Comparison of plasma and neuroimaging biomarkers to predict cognitive decline in non-demented memory clinic patients.

BACKGROUND: Plasma biomarkers of Alzheimer's disease (AD) pathology, neurodegeneration, and neuroinflammation are ideally suited for secondary prevention programs in self-sufficient persons at-risk of dementia. Plasma biomarkers have been shown to be highly correlated with traditional imaging biomarkers. However, their comparative predictive value versus traditional AD biomarkers is still unclear in cognitively unimpaired (CU) subjects and with mild cognitive impairment (MCI). METHODS: Plasma (Aß42/40, p-tau181, p-tau231, NfL, and GFAP) and neuroimaging (hippocampal volume, centiloid of amyloid-PET, and tau-SUVR of tau-PET) biomarkers were assessed at baseline in 218 non-demented subjects (CU = 140; MCI = 78) from the Geneva Memory Center. Global cognition (MMSE) was evaluated at baseline and at follow-ups up to 5.7 years. We used linear mixed-effects models and Cox proportional-hazards regression to assess the association between biomarkers and cognitive decline. Lastly, sample size calculations using the linear mixed-effects models were performed on subjects positive for amyloid-PET combined with tau-PET and plasma biomarker positivity. RESULTS: Cognitive decline was significantly predicted in MCI by baseline plasma NfL (ß=-0.55), GFAP (ß=-0.36), hippocampal volume (ß = 0.44), centiloid (ß=-0.38), and tau-SUVR (ß=-0.66) (all p < 0.05). Subgroup analysis with amyloid-positive MCI participants also showed that only NfL and GFAP were the only significant predictors of cognitive decline among plasma biomarkers. Overall, NfL and tau-SUVR showed the highest prognostic values (hazard ratios of 7.3 and 5.9). Lastly, we demonstrated that adding NfL to the inclusion criteria could reduce the sample sizes of future AD clinical trials by up to one-fourth in subjects with amyloid-PET positivity or by half in subjects with amyloid-PET and tau-PET positivity. CONCLUSIONS: Plasma NfL and GFAP predict cognitive decline in a similar manner to traditional imaging techniques in amyloid-positive MCI patients. Hence, even though they are non-specific biomarkers of AD, both can be implemented in memory clinic workups as important prognostic biomarkers. Likewise, future clinical trials might employ plasma biomarkers as additional inclusion criteria to stratify patients at higher risk of cognitive decline to reduce sample sizes and enhance effectiveness.

Functional neuroimaging and behavioral correlates of multisite tDCS as an add-on to language training in a person with post-stroke non-fluent aphasia: a year-long case study.

Mary, who experienced non-fluent aphasia as a result of an ischemic stroke, received 10 years of personalized language training (LT), resulting in transient enhancements in speech and comprehension. To enhance these effects, multisite transcranial Direct Current Stimulation (tDCS) was added to her LT regimen for 15 sessions. Assessment using the Reliable Change Index showed that this combination improved her left inferior frontal connectivity and speech production for two months and significantly improved comprehension after one month. The results indicate that using multisite transcranial direct current stimulation (tDCS) can improve the effectiveness of language therapy (LT) for individuals with non-fluent aphasia.

Tailoring transcranial alternating current stimulation based on endogenous event-related P3 to modulate premature responses: a feasibility study.

Background: Transcranial alternating current stimulation (tACS) is a brain stimulation method for modulating ongoing endogenous oscillatory activity at specified frequency during sensory and cognitive processes. Given the overlap between event-related potentials (ERPs) and event-related oscillations (EROs), ERPs can be studied as putative biomarkers of the effects of tACS in the brain during cognitive/sensory task performance. Objective: This preliminary study aimed to test the feasibility of individually tailored tACS based on individual P3 (latency and frequency) elicited during a cued premature response task. Thus, tACS frequency was individually tailored to match target-P3 ERO for each participant. Likewise, the target onset in the task was adjusted to match the tACS phase and target-P3 latency. Methods: Twelve healthy volunteers underwent tACS in two separate sessions while performing a premature response task. Target-P3 latency and ERO were calculated in a baseline block during the first session to allow a posterior synchronization between the tACS and the endogenous oscillatory activity. The cue and target-P3 amplitudes, delta/theta ERO, and power spectral density (PSD) were evaluated pre and post-tACS blocks. Results: Target-P3 amplitude significantly increased after activetACS, when compared to sham. Evoked-delta during cue-P3 was decreased after tACS. No effects were found for delta ERO during target-P3 nor for the PSD and behavioral outcomes. Conclusion: The present findings highlight the possible effect of phase synchronization between individualized tACS parameters and endogenous oscillatory activity, which may result in an enhancement of the underlying process (i.e., an increase of target-P3). However, an unsuccessful synchronization between tACS and EEG activity might also result in a decrease in the evoked-delta activity during cue-P3. Further studies are needed to optimize the parameters of endogenous activity and tACS synchronization. The implications of the current results for future studies, including clinical studies, are further discussed since transcranial alternating current stimulation can be individually tailored based on endogenous event-related P3 to modulate responses.

Efficacy and safety of repetitive Transcranial Magnetic Stimulation and transcranial Direct Current Stimulation in memory deficits in patients with Alzheimer's disease: Meta-analysis and systematic review.

Repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) are two of the most used non-pharmacological interventions for Alzheimer's Disease (AD). However, most of the clinical trials have focused on evaluating the effects on global cognition and not on specific cognitive functions. Therefore, considering that memory loss is one of the hallmark symptoms of AD, we aim to assess the efficacy and safety of tDCS and rTMS in memory deficits. For that, multilevel random effect models were performed considering the standardized mean difference (SMD) between active and sham stimulation. A total of 19 studies with 411 participants demonstrated positive effects in memory after tDCS (SMD=0.20, p = 0.04) and rTMS (SMD=0.44, p = 0.001). Subgroup analysis revealed that tDCS had greater efficacy when administered in temporal regions (SMD=0.32, p = 0.04), whereas rTMS was superior when applied in frontal regions (SMD=0.61, p < 0.001). Therefore, depending on the brain region of stimulation, both interventions produced a positive effect on memory symptoms in AD patients. Finally, the safety of both techniques was observed in the AD population after the reporting of almost no serious events.

Transcranial Direct Current Stimulation Decreases P3 Amplitude and Inherent Delta Activity during a Waiting Impulsivity Paradigm: Crossover Study.

The inability to wait for a target before initiating an action (i.e., waiting impulsivity) is one of the main features of addictive behaviors. Current interventions for addiction, such as transcranial Direct Current Stimulation (tDCS), have been suggested to improve this inability. Nonetheless, the effects of tDCS on waiting impulsivity and underlying electrophysiological (EEG) markers are still not clear. Therefore, this study aimed to evaluate the effects of neuromodulation over the right inferior frontal gyrus (rIFG) on the behavior and EEG markers of reward anticipation (i.e., cue and target-P3 and underlying delta/theta power) during a premature responding task. For that, forty healthy subjects participated in two experimental sessions, where they received active and sham tDCS over the rIFG combined with EEG recording during the task. To evaluate transfer effects, participants also performed two control tasks to assess delay discounting and motor inhibition. The active tDCS decreased the cue-P3 and target-P3 amplitudes, as well as delta power during target-P3. While no tDCS effects were found for motor inhibition, active tDCS increased the discounting of future rewards when compared to sham. These findings suggest a tDCS-induced modulation of the P3 component and underlying oscillatory activity during waiting impulsivity and the discounting of future rewards.

Head-to-head study of diagnostic accuracy of plasma and cerebrospinal fluid p-tau217 versus p-tau181 and p-tau231 in a memory clinic cohort.

BACKGROUND AND OBJECTIVE: Phosphorylated tau (p-tau) 217 has recently received attention because it seems more reliable than other p-tau variants for identifying Alzheimer's disease (AD) pathology. Thus, we aimed to compare the diagnostic accuracy of plasma and CSF p-tau217 with p-tau181 and p-tau231 in a memory clinic cohort. METHODS: The study included 114 participants (CU = 33; MCI = 67; Dementia = 14). The p-tau variants were correlated versus continuous measures of amyloid (A) and tau (T)-PET. The p-tau phospho-epitopes were assessed through: (i) effect sizes (δ) between diagnostic and A ± and T ± groups; (ii) receiver operating characteristic (ROC) analyses in A-PET and T-PET. RESULTS: The correlations between both plasma and CSF p-tau217 with A-PET and T-PET (r range 0.64-0.83) were stronger than those of p-tau181 (r range 0.44-0.79) and p-tau231 (r range 0.46-0.76). Plasma p-tau217 showed significantly higher diagnostic accuracy than p-tau181 and p-tau231 in (i) differences between diagnostic and biomarker groups (δrange: p-tau217 = 0.55-0.96; p-tau181 = 0.51-0.67; p-tau231 = 0.53-0.71); (ii) ROC curves to identify A-PET and T-PET positivity (AUCaverage: p-tau217 = 0.96; p-tau181 = 0.76; p-tau231 = 0.79). On the other hand, CSF p-tau217 (AUCaverage = 0.95) did not reveal significant differences in A-PET and T-PET AUC than p-tau181 (AUCaverage = 0.88) and p-tau231 (AUCaverage = 0.89). DISCUSSION: Plasma p-tau217 demonstrated better performance in the identification of AD pathology and clinical phenotypes in comparison with other variants of p-tau in a memory clinic cohort. Furthermore, p-tau217 had comparable performance in plasma and CSF. Our findings suggest the potential of plasma p-tau217 in the diagnosis and screening for AD, which could allow for a decreased use of invasive biomarkers in the future.

Exercise effects on motor function, manual dexterity, and brain oscillatory activity in individuals with Parkinson's disease: Randomized controlled trial protocol.

BACKGROUND: Parkinson's disease (PD) is the second most common progressive neurodegenerative disorder. Exercise protocols are promising interventions to improve PD symptoms, however, the best modality and its neural correlates are still unknown. OBJECTIVES: To evaluate the effects of the aerobic, strength and task-oriented upper-limb exercises in motor function, manual dexterity, and brain oscillations of individuals with PD. METHOD: In this clinical trial, 44 PD patients aged 40-80 years will be randomized in four groups: aerobic training (AT), strength training (ST), task-oriented training (TOT), and waiting list group (CG). The AT group will perform 30 min of a cycle ergometer on 50%-70% of the reserve heart rate. The ST group will use equipment for upper limb muscles and will perform two series of 8-12 repetitions for each exercise, and intensity between 50% and 70% of one maximum repetition will be used. The TOT group will perform a program consisting of three activities to enhance reaching, grasping, and manipulation. All the groups will perform three sessions per week for 8 weeks. We will use the UPDRS Motor function section, Nine-Hole Peg Test, and quantitative electroencephalography to measure motor function, manual dexterity, and brain oscillations, respectively. ANOVA and regression models will be used to compare outcomes within and between groups.

EEG theta and beta bands as brain oscillations for different knee osteoarthritis phenotypes according to disease severity.

This study aims to investigate the multivariate relationship between different sociodemographic, clinical, and neurophysiological variables with resting-state, high-definition, EEG spectral power in subjects with chronic knee osteoarthritis (OA) pain. This was a cross-sectional study. Sociodemographic and clinical data were collected from 66 knee OA subjects. To identify associated factors, we performed independent univariate and multivariate regression models by frequency bands (delta, theta, alpha, beta, low-beta, and high-beta) and by pre-defined regions (frontal, central, and parietal). From adjusted multivariate models, we found that: (1) increased frontocentral high-beta power and reduced central theta activity are positively correlated with pain intensity (ß = 0.012, 95% CI 0.004-0.020; and ß = - 0.008; 95% CI 0.014 to - 0.003; respectively); (2) delta and alpha oscillations have a direct relationship with higher cortical inhibition; (3) diffuse increased power at low frequencies (delta and theta) are associated with poor cognition, aging, and depressive symptoms; and (4) higher alpha and beta power over sensorimotor areas seem to be a maladaptive compensatory mechanism to poor motor function and severe joint degeneration. Subjects with higher pain intensity and higher OA severity (likely subjects with maladaptive compensatory mechanisms to severe OA) have higher frontocentral beta power and lower theta activity. On the other hand, subjects with less OA severity and less pain have higher theta oscillations power. These associations showed the potential role of brain oscillations as a marker of pain intensity and clinical phenotypes in chronic knee OA patients. Besides, they suggest a potential compensatory mechanism of these two brain oscillators according to OA severity.

Modulation of the cognitive event-related potential P3 by transcranial direct current stimulation: Systematic review and meta-analysis.

Transcranial direct current stimulation (tDCS) has been widely used to modulate cognition and behavior. However, only a few studies have been probing the brain mechanism underlying the effects of tDCS on cognitive processing, especially throughout electrophysiological markers, such as the P3. This meta-analysis assessed the effects of tDCS in P3 amplitude and latency during an oddball, n-back, and Go/No-Go tasks, as well as during emotional processing. A total of 36 studies were identified, but only 23 were included in the quantitative analysis. The results show that the parietal P3 amplitude increased during oddball and n-back tasks, mostly after anodal stimulation over the left dorsolateral prefrontal cortex (p = 0.018, SMD = 0.4) and right inferior frontal gyrus (p < 0.001, SMD = 0.669) respectively. These findings suggest the potential usefulness of the parietal P3 ERP as a marker of tDCS-induced effects during task performance. Nonetheless, this study had a low number of studies and the presence of considerable risk of bias, highlighting issues to be addressed in the future.

Home-based transcranial direct current stimulation (tDCS) and motor imagery for phantom limb pain using statistical learning to predict treatment response: an open-label study protocol.

Background: Phantom limb pain (PLP) management has been a challenge due to its response heterogeneity and lack of treatment access. This study will evaluate the feasibility of a remotely home-based M1 anodal tDCS combined with motor imagery in phantom limb patients and assess the preliminary efficacy, safety, and predictors of response of this therapy. Methods: This is a pilot, single-arm, open-label trial in which we will recruit 10 subjects with phantom limb pain. The study will include 20 sessions. All participants will receive active anodal M1 tDCS combined with phantom limb motor imagery training. Our primary outcome will be the acceptability and feasibility of this combined intervention. Moreover, we will assess preliminary clinical (pain intensity) and physiological (motor inhibition tasks and heart rate variability) changes after treatment. Finally, we will implement a supervised statistical learning (SL) model to identify predictors of treatment response (to tDCS and phantom limb motor imagery) in PLP patients. We will also use data from our previous clinical trial (total observations=224 [n=112 x timepoints = 2)) for our statistical learning algorithms. The new prospective data from this open-label study will be used as an independent test dataset. Discussion: This protocol proposes to assess the feasibility of a novel, neuromodulatory combined intervention that will allow the design of larger remote clinical trials, thus increasing access to safe and effective treatments for PLP patients. Moreover, this study will allow us to identify possible predictors of pain response and PLP clinical endotypes.

Changes in vocal emotion recognition across the life span.

The ability to recognize emotions undergoes major developmental changes from infancy to adolescence, peaking in early adulthood, and declining with aging. A life span approach to emotion recognition is lacking in the auditory domain, and it remains unclear how the speaker's and listener's ages interact in the context of decoding vocal emotions. Here, we examined age-related differences in vocal emotion recognition from childhood until older adulthood and tested for a potential own-age bias in performance. A total of 164 participants (36 children [7-11 years], 53 adolescents [12-17 years], 48 young adults [20-30 years], 27 older adults [58-82 years]) completed a forced-choice emotion categorization task with nonverbal vocalizations expressing pleasure, relief, achievement, happiness, sadness, disgust, anger, fear, surprise, and neutrality. These vocalizations were produced by 16 speakers, 4 from each age group (children [8-11 years], adolescents [14-16 years], young adults [19-23 years], older adults [60-75 years]). Accuracy in vocal emotion recognition improved from childhood to early adulthood and declined in older adults. Moreover, patterns of improvement and decline differed by emotion category: faster development for pleasure, relief, sadness, and surprise and delayed decline for fear and surprise. Vocal emotions produced by older adults were more difficult to recognize when compared to all other age groups. No evidence for an own-age bias was found, except in children. These findings support effects of both speaker and listener ages on how vocal emotions are decoded and inform current models of vocal emotion perception. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Neuromodulating Attention and Mind-Wandering Processes with a Single Session Real Time EEG.

Our minds are continuously alternating between external attention (EA) and mind wandering (MW). An appropriate balance between EA and MW is important for promoting efficient perceptual processing, executive functioning, decision-making, auto-biographical memory, and creativity. There is evidence that EA processes are associated with increased activity in high-frequency EEG bands (e.g., SMR), contrasting with the dominance of low-frequency bands during MW (e.g., Theta). The aim of the present study was to test the effects of two distinct single session real-time EEG (rtEEG) protocols (SMR up-training/Theta down-training-SMR⇑Theta⇓; Theta up-training/SMR down-training-Theta⇑SMR⇓) on EA and MW processes. Thirty healthy volunteers were randomly assigned to one of two rtEEG training protocols (SMR⇑Theta⇓; Theta⇑SMR⇓). Before and after the rtEEG training, participants completed the attention network task (ANT) along with several MW measures. Both training protocols were effective in increasing SMR (SMR⇑Theta⇓) and theta (Theta⇑SMR⇓) amplitudes but not in decreasing the amplitude of down-trained bands. There were no significant effects of the rtEEG training in either EA or MW measures. However, there was a significant positive correlation between post-training SMR increases and the use of deliberate MW (rather than spontaneous) strategies. Additionally, for the Theta⇑SMR⇓ protocol, increase in post-training Theta amplitude was significantly associated with a decreased efficiency in the orientation network.

Polarity Specific Effects of Cross-Hemispheric tDCS Coupled With Approach-Avoidance Training on Chocolate Craving.

Transcranial Direct Current Stimulation (tDCS) over the Dorsolateral Prefrontal Cortex (DLPFC) has already been shown to decrease craving for food. However, it remains unclear whether a single session of tDCS combined with a cognitive bias modification (CBM) task may affect explicit and implicit measures of craving for chocolate. Fifty-one healthy volunteers (38 females; mean age: 22.12 ± 3.38) were randomly allocated to CBM training based on the Approach Avoidance task and either Sham, Right anodal-Left cathodal (RALC), or Left anodal-Right cathodal (LARC) tDCS. Results show that there was an increase in the explicit craving for chocolate, as assessed by the Visual Analog Scale [F(2, 46) = 3.239, p = 0.048], from the baseline to post-intervention. Participants which received LARC tDCS were explicitly self-reporting more craving for chocolate than those that received RALC tDCS (p = 0.023). Moreover, this effect was also observed on the implicit measure [F(2, 46) = 4.168, p = 0.022]. LARC tDCS significantly increased the implicit preference for chocolate when comparing to both RALC (p = 0.009) and Sham tDCS (p = 0.034). Previous studies have shown that RALC tDCS over the PFC is able to effectively decrease craving for food. Interestingly, the present data not only does not reproduce such result, but instead it suggests that LARC tDCS can actually increase the preference for chocolate. This result is compatible with recent models of brain laterality, in which cue craving seems to be more dependent on the left hemisphere. Thus, shifting the activity to the left hemisphere (while simultaneously reducing the activity over the homotopic region) may have led to this increased implicit as well as explicit preference for chocolate.

Neuromodulating attention and mind-wandering processes with multi-session real-time electroencephalogram.

Previous studies showed the efficacy of a single session real-time electroencephalogram (rtEEG) protocols in sensorimotor rhythm (SMR) or Theta up-training. However, the impact of this training on sustained or mind-wandering attention was only modest. This could be explained by the lack of specificity in distinct rtEEG training protocols given their limitation in inhibiting or decreasing the amplitude of down-trained bands. Additionally, multiple sessions of rtEEG in up-training/down-training SMR (sensorimotor rhythm) and Theta along with better ways of tracking sustained and mind-wandering attention protocols may be required to achieve consistent effects. Here we describe the effects of a 10-session trial of up-training/down-training SMR or Theta (SMR⇑Theta⇓; Theta⇑SMR⇓), looking at the effects of 2 rtEEG training protocols in 2 n of 1 subject designs. We also tested to impact of this training in sustained and mind-wandering attention during the course of a Sustained Attention Response Task (SART). The present trial confirmed the potentiality of a multi-session protocol in up-training Theta or SMR and, as consequence, increasing sustained attention (Theta up-training) and mind-wandering attention (SMR up-training). However, the simultaneous increase of the Theta amplitude in the SMR⇑Theta⇓ (and the more modest increase of the SMR amplitude in Theta⇑SMR⇓) reduced the specificity of the rtEEG training. Future studies should build on the potentiality of extended rtEEG protocols on this attention paradigm but increasing the specificity of the trained EEG bands choosing less tedious/more motivating feedback instruments (SMR⇑Theta⇓) and conducting the Theta⇑SMR⇓ training eyes closed.