Neuromodulation-induced prehabilitation to leverage neuroplasticity before brain tumor surgery: a single-cohort feasibility trial protocol.

Introduction: Neurosurgery for brain tumors needs to find a complex balance between the effective removal of targeted tissue and the preservation of surrounding brain areas. Neuromodulation-induced cortical prehabilitation (NICP) is a promising strategy that combines temporary inhibition of critical areas (virtual lesion) with intensive behavioral training to foster the activation of alternative brain resources. By progressively reducing the functional relevance of targeted areas, the goal is to facilitate resection with reduced risks of neurological sequelae. However, it is still unclear which modality (invasive vs. non-invasive neuromodulation) and volume of therapy (behavioral training) may be optimal in terms of feasibility and efficacy. Methods and analysis: Patients undertake between 10 and 20 daily sessions consisting of neuromodulation coupled with intensive task training, individualized based on the target site and neurological functions at risk of being compromised. The primary outcome of the proposed pilot, single-cohort trial is to investigate the feasibility and potential effectiveness of a non-invasive NICP protocol on neuroplasticity and post-surgical outcomes. Secondary outcomes investigating longitudinal changes (neuroimaging, neurophysiology, and clinical) are measured pre-NICP, post-NICP, and post-surgery. Ethics and dissemination: Ethics approval was obtained from the Research Ethical Committee of Fundació Unió Catalana d'Hospitals (approval number: CEI 21/65, version 1, 13/07/2021). The results of the study will be submitted to a peer-reviewed journal and presented at scientific congresses. Clinical trial registration: ClinicalTrials.gov, identifier NCT05844605.

Brain Connectivity Correlates of Cognitive Dispersion in a Healthy Middle-Aged Population: Influence of Subjective Cognitive Complaints.

OBJECTIVES: Cognitive dispersion, representing intraindividual fluctuations in cognitive performance, is associated with cognitive decline in advanced age. We sought to elucidate sociodemographic, neuropsychological, and brain connectivity correlates of cognitive dispersion in middle age, and further consider potential influences of the severity of subjective cognitive complaints (SCC). METHODS: Five hundred and twenty healthy volunteers from the Barcelona Brain Health Initiative (aged 40-66 years; 49.6% females, 453 with magnetic resonance imaging acquisitions) were included and stratified into high and low SCC groups. Two analysis steps were undertaken: (1) for the whole sample and (2) by groups. Generalized linear models and analysis of covariance were implemented to study associations between cognitive dispersion and performance (episodic memory, speed of processing, and executive function), white matter integrity, and resting-state functional connectivity (rs-FC) of the default mode network (DMN) and dorsal attentional networks (DAN). RESULTS: Across-domain dispersion was negatively related to cognitive performance, rs-FC within the DMN, and between the DMN and the DAN, but not to white matter integrity. The rs-FC values were not explained by cognitive performance. When considering groups, the above findings were significant only for those with high SCC. DISCUSSION: In healthy middle-aged individuals, high cognitive dispersion was related to poorer cognition and DMN dysregulation, being these associations stronger among subjects with high SCC. The present results reinforce the interest in considering dispersion measures within neuropsychological evaluations, as they may be more sensitive to incipient age-related cognitive and functional brain changes than traditional measures of performance.

Brain system segregation and pain catastrophizing in chronic pain progression.

Pain processing involves emotional and cognitive factors that can modify pain perception. Increasing evidence suggests that pain catastrophizing (PC) is implicated, through pain-related self-thoughts, in the maladaptive plastic changes related to the maintenance of chronic pain (CP). Functional magnetic resonance imaging (fMRI) studies have shown an association between CP and two main networks: default mode (DMN) and dorsoattentional (DAN). Brain system segregation degree (SyS), an fMRI framework used to quantify the extent to which functional networks are segregated from each other, is associated with cognitive abilities in both healthy individuals and neurological patients. We hypothesized that individuals suffering from CP would show worst health-related status compared to healthy individuals and that, within CP individuals, longitudinal changes in pain experience (pain intensity and affective interference), could be predicted by SyS and PC subdomains (rumination, magnification, and helplessness). To assess the longitudinal progression of CP, two pain surveys were taken before and after an in-person assessment (physical evaluation and fMRI). We first compared the sociodemographic, health-related, and SyS data in the whole sample (no pain and pain groups). Secondly, we ran linear regression and a moderation model only in the pain group, to see the predictive and moderator values of PC and SyS in pain progression. From our sample of 347 individuals (mean age = 53.84, 55.2% women), 133 responded to having CP, and 214 denied having CP. When comparing groups, results showed significant differences in health-related questionnaires, but no differences in SyS. Within the pain group, helplessness (ß = 0.325; p = 0.003), higher DMN (ß = 0.193; p = 0.037), and lower DAN segregation (ß = 0.215; p = 0.014) were strongly associated with a worsening in pain experience over time. Moreover, helplessness moderated the association between DMN segregation and pain experience progression (p = 0.003). Our findings indicate that the efficient functioning of these networks and catastrophizing could be used as predictors of pain progression, bringing new light to the influence of the interplay between psychological aspects and brain networks. Consequently, approaches focusing on these factors could minimize the impact on daily life activities.

Purpose in life promotes resilience to age-related brain burden in middle-aged adults.

BACKGROUND: Disease-modifying agents to counteract cognitive impairment in older age remain elusive. Hence, identifying modifiable factors promoting resilience, as the capacity of the brain to maintain cognition and function with aging and disease, is paramount. In Alzheimer's disease (AD), education and occupation are typical cognitive reserve proxies. However, the importance of psychological factors is being increasingly recognized, as their operating biological mechanisms are elucidated. Purpose in life (PiL), one of the pillars of psychological well-being, has previously been found to reduce the deleterious effects of AD-related pathological changes on cognition. However, whether PiL operates as a resilience factor in middle-aged individuals and what are the underlying neural mechanisms remain unknown. METHODS: Data was obtained from 624 middle-aged adults (mean age 53.71 ± 6.9; 303 women) from the Barcelona Brain Health Initiative cohort. Individuals with lower (LP; N = 146) and higher (HP; N = 100) PiL rates, according to the division of this variable into quintiles, were compared in terms of cognitive status, a measure reflecting brain burden (white matter lesions; WMLs), and resting-state functional connectivity, examining system segregation (SyS) parameters using 14 common brain circuits. RESULTS: Neuropsychological status and WMLs burden did not differ between the PiL groups. However, in the LP group, greater WMLs entailed a negative impact on executive functions. Subjects in the HP group showed lower SyS of the dorsal default-mode network (dDMN), indicating lesser segregation of this network from other brain circuits. Specifically, HP individuals had greater inter-network connectivity between specific dDMN nodes, including the frontal cortex, the hippocampal formation, the midcingulate region, and the rest of the brain. Greater functional connectivity in some of these nodes positively correlated with cognitive performance. CONCLUSION: Expanding previous findings on AD pathology and advanced age, the present results suggest that higher rates of PiL may promote resilience against brain changes already observable in middle age. Furthermore, having a purposeful life implies larger functional integration of the dDMN, which may potentially reflect greater brain reserve associated to better cognitive function.

Functional Brain Connectivity Prior to the COVID-19 Outbreak Moderates the Effects of Coping and Perceived Stress on Mental Health Changes: A First Year of COVID-19 Pandemic Follow-up Study.

BACKGROUND: The COVID-19 pandemic provides a unique opportunity to investigate the psychological impact of a global major adverse situation. Our aim was to examine, in a longitudinal prospective study, the demographic, psychological, and neurobiological factors associated with interindividual differences in resilience to the mental health impact of the pandemic. METHODS: We included 2023 healthy participants (age: 54.32 ± 7.18 years, 65.69% female) from the Barcelona Brain Health Initiative cohort. A linear mixed model was used to characterize the change in anxiety and depression symptoms based on data collected both pre-pandemic and during the pandemic. During the pandemic, psychological variables assessing individual differences in perceived stress and coping strategies were obtained. In addition, in a subsample (n = 433, age 53.02 ± 7.04 years, 46.88% female) with pre-pandemic resting-state functional magnetic resonance imaging available, the system segregation of networks was calculated. Multivariate linear models were fitted to test associations between COVID-19-related changes in mental health and demographics, psychological features, and brain network status. RESULTS: The whole sample showed a general increase in anxiety and depressive symptoms after the pandemic onset, and both age and sex were independent predictors. Coping strategies attenuated the impact of perceived stress on mental health. The system segregation of the frontoparietal control and default mode networks were found to modulate the impact of perceived stress on mental health. CONCLUSIONS: Preventive strategies targeting the promotion of mental health at the individual level during similar adverse events in the future should consider intervening on sociodemographic and psychological factors as well as their interplay with neurobiological substrates.

Associations between repetitive negative thinking and resting-state network segregation among healthy middle-aged adults.

Background: Repetitive Negative Thinking (RNT) includes negative thoughts about the future and past, and is a risk factor for depression and anxiety. Prefrontal and anterior cingulate cortices have been linked to RNT but several regions within large-scale networks are also involved, the efficiency of which depends on their ability to remain segregated. Methods: Associations between RNT and system segregation (SyS) of the Anterior Salience Network (ASN), Default Mode Network (DMN) and Executive Control Network (ECN) were explored in healthy middle-aged adults (N = 341), after undergoing resting-state functional magnetic resonance imaging. Regression analyses were conducted with RNT as outcome variable. Explanatory variables were: SyS, depression, emotional stability, cognitive complaints, age and sex. Results: Analyses indicated that RNT was associated with depression, emotional stability, cognitive complaints, age and segregation of the left ECN (LECN) and ASN. Further, the ventral DMN (vDMN) presented higher connectivity with the ASN and decreased connectivity with the LECN, as a function of RNT. Conclusion: Higher levels of perseverative thinking were related to increased segregation of the LECN and decreased segregation of the ASN. The dissociative connectivity of these networks with the vDMN may partially account for poorer cognitive control and increased self-referential processes characteristic of RNT.

Associations of circulating C-reactive proteins, APOE ε4, and brain markers for Alzheimer's disease in healthy samples across the lifespan.

The apolipoprotein E gene ε4 allele (APOE ε4) and higher circulating level of C-reactive protein (CRP) have been extensively investigated as risk factors for Alzheimer's disease (AD). Paradoxically, APOE ε4 has been associated with lower levels of blood CRP in middle-aged and older populations. However, few studies have investigated this intriguing relation and its impact on neurological markers for AD in younger ages, nor across the whole lifespan. Here, we examine associations of blood CRP levels, APOE ε4, and biomarkers for AD in a cognitively healthy lifespan cohort (N up to 749; 20-81 years of age) and replicate the findings in UK Biobank (N = 304 322; 37-72 years of age), the developmental ABCD study (N = 10 283; 9-11 years of age), and a middle-aged sample (N = 339; 40-65 years of age). Hippocampal volume, brain amyloid-ß (Aß) plaque levels, cerebrospinal fluid (CSF) levels of Aß and tau species, and neurofilament protein light protein (NFL) were used as AD biomarkers in subsamples. In addition, we examined the genetic contribution to the variation of CRP levels over different CRP ranges using polygenic scores for CRP (PGS-CRP). Our results show APOE ε4 consistently associates with low blood CRP levels across all age groups (p < 0.05). Strikingly, both ε4 and PGS-CRP associated mainly with blood CRP levels within the low range (<5mg/L). We then show both APOE ε4 and high CRP levels associate with smaller hippocampus volumes across the lifespan (p < 0.025). APOE ε4 was associated with high Aß plaque levels in the brain (FDR-corrected p = 8.69x10-4), low levels of CSF Aß42 (FDR-corrected p = 6.9x10-2), and lower ratios of Aß42 to Aß40 (FDR-corrected p = 5.08x10-5). Blood CRP levels were weakly correlated with higher ratio of CSF Aß42 to Aß40 (p = 0.03, FDR-corrected p = 0.4). APOE ε4 did not correlate with blood concentrations of another 9 inflammatory cytokines, and none of these cytokines correlated with AD biomarkers. CONCLUSION: The inverse correlation between APOEε 4 and blood CRP levels existed before any pathological AD biomarker was observed, and only in the low CRP level range. Thus, we suggest to investigate whether APOEε 4 can confer risk by being associated with a lower inflammatory response to daily exposures, possibly leading to greater accumulation of low-grade inflammatory stress throughout life. A lifespan perspective is needed to understand this relationship concerning risk of developing AD.

Associations Between Cardiorespiratory Fitness, Cardiovascular Risk, and Cognition Are Mediated by Structural Brain Health in Midlife.

Background Evidence in older adults suggests that higher cardiorespiratory fitness and lower cardiovascular risk are associated with greater cognition. However, given that changes in the brain that lead to cognitive decline begin decades before the onset of symptoms, understanding the mechanisms by which modifiable cardiovascular factors are associated with brain health in midlife is critical and can lead to the development of strategies to promote and maintain brain health as we age. Methods and Results In 501 middle-aged (aged 40-65 years) adult participants of the BBHI (Barcelona Brain Health Initiative), we found differential associations among cardiorespiratory fitness, cardiovascular risk, and cognition and cortical thickness. Higher cardiorespiratory fitness was significantly associated with better visuospatial abilities and frontal loading abstract problem solving (ß=3.16, P=0.049) in the older middle-aged group (aged 55-65 years). In contrast, cardiovascular risk was negatively associated with better visuospatial reasoning and problem-solving abilities (ß=-0.046, P=0.002), flexibility (ß=-0.054, P<0.001), processing speed (ß=-0.115, P<0.001), and memory (ß=-0.120, P<0.001). Cortical thickness in frontal regions mediated the relationship between cardiorespiratory fitness and cognition, whereas cortical thickness in a disperse network spanning multiple cortical regions across both hemispheres mediated the relationship between cardiovascular risk and cognition. Conclusions The relationships between modifiable cardiovascular factors, cardiorespiratory fitness, and cardiovascular risk, and cognition are present in healthy middle-aged adults. These relationships are also mediated by brain structure highlighting a potential mechanistic pathway through which higher cardiorespiratory fitness and lower cardiovascular risk can positively impact cognitive function in midlife.

tDCS-Induced Memory Reconsolidation Effects and Its Associations With Structural and Functional MRI Substrates in Subjective Cognitive Decline.

Previous evidence suggests that transcranial direct current stimulation (tDCS) to the left dorsolateral prefrontal cortex (l-DLPFC) can enhance episodic memory in subjects with subjective cognitive decline (SCD), known to be at risk of dementia. Our main goal was to replicate such findings in an independent sample and elucidate if baseline magnetic resonance imaging (MRI) characteristics predicted putative memory improvement. Thirty-eight participants with SCD (aged: 60-65 years) were randomly assigned to receive active (N = 19) or sham (N = 19) tDCS in a double-blind design. They underwent a verbal learning task with 15 words (DAY-1), and 24 h later (DAY-2) stimulation was applied for 15 min at 1.5 mA targeting the l-DLPFC after offering a contextual reminder. Delayed recall and recognition were measured 1 day after the stimulation session (DAY-3), and at 1-month follow-up (DAY-30). Before the experimental session, structural and functional MRI were acquired. We identified a group∗time interaction in recognition memory, being the active tDCS group able to maintain stable memory performance between DAY-3 and DAY-30. MRI results revealed that individuals with superior tDCS-induced effects on memory reconsolidation exhibited higher left temporal lobe thickness and greater intrinsic FC within the default-mode network. Present findings confirm that tDCS, through the modulation of memory reconsolidation, is capable of enhancing performance in people with self-perceived cognitive complaints. Results suggest that SCD subjects with more preserved structural and functional integrity might benefit from these interventions, promoting maintenance of cognitive function in a population at risk to develop dementia.