The dynamic modular fingerprints of the human brain at rest.

The human brain is a dynamic modular network that can be decomposed into a set of modules, and its activity changes continually over time. At rest, several brain networks, known as Resting-State Networks (RSNs), emerge and cross-communicate even at sub-second temporal scale. Here, we seek to decipher the fast reshaping in spontaneous brain modularity and its relationships with RSNs. We use Electro/Magneto-Encephalography (EEG/MEG) to track the dynamics of modular brain networks, in three independent datasets (N = 568) of healthy subjects at rest. We show the presence of strikingly consistent RSNs, and a splitting phenomenon of some of these networks, especially the default mode network, visual, temporal and dorsal attentional networks. We also demonstrate that between-subjects variability in mental imagery is associated with the temporal characteristics of specific modules, particularly the visual network. Taken together, our findings show that large-scale electrophysiological networks have modularity-dependent dynamic fingerprints at rest.

Therapeutic and preventive effects of methylene blue on Alzheimer's disease pathology in a transgenic mouse model.

Methylene blue (MB) belongs to the phenothiazinium family. It has been used to treat a variety of human conditions and has beneficial effects on the central nervous system in rodents with and without brain alteration. The present study was designed to test whether chronic MB treatment taken after (therapeutic effect) or before (preventive effect) the onset of beta-amyloid pathology influences cognition in a transgenic mouse model (APP/PS1). In addition, the present study aims at revealing whether these behavioral effects might be related to brain alteration in beta-amyloid deposition. To this end, we conducted an in vivo study and compared two routes of drug administration, drinking water versus intraperitoneal injection. Results showed that transgenic mice treated with MB orally or following intraperitoneal injection were protected from cognitive impairments in a variety of social, learning, and exploratory tasks. Immunoreactive beta-amyloid deposition was significantly reduced in the hippocampus and adjacent cortex in MB-treated transgenic mice. Interestingly, these beneficial effects were observed independently of beta-amyloid load at the time of MB treatment. This suggests that MB treatment is beneficial at both therapeutic and preventive levels. Using solid-state High Resolution Magic Angle Spinning Nuclear Magnetic Resonance (HRMAS-NMR), we showed that MB administration after the onset of amyloid pathology significantly restored the concentration of two metabolites related to mitochondrial metabolism, namely alanine and lactate. We conclude that MB might be useful for the therapy and prevention of Alzheimer's disease. This article is part of the Special Issue entitled 'The Synaptic Basis of Neurodegenerative Disorders'.

Positive effects of computer-based cognitive training in adults with mild cognitive impairment.

Considering the high risk for individuals with amnestic Mild Cognitive Impairment (A-MCI) to progress towards Alzheimer's disease (AD), we investigated the efficacy of a non-pharmacological intervention, that is, cognitive training that could reduce cognitive difficulties and delay the cognitive decline. For this, we evaluated the efficacy of a 12-week computer-based memory-attention training program based on recognition in subjects with A-MCI and compared their performances with those of A-MCI controls trained in cognitively stimulating activities. The effect of training was assessed by comparing outcome measures in pre- and post-tests 15 days before and after training. To evaluate the duration of training benefits, a follow-up test session was performed 6 months after memory and attention training or cognitively stimulating activities. Outcome measures showed that the trained group, compared to control group, improved episodic recall and recognition. Six months after training, scores remained at the level of the post-test. Since the training program was exclusively based on recognition, our results showed a generalization from recognition to recall processes, which are memory components that represent part of the core cognitive impairments in individuals at risk of converting to AD. Thus, cognitive training based on recognition holds promise as a preventive therapeutic method and could be proposed as a non-pharmacological early-intervention strategy. Future investigations need to focus on methodological constraints and delineating possible neuroplastic mechanisms of action.

[In Alzheimer's disease, the clinical expression of behavioral and psychological signs and symptoms is early and specific of neuropathological stages]. / Dans la maladie d'Alzheimer, l'expression des troubles psychologiques et comportementaux est précoce et spécifique des stades lésionnels.

INTRODUCTION: The early diagnosis of Alzheimer's disease is a new challenge. This study concerns 50 patients, 34 females (68 %) and 16 males (32 %) with Alzheimer (AD), according to NINCDS-ADRDA diagnostic criteria. OBJECTIVES: To systematically evaluate in all patients behavioral and psychological signs and symptoms of dementia (BPSSD), according to the stage of AD, with the patients of our population separated into two MMS groups. METHODS: The first group was composed of patients with an MMS score from 10 to 20 (eight males and 19 females). Patients of the second group had an MMS score between 21 and 28 (eight males and 19 females). The Neuro-Psychiatric Inventory (NPI) was used to collect information on the presence of BPSSD in AD patients. NPI scores were correlated to the cognitive part of the Alzheimer's Disease Assessment Scale (ADAS-Cog) that permits evaluation of the severity of cognitive impairment in AD patients. Before starting the study, all patients gave their informed consent to participate in the study of BPSSD in AD. Statistical treatment of data was performed using STATVIEW. RESULTS: Our study demonstrates that BPSSD are present not only in early but also in moderate stages of AD. As cognitive impairment, BPSSD are an integrate part of the clinical picture. With a frequency of 74 % for the whole population, "anxiety" represented the more predominant BPSSD for all our patients at all stages of AD. At the very early stages of AD, BPSSD appeared to precede cognitive disorders. CONCLUSION: The symptomatic association of "depression", "agitation", and "irritability of mood" may remain in a steady state for a few months before the appearance of verbal episodic memory impairment, which is characteristic of hippocampus involvement. "Irritability" seems to specifically characterise the initial phase of AD. On the other hand, two BPSSD are characteristic of the late stages of AD: "sleep disorder" and "hallucinations".

Behavioral and immunohistological effects of cholinergic damage in immunolesioned rats: alteration of c-Fos and polysialylated neural cell adhesion molecule expression.

The aim of this study was to determine the brain structures as well as the plasticity events associated with the behavioral effects of cholinergic damage. Rats were submitted to injection of 192 IgG-saporin in the medial septum/diagonal band of Broca complex and the nucleus basalis magnocellularis. The immunohistochemical expression of c-Fos protein and PSA-NCAM (polysialylated neural cell adhesion molecule) and the behavioral performances in the nonmatching-to-position task were assessed at various post-lesion times. Thus, 3 days after injection of the immunotoxin, increased c-Fos labeling was observed in the areas of infusion, indicating these cells were undergoing some plastic changes and/or apoptotic processes. A drastic increase was observed in the number of PSA-NCAM positive cells and in their dendritic arborization in the dentate gyrus. At 7 days post-lesion, no behavioral deficit was observed in immunolesioned rats despite the drastic loss of cholinergic neurons. These neurons showed decreased c-Fos protein expression in the piriform and entorhinal cortex and in the dentate gyrus. In the latter, PSA-NCAM induction was high, suggesting that remodeling occurred, which in turn might contribute to sustaining some mnemonic function in immunolesioned rats. At 1 month, cholinergic neurons totally disappeared and behavioral deficits were drastic. c-Fos expression showed no change. In contrast, the increased PSA-NCAM-labeling observed at short post-lesion times was maintained but the plastic changes due to this molecule could not compensate the behavioral deficit caused by the immunotoxin. Thus, as the post-lesion time increases, a gradual degeneration process should occur that may contribute to mnemonic impairments. This neuronal loss leads to molecular and cellular alterations, which in turn may aggravate cognitive deficits.

Visual and visuospatial short-term memory in mild cognitive impairment and Alzheimer disease: role of attention.

It has been proposed that visual recognition memory and certain attentional mechanisms are impaired early in Alzheimer disease (AD). Little is known about visuospatial recognition memory in AD. The crucial role of the hippocampus on spatial memory and its damage in AD suggest that visuospatial recognition memory may also be impaired early. The aim of the present study was to evaluate which modality, i.e. visual or visuospatial, is more implicated in the early memory impairment in AD. First, to determine onset of memory impairment, we compared the performances of patients with AD to those with amnestic mild cognitive impairment (MCI). Second, to determine the relative contribution of attentional impairment on the performance of MCI and AD patients, we tested the influence of a distractor in the interval between the memory image and recognition tests. Results showed that visuospatial short-term deficits appear earlier than visual short-term ones. In addition to mnemonic deficits, results showed attentional deficiency in both MCI and AD patients. Deficits of performances in visual modality seemed of attentional origin whereas those of visuospatial modality seemed of memory origin. The combination of attentional and mnemonic evaluation is likely to be a promising approach to finding predictive markers that distinguish MCI patients that convert to AD.

Time course of behavioral changes following basal forebrain cholinergic damage in rats: Environmental enrichment as a therapeutic intervention.

The present experiment was designed to study changes in behavior following immunolesioning of the basal forebrain cholinergic system. Rats were lesioned at 3 months of age by injection of the 192 IgG-saporin immunotoxin into the medial septum area and the nucleus basalis magnocellularis, and then tested at different times after surgery (from days 7-500) on a range of behavioral tests, administered in the following order: a nonmatching-to-position task in a T-maze, an object-recognition task, an object-location task, and an open-field activity test. The results revealed a two-way interaction between post-lesion behavioral testing time and memory demands. In the nonmatching-to-position task, memory deficits appeared quite rapidly after surgery, i.e. at a post-lesion time as short as 1 month. In the object-recognition test, memory impairments appeared only when rats were tested at late post-lesion times (starting at 15 months), whereas in the object-location task deficits were apparent at early post-lesion times (starting from 2 months). Taking the post-operative time into account, one can hypothesize that at the shortest post-lesion times, behavioral deficits are due to pure cholinergic depletion, while as the post-lesion time increases, one can speculate the occurrence of a non-cholinergic system decompensation process and/or a gradual degeneration process affecting other neuronal systems that may contribute to mnemonic impairments. Interestingly, when middle-aged rats were housed in an enriched environment, 192 IgG-saporin-lesioned rats performed better than standard-lesioned rats on both the nonmatching-to-position and the object-recognition tests. Environment enrichment had significant beneficial effects in 192 IgG-saporin-lesioned rats, suggesting that lesioned rats at late post-lesion times (over 1 year) still have appreciable cognitive plasticity.

Neuromodulation of memory in the hippocampus by vasopressin.

The involvement of [Arg(8)]vasopressin in memory processes was analyzed in the hippocampal structure, since we have reported that this is one of the main central target structures of the vasopressin-enhancing effect on memory. This structure is functionally differentiated along its dorsoventral axis, and the expression of the vasopressinergic system is dependent upon whether the dorsal or ventral part of the hippocampus is involved. For this reason, the effect of vasopressin injected into hippocampus was evaluated on the basis of the site of injection. We have shown, using a Go-No Go visual discrimination task with mice that both parts of the hippocampus are involved in the effect of endogenous or exogenous vasopressin, but with higher sensitivity for the ventral part. Based on the expression of Fos protein following intracerebroventricular injection of vasopressin in unconditioned or conditioned mice, we confirmed the greater involvement of the ventral hippocampus in the enhancing effect of vasopressin on memory processes. The effect of the peptide seems specific, since only a few of the hippocampal cells that expressed Fos protein in the unconditioned mice did so in the conditioned mice (cells in the dentate gyrus and the CA3 hippocampal field). Moreover, we have shown that in the ventral hippocampus, vasopressin generates different behavioral effects whether treatment is performed at the beginning or in the middle of the learning process, suggesting that the mnemonic context is an important factor for understanding the effect of vasopressin on memory in the ventral hippocampus.

Fos protein expression induced by intracerebroventricular injection of vasopressin in unconditioned and conditioned mice.

Arginine8-vasopressin (AVP) has been shown to improve memory consolidation in various mnemonic tasks. Our previous studies have pointed out the involvement of the hippocampus in memory consolidation and retrieval processes during discriminative learning by mice. The present study attempts to determine what other brain areas besides the hippocampus might be involved in the enhancing effect of intracerebroventricularly (i.c.v.) injected AVP on memory consolidation in a visual discrimination task using a polyclonal antibody that acts against Fos and Fos-like proteins. For behavioral testing, AVP was i.c.v. injected at the behaviorally active dose of 2 ng after the last learning session and improvement in consolidation processes was assessed in a retention session. Changes in Fos and Fos-like protein expression were determined in non-conditioned and conditioned mice. In non-conditioned mice, AVP i. c.v. injected at a dose of 2 ng evoked a time-dependent increase in Fos and Fos-like protein expression in the dentate gyrus (DG), CA1 and CA3 hippocampal fields, lateral septum (LS), bed nucleus of the stria terminalis, and basolateral and central amygdaloid nuclei, with a peak 120 min after the injection in most of the these brain areas. In contrast, in conditioned mice, an increase in the level of Fos expression, assessed 120 min after the end of learning and the injection of AVP, was detected only in the DG, ventral CA3 hippocampal field, and LS. Thus, the pattern observed after post-training injection of AVP was not the same as that evoked by AVP alone, since among the limbic structures activated following AVP alone, only the DG, the CA3 hippocampal field, and the LS seem to be involved in the enhancing effect of AVP on memory consolidation in discriminative learning.

The behavioral effect of vasopressin in the ventral hippocampus is antagonized by an oxytocin receptor antagonist.

[Arg8]vasopressin improved long-term retrieval processes and relearning in a go-no go visual discrimination task when bilaterally microinjected at a dose of 25 pg/animal into the ventral hippocampus of mice, 10 min prior to the retention session. We had shown that this enhancing effect is antagonized by pretreatment with equal or lower doses (25 pg or 1 ng) of the vasopressin V1 receptor antagonist, (d(CH2)5Tyr(Me)-vasopressin). The present study was an attempt to determine whether the vasopressin V2 receptor antagonist or oxytocin receptor antagonist is as effective as the vasopressin V1 receptor antagonist to block the behavioral effect of vasopressin in the ventral hippocampus. We tested the effect of 25 pg of [d(CH2)5-D-Ile2,Ile4,Arg8]vasopressin, a vasopressin V2 receptor antagonist, and [d(CH2)5,Tyr(Me)2,Thr4,Tyr-NH9(2)]ornithine vasotocin, an oxytocin receptor antagonist, under the same experimental conditions as those used to test the effect of the vasopressin V1 receptor antagonist. The results showed that the vasopressin V2 receptor antagonist microinjected into the ventral hippocampus did not alter the enhancing effect of vasopressin on retrieval and relearning. In contrast, the oxytocin receptor antagonist blocked the vasopressin-enhancing effect on retention processes. We can conclude from the data that both vasopressin V1 receptors and oxytocin receptors seem to be involved in the enhancing effect of vasopressin on memory retention. In contrast, the vasopressin V2 receptors do not seem to be involved in the effect of the peptide.

Effects of arginine8-vasopressin administered at different times in the learning of an appetitive visual discriminative task in mice.

A visual discrimination task was used to investigate the effect of the intra-hippocampal injection of arginine8-vasopressin (AVP) in male Balb/c mice at different stages of the learning processes. The peptide was bilaterally microinjected at a dose of 25 pg per animal, i.e. 833 pg/kg, into the ventral hippocampus, in a volume of 0.3 microliter 10 min before either the first or the second learning session, or immediately after the first or second learning session. Following pre-session administration of AVP, no effect of the peptide was observed on the session prior to which it was administered. On the other hand, 48 h after the pre-first session treatment, it seems that AVP animals had trouble learning the task. Following post-session injection of AVP, no effect was observed when the treatment was given after the first learning session and a tendency to improve performance was noted when the treatment was given after the second learning session. Thus, whatever time AVP was injected during learning, little or no effect was observed. These results and previous work on the same behavioral task showing a clear enhancing effect of the peptide on retrieval processes, suggest that prior experience or mnemonic context before AVP treatment is as important a factor in understanding the effects of AVP on memory processes as the administration route or the doses used.

Inhibition of the vasopressin-enhancing effect on memory retrieval and relearning by a vasopressin V1 receptor antagonist in mice.

We have previously shown that [Arg8]vasopressin bilaterally administered into the ventral hippocampus of mice at a dose of 0.025 ng/animal 10 min prior to the retention session, improved long-term retrieval processes and relearning of a Go-No-Go visual discrimination task. The purpose of the present study was to determine whether the vasopressin V1 receptor antagonist, -beta-mercapto-beta,beta-cyclopentamethylenepropionyl1, O-Me-Tyr2,Arg8]vasopressin, d(CH2)5Tyr(Me)vasopressin), is able to block the behavioral effect of arginine-vasopressin in the ventral hippocampus. We first tested the effect of three doses of d(CH2)5Tyr(Me)vasopressin (0.025, 1, and 6.3 ng/animal) in the same experimental conditions as used for arginine-vasopressin. The results showed a dose-dependent deleterious effect of the vasopressin V1 receptor antagonist on retrieval and relearning, suggesting the involvement of endogenous arginine-vasopressin in the ventral hippocampus for these memory processes. Second, we tested the ability of d(CH2)5Tyr(Me)vasopressin to block the enhancing effect of experimentally administered arginine-vasopressin. The antagonist was injected at a dose of 0.025 ng, which had no intrinsic effect on behavior, or at a dose of 1 ng, which had a weak deleterious effect on behavior, followed by administration of 0.025 ng of arginine-vasopressin. The results showed that even at the weakest dose (0.025 ng), d(CH2)5Tyr(Me)vasopressin blocked the enhancing effect of arginine-vasopressin on retrieval and relearning. Thus, as for other behaviors and structures, the antagonist microinjected into the ventral hippocampus prevents the enhancing effect of arginine-vasopressin on long-term retrieval and relearning. However, the exclusive involvement of the vasopressin V1 receptors remain to demonstrate vis-a-vis oxytocin receptors.