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Abstract Aims Our study aimed to (1) identify trajectories on different mental health components during a two-year follow-up of the COVID-19 pandemic and contextualise them according to pandemic periods; (2) investigate the associations between mental health trajectories and several exposures, and determine whether there were differences among the different mental health outcomes regarding these associations. Methods We included 5535 healthy individuals, aged 40–65 years old, from the Barcelona Brain Health Initiative (BBHI). Growth mixture models (GMM) were fitted to classify individuals into different trajectories for three mental health-related outcomes (psychological distress, personal growth and loneliness). Moreover, we fitted a multinomial regression model for each outcome considering class membership as the independent variable to assess the association with the predictors. Results For the outcomes studied we identified three latent trajectories, differentiating two major trends, a large proportion of participants was classified into ‘resilient’ trajectories, and a smaller proportion into ‘chronic-worsening’ trajectories. For the former, we observed a lower susceptibility to the changes, whereas, for the latter, we noticed greater heterogeneity and susceptibility to different periods of the pandemic. From the multinomial regression models, we found global and cognitive health, and coping strategies as common protective factors among the studied mental health components. Nevertheless, some differences were found regarding the risk factors. Living alone was only significant for those classified into ‘chronic’ trajectories of loneliness, but not for the other outcomes. Similarly, secondary or higher education was only a risk factor for the ‘worsening’ trajectory of personal growth. Finally, smoking and sleeping problems were risk factors which were associated with the ‘chronic’ trajectory of psychological distress. Conclusions Our results support heterogeneity in reactions to the pandemic and the need to study different mental health-related components over a longer follow-up period, as each one evolves differently depending on the pandemic period. In addition, the understanding of modifiable protective and risk factors associated with these trajectories would allow the characterisation of these segments of the population to create targeted interventions.

Abstract Theta-burst stimulation (TBS) is a patterned form of repetitive transcranial magnetic stimulation (rTMS) that has been used to induce long-term modulation (plasticity) of corticospinal excitability in a drastically shorter duration protocol than conventional rTMS protocols. In this study we tested the reliability of the effects of two well defined TBS protocols, continuous TBS (cTBS) and intermittent TBS (iTBS), especially in relation to sham TBS, within and across the same 24 participants. All TBS protocols were repeated after approximately 1 month to assess the magnitude and reliability of the modulatory effects of each TBS protocol. Baseline and post-TBS changes in motor evoked potentials (MEP—measure of corticospinal excitability) amplitudes were compared across the cTBS, iTBS and sham TBS protocols and between the initial and retest visits. Overall, across participants, at the initial visit, iTBS facilitated MEPs as compared to baseline excitability, with sham eliciting the same effect. cTBS did not show a significant suppression of excitability compared to baseline MEPs at either visit, and even facilitated MEPs above baseline excitability at a single time point during the repeat visit. Otherwise, effects of TBS were generally diminished in the repeat visit, with iTBS and sham TBS replicating facilitation of MEPs above baseline excitability at similar time points. However, no protocol demonstrated consistent intra-individual modulation of corticospinal excitability upon retest. As the first study to test both iTBS and cTBS against sham TBS across repeat visits, our findings challenge the efficacy and reliability of TBS protocols and emphasize the importance of accounting for sham effects of TBS. Furthermore, given that therapeutic effects of TBS are hypothetically derived from consistent and repeated modulation of brain activity, the non-replicability of plasticity and sham effects call into question these basic mechanisms.

Scientists and clinicians have traditionally targeted single brain regions with stimulation to modulate brain function and disease. However, brain regions do not operate in isolation, but interact with other regions through networks. As such, stimulation of one region may impact and be impacted by other regions in its network. Here we test whether the effects of brain stimulation can be enhanced by simultaneously targeting a region and its network, identified with resting state functional connectivity MRI. Fifteen healthy participants received two types of transcranial direct current stimulation (tDCS): a traditional two-electrode montage targeting a single brain region (left primary motor cortex [M1]) and a novel eight-electrode montage targeting this region and its associated resting state network. As a control, 8 participants also received multifocal tDCS mismatched to this network. Network-targeted tDCS more than doubled the increase in left M1 excitability over time compared to traditional tDCS and the multifocal control. Modeling studies suggest these results are unlikely to be due to tDCS effects on left M1 itself, however it is impossible to completely exclude this possibility. It also remains unclear whether multifocal tDCS targeting a network selectively modulates this network and which regions within the network are most responsible for observed effects. Despite these limitations, network-targeted tDCS appears to be a promising approach for enhancing tDCS effects beyond traditional stimulation targeting a single brain region. Future work is needed to test whether these results extend to other resting state networks and enhance behavioral or therapeutic effects.

Low frequency repetitive TMS (rTMS) of a cortical seizure focus is emerging as an antiepileptic treatment. While conventional rTMS stimulators activate only superficial cortical areas, reaching deep epileptic foci, for example in temporal lobe epilepsy (TLE), is possible using specially designed H-coils. We report the results of rTMS in a young adult with pharmacoresistant bilateral TLE who underwent three courses (of 10, 15, and 30 daily sessions) of unilateral rTMS over the hemisphere from which seizures originated most often. Seizure frequency was assessed before and after each block of rTMS sessions, as was the tolerability of the procedure. Seizure frequency declined significantly, by 50 to 70% following each rTMS course. All sessions were well-tolerated.

IntroductionIndividuals with subjective cognitive decline (SCD) express concern about self-perceived cognitive decline despite no objective impairment and are at higher risk of developing Alzheimer’s disease. Despite documented links between SCD and repetitive negative thinking (RNT), the specific impact of RNT on brain integrity and cognition in exacerbating the SCD condition remains unclear. We aimed to investigate the influence of RNT on global cognition and brain integrity, and their interrelationships among healthy middle-aged and older adults experiencing SCD.MethodsOut of 616 individuals with neuroimaging and neuropsychological data available, 89 (mean age = 56.18 years; 68.54% females) met SCD criteria. Eighty-nine non-SCD individuals matched by age, sex, and education were also selected and represented the control group (mean age = 56.09 years; 68.54% females). Global cognition was measured using the preclinical Alzheimer’s cognitive composite (PACC5), which includes dementia screening, episodic memory, processing speed, and category fluency tests. RNT was calculated through three questionnaires assessing intrusive thoughts, persistent worry, and rumination. We generated cortical thickness (CTh) maps and quantified the volume of white matter lesions (WML) in the whole brain, as grey and white matter integrity measures, respectively.ResultsSCD individuals exhibited higher RNT scores, and thinner right temporal cortex compared to controls. No differences were observed in PACC5 and WML burden between groups. Only the SCD group demonstrated positive associations in the CTh-PACC5, CTh-RNT, and WML-RNT relationships.DiscussionIn this cross-sectional study, RNT was exclusively associated with brain integrity in SCD. Even though our findings align with the broader importance of investigating treatable psychological factors in SCD, further research may reveal a modulatory effect of RNT on the relationship between cognition and brain integrity in SCD.

IntroductionProof-of-principle human studies suggest that transcranial direct current stimulation (tDCS) over the dorsolateral prefrontal cortex (DLPFC) may improve depression severity. This open-label multicenter study tested remotely supervised multichannel tDCS delivered at home in patients (N=35) with major depressive disorder (MDD). The primary aim was to assess the feasibility and safety of our protocol. As an exploratory aim, we evaluated therapeutic efficacy: the primary efficacy measure was the median percent change from baseline to the end of the 4-week post-treatment follow-up period in the observer-rated Montgomery-Asberg Depression Mood Rating Scale (MADRS).MethodsParticipants received 37 at-home stimulation sessions (30 minutes each) of specifically designed multichannel tDCS targeting the left DLPFC administered over eight weeks (4 weeks of daily treatments plus 4 weeks of taper), with a follow-up period of 4 weeks following the final stimulation session. The stimulation montage (electrode positions and currents) was optimized by employing computational models of the electric field generated by multichannel tDCS using available structural data from a similar population (group optimization). Conducted entirely remotely, the study employed the MADRS for assessment at baseline, at weeks 4 and 8 during treatment, and at 4-week follow-up visits.Results34 patients (85.3% women) with a mean age of 59 years, a diagnosis of MDD according to DSM-5 criteria, and a MADRS score ≥20 at the time of study enrolment completed all study visits. At baseline, the mean time since MDD diagnosis was 24.0 (SD 19.1) months. Concerning compliance, 85% of the participants (n=29) completed the complete course of 37 stimulation sessions at home, while 97% completed at least 36 sessions. No detrimental effects were observed, including suicidal ideation and/or behavior. The study observed a median MADRS score reduction of 64.5% (48.6, 72.4) 4 weeks post-treatment (Hedge’s g = -3.1). We observed a response rate (≥ 50% improvement in MADRS scores) of 72.7% (n=24) from baseline to the last visit 4 weeks post-treatment. Secondary measures reflected similar improvements.ConclusionsThese results suggest that remotely supervised and supported multichannel home-based tDCS is safe and feasible, and antidepressant efficacy motivates further appropriately controlled clinical studies.Clinical Trial Registrationhttps://clinicaltrials.gov/study/NCT05205915?tab=results, identifier NCT05205915.

BackgroundDual task paradigms are thought to offer a quantitative means to assess cognitive reserve and the brain’s capacity to allocate resources in the face of competing cognitive demands. The most common dual task paradigms examine the interplay between gait or balance control and cognitive function. However, gait and balance tasks can be physically challenging for older adults and may pose a risk of falls. ObjectiveWe introduce a novel, digital dual-task assessment that combines a motor-control task (the “ball balancing” test), which challenges an individual to maintain a virtual ball within a designated zone, with a concurrent cognitive task (the backward digit span task [BDST]). MethodsThe task was administered on a touchscreen tablet, performance was measured using the inertial sensors embedded in the tablet, conducted under both single- and dual-task conditions. The clinical use of the task was evaluated on a sample of 375 older adult participants (n=210 female; aged 73.0, SD 6.5 years). ResultsAll older adults, including those with mild cognitive impairment (MCI) and Alzheimer disease–related dementia (ADRD), and those with poor balance and gait problems due to diabetes, osteoarthritis, peripheral neuropathy, and other causes, were able to complete the task comfortably and safely while seated. As expected, task performance significantly decreased under dual task conditions compared to single task conditions. We show that performance was significantly associated with cognitive impairment; significant differences were found among healthy participants, those with MCI, and those with ADRD. Task results were significantly associated with functional impairment, independent of diagnosis, degree of cognitive impairment (as indicated by the Mini Mental State Examination [MMSE] score), and age. Finally, we found that cognitive status could be classified with >70% accuracy using a range of classifier models trained on 3 different cognitive function outcome variables (consensus clinical judgment, Rey Auditory Verbal Learning Test [RAVLT], and MMSE). ConclusionsOur results suggest that the dual task ball balancing test could be used as a digital cognitive assessment of cognitive reserve. The portability, simplicity, and intuitiveness of the task suggest that it may be suitable for unsupervised home assessment of cognitive function.

IntroductionAlzheimer’s disease and related dementias (ADRD) represent a substantial global public health challenge with multifaceted impacts on individuals, families, and healthcare systems. Brief cognitive screening tools such as the Mini-Cog© can help improve recognition of ADRD in clinical practice, but widespread adoption continues to lag. We compared the Digital Clock and Recall (DCR), a next-generation process-driven adaptation of the Mini-Cog, with the original paper-and-pencil version in a well-characterized clinical trial sample.MethodsDCR was administered to 828 participants in the Bio-Hermes-001 clinical trial (age median ± SD = 72 ± 6.7, IQR = 11; 58% female) independently classified as cognitively unimpaired (n = 364) or as having mild cognitive impairment (MCI, n = 274) or dementia likely due to AD (DLAD, n = 190). MCI and DLAD cohorts were combined into a single impaired group for analysis. Two experienced neuropsychologists rated verbal recall accuracy and digitally drawn clocks using the original Mini-Cog scoring rules. Inter-rater reliability of Mini-Cog scores was computed for a subset of the data (n = 508) and concordance between Mini-Cog rule-based and DCR scoring was calculated.ResultsInter-rater reliability of Mini-Cog scoring was good to excellent, but Rater 2’s scores were significantly higher than Rater 1’s due to variation in clock scores (p

IntroductionA rapid and reliable neuropsychological protocol is essential for the efficient assessment of neurocognitive constructs related to emergent neurodegenerative diseases. We developed an AI-assisted, digitally administered/scored neuropsychological protocol that can be remotely administered in ~10 min. This protocol assesses the requisite neurocognitive constructs associated with emergent neurodegenerative illnesses.MethodsThe protocol was administered to 77 ambulatory care/memory clinic patients (56.40% women; 88.50% Caucasian). The protocol includes a 6-word version of the Philadelphia (repeatable) Verbal Learning Test [P(r)VLT], three trials of 5 digits backward from the Backwards Digit Span Test (BDST), and the “animal” fluency test. The protocol provides a comprehensive set of traditional “core” measures that are typically obtained through paper-and-pencil tests (i.e., serial list learning, immediate and delayed free recall, recognition hits, percent correct serial order backward digit span, and “animal” fluency output). Additionally, the protocol includes variables that quantify errors and detail the processes used in administering the tests. It also features two separate, norm-referenced summary scores specifically designed to measure executive control and memory.ResultsUsing four core measures, we used cluster analysis to classify participants into four groups: cognitively unimpaired (CU; n = 23), amnestic mild cognitive impairment (MCI; n = 17), dysexecutive MCI (n = 23), and dementia (n = 14). Subsequent analyses of error and process variables operationally defined key features of amnesia (i.e., rapid forgetting, extra-list intrusions, profligate responding to recognition foils); key features underlying reduced executive abilities (i.e., BDST items and dysexecutive errors); and the strength of the semantic association between successive responses on the “animal” fluency test. Executive and memory index scores effectively distinguished between all four groups. There was over 90% agreement between how cluster analysis of digitally obtained measures classified patients compared to classification using a traditional comprehensive neuropsychological protocol. The correlations between digitally obtained outcome variables and analogous paper/pencil measures were robust.DiscussionThe digitally administered protocol demonstrated a capacity to identify patterns of impaired performance and classification similar to those observed with standard paper/pencil neuropsychological tests. The inclusion of both core measures and detailed error/process variables suggests that this protocol can detect subtle, nuanced signs of early emergent neurodegenerative illness efficiently and comprehensively.

IntroductionUnderstanding the impact of different lifestyle trajectories on health preservation and disease risk is crucial for effective interventions.MethodsThis study analyzed lifestyle engagement over five years in 3,013 healthy adults aged 40-70 from the Barcelona Brain Health Initiative using K-means clustering. Nine modifiable risk factors were considered, including cognitive, physical, and social activity, vital plan, diet, obesity, smoking, alcohol consumption, and sleep. Self-reported diagnoses of new diseases at different time-points after baseline allowed to explore the association between these five profiles and health outcomes.ResultsThe data-driven analysis classified subjects into five lifestyle profiles, revealing associations with health behaviors and risk factors. Those exhibiting high scores in health-promoting behaviors and low-risk behaviors, demonstrate a reduced likelihood of developing diseases (p < 0.001). In contrast, profiles with risky habits showed distinct risks for psychiatric, neurological, and cardiovascular diseases. Participant’s lifestyle trajectories remained relatively stable over time.DiscussionOur findings have identified risk for distinct diseases associated to specific lifestyle patterns. These results could help in the personalization of interventions based on data-driven observation of behavioral patterns and policies that promote a healthy lifestyle and can lead to better health outcomes for people in an aging society.

Incorporating person-centered outcomes into clinical trials for neurodegenerative diseases has been challenging due to a deficiency in quantitative measures. Meanwhile, the integration of personally meaningful treatment targets in clinical practice remains qualitative, failing to truly inform evaluations, therapeutic interventions and longitudinal monitoring and support. We discuss the current advances and future directions in capturing individualized brain health outcomes and present an approach to integrate person-centered outcome in a scalable manner. Our approach stems from the evidence-based electronic Person-Specific Outcome Measure (ePSOM) program which prompts an individual to define personally meaningful treatment priorities and report level of confidence in managing items that matter to the individual the most (e.g., “Do I feel confident in my ability to contribute to a conversation?”). Deployed either as a single version (person only) or a dyad version (person and care partner), our proposed tool could be used as an endpoint in clinical trials, offering proof of meaningful intervention benefits and in clinical practice, by establishing an anchor for the therapeutic objectives sought by the individual.

Primary brain neoplasms are associated with elevated mortality and morbidity rates. Brain tumour surgery aims to achieve maximal tumour resection while minimizing damage to healthy brain tissue. Research on Neuromodulation Induced Cortical Prehabilitation (NICP) has highlighted the potential, before neurosurgery, of establishing new brain connections and transfer functional activity from one area of the brain to another. Nonetheless, the neural mechanisms underlying these processes, particularly in the context of space-occupying lesions, remain unclear. A patient with a left frontotemporoinsular tumour underwent a prehabilitation protocol providing 20 sessions of inhibitory non-invasive neuromodulation (rTMS and multichannel tDCS) over a language network coupled with intensive task training. Prehabilitation resulted in an increment of the distance between the tumour and the language network. Furthermore, enhanced functional connectivity within the language circuit was observed. The present innovative case-study exposed that inhibition of the functional network area surrounding the space-occupying lesion promotes a plastic change in the network’s spatial organization, presumably through the establishment of novel functional pathways away from the lesion’s site. While these outcomes are promising, prudence dictates the need for larger studies to confirm and generalize these findings.

BackgroundDigital neuropsychological tests reliably capture real-time, process-based behavior that traditional paper/pencil tests cannot detect, enabling earlier detection of neurodegenerative illness. We assessed relations between informant-based subtle and mild functional decline and process-based features extracted from the digital Trail Making Test-Part B (dTMT-B).MethodsA total of 321 community-dwelling participants (56.0% female) were assessed with the Functional Activities Questionnaire (FAQ) and the dTMT-B. Three FAQ groups were constructed: FAQ = 0 (unimpaired); FAQ = 1–4 (subtle impairment); FAQ = 5–8 (mild impairment).ResultsCompared to the FAQ-unimpaired group, other groups required longer pauses inside target circles (p < 0.050) and produced more total pen strokes to complete the test (p < 0.016). FAQ-subtle participants required more time to complete the entire test (p < 0.002) and drew individual lines connecting successive target circles slower (p < 0.001) than FAQ-unimpaired participants. Lines connecting successive circle targets were less straight among FAQ-mild, compared to FAQ-unimpaired participants (p < 0.044). Using stepwise nominal regression (reference group = FAQ-unimpaired), pauses inside target circles classified other participants into their respective groups (p < 0.015, respectively). Factor analysis using six dTMT-B variables (oblique rotation) yielded a two-factor solution related to impaired motor/cognitive operations (48.96% variance explained) and faster more efficient motor/cognitive operations (28.88% variance explained).ConclusionDigital assessment technology elegantly quantifies occult, nuanced behavior not previously appreciated, operationally defines critical underlying neurocognitive constructs related to functional abilities, and yields selected process-based scores that outperform traditional paper/pencil test scores for participant classification. When brought to scale, the dTMT-B test could be a sensitive tool to detect subtle-to-mild functional deficits in emergent neurodegenerative illnesses.

Background As the world population continues to age, the prevalence of neurological diseases, such as dementia, poses a significant challenge to society. Detecting cognitive impairment at an early stage is vital in preserving and enhancing cognitive function. Digital tools, particularly mHealth, offer a practical solution for large-scale population screening and prompt follow-up assessments of cognitive function, thus overcoming economic and time limitations. Objective In this work, two versions of a digital solution called Guttmann Cognitest ® were tested. Methods Two hundred and one middle-aged adults used the first version (Group A), while 132 used the second one, which included improved tutorials and practice screens (Group B). This second version was also validated in an older age group (Group C). Results This digital solution was found to be highly satisfactory in terms of usability and feasibility, with good acceptability among all three groups. Specifically for Group B, the system usability scale score obtained classifies the solution as the best imaginable in terms of usability. Conclusions Guttmann Cognitest ® has been shown to be effective and well-perceived, with a high potential for sustained engagement in tracking changes in cognitive function.

The prevalence of Alzheimer’s disease (AD) and related dementias (ADRD) is increasing. African Americans are twice as likely to develop dementia than other ethnic populations. Traditional cognitive screening solutions lack the sensitivity to independently identify individuals at risk for cognitive decline. The DCTclock is a 3-min AI-enabled adaptation of the well-established clock drawing test. The DCTclock can estimate dementia risk for both general cognitive impairment and the presence of AD pathology. Here we performed a retrospective analysis to assess the performance of the DCTclock to estimate future conversion to ADRD in African American participants from the Rush Alzheimer’s Disease Research Center Minority Aging Research Study (MARS) and African American Clinical Core (AACORE). We assessed baseline DCTclock scores in 646 participants (baseline median age = 78.0 ± 6.4, median years of education = 14.0 ± 3.2, 78% female) and found significantly lower baseline DCTclock scores in those who received a dementia diagnosis within 3 years. We also found that 16.4% of participants with a baseline DCTclock score less than 60 were significantly more likely to develop dementia in 5 years vs. those with the highest DCTclock scores (75–100). This research demonstrates the DCTclock’s ability to estimate the 5-year risk of developing dementia in an African American population. Early detection of elevated dementia risk using the DCTclock could provide patients, caregivers, and clinicians opportunities to plan and intervene early to improve cognitive health trajectories. Early detection of dementia risk can also enhance participant selection in clinical trials while reducing screening costs.