hz frequencies, white noise (WN) and words. Results. The results indicate significant differences in the number of recalled words per day depending on the stimulation frequencies. From the third to the fifth day a significant association was shown between increasing numbers of recalled words at 5 Hz compared with the rest of the frequencies. If we take the number of words recorded during the recording of the magnetoencephalography into account, significant differences with greater numbers of words between 5 Hz and between13 Hz and 5 Hz and WN were found in the second measure. The median frequency only showed significant differences in stimulation at a frequency of 5 Hz. Conclusion. Auditory stimulation over a long time at a frequency of 5 Hz generates a coupling of brain activity that increases the capacity of immediate verbal memory (AU)

Impact of auditory stimulation at a frequency of 5 Hz in verbal memory.

INTRODUCTION: The objective of this study was to establish whether stimulation at 5 Hz enables immediate words recall. METHOD: A total of 20 participants received auditory stimulation at 5 Hz-theta, beta-13 Hz frequencies, white noise (WN) and words. RESULTS: The results indicate significant differences in the number of recalled words per day depending on the stimulation frequencies. From the third to the fifth day a significant association was shown between increasing numbers of recalled words at 5 Hz compared with the rest of the frequencies. If we take the number of words recorded during the recording of the magnetoencephalography into account, significant differences with greater numbers of words between 5 Hz and between 13 Hz and 5 Hz and WN were found in the second measure. The median frequency only showed significant differences in stimulation at a frequency of 5 Hz. CONCLUSION: Auditory stimulation over a long time at a frequency of 5 Hz generates a coupling of brain activity that increases the capacity of immediate verbal memory.

Cambios en la actividad cerebral en el envejecimiento normal en una tarea con interferencia valorados mediante magnetoencefalografía / Magnetoencephalographic assessment of changes in brain activity in normal aging when performing a task under interference conditions

Objetivo: determinar si la realización de una tarea de reconocimiento con interferencia activa, producía cambios en los patrones de activación cerebral con respecto a la presentación de otra con interferencia pasiva. Población y metodología: en veinte ancianos sanos se midió con magnetoencefalografía. Se realizó a cada uno de ellos la escala de Memoria de Wechsler-III (WMS-III), la escala de Inteligencia de Wechsler, el Boston Naming Test, el test de fluidez verbal, el test de clasificación de tarjetas de Wisconsin, el trail Making Test y el test de colores y palabras (STROOP). Los registros se llevaron a cabo mediante un magnetoencefalógrafo de 148 canales capaz de medir la actividad magnética generada en toda la convexidad craneal. Resultados: encontramos una mayor activación en la condición de interferencia activa en las regiones mediales temporales, corteza visual, y región ventral anterior durante los primeros 400 milisegundos en el hemisferio izquierdo y únicamente en el derecho para la corteza visual, mientras que en la condición de interferencia pasiva, se obtuvo una mayor activación en la región ventral anterior durante los 700-800 milisegundos en el hemisferio izquierdo. Conclusión: la presentación de estos dos tipos de interferencia, activa y pasiva, modula los patrones de activación fronto-temporales en el envejecimiento normal (AU)

Objective: To determine whether performing a recognition task under interference conditions produces changes in brain activity pattern compared with the activity seen under conditions of passive interference. Population and methods: Twenty healthy elderly subjects were subjected to magnetoencephalography. In each patient we applied the Wechsler Memory Scale-III (WMS-III), the Wechsler Intelligence Scale, the Boston Naming Test, the verbal fluency test, the Wisconsin card classification test, the Trail Making Test and the colors and words test (STROOP). The recordings were made using a 148-channel magnetoencephalograph capable of measuring the magnetic activity generated within the entire cranial convexity. Results: Greater activation was recorded under active interference conditions in the medial temporal regions, visual cortex and anterior ventral area in the first 400 ms in the left hemisphere and only in the right hemisphere for the visual cortex, while under passive interference conditions, increased activation was obtained in the anterior ventral region during the 700-800 ms in the left hemisphere. Conclusion: The presentation of both types of interference, active and passive, modulates the fronto-temporal activation patterns in normal aging (AU)