Effectiveness of Personalized Hippocampal Network-Targeted Stimulation in Alzheimer Disease: A Randomized Clinical Trial.

Importance: Repetitive transcranial magnetic stimulation (rTMS) has emerged as a safe and promising intervention for Alzheimer disease (AD). Objective: To investigate the effect of a 4-week personalized hippocampal network-targeted rTMS on cognitive and functional performance, as well as functional connectivity in AD. Design, Setting, and Participants: This randomized clinical trial, which was sham-controlled and masked to participants and evaluators, was conducted between May 2020 and April 2022 at a single Korean memory clinic. Eligible participants were between ages 55 and 90 years and had confirmed early AD with evidence of an amyloid biomarker. Participants who met the inclusion criteria were randomly assigned to receive hippocampal network-targeted rTMS or sham stimulation. Participants received 4-week rTMS treatment, with assessment conducted at weeks 4 and 8. Data were analyzed between April 2022 and January 2024. Interventions: Each patient received 20 sessions of personalized rTMS targeting the left parietal area, functionally connected to the hippocampus, based on fMRI connectivity analysis over 4 weeks. The sham group underwent the same procedure, excluding actual magnetic stimulation. A personalized 3-dimensional printed frame to fix the TMS coil to the optimal target site was produced. Main Outcomes and Measures: The primary outcome was the change in the AD Assessment Scale-Cognitive Subscale test (ADAS-Cog) after 8 weeks from baseline. Secondary outcomes included changes in the Clinical Dementia Rating-Sum of Boxes (CDR-SOB) and Seoul-Instrumental Activity Daily Living (S-IADL) scales, as well as resting-state fMRI connectivity between the hippocampus and cortical areas. Results: Among 30 participants (18 in the rTMS group; 12 in the sham group) who completed the 8-week trial, the mean (SD) age was 69.8 (9.1) years; 18 (60%) were female. As the primary outcome, the change in ADAS-Cog at the eighth week was significantly different between the rTMS and sham groups (coefficient [SE], -5.2 [1.6]; P = .002). The change in CDR-SOB (-4.5 [1.4]; P = .007) and S-IADL (1.7 [0.7]; P = .004) were significantly different between the groups favoring rTMS groups. The fMRI connectivity analysis revealed that rTMS increased the functional connectivity between the hippocampus and precuneus, with its changes associated with improvements in ADAS-Cog (r = -0.57; P = .005). Conclusions and Relevance: This randomized clinical trial demonstrated the positive effects of rTMS on cognitive and functional performance, and the plastic changes in the hippocampal-cortical network. Our results support the consideration of rTMS as a potential treatment for AD. Trial Registration: ClinicalTrials.gov Identifier: NCT04260724.

Corticostriatal activity related to performance during continuous de novo motor learning.

Corticostriatal regions play a pivotal role in visuomotor learning. However, less research has been done on how fMRI activity in their subregions is related to task performance, which is provided as visual feedback during motor learning. To address this, we conducted an fMRI experiment in which participants acquired a complex de novo motor skill using continuous or binary visual feedback related to performance. We found a highly selective response related to performance in the entire striatum in both conditions and a relatively higher response in the caudate nucleus for the binary feedback condition. However, the ventromedial prefrontal cortex (vmPFC) response was significant only for the continuous feedback condition. Furthermore, we also found functional distinction of the striatal subregions in random versus goal-directed motor control. These findings underscore the substantial effects of the visual feedback indicating performance on distinct corticostriatal responses, thereby elucidating its significance in reinforcement-based motor learning.

Transcranial alternating current stimulation over multiple brain areas with non-zero phase delays other than 180 degrees modulates visuospatial working memory performance.

While zero-phase lag synchronization between multiple brain regions has been widely observed, relatively recent reports indicate that systematic phase delays between cortical regions reflect the direction of communications between cortical regions. For example, it has been suggested that a non-zero phase delay of electroencephalography (EEG) signals at the gamma frequency band between the bilateral parietal areas may reflect the direction of communication between these areas. We hypothesized that the direction of communication between distant brain areas might be modulated by multi-site transcranial alternating current stimulation (tACS) with specific phase delays other than 0° and 180°. In this study, a new noninvasive brain stimulation (NIBS) method called multi-site multi-phase tACS (msmp-tACS) was proposed. The efficacy of the proposed method was tested in a case study using a visuospatial working memory (VWM) paradigm in which the optimal stimulation conditions including amplitudes and phases of multiple scalp electrodes were determined using finite element analysis adopting phasor representation. msmp-tACS was applied over the bilateral intraparietal sulci (IPS) and showed that 80 Hz tACS with the phase for the right IPS leading that for the left IPS by 90° (= 3.125 ms) partialized VWM performance toward the right visual hemifield. The three stimulation conditions were synchronized, RL, and LR, which refers to stimulation condition with no phase lag, stimulation phase of right IPS (rIPS) leading left IPS (lIPS) by 90° and the stimulation of lIPS leading rIPS by 90°, respectively. The lateralization of VWM significantly shifted towards right visual hemifield under the RL condition compared to the synchronized and LR conditions. The shift in VWM was the result of the stimulation affecting both left and right visual hemifield trials to certain degrees, rather than significantly increasing or decreasing VWM capacity of a specific visual hemifield. Altered brain dynamics caused by msmp-tACS partialized VWM performance, likely due to modulation of effective connectivity between the rIPS and lIPS. Our results suggest that msmp-tACS is a promising NBS method that can effectively modulate cortical networks that cannot be readily modulated with conventional multi-site stimulation methods.

Requirements for Universally Accessible Upper-Body Exercise Equipment: The Case of People with Spinal Cord Injuries in Korea.

Background: People with disabilities face considerable obstacles when exercising, which precludes them from the social and health benefits of physical activity. Especially for individuals with paraplegia with spinal cord injuries, it is necessary to maintain continuous participation in physical activity even after discharge, as it helps to maintain mobility and daily living activities through upper body strength. However, the participation rate of people with disabilities in physical activity in Korea is still low, mainly due to the lack of exercise equipment and facilities. Objectives: The aim of this study is to identify aspects that can be improved for better accessibility to exercise equipment for individuals with paraplegia with spinal cord injuries and to reach a consensus on possible guidelines for accessible exercise equipment. Methods: This study reviews and evaluated the usability of four existing upper-body exercise equipment for individuals with paraplegia with spinal cord injuries. To assess usability, task performance scores and time were measured, and a survey was conducted on safety and satisfaction. Based on these results, areas for improvement were identified. Through literature review, usability results, and opinions from various stakeholders, eight requirements for universal accessibility were proposed. Results: It is necessary to consider how wheelchair users access the exercise equipment. The access method to the exercise area (facility regulations, auxiliary equipment to be provided, etc.) and placement of exercise equipment should also be considered. Information such as explanations of the exercise equipment and how to use it should be located within the wheelchair user's field of vision. Considering the participation rate in sports for people with disabilities in Korea, it is necessary to explain the exact exercise equipment and exercise method. It is also necessary to consider how wheelchair users transfer from the wheelchair to the seat of the exercise equipment. Parts that require manipulation of each exercise equipment must be within the wheelchair user's range of motion. Various supports or assistive devices that provide body support according to each piece of equipment are needed. In addition to the wheelchair's own brake, it is necessary to provide a fixing device so that the wheelchair does not move during the exercise. Conclusion: For people with spinal cord injuries, the arm ergometer, aerobic exercise equipment, showed higher scores in performance, stability, and satisfaction compared to other exercise equipment. Among the strength exercise equipment, shoulder press had an effect on performance, seated lat pull-down had an effect on stability, and seated chest press had an effect on satisfaction. Therefore, when selecting exercise equipment, it is necessary to recommend aerobic and strength exercise equipment according to the preferences of people with spinal cord injuries. When developing strength exercise equipment, it is necessary to consider usability evaluation factors for individuals with spinal cord injury.

Novel Supercapacitor Electrode Derived from One Dimensional Cerium Hydrogen Phosphate (1D-Ce(HPO4)2.xH2O).

In this manuscript, we are reporting for the first time one dimensional (1D) cerium hydrogen phosphate (Ce(HPO4)2.xH2O) electrode material for supercapacitor application. In short, a simple hydrothermal technique was employed to prepare Ce(HPO4)2.xH2O. The maximum surface area of 82 m2 g-1 was obtained from nitrogen sorption isotherm. SEM images revealed Ce(HPO4)2.xH2O exhibited a nanorod-like structure along with particles and clusters. The maximum specific capacitance of 114 F g-1 was achieved at 0.2 A g-1 current density for Ce(HPO4)/NF electrode material in a three-electrode configuration. Furthermore, the fabricated symmetric supercapacitor (SSC) based on Ce(HPO4)2.xH2O//Ce(HPO4)2.xH2O demonstrates reasonable specific energy (2.08 Wh kg-1), moderate specific power (499.88 W kg-1), and outstanding cyclic durability (retains 92.7% of its initial specific capacitance after 5000 GCD cycles).

Spatiotemporal dissociation of fMRI activity in the caudate nucleus underlies human de novo motor skill learning.

Motor skill learning involves a complex process of generating novel movement patterns guided by evaluative feedback, such as a reward. Previous literature has suggested anteroposteriorly separated circuits in the striatum to be implicated in early goal-directed and later automatic stages of motor skill learning, respectively. However, the involvement of these circuits has not been well elucidated in human de novo motor skill learning, which requires learning arbitrary action-outcome associations and value-based action selection. To investigate this issue, we conducted a human functional MRI (fMRI) experiment in which participants learned to control a computer cursor by manipulating their right fingers. We discovered a double dissociation of fMRI activity in the anterior and posterior caudate nucleus, which was associated with performance in the early and late learning stages. Moreover, cognitive and sensorimotor cortico-caudate interactions predicted individual learning performance. Our results suggest parallel cortico-caudate networks operating in different stages of human de novo motor skill learning.

Bidirectional competitive interactions between motor memory and declarative memory during interleaved learning.

Distinct motor and declarative memory systems are widely thought to compete during memory consolidation and retrieval, yet the nature of their interactions during learning is less clear. Recent studies have suggested motor learning not only depend on implicit motor memory system supporting gradual tuning of responses by feedback but also depend on explicit declarative memory system. However, this competition has been identified when both systems are engaged in learning the same material (motor information), and so competition might be emphasized. We tested whether such competition also occurs when learning involved separate motor memory and declarative information presented distinctly but yet in close temporal proximity. We measured behavioral and brain-activity correlates of motor-declarative competition during learning using a novel task with interleaved motor-adaptation and declarative-learning demands. Despite unrelated motor versus declarative information and temporal segregation, motor learning interfered with declarative learning and declarative learning interfered with motor learning. This reciprocal competition was tightly coupled to corresponding reductions of fMRI activity in motor versus declarative learning systems. These findings suggest that distinct motor and declarative learning systems compete even when they are engaged by system-specific demands in close temporal proximity during memory formation.

Correction: Large-scale network interactions supporting item-context memory formation.

[This corrects the article DOI: 10.1371/journal.pone.0210167.].

Large-scale network interactions supporting item-context memory formation.

Episodic memory is thought to involve functional interactions of large-scale brain networks that dynamically reconfigure depending on task demands. Although the hippocampus and closely related structures have been implicated, little is known regarding how large-scale and distributed networks support different memory formation demands. We investigated patterns of interactions among distributed networks while human individuals formed item-context memories for two stimulus categories. Subjects studied object-scene and object-location associations in different fMRI sessions. Stimulus-responsive brain regions were organized based on their fMRI interconnectivity into networks and modules using probabilistic module-detection algorithms to maximize measurement of individual differences in modular structure. Although there was a great deal of consistency in the modular structure between object-scene and object-location memory formation, there were also significant differences. Interactions among functional modules predicted later memory accuracy, explaining substantial portions of variability in memory formation success. Increased interactivity of modules associated with internal thought and anti-correlation of these modules with those related to stimulus-evoked processing robustly predicted object-scene memory, whereas decreased interactivity of stimulus-evoked processing modules predicted object-location memory. Assessment of individual differences in network organization therefore allowed identification of distinct patterns of functional interactions that robustly predicted memory formation. This highlights large-scale brain network interactions for memory formation and indicates that although networks are largely robust to task demands, reconfiguration nonetheless occurs to support distinct memory formation demands.

Selective and coherent activity increases due to stimulation indicate functional distinctions between episodic memory networks.

Posterior-medial and anterior-temporal cortical networks interact with the hippocampus and are thought to distinctly support episodic memory. We causally tested this putative distinction by determining whether targeted noninvasive stimulation could selectively affect neural signals of memory formation within the posterior-medial network. Stimulation enhanced the posterior-medial network's evoked response to stimuli during memory formation, and this activity increase was coherent throughout the network. In contrast, there was no increase in anterior-temporal network activity due to stimulation. In addition, control stimulation of an out-of-network prefrontal cortex location in a separate group of subjects did not influence memory-related activity in either network. The posterior-medial network is therefore a functional unit for memory processing that is distinct from the anterior-temporal network. These findings suggest that targeted stimulation can lead to network-specific increases in excitability during memory formation and hold promise for efforts to fine-tune network involvement in episodic memory via brain stimulation.

A computational model that predicts behavioral sensitivity to intracortical microstimulation.

OBJECTIVE: Intracortical microstimulation (ICMS) is a powerful tool to investigate the neural mechanisms of perception and can be used to restore sensation for patients who have lost it. While sensitivity to ICMS has previously been characterized, no systematic framework has been developed to summarize the detectability of individual ICMS pulse trains or the discriminability of pairs of pulse trains. APPROACH: We develop a simple simulation that describes the responses of a population of neurons to a train of electrical pulses delivered through a microelectrode. We then perform an ideal observer analysis on the simulated population responses to predict the behavioral performance of non-human primates in ICMS detection and discrimination tasks. MAIN RESULTS: Our computational model can predict behavioral performance across a wide range of stimulation conditions with high accuracy (R 2 = 0.97) and generalizes to novel ICMS pulse trains that were not used to fit its parameters. Furthermore, the model provides a theoretical basis for the finding that amplitude discrimination based on ICMS violates Weber's law. SIGNIFICANCE: The model can be used to characterize the sensitivity to ICMS across the range of perceptible and safe stimulation regimes. As such, it will be a useful tool for both neuroscience and neuroprosthetics.

Correlation between accelerometry and clinical balance testing in stroke.

[Purpose] The purpose of this study was to determine the correlation between the Berg Balance Scale (BBS) and acceleration of postural sway in the Clinical Test of Sensory Interaction and Balance (CTSIB) by using a triaxial accelerometer for quantitative assessment. [Subjects and Methods] Twenty-seven stroke patients participated in this study. Balance ability was evaluated with the BBS, and postural sway was evaluated with a triaxial accelerometer. The data were then analyzed for frequency and correlation by using statistical software (SPSS 18.0). [Result] Acceleration in left-right and forward-backward directions in all conditions of the CTSIB assessment showed a significant correlation with BBS assessment. Acceleration in Signal Vector Magnitude values in condition 3 of the CTSIB assessment showed a significant correlation with BBS assessment. [Conclusion] This study revealed that postural sway represented balance ability as acceleration in the quantitative measurement of kinematic analysis. This finding suggests that the triaxial accelerometer could be used as a measurement tool in clinical conditions.

Neural Substrates Related to Motor Memory with Multiple Timescales in Sensorimotor Adaptation.

Recent computational and behavioral studies suggest that motor adaptation results from the update of multiple memories with different timescales. Here, we designed a model-based functional magnetic resonance imaging (fMRI) experiment in which subjects adapted to two opposing visuomotor rotations. A computational model of motor adaptation with multiple memories was fitted to the behavioral data to generate time-varying regressors of brain activity. We identified regional specificity to timescales: in particular, the activity in the inferior parietal region and in the anterior-medial cerebellum was associated with memories for intermediate and long timescales, respectively. A sparse singular value decomposition analysis of variability in specificities to timescales over the brain identified four components, two fast, one middle, and one slow, each associated with different brain networks. Finally, a multivariate decoding analysis showed that activity patterns in the anterior-medial cerebellum progressively represented the two rotations. Our results support the existence of brain regions associated with multiple timescales in adaptation and a role of the cerebellum in storing multiple internal models.

Between-Trial Forgetting Due to Interference and Time in Motor Adaptation.

Learning a motor task with temporally spaced presentations or with other tasks intermixed between presentations reduces performance during training, but can enhance retention post training. These two effects are known as the spacing and contextual interference effect, respectively. Here, we aimed at testing a unifying hypothesis of the spacing and contextual interference effects in visuomotor adaptation, according to which forgetting between trials due to either spaced presentations or interference by another task will promote between-trial forgetting, which will depress performance during acquisition, but will promote retention. We first performed an experiment with three visuomotor adaptation conditions: a short inter-trial-interval (ITI) condition (SHORT-ITI); a long ITI condition (LONG-ITI); and an alternating condition with two alternated opposite tasks (ALT), with the same single-task ITI as in LONG-ITI. In the SHORT-ITI condition, there was fastest increase in performance during training and largest immediate forgetting in the retention tests. In contrast, in the ALT condition, there was slowest increase in performance during training and little immediate forgetting in the retention tests. Compared to these two conditions, in the LONG-ITI, we found intermediate increase in performance during training and intermediate immediate forgetting. To account for these results, we fitted to the data six possible adaptation models with one or two time scales, and with interference in the fast, or in the slow, or in both time scales. Model comparison confirmed that two time scales and some degree of interferences in either time scale are needed to account for our experimental results. In summary, our results suggest that retention following adaptation is modulated by the degree of between-trial forgetting, which is due to time-based decay in single adaptation task and interferences in multiple adaptation tasks.

Behavioral assessment of sensitivity to intracortical microstimulation of primate somatosensory cortex.

Intracortical microstimulation (ICMS) is a powerful tool to investigate the functional role of neural circuits and may provide a means to restore sensation for patients for whom peripheral stimulation is not an option. In a series of psychophysical experiments with nonhuman primates, we investigate how stimulation parameters affect behavioral sensitivity to ICMS. Specifically, we deliver ICMS to primary somatosensory cortex through chronically implanted electrode arrays across a wide range of stimulation regimes. First, we investigate how the detectability of ICMS depends on stimulation parameters, including pulse width, frequency, amplitude, and pulse train duration. Then, we characterize the degree to which ICMS pulse trains that differ in amplitude lead to discriminable percepts across the range of perceptible and safe amplitudes. We also investigate how discriminability of pulse amplitude is modulated by other stimulation parameters-namely, frequency and duration. Perceptual judgments obtained across these various conditions will inform the design of stimulation regimes for neuroscience and neuroengineering applications.

Sensitivity to microstimulation of somatosensory cortex distributed over multiple electrodes.

Meaningful and repeatable tactile sensations can be evoked by electrically stimulating primary somatosensory cortex. Intracortical microstimulation (ICMS) may thus be a viable approach to restore the sense of touch in individuals who have lost it, for example tetraplegic patients. One of the potential limitations of this approach, however, is that high levels of current can damage the neuronal tissue if the resulting current densities are too high. The limited range of safe ICMS amplitudes thus limits the dynamic range of ICMS-evoked sensations. One way to get around this limitation would be to distribute the ICMS over multiple electrodes in the hopes of intensifying the resulting percept without increasing the current density experienced by the neuronal tissue. Here, we test whether stimulating through multiple electrodes is a viable solution to increase the dynamic range of ICMS-elicited sensations without increasing the peak current density. To this end, we compare the ability of non-human primates to detect ICMS delivered through one vs. multiple electrodes. We also compare their ability to discriminate pulse trains differing in amplitude when these are delivered through one or more electrodes. We find that increasing the number of electrodes through which ICMS is delivered only has a marginal effect on detectability or discriminability despite the fact that 2-4 times more current is delivered overall. Furthermore, the impact of multielectrode stimulation (or lack thereof) is found whether pulses are delivered synchronously or asynchronously, whether the leading phase of the pulses is cathodic or anodic, and regardless of the spatial configuration of the electrode groups.

Delayed healing and induction of secretory leukocyte protease inhibitor in polycystic ovary syndrome rat skin wounds.

Secretory leukocyte protease inhibitor (SLPI) and estrogen promote wound healing through a decrease in the excessive inflammatory response, accelerating re-epithelialization and increasing the amount of collagen deposition. The excessive administration of estradiol valerate (EV) using hormonal therapy decreases the concentration of estrogen abruptly and induces the polycystic ovary syndrome (PCOS). In this study, the PCOS rat skin wound area was wider than that of the normal groups and the rate of keratinocyte migration in PCOS was lower than the normal group. The numbers of inflammatory cells and macrophages recruited in the PCOS group were larger than that of the normal group. More collagen was deposited in the healing area of the normal group than in the PCOS group. The level of SLPI expression was higher in the PCOS group than the normal group after wounding, with the exception of the epithelium. On the other hand, mRNA and protein expression levels of transforming growth factor-ß1 (TGF-ß1) were lower in the PCOS group than in the normal group. Matrix metalloproteinase-2 (MMP-2) and MMP-9 levels in the PCOS group were significantly lower than that of the normal group. Therefore, increased SLPI in PCOS skin wounds may help prevent an excessive inflammatory response and aberrant collagen deposition but not are sufficient to accelerate PCOS skin wound healing, suggesting that SLPI may act as a local rather than a systemic modulating molecule in PCOS rat skin wounds.

Learning Bayesian networks based diagnosis system for wastewater treatment process with sensor data.

Contemporary technical capabilities allow an operator to easily monitor and control several remote wastewater treatment processes simultaneously but an on-line automatic diagnostic system has not yet been installed. In this paper, an on-line diagnostic system is proposed, designed and implemented for the lab-scale five-stage step-feed Enhanced Biological Phosphorus Removal plant based upon a learning Bayesian network. In order to practically diagnose wastewater treatment processes, a lab-scale pilot plant was built and the proposed on-line diagnostic method was applied to evaluate the performance of the algorithm. In experimental results, real abnormal conditions occurred 21 times in a three month period. The suggested on-line diagnosis system made correct predictions 14 times and incorrect predictions 7 times. Moreover, a comparison of the prediction results of the Bayesian model and learning Bayesian model clearly show that learning algorithm became more effective as time passed.