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Beside the well‐documented involvement of secondary somatosensory area, the cortical network underlying late somatosensory evoked potentials (P60/N60 and P100/N100) is still unknown. Electroencephalogram and magnetoencephalogram source imaging were performed to further investigate the origin of the brain cortical areas involved in late somatosensory evoked potentials, using sensory inputs of different strengths and by testing the correlation between cortical sources. Simultaneous high‐density electroencephalograms and magnetoencephalograms were performed in 19 participants, and electrical stimulation was applied to the median nerve (wrist level) at intensity between 1.5 and 9 times the perceptual threshold. Source imaging was undertaken to map the stimulus‐induced brain cortical activity according to each individual brain magnetic resonance imaging, during three windows of analysis covering early and late somatosensory evoked potentials. Results for P60/N60 and P100/N100 were compared with those for P20/N20 (early response). According to literature, maximal activity during P20/N20 was found in central sulcus contralateral to stimulation site. During P60/N60 and P100/N100, activity was observed in contralateral primary sensorimotor area, secondary somatosensory area (on both hemispheres) and premotor and multisensory associative cortices. Late responses exhibited similar characteristics but different from P20/N20, and no significant correlation was found between early and late generated activities. Specific clusters of cortical activities were activated with specific input/output relationships underlying early and late somatosensory evoked potentials. Cortical networks, partly common to and distinct from early somatosensory responses, contribute to late responses, all participating in the complex somatosensory brain processing. [ABSTRACT FROM AUTHOR]

Problem‐solving often requires creativity and is critical in everyday life. However, the neurocognitive mechanisms underlying creative problem‐solving remain poorly understood. Two mechanisms have been highlighted: the formation of new connections among problem elements and insight solving, characterized by sudden realization of a solution. In this study, we investigated EEG activity during a modified version of the remote associates test, a classical insight problem task that requires finding a word connecting three unrelated words. This allowed us to explore the brain correlates associated with the semantic remoteness of connections (by varying the remoteness of the solution word across trials) and with insight solving (identified as a Eurêka moment reported by the participants). Semantic remoteness was associated with power increase in the alpha band (8–12 Hz) in a left parieto‐temporal cluster, the beta band (13–30 Hz) in a right fronto‐temporal cluster in the early phase of the task, and the theta band (3–7 Hz) in a bilateral frontal cluster just prior to participants' responses. Insight solving was associated with power increase preceding participants' responses in the alpha and gamma (31–60 Hz) bands in a left temporal cluster and the theta band in a frontal cluster. Source reconstructions revealed the brain regions associated with these clusters. Overall, our findings shed new light on some of the mechanisms involved in creative problem‐solving. [ABSTRACT FROM AUTHOR]

Background: Episodic memory (EM) deficits are a hallmark of Alzheimer's disease (AD). The Free and Cued Selective Reminding Test (FCSRT) is the most specific official diagnostic tool detecting AD‐linked EM alterations in advanced preclinical stages (Grober et al., 2021). However, new tools that anticipate diagnosis to the at‐risk phase are needed, to reach more meaningful therapies. Based on existing research, we aim to investigate the Memory Binding Test (MBT) promising capacity to detect the appearance of subtle AD‐linked EM alterations and anticipate AD‐diagnosis to an at‐risk phase (Bushcke ey al., 2017; Mowrey et al., 2018). Methods: FCSRT and MBT scores were collected yearly during 5 years from the INSIGHT‐preAD cohort. We selected 3 groups controlled for age, education level, gender, beta‐amyloid burden (AB+), and neurodegeneration status based on 15 individuals who converted to prodromal‐AD during follow‐up, as follows: converters/AB+; non‐converters/AB+; controls/AB‐. Evaluation of both list‐learning tests is mainly based on free recall (FR) and total (cued) recall (TR) scores. The FCSRT uses 1‐list of words to remember while the MBT uses 2‐lists, introducing a binding component sensitive to subtle EM alterations. Data was analysed using mixed effect models including age, gender, and education as covariates. Results: When compared with the FCSRT, the MBT anticipated the detection of AD‐linked EM alterations in the converters/AB+ versus the other groups. In the MBT decline started up to 5 years prior to diagnosis, in delayed FR (mainly associated to executive dysfunction), followed by decline in 4 binding‐associated scores 1 year later (linked to storage deficits associated with the amnesic hippocampal syndrome characteristic of AD). Therefore, at an at‐risk phase, MBT outperformed FCSRT, both in the year of diagnosis and in the number of scores confirming AD‐linked EM deficits. Conclusion: We show the MBT capacity to detect the initial subtle EM alterations and to anticipate diagnosis to the at‐risk phase, while participants remain cognitively normal. We argue that the MBT (at‐risk phase detection) and the FCSRT (preclinical phase classification) could be complementary rather than concurrent tools, fostering meaningful innovative treatments to prolong quality of life in AD, a disease that remains without a cure. [ABSTRACT FROM AUTHOR]

Background: The challenge in Alzheimer's disease (AD) research ‐the world most prevalent dementia‐remains on finding preclinical markers that can predict progression to the disease. In this respect electrophysiological (EEG) measures seem promising, based on their sensitivity to the appearance of subtle episodic memory (EM) alterations, which become an AD risk‐factor when in the presence of B‐amyloid burden (AB+; AD‐biomarker) (Paitel et al., 2021; Olichney et al., 2011). We aimed to identify event‐related potential (ERP) signatures of AD‐linked EM alterations in elder cognitively normal subjects at‐risk for AD. Methods: EEG data was collected longitudinally with an EGI 256‐channels cap, over 6 yearly sessions, in 15 controls (AB‐), 15 non‐converters (AB+), and 15 converters to prodromal‐AD (AB+; who converted during follow‐up but were only considered before diagnosis) from the INSIGHTpre‐AD cohort. We analysed the typical ERP response to a classic task of verbal memory recognition of old or new words (i.e. P3 and FN400 [0.25‐0.34 and 0.51‐0.57ms], P600 [0.62‐0.77ms], and monitoring [0.87‐1.04ms]). The new words were related to the old words (previously encoded) either in their number of repetitions (NR) or in their semantic content but presented once (NU). Source‐localization analysis of these data is currently underway. Results: During follow‐up, the converters showed increased reaction time and decreased accuracy in word recognition when compared with the other groups. The converters significantly showed greater mean amplitude in the fronto‐parietal left and parieto‐occipital central regions typically linked to EM recollection, in the 0.25‐0.34 ms time‐window when compared with the controls, and in the 0.51‐0.57ms time‐window when compared with the non‐converters. Through our period of interest, old words activated mostly central‐posterior left regions (semantic networks/familiarity), NR words activated the frontal right region (i.e. novelty detection), and NU words frontal‐temporal right regions (semantic interference detection). Conclusion: Our findings show amplitude differences associated with AD‐linked EM alterations years before individuals are diagnosed, representing potential ERP signatures of progression to AD in at‐risk individuals, while they remain cognitively normal. Anticipation of diagnosis contributes to the development of more effective tailor‐made treatments that potentially ease quality of life of patients and caregivers. [ABSTRACT FROM AUTHOR]

Prion immunotherapy may hold great potential, but antibodies against certain PrP epitopes can be neurotoxic. Here, we identified > 6,000 PrP‐binding antibodies in a synthetic human Fab phage display library, 49 of which we characterized in detail. Antibodies directed against the flexible tail of PrP conferred neuroprotection against infectious prions. We then mined published repertoires of circulating B cells from healthy humans and found antibodies similar to the protective phage‐derived antibodies. When expressed recombinantly, these antibodies exhibited anti‐PrP reactivity. Furthermore, we surveyed 48,718 samples from 37,894 hospital patients for the presence of anti‐PrP IgGs and found 21 high‐titer individuals. The clinical files of these individuals did not reveal any enrichment of specific pathologies, suggesting that anti‐PrP autoimmunity is innocuous. The existence of anti‐prion antibodies in unbiased human immunological repertoires suggests that they might clear nascent prions early in life. Combined with the reported lack of such antibodies in carriers of disease‐associated PRNP mutations, this suggests a link to the low incidence of spontaneous prion diseases in human populations. Synopsis: This study assessed the anti‐prion protein (PrP) immunoreactivity in human immunoglobulin repertoires and patient samples. Anti‐PrP autoimmunity can exist in human communities, appears to be innocuous, and may protect against prion infections. >6,000 antibodies against various PrP epitopes were recovered from a synthetic human antibody (Fab) phage library.Of the phage display derived Fabs, 49 Fabs were characterized in detail. Fabs directed against the N‐terminal flexible tail of PrP conferred neuroprotection against infectious prions.HCDR3 sequences similar to a protective phage‐derived Fab were identified in published repertoires of B cells from healthy humans. When expressed recombinantly, these antibodies reacted to human PrP.By interrogating a large cohort of 37,894 hospital patients, twenty‐one individuals with high‐titer anti‐PrP autoreactivity in the plasma were found.The presence of anti‐PrP autoantibodies did not correlate to any neurological condition or any other diseases. [ABSTRACT FROM AUTHOR]

Background: Cognitive reserve (CR) is present in Alzheimer's disease (AD) seniors with high education attainment making them clinically resilient to extended brain neuropathology and neurodegeneration. Here we tested whether subjective memory complaint (SMC) seniors with AD neuropathology and high education attainment may present abnormal eyes‐closed resting state posterior electroencephalographic (rsEEG) rhythms around individual alpha frequency peak (IAFp), typically altered in AD patients with mild cognitive impairment and dementia. Method: We selected all individual baseline data of the prospective INSIGHT‐preAD cohort (Paris) including mini mental state examination score ≥ 28, artifact‐free markers of 18F‐florbetapir positron emission tomography (amyPET), structural magnetic resonance imaging, and rsEEG rhythms (e.g., 172 SMC seniors). Delta, theta, alpha1, alpha2, and alpha3 bands were determined on individual basis based on IAFp, while beta1 (14‐20 Hz), beta2 (20‐30 Hz), and gamma (30‐40 Hz) were standard fixed bands. Result: The SMC participants negative to amyPET AD markers (SMCneg) with high (over low‐moderate) education level showed higher posterior alpha 2 power density (possibly "neuroprotective"). Furthermore, amyPET‐positive SMC (SMCpos) participants with high (over low‐moderate) education level showed higher temporal alpha 3 power density (possibly "neuroprotective") and lower posterior alpha 2 power density (possibly "compensatory"; Figure 1). This effect may reflect CR as no differences in brain gray‐white matter and cognitive functions were observed between these SMCpos/SMCneg sub‐groups. Conclusion: Preclinical Alzheimer's neuropathology may interact with education attainment and neurophysiological mechanisms generating cortical alpha rhythms around IAFp (i.e., alpha 2 and 3) in quiet wakefulness. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) patients are often unaware of their memory deficits even at early stage of disease. Anosognosia has been related to frontal dysfunction although its underlying neural mechanism is still unknown. We hypothesized that it may result from an inability to monitor ongoing behavior due to a failure in the error‐monitoring system. Our main objective was to study this system in individuals at risk for AD. Method: The study involved the 318 cognitively normal individuals of the INSIGHT cohort. All were age 70 and over at entry with a known brain amyloid status assessed by PET. We recorded the error negativity (ERN) and error positivity (Pe) of event‐related potentials (ERPs) in each of these individuals annually over 5 years. The cognitive task was the recognition of words, which had been memorized one hour before. ERPs were obtained by averages that were time‐locked to the erroneous response. All differences were tested through linear mixed‐effects models with group (Prog A+, NotProg A+; i.e., amyloid positive individuals who progressed or not to AD) and time (M0, M60, or Mdiag; i.e., months from study admission or month of AD diagnosis), as well as interaction between both as fixed effects, the subject identifier as a random effect to account for the paired measurements at M0 and M60 or Mdiag, and inclusion of age at M0 for covariate adjustment. Post hoc tests were performed on the interaction. Result: Our study focused on two subgroups identified after 5 years of follow‐up: 1) amyloid positive (A+) individuals who progressed to AD (Prog A+, n=15); and 2) A+ individuals who did not progress to AD (NotProg A+, n=35). When compared to M0 for intragroup analysis or to M60 for intergroup analysis, the Prog A+ group at Mdiag displayed significantly slower reactions and higher error rates, and its Pe amplitude was also significantly lower. Conclusion: Our results indicate the existence of a monitoring system failure in early stages of AD, which may be the substrate of anosognosia. [ABSTRACT FROM AUTHOR]

Abstract: Fluorescence resonance energy transfer (FRET) is a powerful technique to reveal interactions between membrane proteins in live cells. Fluorescence labeling for FRET is typically performed by fusion with fluorescent proteins (FP) with the drawbacks of a limited choice of fluorophores, an arduous control of donor–acceptor ratio and high background fluorescence arising from intracellular FPs. Here we show that these shortcomings can be overcome by using the acyl carrier protein labeling technique. FRET revealed interactions between cell-surface neurokinin-1 receptors simultaneously labeled with a controlled ratio of donors and acceptors. Moreover, using FRET the specific binding of fluorescent agonists could be monitored. [Copyright &y& Elsevier]

In this study, long (∼1,300 ms) and short duration (∼450 ms) estimation trials in an event-related functional MRI (fMRI) study were contrasted in order to reveal the regions within a time estimation network yielding increased activation with the increase of the duration to be estimated. In accordance with numerous imaging studies, our results showed that the presupplementary motor area (preSMA), the anterior cingulate, the prefrontal and parietal cortices, and the basal ganglia were involved in the estimation trials whatever the duration to be estimated. Moreover, only a subset of the regions within this distributed cortical and subcortical network yielded increased activation with increasing time, namely, the preSMA, the anterior cingulate cortex, the right inferior frontal gyrus (homolog to Broca's area), the bilateral premotor cortex, and the right caudate nucleus. This suggests that these regions are directly involved in duration estimation. We propose that the caudate-preSMA circuit, the anterior cingulate, and the premotor-inferior frontal regions may support a clock mechanism, decision and response-related processes, and active maintenance of temporal information, respectively. Hum. Brain Mapping, 2005. © 2005 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Response inhibition is a crucial component of executive control. Although mainly studied in upper limb tasks, it is fully implicated in gait initiation. Here, we assessed the influence of proactive and reactive inhibitory control during gait initiation in healthy adult participants. For this purpose, we measured kinematics and electroencephalography (EEG) activity (event‐related potential [ERP] and time‐frequency data) during a modified Go/NoGo gait initiation task in 23 healthy adults. The task comprised Go‐certain, Go‐uncertain, and NoGo conditions. Each trial included preparatory and imperative stimuli. Our results showed that go‐uncertainty resulted in delayed reaction time, without any difference for the other parameters of gait initiation. Proactive inhibition, that is, Go uncertain versus Go certain conditions, influenced EEG activity as soon as the preparatory stimulus. Moreover, both proactive and reactive inhibition influenced the amplitude of the ERPs (central P1, occipito‐parietal N1, and N2/P3) and theta and alpha/low beta band activities in response to the imperative—Go‐uncertain versus Go‐certain and NoGo versus Go‐uncertain—stimuli. These findings demonstrate that the uncertainty context; induced proactive inhibition, as reflected in delayed gait initiation. Proactive and reactive inhibition elicited extended and overlapping modulations of ERP and time‐frequency activities. This study shows the protracted influence of inhibitory control in gait initiation. [ABSTRACT FROM AUTHOR]