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

Biomarcadores de salud cerebral medidos con estimulación magnética transcraneal combinada con electroencefalografía y electromiografía

El manteniment de la salut cerebral és cada vegada més important en la població espanyola, on l'esperança de vida augmenta. Al llarg del temps, l'escorça cerebral experimenta canvis, per la qual cosa, trobar i caracteritzar potencials biomarcadors podria ajudar en la preservació de la salut cerebral. Entre ells, l'excitabilitat cortical és molt rellevant per al funcionament cerebral i la cognició, i tant l'excitabilitat en M1 com la de l'escorça prefrontal s'han relacionat amb les funcions cognitives en població clínica. No obstant això, és necessari aprofundir en persones adultes cognitivament sanes. L'objectiu principal va ser caracteritzar nous marcadors de salut cerebral mitjançant l'aplicació d'EMT en l'escorça prefrontal i motora, i millorar la comprensió sobre els mecanismes de cognició en la població adulta sana. En el primer estudi plantejat es va voler explorar si existia una relació entre l'equilibri excitatori i inhibitori en l'escorça motora primària (mesurat amb l'UM i el LICI) i les funcions cognitives (atenció, memòria episòdica, memòria de treball i raonament). Amb aquesta finalitat, es va utilitzar una mostra de 97 adults cognitivament sans i de mitjana edat (entre 41 i 65 anys). Es va demostrar que, en aplicar un protocol de polsos aparellats EMT sobre l'escorça motora esquerra, la inhibició intracortical estava positivament associada amb la memòria de treball. Així mateix, quan es va segmentar la mostra per gènere, en el grup d'homes es va obtenir una relació amb la memòria de treball, el raonament i la cognició global. Totes les anàlisis es van realitzar mitjançant regressions múltiples multivariades, i en aquells models on els resultats van ser significatius, es van executar regressions múltiples linears per a valorar la direcció de la predicció. En cada model es va incloure la funció cognitiva com a variable dependent, i LICI, UM, amplitud MEP, edat, gènere i educació com regresors. En el segon estudi es va voler relacionar l'excitabilitat de la regió prefrontal, després d'aplicar EMT sobre la mateixa (mesurat amb LMFP i GMFP), i les funcions cognitives esmentades anteriorment. Secundàriament, es va valorar si aquesta possible relació era independent al dany axonal (mesurat mitjançant NfL en plasma). Per a això, es va emprar una mostra de 52 persones cognitivament sanes i de mitjana edat. Es va obtenir evidència de què existia una relació positiva entre l'excitabilitat local en l'escorça prefrontal (mesurada després de l'estimulació) amb la memòria de treball i el raonament. A més, es va demostrar una correlació directa significativa entre el nivell de NfL i les funcions cognitives. Tot i això, aquest efecte desapareixia en controlar per l'edat, demostrant que el dany axonal individual no juga un paper rellevant en les associacions entre l'excitabilitat cortical prefrontal i la cognició. Es van aplicar regressions multivariades per a cada regió d'estimulació, i en cada model es van utilitzar les funcions cognitives com a variables dependents i el «tipus de camp elèctric», el mètode de selecció de coordenades (anatòmic o funcional), el nivell de NfL, l'edat, el gènere i l'educació com regresors. En conclusió, es van descriure dos possibles biomarcadors de salut cerebral en una població de mitjana edat cognitivament sana amb EMT: la inhibició intracortical motora (mesura amb LICI) i l'excitabilitat prefrontal (mesura amb LMFP). Aquests resultats brindarien una millor comprensió del vincle entre la neurofisiologia i la cognició, i podrien ser objectius potencials per al desenvolupament d'intervencions que ajudin a monitorar o mantenir la salut cerebral i, per tant, la funció cognitiva. Si aquests marcadors mostressin canvis, podríem suggerir programes que modulessin l'activitat cerebral fent servir EMT o altres eines neuromoduladores per a revertir aquests canvis.El mantenimiento de la salud cerebral es cada vez más importante en la población española, donde la esperanza de vida aumenta. A lo largo del tiempo, la corteza cerebral experimenta cambios, por lo que encontrar y caracterizar potenciales biomarcadores podría ayudar en la preservación de la salud cerebral. Entre ellos, la excitabilidad cortical es muy relevante para el funcionamiento cerebral y la cognición, y tanto la excitabilidad en M1 como la de la corteza prefrontal se han relacionado con las funciones cognitivas en población clínica. Sin embargo, es necesario profundizar en personas adultas cognitivamente sanas. El objetivo principal fue caracterizar nuevos marcadores de salud cerebral mediante la aplicación de EMT en la corteza prefrontal y motora, y mejorar la comprensión sobre los mecanismos de cognición en la población adulta sana. En el primer estudio planteado se quiso explorar si existía una relación entre el equilibrio excitatorio e inhibitorio en la corteza motora primaria (medido con el UM y el LICI) y las funciones cognitivas (atención, memoria episódica, memoria de trabajo y razonamiento). Con esta finalidad, se utilizó una muestra de 97 adultos cognitivamente sanos y de mediana edad (entre 41 y 65 años). Se demostró que, al aplicar un protocolo de pulsos apareados EMT sobre la corteza motora izquierda, la inhibición intracortical estaba positivamente asociada con la memoria de trabajo. Asimismo, cuando se segmentó la muestra por género, en el grupo de hombres se obtuvo una relación con la memoria de trabajo, el razonamiento y la cognición global. Todos los análisis se realizaron mediante regresiones múltiples multivariadas, y en aquellos modelos cuyos resultados fueron significativos se ejecutaron regresiones múltiples lineares para valorar la dirección de la predicción. En cada modelo se incluyó la función cognitiva como variable dependiente, y LICI, UM, amplitud MEP, edad, género y educación como regresores. En el segundo estudio se quiso relacionar la excitabilidad de la región prefrontal, después de aplicar EMT sobre la misma (medido con LMFP y GMFP), y las funciones cognitivas mencionadas anteriormente. Secundariamente, se valoró si dicha posible relación era independiente al daño axonal (medido mediante NfL en plasma). Para ello, se empleó una muestra de 52 personas cognitivamente sanas y de mediana edad. Se obtuvo evidencia de que existía una relación positiva entre la excitabilidad local en la corteza prefrontal (medida después de la estimulación) con la memoria de trabajo y el razonamiento. Además, se demostró una correlación directa significativa entre el nivel de NfL y las funciones cognitivas, aunque dicho efecto desaparecía al controlar por la edad, por lo que se ha demostrado que el daño axonal de cada individuo no juega un papel relevante en las asociaciones entre la excitabilidad cortical prefrontal y la cognición. Se aplicaron regresiones multivariadas para cada región de estimulación, y en cada modelo se utilizaron las funciones cognitivas como variables dependientes y el «tipo de campo eléctrico», el método de selección de coordenadas (anatómico o funcional), el nivel de NfL, la edad, el género y la educación como regresores. En conclusión, se describieron dos posibles biomarcadores de salud cerebral en una población de mediana edad cognitivamente sana con EMT: la inhibición intracortical motora (medida con LICI) y la excitabilidad prefrontal (medida con LMFP). Estos resultados brindarían una mejor comprensión del vínculo entre la neurofisiología y la cognición, y podrían ser objetivos potenciales para el desarrollo de intervenciones que ayuden a monitorear o mantener la salud cerebral y, por lo tanto, la función cognitiva. Si estos marcadores mostraran cambios, podríamos sugerir programas que modularan la actividad cerebral usando EMT u otras herramientas neuromoduladoras para revertir dichos cambios.Maintaining brain health is increasingly important in the Spanish population, where life expectancy is increasing. Over time, the cerebral cortex undergoes changes, so finding and characterizing potential biomarkers could help in the preservation of brain health. Among them, cortical excitability has been shown to be very relevant for brain functioning and cognition, and both M1 and prefrontal cortex excitability have been related to cognitive functions in clinical population. Nevertheless, there is a need to further investigate in cognitively healthy adults. The main objective of this study was to characterize new markers of brain health by applying TMS to the prefrontal and motor cortex, and to improve understanding of the mechanisms of cognition in the healthy adult population. A first study aimed to explore whether there was a relationship between excitatory and inhibitory balance in the primary motor cortex (measured with the RMT and LICI) and cognitive functions (attention, episodic memory, working memory, and reasoning). Secondarily, we also examined how gender might impact these outcomes. To this end, a sample of 97 cognitively healthy, middle-aged adults (aged 41-65 years) was used. It was shown that when applying a paired-pulse TMS protocol over the left motor cortex, intracortical inhibition was positively associated with working memory. Likewise, when the sample was segmented by gender, in the male group, a relationship with working memory, reasoning and global cognition was obtained. In no case was it possible to describe a significant association between the RMT measure and cognition. All analyses were performed using multivariate multiple regressions, and in those models whose results were significant, linear multiple regressions were run to assess the direction of prediction. In each model, cognitive function was included as the dependent variable, and LICI, RMT, MEP amplitude, age, gender, and education as regressors. In the second study we wanted to relate the excitability of the prefrontal region, after applying TMS to it (measured with LMFP and GMFP), and the cognitive functions mentioned above. The parietal region was used as a control condition to test whether the associations were specific to the prefrontal cortex. As a secondary objective, we assessed whether this possible relationship was independent of axonal damage (measured by plasma NfL). For this purpose, a sample of 52 cognitively healthy, middle-aged (between 41 and 65 years) individuals was used. Evidence was obtained that there was a positive relationship between local excitability in the prefrontal cortex (measured after stimulation) with working memory and reasoning. In addition, a significant direct correlation between NfL level and cognitive functions was demonstrated, although this effect disappeared when controlling for age, thus demonstrating that individual axonal damage does not play a relevant role in the associations between prefrontal cortical excitability and cognition. Multivariate regressions were applied for each stimulation region (prefrontal and parietal cortex), and in each model cognitive functions were used as dependent variables, and "electric field type", the method used in coordinate selection (anatomical or functional), NfL level, age, gender, and educational years as regressors. In conclusion, two potential biomarkers of brain health in a cognitively healthy middle-aged population with TMS were described: motor intracortical inhibition (measured with LICI) and prefrontal excitability (measured with LMFP). These results would provide a better understanding of the link between neurophysiology and cognition and could be potential targets for the development of interventions to help monitor or maintain brain health, and thus cognitive function. If these markers were to show changes, we could suggest programs that modulate brain activity using TMS or other neuromodulatory tools to reverse such changes

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