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

Aspectes cognitius, emocionals i neurobiològics en la percepció del dolor crònic

Com un individu percep el dolor és altament variable i està influenciat en gran mesura per factors sensorials, emocionals i cognitius, que alhora poden modular l'impacte i severitat del dolor, participant en la seva cronificació. Els mecanismes neurobiològics subjacents podrien explicar el cercle viciós del dolor i la pobra resposta als tractaments analgèsics convencionals. En aquesta tesi primer detallarem com funciona el dolor, especialment com es percep, processa i modula a nivell cerebral i el paper que tenen els aspectes emocionals i cognitius en aquestes etapes. Factors com la resiliència o la reserva cognitiva, que promouen un funcionament cerebral més efectiu davant de moments de dificultat, com el dolor crònic, podrien tenir un paper clau per col·laborar en el trencament del cercle viciós del dolor. Fomentar activitats cognitivament estimulants, exercici físic o la involucració en esdeveniments socials provoquen una sèrie de canvis a nivell de la connectivitat funcional del cervell, que podrien millorar la qualitat de vida i disminuir aspectes com el catastrofisme en pacients amb dolor crònic. Finalment, a través d'un funcionament òptim del cervell i d'una disminució de factors que afavoreixen i faciliten el processament del dolor, com el ja esmentat catastrofisme o la por al moviment, la pròpia percepció de intensitat o d'interferència del dolor disminueix. Aquesta tesi, per tant, s'uneix al muntant d'evidència sobre l'abordatge biopsicosocial del dolor, però amb una aportació innovadora sobre el funcionament cerebral, cognitiu i emocional en pacients amb dolor crònic de mitjana edat (40-65 anys), centrada en factors protectors del dolor.Como un individuo percibe el dolor es altamente variable y está influenciado en gran medida por factores sensoriales, emocionales y cognitivos, que a su vez pueden modular el impacto y la gravedad del dolor, participando en su cronificación. Los mecanismos neurobiológicos subyacentes podrían explicar el círculo vicioso del dolor y la pobre respuesta a los tratamientos analgésicos convencionales. En esta tesis, primero detallaremos cómo funciona el dolor, especialmente cómo se percibe, procesa y modula a nivel cerebral y el papel que tienen los aspectos emocionales y cognitivos en estas etapas. Factores como la resiliencia o la reserva cognitiva, que promueven un funcionamiento cerebral más efectivo ante momentos de dificultad, como el dolor crónico, podrían tener un papel clave para colaborar en la ruptura del círculo vicioso del dolor. Fomentar actividades cognitivamente estimulantes, ejercicio físico o la participación en eventos sociales provocan una serie de cambios a nivel de la conectividad funcional del cerebro, que podrían mejorar la calidad de vida y disminuir aspectos como el catastrofismo en pacientes con dolor crónico. Finalmente, a través de un funcionamiento óptimo del cerebro y una disminución de factores que favorecen y facilitan el procesamiento del dolor, como el mencionado catastrofismo o el miedo al movimiento, la propia percepción de intensidad o interferencia del dolor disminuye. Esta tesis, por lo tanto, se une al montante de evidencia sobre el abordaje biopsicosocial del dolor, pero con una aportación innovadora sobre el funcionamiento cerebral, cognitivo y emocional en pacientes con dolor crónico de mediana edad (40-65 años), centrada en factores protectores del dolor.How an individual perceives pain is highly variable and largely influenced by sensory, emotional, and cognitive factors, which can in turn modulate the impact and severity of pain, contributing to its chronicity. The underlying neurobiological mechanisms could explain the vicious cycle of pain and the low likelihood of success of most treatments. In this thesis, we will first detail how pain works, particularly how it is perceived, processed, and modulated at the cerebral level, as well as the role of emotional and cognitive aspects in these stages. Factors such as resilience or cognitive reserve, which promote more effective brain functioning to face difficulties, like chronic pain, could play a key role in breaking the cycle of pain. Encouraging cognitively stimulating activities, physical exercise, or engagement in social events induce a series of changes in the functional connectivity of the brain, which could improve quality of life and reduce aspects such as catastrophizing in patients with chronic pain. Finally, through optimal brain functioning and a decreasing in factors that facilitate and promote pain processing, such as the catastrophizing or fear of movement, the perception of pain intensity or interference could decrease. Therefore, this thesis adds to the body of evidence on the biopsychosocial approach to pain, but with an innovative contribution regarding brain, cognitive, and emotional functioning in middle-aged patients (aged 40-65) with chronic pain, focusing on protective factors against the worsening of pain.Universitat Autònoma de Barcelona. Programa de Doctorat en Medicin