TYPE Original Research PUBLISHED 28 September 2022 DOI 10.3389/fpsyg.2022.998062 Long-interval intracortical OPEN ACCESS inhibition in primary motor cortex related to working EDITED BY Ti-Fei Yuan, Shanghai Jiao Tong University, China REVIEWED BY Yujing Wang, memory in middle-aged adults Wenzhou Medical University, China Yi Zhang, María Redondo-Camós 1,2,3, Gabriele Cattaneo 1,2,3, Shanghai Jiao Tong University, China Vanessa Alviarez-Schulze 4,5, Selma Delgado-Gallén 1,2,3, *CORRESPONDENCE Alvaro Pascual-Leone Goretti España-Irla 1,2,3, Javier Solana-Sanchez 1,2,3, apleone@hsl.harvard.edu David Bartres-Faz Ruben Perellón-Alfonso 5,6, Sergiu Albu 1,2,3, dbartres@ub.edu José M. Tormos 1,2,3, Alvaro Pascual-Leone 1,7,8*† and † These authors have contributed equally to this work David Bartres-Faz 1,5,6*† SPECIALTY SECTION This article was submitted to 1 Institut Guttmann, Institut Universitari de Neurorehabilitació adscrit a la Universitat Autònoma de Cognition, Barcelona, Barcelona, Spain, 2 Departament de Medicina, Facultat de Medicina, Universitat a section of the journal Autònoma de Barcelona, Barcelona, Spain, 3 Fundació Institut d’Investigació en Ciències de la Salut Frontiers in Psychology Germans Trias i Pujol, Barcelona, Spain, 4 Departamento de Ciencias del Comportamiento, Escuela de Psicología, Universidad Metropolitana, Caracas, Venezuela, 5 Departament de Medicina, Facultat RECEIVED 19July 2022 de Medicina i Ciències de la Salut, i Institut de Neurociències, Universitat de Barcelona, Barcelona, ACCEPTED 31 August 2022 Spain, 6 Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain, 7 Hinda PUBLISHED 28 September 2022 and Arthur Marcus Institute for Aging Research and Deanna and Sidney Wolk Center for Memory Health, Hebrew SeniorLife, Boston, MA, United States, 8 Department of Neurology, Harvard Medical CITATION School, Boston, MA, United States Redondo-Camós M, Cattaneo G, Alviarez-Schulze V, Delgado-Gallén S, España-Irla G, Solana-Sanchez J, Perellón-Alfonso R, Albu S, Tormos JM, Pascual-Leone A and Bartres-Faz D (2022) Introduction: Excitability of the primary motor cortex measured with TMS has Long-interval intracortical inhibition in primary motor cortex related to working been associated with cognitive dysfunctions in patient populations. However, memory in middle-aged adults. only a few studies have explored this relationship in healthy adults, and even Front. Psychol. 13:998062. doi: 10.3389/fpsyg.2022.998062 fewer have considered the role of biological sex. COPYRIGHT Methods: Ninety-seven healthy middle-aged adults (53 male) completed © 2022 Redondo-Camós, Cattaneo, Alviarez-Schulze, Delgado-Gallén, a TMS protocol and a neuropsychological assessment. Resting Motor España-Irla, Solana-Sanchez, Threshold (RMT) and Long-Interval Intracortical Inhibition (LICI) were Perellón-Alfonso, Albu, Tormos, assessed in the left motor cortex and related to attention, episodic memory, Pascual-Leone and Bartres-Faz. This is an open-access article distributed under the working memory, reasoning, and global cognition composite scores terms of the Creative Commons Attribution to evaluate the relationship between cortical excitability and cognitive License (CC BY). The use, distribution or functioning. reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that Results: In the whole sample, there was a significant association between the original publication in this journal is LICI and cognition; specifically, higher motor inhibition was related to better cited, in accordance with accepted working memory performance. When the sample was broken down by academic practice. No use, distribution or reproduction is permitted which does not biological sex, LICI was only associated with working memory, reasoning, comply with these terms. and global cognition in men. No associations were found between RMT and cognitive functions. Conclusion: 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. Frontiers in Psychology 01 frontiersin.org Redondo-Camós et al. 10.3389/fpsyg.2022.998062 KEYWORDS transcranial magnetic stimulation, electromyography, long-interval cortical inhibition, motor cortex, cognition, resting motor threshold Introduction (Kobayashi and Pascual-Leone, 2003; Ferreri and Rossini, 2013). Specifically, single-pulse TMS (spTMS) has been used to explore The balance of cortical excitation and inhibition (E/I balance) cortical excitability by measuring Resting Motor Threshold is a core neurophysiologic metric of neuronal and brain network (RMT), which is the minimum intensity that elicits a Motor activity believed to determine optimal brain functioning (Sukenik Evoked Potential (MEP) of more than 50 μV in 50% of trials et al., 2021). In patient populations, including autism spectrum (Rossini et al., 2015). Long-Interval Intracortical Inhibition disorders or schizophrenia, an E/I imbalance has been observed (LICI), where two suprathreshold stimuli separated by an in different cortical areas and shown to be associated with interstimulus interval (ISI) between 50 and 200 ms are applied, has behavioral and cognitive symptoms (Sohal and Rubenstein, 2019; been used to study cortical inhibition (Valls-Solé et al., 1992; Bruining et al., 2020; Calvin and Redish, 2021; Maestú et al., Nakamura et al., 1997) and reflects the activity of GABA-B 2021). In Alzheimer’s disease, cortical motor hyperexcitability has receptors (McDonnell et al., 2006; Opie et al., 2017). While many been negatively related to cognitive performance (Zadey et al., studies have shown that RMT and LICI offer valuable biological 2021), possibly due to enhanced intracortical excitatory circuits markers in different neurological disorders (Fatih et al., 2021; (Di Lazzaro et al., 2004; Meder et al., 2021) or/and an inhibitory Guerra et al., 2021; Mimura et al., 2021; Versace et al., 2021), only deficit (Khedr et al., 2011; Pennisi et al., 2011; Joseph et al., 2021; a few have explored their association with brain health and Mimura et al., 2021). cognitive performance in healthy, cognitive-unimpaired, middle- Past research exploring cortical excitability and cognition has aged adults, and how biological sex affects the results (Schicktanz produced inconsistent results in healthy, cognitive-unimpaired et al., 2014; Akilan et al., 2020). adults. This variability may be due to differences depending on the This study aimed to fill this knowledge gap by investigating cortical area or specific cognitive functions assessed. For example, the relationship between E/I balance in the primary motor cortex while higher excitability after stimulation of the left prefrontal measured with RMT and LICI and cognition in healthy middle- cortex has been related to better executive functions and working aged adults. Since the GABA-B receptor might be a target for memory (Redondo-Camós et al., 2022), other studies have improving cognitive dysfunction and memory/learning observed that excessive excitability of the primary motor cortex impairment (Vlachou, 2022), we hypothesized that better was associated with impaired attention and global cognition cognitive performance would be associated with more intracortical (Bolden et al., 2017; Akilan et al., 2020). Other aspects that may inhibition, estimated with LICI, and reduced cortical excitability, modulate the association between cortical E/I balance and measured with RMT. Also, differences between women and men cognitive functioning may relate to age, given the different degrees were expected, at least for LICI, considering biological sex of preservation of gamma-aminobutyric acid (GABA) circuits differences in GABA neurotransmitters highlighted above. linked to physiological aging (McGinley et al., 2010; Opie and Semmler, 2014; Hermans et al., 2018). Indeed, age-related cortical excitability changes have been previously linked to differences in Materials and methods attention and inhibitory control in healthy adults (Cespón et al., 2022). Also, biological sex could play a key role since differences Subjects and study design in brain anatomy and connectivity between men and women, as well as hormonal influences associated with menstrual cycle Ninety-seven healthy and right-handed volunteers [53 male; variations in women, may lead to distinct neural processes laterality ≥75%, (Oldfield, 1971)], between 41 and 65 years involved in cognitive and motor control (Korzhyk et al., 2019; (M = 54; SD = 7.14), participated in this study. They were part of Rezzani et al., 2019). Gender-associated differences could be due the Barcelona Brain Health Initiative (BBHI), an ongoing, to genetic determinants, lifestyle factors including physical longitudinal cohort study (Cattaneo et al., 2018). They underwent activity, alcohol, or tobacco consumption (Rezzani et al., 2019; a TMS session with EMG registration and neuropsychological Travica et al., 2020), or steroid hormone levels, which are higher testing. Exclusion criteria included any neurological or psychiatric in women and have been related to GABA neurotransmission, diagnosis, currently taking medication that could affect the central mood and memory (Cosgrove et al., 2007; Rezzani et al., 2019). nervous system, substance abuse or dependence (alcohol, caffeine, Transcranial Magnetic Stimulation (TMS) combined with drugs), pregnancy (Rossini et al., 2015; Rossi et al., 2021), and any Electromyography (EMG) is a widely used technique to study contraindication for TMS or magnetic resonance imaging (MRI). inhibitory and excitatory mechanisms in the motor cortex All participants gave written informed consent, and the local Frontiers in Psychology 02 frontiersin.org Redondo-Camós et al. 10.3389/fpsyg.2022.998062 FIGURE 1 Flowchart of the participant selection for the current analysis. BBHI methodology was used to select volunteers (see Cattaneo et al., 2018, 2020). BBHI, Barcelona Brain Health Initiative; NP, Neuropsychological assessment; MRI, Magnetic resonance imaging; RMT, Resting Motor Threshold. ethics committee (Comité d’Ètica i Investigació Clínica de la Unió Montreal, QC Canada) guided by each subject’s T1 weighted Catalana d’Hospitals) approved the study protocol, which followed structural MRI (previously obtained from a 3 T Siemens the Declaration of Helsinki. A cohort diagram from the BBHI Magnetom Prisma). MRI was completed for this purpose to study and the specific selection of this study participants is shown increase safety during TMS sessions and exclude any brain lesion in Figure 1. that could act as a confounder in interpreting the results. The TMS procedure lasted approximately 1 h. First, RMT was determined as the minimum TMS intensity that elicited MEPs of TMS protocol more than 50 μV in five out of 10 trials in the relaxed, contralateral first dorsal interosseus muscle (FDI; Rossini et al., 2015). MEP Participants were asked to sit as still as possible in a amplitude was defined as the peak-to-peak difference in EMG comfortable armchair, keep their eyes open, and look at a fixation activity from the evoked response in this muscle. Next, 120 paired- cross at a distance of approximately 1.5 m. A figure of eight TMS pulse TMS stimuli were delivered to the left-M1 at random coil was placed at a 45-degree angle (relative to the mid-sagittal intervals between 3 and 6 s. The intensities of both pulses were plane) over the left primary motor cortex (left-M1), resulting in a applied at 120% of RMT, and the ISI was 100 ms, selecting this posterior-to-anterior current flow. Consistency in the stimulation interval because it was reportedly optimal (Sanger et al., 2001), targeting was ensured using a frameless stereotactic and previous research has suggested age-related changes at it neuronavigation system (Brainsight, Rogue Research Inc., (McGinley et al., 2010; Opie et al., 2015, 2018). From this Frontiers in Psychology 03 frontiersin.org Redondo-Camós et al. 10.3389/fpsyg.2022.998062 stimulation, LICI was calculated using the following formula fourth factor contained Block design (0.758), Corsi blocks (0.678), (Guerra et al., 2021): and matrix reasoning (0.620), representing a reasoning component. Ultimately, a global cognition score was created as the æ MEP amplitude conditioned stimulus ö sum of the individual z-scores on each neuropsychological test. LICI = ç ÷ *100 è MEP amplitude uncondittioned stimulus ø Cognitive composite scores were used as dependent variables (attention, working memory, episodic memory, reasoning, and global cognition) and RMT, LICI, MEP amplitude, age, biological Consequently, a greater LICI value indicates lower cortical sex, and years of education as predictors. We ran multiple inhibition, while a smaller LICI indicates greater inhibition. multivariate regressions to identify possible associations between The protocol was completed using a figure-of-eight motor cortical excitability (measured by RMT), inhibition (LICI), Cool-B65 coil connected to a Medtronic MagPro X100 and cognition. Then, for significant results, we ran multiple linear stimulator (MagVenture A/S, Denmark). For the regressions to assess the direction of the prediction. Assumptions electromyography, a Biopac EMG100C amplifier (BIOPAC of linearity, independence of residuals, homoscedasticity, Systems INC., California, United States) was used with surface multicollinearity, and normality were met in all models. electrodes placed in a belly-tendon montage and the ground Furthermore, to study how biological sex could affect the electrode on the ulnar styloid. predictions, we did all the previous analysis segmenting by biological sex. Lastly, to explore possible differences between means of women and men on each variable, a t-test analysis Neuropsychological assessment was performed. A licensed neuropsychologist performed a battery of neurocognitive paper and pencil evaluations. The battery included Results the following tests: Trail Making Test A and B (TMT) (Reitan and Wolfson, 1985; Peña-Casanova et al., 2012), Digit-Span Forward Sample descriptive statistics of RMT, LICI, MEP Amplitude, and Backward, Corsi block tapping test, Letter-Number age, biological sex, and educational level are presented in Table 1, Sequencing test (Peña-Casanova et al., 2012), Matrix Reasoning while cognitive scores are in Table 2. and Block design, the Digit symbol task, the Cancelation test (Wechsler, 2012), the Rey Auditory Verbal Learning Test (RAVLT; Schmidt, 1996; Alviarez-Schulze et al., 2022b), and the Spanish Associations between RMT, LICI, and Version of the Face Name Associative Memory Exam (S-FNAME; cognitive functions Alegret et al., 2015; Alviarez-Schulze et al., 2022a). Multivariate regression analysis for all the subjects revealed statistically significant associations between LICI and working Statistical analysis memory [F(1, 89) = 7.59, p = 0.007; partial η2 = 0.079], and biological sex and episodic memory [F(1, 89) = 9.50, p = 0.003; All statistical analyses were performed in SPSS version 22.0 partial η2 = 0.0996] and reasoning [F(1, 89) = 4.26, p = 0.042; (Statistical Package for Social Sciences, Chicago, IL, United States). partial η2 = 0.046]. Finally, age was significantly associated to all First, raw scores of each cognitive test were z-score normalized, and principal component analysis (PCA) was run to group them into cognitive domains, in line with our and other TABLE 1 Demographic Variables, RMT and LICI (n=97). research group’s previous studies (España-Irla et al., 2021; All (n = 97) Male (n = 53) Female Cattaneo et al., 2022; Hinchman et al., 2022; Redondo-Camós (n = 44) et al., 2022). Loading values were above 0.3. Kaiser–Meyer–Olkin Mean SD Mean SD Mean SD p (KMO = 0.689) and Bartlett’s test of sphericity (χ2 = 1074.67, df = 105; p < 0.001) were satisfactory. PCA revealed four Age 53.69 7.13 53.49 7.40 53.93 6.87 0.762 components of cognitive domains. The first factor contained TMT Years of 17.85 3.81 17.66 4.17 18.07 3.35 0.595 B (−0.927), TMT B-A (−0.884), TMT A (−0.615), Digit symbol education task (0.554), and cancelation test (0.423), reflecting what can RMT (%) 62.28 9.60 61.64 10.54 63.05 8.4 0.467 be considered an attentional domain. The second factor LICI (%) 14.68 18.81 17.35 20.33 11.46 16.45 0.118 characterized memory and involved face name (0.609) and MEP 0.305 0.201 0.309 0.173 0.323 0.232 0.747 RAVLT measures such as immediate recall (0.885), delayed recall amplitude (0.872), and recognition (0.830). The third factor reflected a (mV) working memory domain and included the digit forward (0.780), RMT, resting motor threshold; LICI, long-interval intracortical inhibition; MEP, motor digit backward (0.777), and letter-number sequencing (0.504). The evoked potential. Frontiers in Psychology 04 frontiersin.org Redondo-Camós et al. 10.3389/fpsyg.2022.998062 TABLE 2 Cognitive scores (n=97). [F(6, 89) = 2.630, p = 0.021, adj. R2 = 0.093], and LICI resulted All (n = 97) Male (n = 53) Female negatively associated with it (Standardized β = −0.282, t = −2.754, (n = 44) p = 0.007), being greater motor cortical inhibition related to better Cognitive Mean SD Mean SD Mean SD p working memory (Figure 2). task S-FNAME 41.62 14.65 39.00 14.12 44.77 14.81 0.054 RAVLT 52.19 9.65 50.60 9.93 54.10 9.06 0.074 Effect of biological sex immediate recall To investigate possible differences in the association between RAVLT 11.46 2.79 11.04 2.78 11.98 2.74 0.098 cognitive performance and cortical E/I, we split the sample delayed recall according to biological sex and repeated regressions for RAVLT 14.28 1.25 14.17 1.27 14.41 1.23 0.348 both groups. recognition Digit-span 10.63 2.86 11.02 2.87 10.16 2.79 0.140 Men forward Multivariate regressions were done to test the direct effects of Digit-span 11.38 2.60 11.68 2.66 11.02 2.50 0.214 RMT, LICI, MEP amplitude, and covariates on each cognitive backward domain. They revealed an association between LICI and working Corsi block 14.35 2.41 14.38 2.51 14.32 2.31 0.904 memory [F(1, 47) = 6.60, p = 0.013, partial η2 = 0.123], reasoning tapping [F(1, 47) = 5.82, p = 0.020, partial η2 = 0.110], and global cognition Letter-number 5.72 1.08 5.66 1.14 5.80 1.00 0.542 [F(1, 47) = 9.22, p = 0.004, partial η2 = 0.164]. Also, education was sequencing related to reasoning [F(1, 47) = 6.02, p = 0.018, partial η2 = 0.114] Matrix 13.91 2.58 14.32 2.38 13.41 2.75 0.087 and episodic memory [F(1, 47) = 4.15, p = 0.047, partial η2 = 0.081], reasoning and age to all cognitive domains (attention [F(1, 47) = 4.18, WAIS-IV p = 0.047; partial η2 = 0.082], episodic memory [F(1, 47) = 8.37, Block design 12.00 3.14 12.74 3.01 11.11 3.10 0.011* p = 0.006; partial η2 = 0.151], working memory [F(1, 47) = 4.64, WAIS-IV p = 0.03; partial η2 = 0.090], reasoning [F(1, 47) = 9.01, p = 0.004; TMT A 11.26 2.51 11.28 2.76 11.23 2.22 0.912 partial η2 = 0.161], and global cognition [F(1, 47) = 7.40, p = 0.009; TMT B 8.65 2.18 8.91 2.14 8.34 2.22 0.208 partial η2 = 0.136]). Cancelation 42.09 8.17 42.04 8.67 42.16 7.63 0.942 Furthermore, multiple regression models including covariates test showed that working memory was associated with LICI Digit symbol 13.84 2.56 13.51 2.49 14.23 2.60 0.171 (Standardized β = −0.347, t = −2.569, p = 0.013) and age task (Standardized β = 0.284, t = 2.155, p = 0.036). Also, reasoning was related to LICI (Standardized β = −0.302, t = −2.411, p = 0.020), age S-FNAME, Spanish Version of the Face Name Associative Memory Exam; RAVLT (Standardized β = −0.367, t = −3.022, p = 0.004) and education immediate recall, Recall a list of words immediately after hearing it of Rey Auditory Verbal Learning Test; RAVLT delayed recall, RAVLT recall after 30 min; RAVLT level (Standardized β = 0.307, t = 2.454, p = 0.018). Finally, global recognition, Recognition of words from a word list of RAVLT; Digit-Span cognition was also associated with LICI (Standardized β = −0.380, Forward, Immediate recall a series of numbers in the same order; Letter-Number Sequencing, Sequence a random order of numbers and letter; Matrix Reasoning WAIS- t = −3.036, p = 0.004) and age (Standardized β = −0.332, t = −2.721, IV, Logical sequences and series of Wechsler Adult Intelligence Scale-IV; Block Design p = 0.009). In all three models, LICI was negatively associated with WAIS-IV, Block Design of Wechsler Adult Intelligence Scale-IV; TMT B, Trail Making working memory, reasoning, and global cognition in men Test part B; TMT A, Trail Making Test part A; Digit symbol task, Digit symbol association; Cancelation test, cancelation task of WAIS-IV. All punctuations presented in (Figure 3). this table are normalized scores except RAVLT tests that are raw scores. *p < 0.05. Women Only were significant associations between age and attention cognitive functions (attention [F (1, 89) = 17.38, p < 0.001; partial [F(1, 37) = 11.65, p = 0.002; partial η2 = 0.240]. No significant η2 = 0.163], episodic memory [F(1, 89) = 10.01, p = 0.002; partial results were seen between women’s cognition and cortical η2 = 0.101], working memory [F(1, 89) = 5.45, p = 0.022; partial excitability or inhibition. η2 = 0.058], reasoning [F(1, 89) = 6.66, p = 0.011; partial η2 = 0.070], and global cognition [F(1, 89) = 14.50, p < 0.001; partial η2 = 0.140]). Discussion After running this model, we ran a multiple regression to assess the direction of the prediction using the working memory The current study explored the relationship between cortical domain as a dependent variable and LICI, RMT, MEP amplitude, measures of E/I balance in the primary motor cortex, using TMS age, biological sex, and education as regressors. The model measures of RMT and LICI, and cognitive performance in healthy, significantly explained working memory performance, cognitively-unimpaired middle-aged adults. Moreover, we studied Frontiers in Psychology 05 frontiersin.org Redondo-Camós et al. 10.3389/fpsyg.2022.998062 A FIGURE 2 B Multiple regression scatterplots between LICI and working memory after controlling age, biological sex, and years of education. Z-scores were used on the Y-axis and unstandardized Predicted Values on the X-axis (%). A lower LICI value, indicative of more intracortical motor inhibition, was related to better working memory performance. the impact of biological sex on this association. Our results reveal that lower LICI in the motor cortex is associated with better working memory performance in the whole sample. The effect appears primarily accounted for by men, in whom LICI was found to be related to increased working memory, reasoning, and global cognition. RMT was not associated with cognitive functions in C men or women. Our results are in line with previous research investigating physiological mechanisms of neurological disorders, showing that motor hyperexcitability is related to global cognitive dysfunction (Takahashi et al., 2013; Higashihara et al., 2021; Zadey et al., 2021) due to increased excitatory activity or/and an inhibitory deficit (Joseph et al., 2021; Meder et al., 2021; Mimura et al., 2021). Similarly, in healthy subjects, it has been found that hyperexcitability of the motor cortex is associated with impaired attention (Bolden et al., 2017; Akilan et al., 2020), suggesting that cortical excitatory and inhibitory balance is necessary for optimal brain and cognitive functioning (Páscoa dos Santos and FIGURE 3 Verschure, 2022). Multiple regression scatterplots between LICI and working The relationship between cognition and motor cortex activity memory (A), reasoning (B), and global cognition (C) after controlling age and years of education in men. Z-scores were could result from the functional connectivity between brain used on the Y-axis and unstandardized Predicted Values on the regions involved in cognitive processing (Bates and Goldman- X-axis (%). Rakic, 1993; Hasan et al., 2013). For example, the prefrontal cortex is essential for the performance of higher cognitive functions, and the perturbation of its structure or functionality, such as occurs in some of the cognitive functions that have been related to aging or Alzheimer’s disease (Salat et al., 2001; Peters, 2006), could motor processes. alter the cortical excitability of it (Noda et al., 2017) and highly Interestingly, only intracortical motor inhibition was connected areas such as motor cortex (Freeman et al., 2016). These positively associated with cognitive performance, particularly areas could share evolutive roots, and their interaction is needed working memory, necessary to serve other cognitive functions to govern the executive function and the intentionality of (Mansouri et al., 2015), and defined as a limited capacity system movements (Mendoza and Merchant, 2014; Leisman et al., 2016). allowing the temporary storage and manipulation of information Working memory (Carruthers, 2013; Liao et al., 2014; Leisman required for such complex processes (Baddeley, 2000). Indeed, et al., 2016), attention, and learning (Bhattacharjee et al., 2021) are we found that LICI was also related to reasoning and global Frontiers in Psychology 06 frontiersin.org Redondo-Camós et al. 10.3389/fpsyg.2022.998062 cognition in men, possibly because working memory could play a (Schicktanz et al., 2014; Akilan et al., 2020) in the relation between role in these cognitive functions (Hambrick and Engle, 2003; cortical excitability/inhibition and cognition. Wiley and Jarosz, 2012). Given that in our study, intracortical This research increases our knowledge of this association and motor inhibition was measured using the LICI paradigm that suggests that greater intracortical inhibition, measured by LICI, is reflects GABA-B inhibitory neurotransmission (Valls-Solé et al., a possible marker of interindividual differences in working 1992), we believe that its alteration was associated with cognitive memory performance among healthy middle-aged adults, changes. GABA-B receptor indeed has been previously linked to extending previous suggestions as a biomarker of neuropsychiatric memory formation (Terunuma et al., 2014; Almasi et al., 2018) disorders (Fatih et al., 2021). and working memory (Bañuelos et al., 2014; Schmidt-Wilcke Finally, the findings in this report are subject to some et al., 2018). Furthermore, Freeman et al. (2016) found increased limitations. First, this is a cross-sectional study, and we cannot intracortical inhibition in the motor cortex under high working determine a cause-effect relationship between cortical excitability memory load tasks, indicating an association between it and the measures and cognitive performance. It is necessary to deepen in balance of excitatory/inhibitory activity. These results demonstrate future research the relationship described in our study, including that working memory, even if it strongly involves prefrontal cortex visuospatial working memory tests and other tasks with different activity, depending on the task’s difficulty, requires motor levels of cognitive load and, within the manipulation process, not inhibition to work efficiently (Freeman et al., 2016). It was also only serial ordering but updating processing, such as n-back supported by the results of Liao et al. (2014), which demonstrated paradigm. Defining which specific working components are the specific involvement of the primary motor cortex and the related to the TMS measure studied is essential. Also, these motor network in working memory processing (Liao et al., 2014). processes differ in their sensitivity to advancing age (Jablonska Specifically, the psychometric measures included in the et al., 2020); hence, future investigations should be conducted in working memory domain are exclusively auditory-verbal tests. other age groups, including middle and older age samples. Within the multicomponent working memory model (Baddeley, Furthermore, we explored two TMS measures (RMT and LICI), 2000), one of the most cited in the literature (Chai et al., 2018), our but it would be interesting to consider other LICI ISI (50 ms, study data reflect the phonological loop subcomponent, 150 ms, and 200 ms) and paradigms such as short-interval responsible for holding verbal information using a temporary intracortical inhibition or intracortical facilitation. Ultimately, store and an articulatory rehearsal system, and the central emotional state, sleep quality, and menstrual cycle variations (in executive subcomponent responsible for the active manipulation particular when considering younger women populations) should (serial ordering) of the information. Previous findings have shown be considered in future analysis, being this latter one relevant due a double anatomical dissociation in which the subprocess of to its impact on the female brain and needing specific temporal retention of verbal information depends predominantly investigations on this gender group (Hidalgo-Lopez et al., 2020; on the superior temporal gyrus. However, the subprocess of Meeker et al., 2020). information manipulation in backward items with higher cognitive load involves, in addition to, the prefrontal area, motor, and somatosensory cortex (Ghaleh et al., 2020). Data availability statement Furthermore, when we split the sample for biological sex, we observed that women presented subtly higher inhibition than The raw data supporting the conclusions of this article will men, which was not statistically significant. This result is in line be made available by the authors, without undue reservation. with previous studies showing that inhibition, usually superior in women, could be influenced by different functional brain maturation of the inhibitory system (Rubia et al., 2013), variations Ethics statement of the brain areas activated (Bell et al., 2006; Li et al., 2006; Korzhyk et al., 2019), and ovarian hormones (Hosseini-Kamkar The studies involving human participants were reviewed and and Bruce Morton, 2014; Shibuya et al., 2016). approved by Comité d’Ètica i Investigació Clínica de la Unió Crucially, we found a positive association between cognition Catalana d’Hospitals. The patients/participants provided their (working memory and reasoning) and intracortical inhibition written informed consent to participate in this study. only in men. Very little is present in the literature on this issue, and the few existing pieces of evidence appear somehow contradictory. Schicktanz et al. (2014) observed that lower motor Author contributions cortical excitability was related to better working memory in men (Schicktanz et al., 2014), while Akilan et al. (2020) observed that AP-L, DB-F, and JT participated in the initial conception an increase in cortical excitability was related to global cognition of the design of the BBHI project. MR-C, DB-F, AP-L, and GC in women (Akilan et al., 2020). However, beyond these contributed to the conception and design of the present study. inconsistencies, which need and deserve deeper study, previous MR-C, SD-G, GE-I, VA-S, SA, RP-A, and JS-S contributed to and our results confirm the existence of biological sex differences the data acquisition. MR-C and GC analyzed the data. MR-C, Frontiers in Psychology 07 frontiersin.org Redondo-Camós et al. 10.3389/fpsyg.2022.998062 GC, and DB-F contributed to the first draft of the manuscript. Comunicaciones Avanzadas, Neuroelectrics, Corporació Catalana All authors contributed to the article and approved the de Mitjans Audiovisuals, Club Metropolitan, Casa Ametller, and submitted version. Agència de Qualitat i Avaluació Sanitàries de Catalunya-AQuAS) for their collaboration. The organisations listed were not involved in the study design, collection, analysis, interpretation of data, the Funding writing of this article or the decision to submit it for publication. DB-F and RP-A were funded by a Spanish Ministry of Science, Innovation and Universities (MICIU/FEDER; RTI2018- Conflict of interest 095181-B-C21) and also supported by an ICREA Academia 2019 grand award. RP-A was supported by a fellowship from “la Caixa” AP-L is a co-founder of Linus Health and TI Solutions AG; Foundation (ID 100010434, Fellowship code: LCF/BQ/ serves on the scientific advisory boards for Starlab Neuroscience, DI19/11730050), JT was partly supported Fundació Joan Ribas Magstim Inc., Radiant Hearts, Skin2Neuron, TetraNeuron, and (Araquistain_FJRA), AGAUR, Agència de Gestió d’Ajuts MedRhythms; is listed as an inventor on several issued and Universitaris i de Recerca. Convocatòria 2018 d’Indústria del pending patents on the real-time integration of noninvasive brain Coneixement (modalitat PRODUCTE) and FEDER, Fons stimulation with electroencephalography and magnetic Europeu de Desenvolupament Regional (2018 PROD 00172), resonance imaging. Fundació La Marató De TV3 (201735.10), and European The remaining authors declare that the research was Commission—H2020/Call H2020-SC1-2016-2017 (RIA; grant conducted in the absence of any commercial or financial agreement no. 777107). AP-L was partly supported by the National relationships that could be construed as a potential conflict Institutes of Health (R24AG06142 and P01 AG031720) and the of interest. Barcelona Brain Health Initiative funded primarily by “La Caixa” (LCF/PR/PR16/11110004). The funders were not involved in the study design, collection, analysis, interpretation of data, the Publisher’s note writing of this article or the decision to submit it for publication. All claims expressed in this article are solely those of the authors and do not necessarily represent those Acknowledgments of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be A special thanks is extended to all BBHI participants, the evaluated in this article, or claim that may be made by project team and research assistants, and other partners its manufacturer, is not guaranteed or endorsed by (Ad-Salutem Institute, Sodexo, I.C.A. Informàtica y the publisher. References Akilan, K., Kumar, S., Zomorrodi, R., Blumberger, D. M., Daskalakis, Z. J., and Bates, J. F., and Goldman-Rakic, P. S. (1993). Prefrontal connections of medial Rajji, T. K. (2020). Gender impact on transcranial magnetic stimulation-based motor areas in the rhesus monkey. J. Comp. Neurol. 336, 211–228. doi: 10.1002/ cortical excitability and cognition relationship in healthy individuals. Neuroreport cne.903360205 31, 287–292. doi: 10.1097/WNR.0000000000001392 Bell, E. C., Willson, M. C., Wilman, A. H., Dave, S., and Silverstone, P. H. (2006). Alegret, M., Valero, S., Ortega, G., Espinosa, A., Sanabria, A., Hernández, I., et al. Males and females differ in brain activation during cognitive tasks. Neuroimage 30, (2015). Validation of the Spanish version of the face name associative memory exam 529–538. doi: 10.1016/j.neuroimage.2005.09.049 (S-FNAME) in cognitively normal older individuals. Arch. Clin. Neuropsychol. 30, Bhattacharjee, S., Kashyap, R., Abualait, T., Annabel Chen, S. H., Yoo, W. K., and 712–720. doi: 10.1093/arclin/acv050 Bashir, S. (2021). The role of primary motor cortex: more than movement execution. Almasi, A., Zarei, M., Raoufi, S., Sarihi, A., Salehi, I., Komaki, A., et al. (2018). J. Mot. Behav. 53, 258–274. doi: 10.1080/00222895.2020.1738992 Influence of hippocampal GABAB receptor inhibition on memory in rats with acute Bolden, L. B., Griffis, J. C., Pati, S., and Szaflarski, J. P. (2017). Cortical excitability β-amyloid toxicity. Metab. Brain Dis. 33, 1859–1867. doi: 10.1007/s11011-018-0292-5 and neuropsychological functioning in healthy adults. Neuropsychologia 102, Alviarez-Schulze, V., Cattaneo, G., Pachón-García, C., Solana-Sánchez, J., 190–196. doi: 10.1016/j.neuropsychologia.2017.06.028 Tormos, J. M., Pascual-Leone, A., et al. (2022b). Validation and normative data of Bruining, H., Hardstone, R., Juarez-Martinez, E. L., Sprengers, J., Avramiea, A. E., the Spanish version of the Rey auditory verbal learning test and associated long- Simpraga, S., et al. (2020). Measurement of excitation-inhibition ratio in autism Term forgetting measures in middle-aged adults. Front. Aging Neurosci. 14:809019. spectrum disorder using critical brain dynamics. Sci. Rep. 10, 9195–9115. doi: doi: 10.3389/fnagi.2022.809019 10.1038/s41598-020-65500-4 Alviarez-Schulze, V., Cattaneo, G., Pachón-García, C., Solana-Sánchez, J., Calvin, O. L., and Redish, A. D. (2021). Global disruption in excitation-inhibition Tormos-Muñoz, J. M., Alegret, M., et al. (2022a). Validation and normative data of balance can cause localized network dysfunction and schizophrenia-like context- the Spanish version of the face name associative memory exam (S-FNAME). J. Int. integration deficits. PLoS Comput. Biol. 17:e1008985. doi: 10.1371/journal. Neuropsychol. Soc. 28, 74–84. doi: 10.1017/S1355617721000084 pcbi.1008985 Baddeley, A. (2000). The episodic buffer: a new component of working memory? Carruthers, P. (2013). Evolution of working memory. Proc. Natl. Acad. Sci. U. S. A. Trends Cogn. Science 4, 417–423. doi: 10.1016/S1364-6613(00)01538-2 110, 10371–10378. doi: 10.1073/PNAS.1301195110 Bañuelos, C., Sofia Beas, B., McQuail, J. A., Gilbert, R. J., Frazier, C. J., Setlow, B., et al. Cattaneo, G., Bartrés-Faz, D., Morris, T. P., Sánchez, J. S., Macià, D., Tarrero, C., et al. (2014). Prefrontal cortical GABAergic dysfunction contributes to age-related working (2018). The Barcelona brain health initiative: a cohort study to define and promote memory impairment. J. Neurosci. 34, 3457–3466. doi: 10.1523/JNEUROSCI.5192-13.2014 determinants of brain health. Front. Aging Neurosci. 10:321. doi: 10.3389/fnagi.2018.00321 Frontiers in Psychology 08 frontiersin.org Redondo-Camós et al. 10.3389/fpsyg.2022.998062 Cattaneo, G., Bartrés-Faz, D., Morris, T. P., Sánchez, J. S., Macià, D., Tormos, J. M., Joseph, S., Patterson, R., Wang, W., Blumberger, D. M., Rajji, T., and Kumar, S. et al. (2020). The Barcelona brain health initiative: cohort description and first (2021). Quantitative assessment of cortical excitability in Alzheimer’s dementia and follow-up. PLoS One 15:e0228754. doi: 10.1371/JOURNAL.PONE.0228754 its association with clinical symptoms: a systematic review and meta-analyses. J. Alzheimers Dis. 88, 867–891. doi: 10.3233/jad-210311 Cattaneo, G., Solana-Sánchez, J., Abellaneda-Pérez, K., Portellano-Ortiz, C., Delgado-Gallén, S., Alviarez Schulze, V., et al. (2022). Sense of coherence mediates Khedr, E. M., Ahmed, M. A., Darwish, E. S., and Ali, A. M. (2011). The the relationship between cognitive reserve and cognition in middle-aged adults. relationship between motor cortex excitability and severity of Alzheimer’s disease: Front. Psychol. 13:835415. doi: 10.3389/fpsyg.2022.835415 a transcranial magnetic stimulation study. Neurophysiol. Clin. 41, 107–113. doi: 10.1016/j.neucli.2011.03.002 Cespón, J., Pellicciari, M. C., Casula, E. P., and Miniussi, C. (2022). Age-related changes in cortical excitability linked to decreased Attentional and inhibitory Kobayashi, M., and Pascual-Leone, A. (2003). Transcranical magnetic stimulation control. Neuroscience 495, 1–14. doi: 10.1016/j.neuroscience.2022.05.021 in neurology. Lancet 2, 145–156. doi: 10.1016/S1474-4422(03)00321-1 Chai, W. J., Abd Hamid, A. I., and Abdullah, J. M. (2018). Working memory from Korzhyk, O., Morenko, O., Morenko, A., and Kotsan, I. (2019). Gender differences the psychological and neurosciences perspectives: a review. Front. Psychol. 9:401. in brain processes during inhibition of manual movements programs. Ann. Neurosci. doi: 10.3389/FPSYG.2018.00401 26, 4–9. doi: 10.5214/ans.0972.7531.260103 Cosgrove, K. P., Mazure, C. M., and Staley, J. K. (2007). Evolving knowledge of sex Leisman, G., Moustafa, A. A., and Shafir, T. (2016). Thinking, walking, talking: differences in brain structure, function, and chemistry. Biol. Psychiatry 62, 847–855. Integratory motor and cognitive brain function. Front. Public Health 4:94. doi: doi: 10.1016/j.biopsych.2007.03.001 10.3389/fpubh.2016.00094 Di Lazzaro, V., Oliviero, A., Pilato, F., Saturno, E., Dileone, M., Marra, C., et al. Li, C., Shan, R., Huang, C., Constable, R. T., and Sinha, R. (2006). Gender (2004). Motor cortex hyperexcitability to transcranial magnetic stimulation in differences in the neural correlates of response inhibition during a stop signal task. Alzheimer's disease. J. Neurol. Neurosurg. Psychiatry 75, 555–559. doi: 10.1136/ Neuroimage 32, 1918–1929. doi: 10.1016/j.neuroimage.2006.05.017 jnnp.2003.018127 Liao, D. A., Kronemer, S. I., Yau, J. M., Desmond, J. E., and Marvel, C. L. (2014). España-Irla, G., Gomes-Osman, J., Cattaneo, G., Albu, S., Cabello-Toscano, M., Motor system contributions to verbal and non-verbal working memory. Front. Hum. Solana-Sanchéz, J., et al. (2021). Associations between cardiorespiratory fitness, Neurosci. 8:753. doi: 10.3389/fnhum.2014.00753 cardiovascular risk, and cognition are mediated by structural brain health in midlife. Maestú, F., de Haan, W., Busche, M. A., and DeFelipe, J. (2021). Neuronal excitation/ J. Am. Heart Assoc. 10:e020688. doi: 10.1161/JAHA.120.020688 inhibition imbalance: core element of a translational perspective on Alzheimer Fatih, P., Kucuker, M. U., Vande Voort, J. L., Doruk Camsari, D., Farzan, F., and pathophysiology. Ageing Res. Rev. 69:101372. doi: 10.1016/j.arr.2021.101372 Croarkin, P. E. (2021). A systematic review of long-interval Intracortical inhibition Mansouri, F. A., Rosa, M. G. P., Atapour, N., Sigala, N., Pardo-Vazquez, J. L., as a biomarker in neuropsychiatric disorders. Front. Psych. 12:678088. doi: 10.3389/ Champalimaud, F., et al. (2015). Working memory in the Service of Executive fpsyt.2021.678088 Control Functions SHORT-TERM STORAGE OF INFORMATION REQUIRED Ferreri, F., and Rossini, P. M. (2013). TMS and TMS-EEG techniques in the study TO GUIDE ONGOING OR UPCOMING BEHAVIOR. Front. Syst. Neurosci. 9:166. of the excitability, connectivity, and plasticity of the human motor cortex. Rev. doi: 10.3389/fnsys.2015.00166 Neurosci. 24, 431–442. doi: 10.1515/revneuro-2013-0019 McDonnell, M. N., Orekhov, Y., and Ziemann, U. (2006). The role of GABAB Freeman, S. M., Itthipuripat, S., and Aron, A. R. (2016). High working memory load receptors in intracortical inhibition in the human motor cortex. Exp. Brain Res. 173, increases intracortical inhibition in primary motor cortex and diminishes the motor 86–93. doi: 10.1007/s00221-006-0365-2 affordance effect. J. Neurosci. 36, 5544–5555. doi: 10.1523/JNEUROSCI.0284-16.2016 McGinley, M., Hoffman, R. L., Russ, D. W., Thomas, J. S., and Clark, B. C. (2010). Ghaleh, M., Lacey, E. H., Fama, M. E., Anbari, Z., Demarco, A. T., and Older adults exhibit more intracortical inhibition and less intracortical facilitation Turkeltaub, P. E. (2020). Dissociable mechanisms of verbal working memory than young adults. Exp. Gerontol. 45, 671–678. doi: 10.1016/j.exger.2010.04.005 revealed through multivariate lesion mapping. Cereb. Cortex 30, 2542–2554. doi: Meder, A., Liepelt-Scarfone, I., Sulzer, P., Berg, D., Laske, C., Preische, O., et al. 10.1093/CERCOR/BHZ259 (2021). Motor cortical excitability and paired-associative stimulation-induced Guerra, A., Rocchi, L., Grego, A., Berardi, F., Luisi, C., and Ferreri, F. (2021). plasticity in amnestic mild cognitive impairment and Alzheimer's disease. Clin. Contribution of TMS and TMS-EEG to the understanding of mechanisms Neurophysiol. 132, 2264–2273. doi: 10.1016/j.clinph.2021.01.011 underlying physiological brain aging. Brain Sci. 11:405. doi: 10.3390/ Meeker, T. J., Veldhuijzen, D. S., Keaser, M. L., Gullapalli, R. P., and Greenspan, J. D. brainsci11030405 (2020). Menstrual cycle variations in gray matter volume, white matter volume and Hambrick, D. Z., and Engle, R. W. (2003). “The role of working memory in functional connectivity: critical impact on parietal lobe. Front. Neurosci. 14:594588. problem solving,” in The psychology of problem solving. eds. J. E. Davidson and doi: 10.3389/fnins.2020.594588 R. J. Sternberg (Cambridge: Cambridge University Press), 176–206. Mendoza, G., and Merchant, H. (2014). Motor system evolution and the Hasan, A., Galea, J. M., Casula, E. P., Falkai, P., Bestmann, S., and Rothwell, J. C. emergence of high cognitive functions. Prog. Neurobiol. 122, 73–93. doi: 10.1016/J. (2013). Muscle and timing-specific functional connectivity between the dorsolateral PNEUROBIO.2014.09.001 prefrontal cortex and the primary motor cortex. J. Cogn. Neurosci. 25, 558–570. doi: Mimura, Y., Nishida, H., Nakajima, S., Tsugawa, S., Morita, S., Yoshida, K., et al. 10.1162/jocn_a_00338 (2021). Neurophysiological biomarkers using transcranial magnetic stimulation in Hermans, L., Levin, O., Maes, C., van Ruitenbeek, P., Heise, K. F., Edden, R. A. E., Alzheimer's disease and mild cognitive impairment: a systematic review and meta- et al. (2018). GABA levels and measures of intracortical and interhemispheric analysis. Neurosci. Biobehav. Rev. 121, 47–59. doi: 10.1016/j.neubiorev.2020.12.003 excitability in healthy young and older adults: an MRS-TMS study. Neurobiol. Aging Nakamura, H., Kitagawa, H., Kawaguchi, Y., and Tsuji, H. (1997). Intracortical 65, 168–177. doi: 10.1016/j.neurobiolaging.2018.01.023 facilitation and inhibition after transcranial magnetic stimulation in conscious Hidalgo-Lopez, E., Mueller, K., Harris, T. A., Aichhorn, M., Sacher, J., and humans. J. Physiol. 498, 817–823. doi: 10.1113/jphysiol.1997.sp021905 Pletzer, B. (2020). Human menstrual cycle variation in subcortical functional brain Noda, Y., Zomorrodi, R., Cash, R. F. H., Barr, M. S., Farzan, F., Rajji, T. K., et al. connectivity: a multimodal analysis approach. Brain Struct. Funct. 225, 591–605. (2017). Characterization of the influence of age on GABAA and glutamatergic doi: 10.1007/s00429-019-02019-z mediated functions in the dorsolateral prefrontal cortex using paired-pulse TMS- Higashihara, M., Pavey, N., van den Bos, M., Menon, P., Kiernan, M. C., and EEG. Aging (Albany. NY). 9, 556–572. doi: 10.18632/aging.101178 Vucic, S. (2021). Association of Cortical Hyperexcitability and Cognitive Oldfield, R. C. (1971). The assessment and analysis of handedness. Impairment in patients with amyotrophic lateral sclerosis. Neurology 96, e2090– Neuropsychologia 9, 97–113. doi: 10.1016/0028-3932(71)90067-4 e2097. doi: 10.1212/WNL.0000000000011798 Opie, G. M., Ridding, M. C., and Semmler, J. G. (2015). Age-related differences in Hinchman, C. A., Cabral, D. F., Ciesla, M., Flothmann, M., Nunez, C., Rice, J., pre- and post-synaptic motor cortex inhibition are task dependent. Brain Stimul. 8, et al. (2022). Exercise engagement drives changes in cognition and cardiorespiratory 926–936. doi: 10.1016/J.BRS.2015.04.001 fitness after 8 weeks of aerobic training in sedentary aging adults at risk of cognitive decline. Front. Rehabil. Sci. 3:923141. doi: 10.3389/FRESC.2022.923141 Opie, G. M., Rogasch, N. C., Goldsworthy, M. R., Ridding, M. C., and Semmler, J. G. (2017). Investigating TMS–EEG indices of long-interval Intracortical inhibition at Hosseini-Kamkar, N., and Bruce Morton, J. (2014). Sex differences in self- different Interstimulus intervals. Brain Stimul. 10, 65–74. doi: 10.1016/j.brs.2016.08.004 regulation: an evolutionary perspective. Front. Neurosci. 8:233. doi: 10.3389/ fnins.2014.00233 Opie, G. M., and Semmler, J. G. (2014). Age-related differences in short- and long-interval intracortical inhibition in a human hand muscle. Brain Stimul. 7, Jablonska, K., Piotrowska, M., Bednarek, H., Szymaszek, A., Marchewka, A., 665–672. doi: 10.1016/j.brs.2014.06.014 Wypych, M., et al. (2020). Maintenance vs. manipulation in auditory verbal working memory in the elderly: new insights based on temporal dynamics of information Opie, G. M., Sidhu, S. K., Rogasch, N. C., Ridding, M. C., Semmler, J. G., and processing in the millisecond time range. Front. Aging Neurosci. 12:194. doi: John, G. (2018). Cortical inhibition assessed using paired-pulse TMS-EEG is 10.3389/FNAGI.2020.00194 increased in older adults. Brain Stimul. 11, 545–557. doi: 10.1016/j.brs.2017.12.013 Frontiers in Psychology 09 frontiersin.org Redondo-Camós et al. 10.3389/fpsyg.2022.998062 Páscoa dos Santos, F., and Verschure, P. F. M. J. (2022). Excitatory-inhibitory Schmidt-Wilcke, T., Fuchs, E., Funke, K., Vlachos, A., Müller-Dahlhaus, F., homeostasis and Diaschisis: tying the local and global scales in the post-stroke Puts, N. A. J., et al. (2018). GABA—from inhibition to cognition: emerging concepts. cortex. Front. Syst. Neurosci. 15:806544. doi: 10.3389/fnsys.2021.806544 Neuroscientist 24, 501–515. doi: 10.1177/1073858417734530 Peña-Casanova, J., Casals-Coll, M., Quintana, M., Sánchez-Benavides, G., Shibuya, K., Park, S. B., Geevasinga, N., Huynh, W., Simon, N. G., Menon, P., et al. Rognoni, T., Calvo, L., et al. (2012). Estudios normativos españoles en población (2016). Threshold tracking transcranial magnetic stimulation: effects of age and adulta joven (Proyecto NEURONORMA jóvenes): métodos y características de la gender on motor cortical function. Clin. Neurophysiol. 127, 2355–2361. doi: muestra. Neurologia 27, 253–260. doi: 10.1016/j.nrl.2011.12.019 10.1016/j.clinph.2016.03.009 Pennisi, G., Ferri, R., Lanza, G., Cantone, M., Pennisi, M., Puglisi, V., et al. (2011). Sohal, V. S., and Rubenstein, J. L. R. (2019). Excitation-inhibition balance as a Transcranial magnetic stimulation in Alzheimer’s disease: a neurophysiological framework for investigating mechanisms in neuropsychiatric disorders. Mol. marker of cortical hyperexcitability. J. Neural Transm. 118, 587–598. doi: 10.1007/ Psychiatry 24, 1248–1257. doi: 10.1038/s41380-019-0426-0 s00702-010-0554-9 Sukenik, N., Vinogradov, O., Weinreb, E., Segal, M., Levina, A., and Moses, E. Peters, R. (2006). Ageing and the brain. Postgrad. Med. J. 82, 84–88. doi: 10.1136/ (2021). Neuronal circuits overcome imbalance in excitation and inhibition by pgmj.2005.036665 adjusting connection numbers. Proc. Natl. Acad. Sci. U. S. A. 118:e2018459118. doi: 10.1073/pnas.2018459118 Redondo-Camós, M., Cattaneo, G., Perellón-Alfonso, R., Alviarez-Schulze, V., Morris, T. P., Solana-Sanchez, J., et al. (2022). Local prefrontal cortex TMS-induced Takahashi, S., Ukai, S., Kose, A., Hashimoto, T., Iwatani, J., Okumura, M., et al. reactivity is related to working memory and reasoning in middle-aged adults. Front. (2013). Reduction of cortical GABAergic inhibition correlates with working Psychol. 13:813444. doi: 10.3389/fpsyg.2022.813444 memory impairment in recent onset schizophrenia. Schizophr. Res. 146, 238–243. doi: 10.1016/j.schres.2013.02.033 Reitan, R. M., and Wolfson, D. (1985). The Halstead-Reitan neuropsychological test battery: Theory and Interpretattion. Tucson, AZ: Neuropsychology Press. Terunuma, M., Revilla-Sanchez, R., Quadros, I. M., Deng, Q., Deeb, T. Z., Rezzani, R., Franco, C., and Rodella, L. F. (2019). Sex differences of brain and their Lumb, M., et al. (2014). Postsynaptic GABAB receptor activity regulates excitatory implications for personalized therapy. Pharmacol. Res. 141, 429–442. doi: 10.1016/j. neuronal architecture and spatial memory. J. Neurosci. 34, 804–816. doi: 10.1523/ phrs.2019.01.030 JNEUROSCI.3320-13.2013 Rossi, S., Antal, A., Bestmann, S., Bikson, M., Brewer, C., Brockmöller, J., et al. Travica, N., Ried, K., Hudson, I., Sali, A., Scholey, A., and Pipingas, A. (2020). (2021). Safety and recommendations for TMS use in healthy subjects and patient Gender differences in plasma vitamin C concentrations and cognitive function: a populations, with updates on training, ethical and regulatory issues: expert pilot cross-sectional study in healthy adults. Curr. Dev. Nutr. 4:nzaa038. doi: guidelines. Clin. Neurophysiol. 132, 269–306. doi: 10.1016/j.clinph.2020.10.003 10.1093/CDN/NZAA038 Rossini, P. M., Burke, D., Chen, R., Cohen, L. G., Daskalakis, Z., Di Iorio, R., et al. Valls-Solé, J., Pascual-Leone, A., Wassermann, E. M., and Hallett, M. (1992). (2015). Non-invasive electrical and magnetic stimulation of the brain, spinal cord, Human motor evoked responses to paired transcranial magnetic stimuli. roots and peripheral nerves: basic principles and procedures for routine clinical and Electroencephalogr. Clin. Neurophysiol. Evoked Potentials 85, 355–364. doi: research application: an updated report from an I.F.C.N. Committee. Clin. 10.1016/0168-5597(92)90048-G Neurophysiol. 126, 1071–1107. doi: 10.1016/j.clinph.2015.02.001 Versace, V., Sebastianelli, L., Ferrazzoli, D., Romanello, R., Ortelli, P., Saltuari, L., Rubia, K., Lim, L., Ecker, C., Halari, R., Giampietro, V., Simmons, A., et al. (2013). et al. (2021). Intracortical GABAergic dysfunction in patients with fatigue and Effects of age and gender on neural networks of motor response inhibition: from dysexecutive syndrome after COVID-19. Clin. Neurophysiol. 132, 1138–1143. doi: adolescence to mid-adulthood. Neuroimage 83, 690–703. doi: 10.1016/j. 10.1016/j.clinph.2021.03.001 neuroimage.2013.06.078 Vlachou, S. (2022). GABAB receptors and cognitive processing in health and Salat, D. H., Kaye, J. A., and Janowsky, J. S. (2001). Selective preservation and disease. Curr. Top Behav. Neurosci. 52, 291–329. doi: 10.1007/7854_ degeneration within the prefrontal cortex in aging and Alzheimer disease. Arch. 2021_231 Neurol. 58, 1403–1408. doi: 10.1001/archneur.58.9.1403 Wechsler, D. (2012). “WAIS-IV. Escala de inteligencia de Wechsler para adultos- Sanger, T. D., Garg, R. R., and Chen, R. (2001). Interactions between two different IV” in Manual De Aplicación Y Corrección (Madrid: NCS Pearson, Inc.) inhibitory systems in the human motor cortex. J. Physiol. 530, 307–317. doi: Wiley, J., and Jarosz, A. F. (2012). How working memory capacity affects problem 10.1111/J.1469-7793.2001.0307L.X solving. Psychol. Learn. Motiv. Adv. Res. Theory 56, 185–227. doi: 10.1016/ Schicktanz, N., Schwegler, K., Fastenrath, M., Spalek, K., Milnik, A., B978-0-12-394393-4.00006-6 Papassotiropoulos, A., et al. (2014). Motor threshold predicts working memory Zadey, S., Buss, S. S., McDonald, K., Press, D. Z., Pascual-Leone, A., and Fried, P. J. performance in healthy humans. Ann. Clin. Transl. Neurol. 1, 69–73. doi: 10.1002/acn3.22 (2021). Higher motor cortical excitability linked to greater cognitive dysfunction in Schmidt, M. (1996). Rey auditory and verbal learning test: A handbook. Los Alzheimer's disease: results from two independent cohorts. Neurobiol. Aging 108, Ángeles: Western Psychological Services. 24–33. doi: 10.1016/j.neurobiolaging.2021.06.007 Frontiers in Psychology 10 frontiersin.org