Prefrontal reactivity to TMS perturbation as a toy model of mental health outcomes during the COVID-19 pandemic

Psychosocial hardships associated with the COVID-19 pandemic led many individuals to suffer adverse mental health consequences, however, others show no negative effects. We hypothesized that the electroencephalographic (EEG) response to transcranial magnetic stimulation (TMS) could serve as a toy-model of an individual's capacity to resist psychological stress, in this case linked to the COVID-19 pandemic. We analyzed data from 74 participants who underwent mental health monitoring and concurrent electroencephalography with transcranial magnetic stimulation of the left dorsolateral prefrontal cortex (L-DLPFC) and left inferior parietal lobule (L-IPL). Within the following 19 months, mental health was reassessed at three timepoints during lock-down confinement and different phases of de-escalation in Spain. Compared with participants who remained stable, those who experienced increased mental distress showed, months earlier, significantly larger late EEG responses locally after L-DLPFC stimulation (but not globally nor after L-IPL stimulation). This response, together with years of formal education, was significantly predictive of mental health status during the pandemic. These findings reveal that the effect of TMS perturbation offers a predictive toy model of psychosocial stress response, as exemplified by the COVID-19 pandemic

Local Prefrontal Cortex TMS-Induced Reactivity Is Related to Working Memory and Reasoning in Middle-Aged Adults

Introduction: The prefrontal cortex (PFC) plays a crucial role in cognition, particularly in executive functions. Cortical reactivity measured with Transcranial Magnetic Stimulation combined with Electroencephalography (TMS-EEG) is altered in pathological conditions, and it may also be a marker of cognitive status in middle-aged adults. In this study, we investigated the associations between cognitive measures and TMS evoked EEG reactivity and explored whether the effects of this relationship were related to neurofilament light chain levels (NfL), a marker of neuroaxonal damage. Methods: Fifty two healthy middle-aged adults (41-65 years) from the Barcelona Brain Health Initiative cohort underwent TMS-EEG, a comprehensive neuropsychological assessment, and a blood test for NfL levels. Global and Local Mean-Field Power (GMFP/LMFP), two measures of cortical reactivity, were quantified after left prefrontal cortex (L-PFC) stimulation, and cognition was set as the outcome of the regression analysis. The left inferior parietal lobe (L-IPL) was used as a control stimulation condition. Results: Local reactivity was significantly associated with working memory and reasoning only after L-PFC stimulation. No associations were found between NfL and cognition. These specific associations were independent of the status of neuroaxonal damage indexed by the NfL biomarker and remained after adjusting for age, biological sex, and education. Conclusion: Our results demonstrate that TMS evoked EEG reactivity at the L-PFC, but not the L-IPL, is related to the cognitive status of middle-aged individuals and independent of NfL levels, and may become a valuable biomarker of frontal lobe-associated cognitive function. Keywords: Electroencephalography; TMS-EEG; cognition; cortical reactivity; prefrontal cortex (PFC); transcranial magnetic stimulation (TMS)

Long-interval intracortical inhibition in primary motor cortex related to working memory in middle-aged adults

Excitability of the primary motor cortex measured with TMS has been associated with cognitive dysfunctions in patient populations. However, only a few studies have explored this relationship in healthy adults, and even fewer have considered the role of biological sex. Ninety-seven healthy middle-aged adults (53 male) completed a TMS protocol and a neuropsychological assessment. Resting Motor Threshold (RMT) and Long-Interval Intracortical Inhibition (LICI) were assessed in the left motor cortex and related to attention, episodic memory, working memory, reasoning, and global cognition composite scores to evaluate the relationship between cortical excitability and cognitive functioning. In the whole sample, there was a significant association between LICI and cognition; specifically, higher motor inhibition was related to better working memory performance. When the sample was broken down by biological sex, LICI was only associated with working memory, reasoning, and global cognition in men. No associations were found between RMT and cognitive functions. Greater intracortical inhibition, measured by LICI, could be a possible marker of working memory in healthy middle-aged adults, and biological sex plays a critical role in this association

The age-related contribution of cognitive function to dual-task gait in middle-aged adults in Spain : observations from a population-based study

Poor dual-task gait performance is associated with a risk of falls and cognitive decline in adults aged 65 years or older. When and why dual-task gait performance begins to deteriorate is unknown. This study aimed to characterise the relationships between age, dual-task gait, and cognitive function in middle age (ie, aged 40-64 years). We conducted a secondary analysis of data from community-dwelling adults aged 40-64 years that took part in the Barcelona Brain Health Initiative (BBHI) study, an ongoing longitudinal cohort study in Barcelona, Spain. Participants were eligible for inclusion if they were able to walk independently without assistance and had completed assessments of both gait and cognition at the time of analysis and ineligble if they could not understand the study protocol, had any clinically diagnosed neurological or psychiatric diseases, were cognitively impaired, or had lower-extremity pain, osteoarthritis, or rheumatoid arthritis that could cause abnormal gait. Stride time and stride time variability were measured under single-task (ie, walking only) and dual-task (ie, walking while performing serial subtractions) conditions. Dual-task cost (DTC; the percentage increase in the gait outcomes from single-task to dual-task conditions) to each gait outcome was calculated and used as the primary measure in analyses. Global cognitive function and composite scores of five cognitive domains were derived from neuropsychological testing. We used locally estimated scatterplot smoothing to characterise the relationship between age and dual-task gait, and structural equation modelling to establish whether cognitive function mediated the association between observed biological age and dual tasks. 996 people were recruited to the BBHI study between May 5, 2018, and July 7, 2020, of which 640 participants completed gait and cognitive assessments during this time (mean 24 days [SD 34] between first and second visit) and were included in our analysis (342 men and 298 women). Non-linear associations were observed between age and dual-task performance. Starting at 54 years, the DTC to stride time (β=0·27 [95% CI 0·11 to 0·36]; p<0·0001) and stride time variability (0·24 [0·08 to 0·32]; p=0·0006) increased with advancing age. In individuals aged 54 years or older, decreased global cognitive function correlated with increased DTC to stride time (β=−0·27 [−0·38 to −0·11]; p=0·0006) and increased DTC to stride time variability (β=−0·19 [−0·28 to −0·08]; p=0·0002). Dual-task gait performance begins to deteriorate in the sixth decade of life and, after this point, interindividual variance in cognition explains a substantial portion of dual-task performance

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 (β=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 (β=−0.046, P =0.002), flexibility (β=−0.054, P <0.001), processing speed (β=−0.115, P <0.001), and memory (β=−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

Modifiable factors, cardiorespiratory fitness and cardiovascular risk are associated with cognitive and structural brain health in midlife: Results from the BBHI

Background Neurodegenerative brain changes that lead to cognitive decline generally begin decades prior to the onset of symptoms. On the other hand, brain health relates to overall, and specifically cardio‐vascular health, and vice‐versa. The objective of this investigation was to assess the relationships between two important domains of cardiovascular health (cardiorespiratory fitness, CRF, and cardiovascular risk, CVR) and two important markers of brain health (cognitive performance and volumetric measures of brain structure) in late middle age. Method In a relatively large sample (n=327) of middle‐aged adults in the Barcelona Brain Health Initiative (Cattaneo et al., 2018), we assessed the associations between CRF (measured by VO2 max), CVR (measured by Framingham risk score), domain‐specific cognitive performance (measured by performance in a neuropsychological test battery) and brain volumes (measured by high‐resolution brain MRI). All regression models were corrected for age and education. Result We found differential associations between CRF and CVR and cognitive performance. CRF was significantly associated with visuo‐spatial abilities and frontal loading problem solving (p=.003), whereas CVR was associated with visuo‐spatial abilities (p=.023), flexibility (p=.005), processing speed (p<.001) and memory (p<.001). Moreover we found that CRF was associated with frontal (p=.042), temporal (p=.016) and sensorimotor (p=.013) cortical volume, whereas CVR was significantly associated with all cortical volume measures (frontal, temporal, parietal, occipital and sensorimotor; ps<0.05). Conclusion We found that two modifiable factors in mid‐life (CRF and CVR) are significantly associated with a number of metrics of brain health in a cross‐sectional analysis. Future longitudinal analyses of this cohort will show whether these associations have predictive value for the maintenance of brain health across the lifespan. Finally, our findings suggest that lifestyle habits that promote CRF and reduce CVR, e.g. sufficient physical activity and appropriate nutrition, might help sustain brain health across the lifespan and prevent cognitive decline