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.

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.

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.

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.

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.

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.

Increased biomagnetic activity in the ventral pathway in mild cognitive impairment.

OBJECTIVE: Mild cognitive impairment (MCI) patients represent an intermediary state between healthy aging and dementia. MCI activation profiles, recorded during a memory task, have been studied either through high spatial resolution or high temporal resolution techniques. However, little is known about the benefit of combining both dimensions. Here, we investigate, by means of magnetoencephalography (MEG), whether spatio-temporal profiles of neuromagnetic activity could differentiate between MCI and age-matched elderly participants. METHODS: Taking the advantage of the high temporal resolution and good spatial resolution of MEG, neuromagnetic activity from 15 elderly MCI patients and 20 age-matched controls was recorded during the performance of a modified version of the Sternberg paradigm. RESULTS: Behavioral performance was similar in both groups. A between group analysis revealed that MCI patients showed bilateral higher activity in the ventral pathway, in both the target and the non-target stimuli. A within-group analysis of the target stimuli, indicates a lack of asymmetry through all late latency windows in both groups. CONCLUSIONS: MCI patients showed a compensatory mechanism represented by an increased bilateral activity of the ventral pathway in order to achieve a behavioral performance similar to the control group. SIGNIFICANCE: This spatio-temporal pattern of activity could be another tool to differentiate between healthy aging and MCI patients.

Magnetoencephalographic pattern of epileptiform activity in children with early-onset autism spectrum disorders.

OBJECTIVE: To provide further data around magnetoencephalographic (MEG) findings in early-onset autism spectrum disorders (ASD). METHODS: Thirty-six children (mean age 7 years) diagnosed of PDD (DSM-IV, ICD-10) were studied. There were 22 children with autistic disorder, 9 with Asperger's syndrome, and 5 with pervasive developmental disorder not otherwise specified (PDD-NOS). According to the Childhood Autism Rating Scale (CARS), the autistic disorder was mild to moderate in 11, and severe in 11. Neuroimaging studies using three-dimensional MRI as well as simultaneous MEG-EEG and fusion techniques through magnetic source imaging (MSI) were performed, with the aid of anesthesia in non-cooperative patients. RESULTS: Most patients had no EEG abnormalities. All ASD children showed common specific abnormalities in the shape of low amplitude monophasic and biphasic spikes (isolated or short bursts) as well as acute waves, predominantly distributed in the perisylvian areas. In Asperger's syndrome, epileptiform spikes were mostly found in the right hemisphere. No lateralized epileptiform activity was observed in non-Asperger's autistic patients. CONCLUSIONS: MEG epileptiform activity is frequently documented in children with early-onset ASD. SIGNIFICANCE: Subclinical epileptiform activity is present especially in the perisylvian regions for many patients with ASD.

Medial temporal lobe neuromagnetic hypoactivation and risk for developing cognitive decline in elderly population: a 2-year follow-up study.

Cognition declines as a function of age. However, some elders could develop more severe status such as mild cognitive impairment (MCI). The aim of this study was the early detection of neurophysiological patterns of brain activity that may predict the possibility of certain subjects to develop MCI. Brain magnetic activity was recorded from 15 healthy subjects during a memory task by means of magnetoencephalography. None of the participants could be considered as MCI at the time of the first clinical evaluation. After 2-year follow-up, five subjects developed MCI and 10 maintained their cognitive status across time. The subjects who developed cognitive decline showed a lower number of activity sources in the left medial temporal lobe between 400 and 800 ms after stimulus onset, as compared to the non-cognitive decline group. These findings may help with the early identification of elderly subjects at high risk of cognitive decline, allowing the possibility of neuropsychological or pharmaceutical treatment that delay or prevent the progression of the cognitive impairment.

Paroxysmal MEG activity in obsessive compulsive patients without SSRIs therapy.

We describe a fronto-temporal paroxysmal rhythmic activity registered by magnetoencephalography (MEG) in two patients with obsessive compulsive disorder (OCD) without SSRIs treatment. The localization of the activity involves cingulate cortex and frontal areas. We think that these MEG findings are related to the disease itself, rather than representing pharmacological SSRIs effect.

[Executive dysfunction in attention deficit hyperactivity disorder in childhood]. / Disfunción ejecutiva en el trastorno por déficit de atención con hiperactividad en la infancia.

INTRODUCTION: The principal problem of ADHD is the difficulty to execute inhibitory control. The inhibition is an executive function that is develop during childhood. AIM: To know if other executive functions shower a lower performance in ADHD versus control group and these were different between ADHD-I and ADHD-C. PATIENTS AND METHODS: Fifty three children, between 7 to 10 years old, participated and were assess with EMIC and Simon task. RESULTS: The results showed similar profile in working memory and verbal span. In contrast, ADHD-C showed lower performance in Simon task and more impulsively. On an other hand, ADHD-I showed lower performance in memory working tasks and planning. CONCLUSIONS: These results suggest differences in the executive profile between ADHD-I and ADHD-C and these support the hypothesis of Barkley about the necessity to differ both clinical subtypes.

[Plasticity of the central nervous system and treatment strategies for sensory and motor reprogram: comparison between two cases of cerebrovascular disease in the middle cerebral artery territory]. / Plasticidad del sistema nervioso central y estrategias de tratamiento para la reprogramación sensoriomotora: comparación de dos casos de accidente cerebrovascular isquémico en el territorio de la arteria cerebral media.

INTRODUCTION: Injury to the central nervous system causes a series of symptoms, which lead to a process of cerebral plasticity. Proprioceptive and exteroceptive information processing from the outside to the brain, influence the development of neuroplasticity, which contributes to either the recovery or maintenance of sensory-motor alterations after a stroke. CASE REPORTS: Two patients with cerebrovascular accident in the left middle cerebral artery territory, one of them ischemic and the other hemorrhagic, whose sensory and motor therapy applied show big differences. CONCLUSIONS: Treatment strategies for functional rehabilitation following a cerebrovascular accident, must be established in relation to current hypotheses on cerebral neuroplasticity and central nervous system pathways, which shows less damage or better sensory motor response. The assessment of neurological signs and symptoms, can indicate which tracts show more or less damage and which ones show greater response to motor recovery treatment. Nevertheless, functional neuroimaging diagnosis provides us with the data in a more reliable way. Even so, among patients that show similar lesion zones, according to diagnosis of computerized tomography or magnetic resonance imaging, there exists a significant clinical variability among different cases, in which case we confirm, in reference to physical treatment, that there are no patients alike, or identical patients even if they have the same clinical diagnosis of the disease.

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.

[Movement alterations following cerebrovascular damage in the intact hemisphere ipsilateral to the affected upper limb]. / Alteraciones en el movimiento tras accidente cerebrovascular en el hemicuerpo ipsilateral al hemisferio cerebral lesionado.

OBJECTIVE: We analyze the explanatory hypotheses proposed in most relevant studies on the different altered movements (AM) in the unaffected part of the body following a stroke. We report 25 cases of AM patients whose clinical signs do not correspond with the AM described in previous studies. A possible explanation could be established from a different neuroplastic hypothesis. DEVELOPMENT: To review the main hypotheses which try to explain the presence of AM in the part of the body ipsilesional to the injured hemisphere of the brain. To this end we overview some updated studies concerning the corticospinal tract function, and the neuroplastic capacity after a stroke. Simultaneously, we study 25 cases of patients with cerebrovascular disease and some clinical findings which present a different type of AM from those previously reported. CONCLUSIONS: Motor alterations described in most studies concerning stroke patients correspond well to a diminished selectivity of movements of the unaffected hand, to associated movements in both upper limbs or to mirror movements. Explanations of these hypothesis are: the effect of injured fibres of the uncrossed corticospinal tract and neuroplastic reorganization of the ipsilateral pathways. The existence of different AM is observed in some clinical cases which we found to be scarcely studied in published research. These movements appear in the non-affected part of the body throughout cerebrovascular disease evolution, and which could be caused by maintained hypersolicitation of the unaffected part of the body and the neuroplastic process following a stroke. Further functional neuroimaging investigations are needed to confirm this clinical hypothesis.

[Frontal seizures recorded by magnetoencephalography. Case report]. / Crisis frontales registradas mediante magnetoencefalografía. Caso clínico.

INTRODUCTION: This paper reports the usefulness of magnetoencephalography (MEG) in the anatomical localization of the onset and spread of seizures. CASE REPORT: In a 34-year-old male patient who suffered from drug-resistant complex partial seizures (sometimes generalized) with loss of awareness, magnetic resonance imaging revealed a probable left frontobasal cortical dysplasia. Ictal scalp electroencephalogram showed left frontotemporal theta waves. Electrocorticography (ECoG) registered interictal polyspike discharges and located the seizure onset in the lateral orbital side of the left frontal lobe. Three seizures were registered by MEG, clinically similar to the ones usually experienced by the patient. MEG ictal spike dipole location showed seizure onset coming from the left inferior frontal gyrus (as the ECoG), spreading on to other frontal areas, insula and temporal lobe, all in the left hemisphere. CONCLUSION: MEG may be considered as a useful diagnosis modality in the study of partial seizure physiopathology as well as in its presurgical evaluation.

[Pharmacoresistant temporal-lobe epilepsy. Exploration with foramen ovale electrodes and surgical outcomes]. / Epilepsia farmacorresistente del lóbulo temporal. Exploración con electrodos del foramen oval y resultados quirúrgicos.

AIM: To report our experience in the surgical treatment of temporal-lobe epilepsy. PATIENTS AND METHODS: An analysis was performed of the outcomes of 137 patients submitted to surgery between 1990 and 2001, with a follow-up of more than two years. A study was conducted of the percentages of successful detection by the different complementary tests--MRI, EEG, interictal SPECT, video-EEG with foramen ovale electrodes (FOE), neuropsychological study (NPS)--and the precision with which they reported the epileptogenic focus. RESULTS AND CONCLUSIONS: Successful surgical outcomes (Engel grades I-II): 73.4%. No surgical mortality occurred, although some mild, reversible morbidity was observed. Surgical outcomes were not affected by sex, age, age of onset and the length of time the patient had had the disease, or the frequency of the seizures. No association was found between seizures in the immediate post-operative period and a poorer long term control of the epilepsy. MR images were normal in 25% of patients; in these cases the surgical outcomes (Engel grades I-II at two years: 62%) were significantly poorer than in cases of tumours/cavernomas (86%); RMI studies of other types of lesions gave intermediate results (72%). With respect to the capacity of the different tests to lateralise/locate the epileptogenic focus, video-EEG-FOE proved to be the best, followed by MRI, SPECT, EEG and NPS.

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.

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.

Cortical organization for receptive language functions in Chinese, English, and Spanish: a cross-linguistic MEG study.

Chinese differs from Indo-European languages in both its written and spoken forms. Being a tonal language, tones convey lexically meaningful information. The current study examines patterns of neurophysiological activity in temporal and temporoparietal brain areas as speakers of two Indo-European languages (Spanish and English) and speakers of Mandarin-Chinese were engaged in a spoken-word recognition task that is used clinically for the presurgical determination of hemispheric dominace for receptive language functions. Brain magnetic activation profiles were obtained from 92 healthy adult volunteers: 30 monolingual native speakers of Mandarin-Chinese, 20 Spanish-speaking, and 42 native speakers of American English. Activation scans were acquired in two different whole-head MEG systems using identical testing methods. Results indicate that (a) the degree of hemispheric asymmetry in the duration of neurophysiological activity in temporal and temporoparietal regions was reduced in the Chinese group, (b) the proportion of individuals who showed bilaterally symmetric activation was significantly higher in this group, and (c) group differences in functional hemispheric asymmetry were first noted after the initial sensory processing of the word stimuli. Furthermore, group differences in the degree of hemispheric asymmetry were primarily due to greater degree of activation in the right temporoparietal region in the Chinese group, suggesting increased participation of this region in the spoken word recognition in Mandarin-Chinese.