Early Detection of Alzheimer's Disease From Cortical and Hippocampal Local Field Potentials Using an Ensembled Machine Learning Model.

Early diagnosis of Alzheimer's disease (AD) is a very challenging problem and has been attempted through data-driven methods in recent years. However, considering the inherent complexity in decoding higher cognitive functions from spontaneous neuronal signals, these data-driven methods benefit from the incorporation of multimodal data. This work proposes an ensembled machine learning model with explainability (EXML) to detect subtle patterns in cortical and hippocampal local field potential signals (LFPs) that can be considered as a potential marker for AD in the early stage of the disease. The LFPs acquired from healthy and two types of AD animal models (n = 10 each) using linear multielectrode probes were endorsed by electrocardiogram and respiration signals for their veracity. Feature sets were generated from LFPs in temporal, spatial and spectral domains and were fed into selected machine-learning models for each domain. Using late fusion, the EXML model achieved an overall accuracy of 99.4%. This provided insights into the amyloid plaque deposition process as early as 3 months of the disease onset by identifying the subtle patterns in the network activities. Lastly, the individual and ensemble models were found to be robust when evaluated by randomly masking channels to mimic the presence of artefacts.

Reward prospect affects strategic adjustments in stop signal task.

Interaction with the environment requires us to predict the potential reward that will follow our choices. Rewards could change depending on the context and our behavior adapts accordingly. Previous studies have shown that, depending on reward regimes, actions can be facilitated (i.e., increasing the reward for response) or interfered (i.e., increasing the reward for suppression). Here we studied how the change in reward perspective can influence subjects' adaptation strategy. Students were asked to perform a modified version of the Stop-Signal task. Specifically, at the beginning of each trial, a Cue Signal informed subjects of the value of the reward they would receive; in one condition, Go Trials were rewarded more than Stop Trials, in another, Stop Trials were rewarded more than Go Trials, and in the last, both trials were rewarded equally. Subjects participated in a virtual competition, and the reward consisted of points to be earned to climb the leaderboard and win (as in a video game contest). The sum of points earned was updated with each trial. After a learning phase in which the three conditions were presented separately, each subject performed 600 trials testing phase in which the three conditions were randomly mixed. Based on the previous studies, we hypothesized that subjects could employ different strategies to perform the task, including modulating inhibition efficiency, adjusting response speed, or employing a constant behavior across contexts. We found that to perform the task, subjects preferentially employed a strategy-related speed of response adjustment, while the duration of the inhibition process did not change significantly across the conditions. The investigation of strategic motor adjustments to reward's prospect is relevant not only to understanding how action control is typically regulated, but also to work on various groups of patients who exhibit cognitive control deficits, suggesting that the ability to inhibit can be modulated by employing reward prospects as motivational factors.

Restart errors reaction time of a two-step inhibition process account for the violation of the race model's independence in multi-effector selective stop signal task.

Goal-oriented actions often require the coordinated movement of two or more effectors. Sometimes multi-effector movements need to be adjusted according to a continuously changing environment, requiring stopping an effector without interrupting the movement of the others. This form of control has been investigated by the selective Stop Signal Task (SST), requiring the inhibition of an effector of a multicomponent action. This form of selective inhibition has been hypothesized to act through a two-step process, where a temporary global inhibition deactivating all the ongoing motor responses is followed by a restarting process that reactivates only the moving effector. When this form of inhibition takes place, the reaction time (RT) of the moving effector pays the cost of the previous global inhibition. However, it is poorly investigated if and how this cost delays the RT of the effector that was required to be stopped but was erroneously moved (Stop Error trials). Here we measure the Stop Error RT in a group of participants instructed to simultaneously rotate the wrist and lift the foot when a Go Signal occurred, and interrupt both movements (non-selective Stop version) or only one of them (selective Stop version) when a Stop Signal was presented. We presented this task in two experimental conditions to evaluate how different contexts can influence a possible proactive inhibition on the RT of the moving effector in the selective Stop versions. In one context, we provided the foreknowledge of the effector to be inhibited by presenting the same selective or non-selective Stop versions in the same block of trials. In a different context, while providing no foreknowledge of the effector(s) to be stopped, the selective and non-selective Stop versions were intermingled, and the information on the effector to be stopped was delivered at the time of the Stop Signal presentation. We detected a cost in both Correct and Error selective Stop RTs that was influenced by the different task conditions. Results are discussed within the framework of the race model related to the SST, and its relationship with a restart model developed for selective versions of this paradigm.

Neuronal population dynamics during motor plan cancellation in nonhuman primates.

To understand the cortical neuronal dynamics behind movement generation and control, most studies have focused on tasks where actions were planned and then executed using different instances of visuomotor transformations. However, to fully understand the dynamics related to movement control, one must also study how movements are actively inhibited. Inhibition, indeed, represents the first level of control both when different alternatives are available and only one solution could be adopted and when it is necessary to maintain the current position. We recorded neuronal activity from a multielectrode array in the dorsal premotor cortex (PMd) of monkeys performing a countermanding reaching task that requires, in a subset of trials, them to cancel a planned movement before its onset. In the analysis of the neuronal state space of PMd, we found a subspace in which activities conveying temporal information were confined during active inhibition and position holding. Movement execution required activities to escape from this subspace toward an orthogonal subspace and, furthermore, surpass a threshold associated with the maturation of the motor plan. These results revealed further details in the neuronal dynamics underlying movement control, extending the hypothesis that neuronal computation confined in an "output-null" subspace does not produce movements.

Nonparametric combination tests for comparing two survival curves with informative and non-informative censoring.

This paper looks at permutation methods used to deal with hypothesis testing within the survival analysis framework. In the literature, several attempts have been made to deal with the comparison of survival curves and, depending on the survival and hazard functions of two groups, they can be more or less efficient in detecting differences. Furthermore, in some situations, censoring can be informative in that it depends on treatment effect. Our proposal is based on the nonparametric combination approach and has proven to be very effective under different configurations of survival and hazard functions. It allows the practitioner to test jointly on primary and censoring events and, by using multiple testing methods, to assess the significance of the treatment effect separately on the survival and the censoring process.

Early hippocampal hyperexcitability in PS2APP mice: role of mutant PS2 and APP.

Alterations of brain network activity are observable in Alzheimer's disease (AD) together with the occurrence of mild cognitive impairment, before overt pathology. However, in humans as well in AD mouse models, identification of early biomarkers of network dysfunction is still at its beginning. We performed in vivo recordings of local field potential activity in the dentate gyrus of PS2APP mice expressing the human amyloid precursor protein (APP) Swedish mutation and the presenilin-2 (PS2) N141I. From a frequency-domain analysis, we uncovered network hyper-synchronicity as early as 3 months, when intracellular accumulation of amyloid beta was also observable. In addition, at 6 months of age, we identified network hyperactivity in the beta/gamma frequency bands, along with increased theta-beta and theta-gamma phase-amplitude cross-frequency coupling, in coincidence with the histopathological traits of the disease. Although hyperactivity and hypersynchronicity were respectively detected in mice expressing the PS2-N141I or the APP Swedish mutant alone, the increase in cross-frequency coupling specifically characterized the 6-month-old PS2APP mice, just before the surge of the cognitive decline.

A tunable local field potentials computer simulator to assess minimal requirements for phase-amplitude cross-frequency-coupling estimation.

The quantitative study of cross-frequency coupling (CFC) is a relevant issue in neuroscience. In local field potentials (LFPs), measured either in the cortex or in the hippocampus, how γ-oscillation amplitude is modulated by changes in θ-rhythms-phase is thought to be important in memory formation. Several methods were proposed to quantify CFC, but reported evidence suggests that experimental parameters affect the results. Therefore, a simulation tool to support the determination of minimal requirements for CFC estimation in order to obtain reliable results is particularly useful. An approach to generate computer-simulated signals having CFC intensity, sweep duration, signal-to-noise ratio (SNR), and multiphasic-coupling tunable by the user has been developed. Its utility has been proved by a study evaluating minimal sweep duration and SNR required for reliable θ-γ CFC estimation from signals simulating LFP measured in the mouse hippocampus. A MATLAB® software was made available to facilitate methodology reproducibility. The analysis of the synthetic LFPs created by the simulator shows how the minimal sweep duration for achieving accurate θ-γ CFC estimates increases as SNR decreases and the number of CFC levels to discriminate increases. In particular, a sufficient reliability in discriminating five different predetermined CFC levels is reached with 35-s sweep with SNR = 20, while SNR = 5 requires at least 140-s sweep.

Annual Reproductive Cycle and Unusual Embryogenesis of a Temperate Coral in the Mediterranean Sea.

The variety of reproductive processes and modes among coral species reflects their extraordinary regeneration ability. Scleractinians are an established example of clonal animals that can exhibit a mixed strategy of sexual and asexual reproduction to maintain their populations. This study provides the first description of the annual reproductive cycle and embryogenesis of the temperate species Caryophyllia inornata. Cytometric analyses were used to define the annual development of germ cells and embryogenesis. The species was gonochoric with three times more male polyps than female. Polyps were sexually mature from 6 to 8 mm length. Not only females, but also sexually inactive individuals (without germ cells) and males were found to brood their embryos. Spermaries required 12 months to reach maturity, while oogenesis seemed to occur more rapidly (5-6 months). Female polyps were found only during spring and summer. Furthermore, the rate of gamete development in both females and males increased significantly from March to May and fertilization was estimated to occur from April to July, when mature germ cells disappeared. Gametogenesis showed a strong seasonal influence, while embryos were found throughout the year in males and in sexually inactive individuals without a defined trend. This unusual embryogenesis suggests the possibility of agamic reproduction, which combined with sexual reproduction results in high fertility. This mechanism is uncommon and only four other scleractinians (Pocillopora damicornis, Tubastraea diaphana, T. coccinea and Oulastrea crispata) have been shown to generate their broods asexually. The precise nature of this process is still unknown.