Dense attention network identifies EEG abnormalities during working memory performance of patients with schizophrenia

IntroductionPatients with schizophrenia typically exhibit deficits in working memory (WM) associated with abnormalities in brain activity. Alterations in the encoding, maintenance and retrieval phases of sequential WM tasks are well established. However, due to the heterogeneity of symptoms and complexity of its neurophysiological underpinnings, differential diagnosis remains a challenge. We conducted an electroencephalographic (EEG) study during a visual WM task in fifteen schizophrenia patients and fifteen healthy controls. We hypothesized that EEG abnormalities during the task could be identified, and patients successfully classified by an interpretable machine learning algorithm.MethodsWe tested a custom dense attention network (DAN) machine learning model to discriminate patients from control subjects and compared its performance with simpler and more commonly used machine learning models. Additionally, we analyzed behavioral performance, event-related EEG potentials, and time-frequency representations of the evoked responses to further characterize abnormalities in patients during WM.ResultsThe DAN model was significantly accurate in discriminating patients from healthy controls, ACC = 0.69, SD = 0.05. There were no significant differences between groups, conditions, or their interaction in behavioral performance or event-related potentials. However, patients showed significantly lower alpha suppression in the task preparation, memory encoding, maintenance, and retrieval phases F(1,28) = 5.93, p = 0.022, η2 = 0.149. Further analysis revealed that the two highest peaks in the attention value vector of the DAN model overlapped in time with the preparation and memory retrieval phases, as well as with two of the four significant time-frequency ROIs.DiscussionThese results highlight the potential utility of interpretable machine learning algorithms as an aid in diagnosis of schizophrenia and other psychiatric disorders presenting oscillatory abnormalities

Tele-supervised home-based transcranial alternating current stimulation (tACS) for Alzheimer's disease : a pilot study

Over 55 million people worldwide are currently diagnosed with Alzheimer's disease (AD) and live with debilitating episodic memory deficits. Current pharmacological treatments have limited efficacy. Recently, transcranial alternating current stimulation (tACS) has shown memory improvement in AD by normalizing high-frequency neuronal activity. Here we investigate the feasibility, safety, and preliminary effects on episodic memory of an innovative protocol where tACS is administered within the homes of older adults with AD with the help of a study companion (HB-tACS). Eight participants diagnosed with AD underwent multiple consecutive sessions of high-definition HB-tACS (40 Hz, 20-min) targeting the left angular gyrus (AG), a key node of the memory network. The Acute Phase comprised 14-weeks of HB-tACS with at least five sessions per week. Three participants underwent resting state electroencephalography (EEG) before and after the 14-week Acute Phase. Subsequently, participants completed a 2-3-month Hiatus Phase not receiving HB-tACS. Finally, in the Taper phase, participants received 2-3 sessions per week over 3-months. Primary outcomes were safety, as determined by the reporting of side effects and adverse events, and feasibility, as determined by adherence and compliance with the study protocol. Primary clinical outcomes were memory and global cognition, measured with the Memory Index Score (MIS) and Montreal Cognitive Assessment (MoCA), respectively. Secondary outcome was EEG theta/gamma ratio. Results reported as mean ± SD. All participants completed the study, with an average of 97 HB-tACS sessions completed by each participant; reporting mild side effects during 25% of sessions, moderate during 5%, and severe during 1%. Acute Phase adherence was 98 ± 6.8% and Taper phase was 125 ± 22.3% (rates over 100% indicates participants completed more than the minimum of 2/week). After the Acute Phase, all participants showed memory improvement, MIS of 7.25 ± 3.77, sustained during Hiatus 7.00 ± 4.90 and Taper 4.63 ± 2.39 Phases compared to baseline. For the three participants that underwent EEG, a decreased theta/gamma ratio in AG was observed. Conversely, participants did not show improvement in the MoCA, 1.13 ± 3.80 after the Acute Phase, and there was a modest decrease during the Hiatus −0.64 ± 3.28 and Taper −2.56 ± 5.03 Phases. This pilot study shows that the home-based, remotely-supervised, study companion administered, multi-channel tACS protocol for older adults with AD was feasible and safe. Further, targeting the left AG, memory in this sample was improved. These are preliminary results that warrant larger more definite trials to further elucidate tolerability and efficacy of the HB-tACS intervention. NCT04783350. , identifier NCT04783350

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

Tele-supervised home-based transcranial alternating current stimulation (tACS) for Alzheimer’s disease: a pilot study

BackgroundOver 55 million people worldwide are currently diagnosed with Alzheimer’s disease (AD) and live with debilitating episodic memory deficits. Current pharmacological treatments have limited efficacy. Recently, transcranial alternating current stimulation (tACS) has shown memory improvement in AD by normalizing high-frequency neuronal activity. Here we investigate the feasibility, safety, and preliminary effects on episodic memory of an innovative protocol where tACS is administered within the homes of older adults with AD with the help of a study companion (HB-tACS).MethodsEight participants diagnosed with AD underwent multiple consecutive sessions of high-definition HB-tACS (40 Hz, 20-min) targeting the left angular gyrus (AG), a key node of the memory network. The Acute Phase comprised 14-weeks of HB-tACS with at least five sessions per week. Three participants underwent resting state electroencephalography (EEG) before and after the 14-week Acute Phase. Subsequently, participants completed a 2–3-month Hiatus Phase not receiving HB-tACS. Finally, in the Taper phase, participants received 2–3 sessions per week over 3-months. Primary outcomes were safety, as determined by the reporting of side effects and adverse events, and feasibility, as determined by adherence and compliance with the study protocol. Primary clinical outcomes were memory and global cognition, measured with the Memory Index Score (MIS) and Montreal Cognitive Assessment (MoCA), respectively. Secondary outcome was EEG theta/gamma ratio. Results reported as mean ± SD.ResultsAll participants completed the study, with an average of 97 HB-tACS sessions completed by each participant; reporting mild side effects during 25% of sessions, moderate during 5%, and severe during 1%. Acute Phase adherence was 98 ± 6.8% and Taper phase was 125 ± 22.3% (rates over 100% indicates participants completed more than the minimum of 2/week). After the Acute Phase, all participants showed memory improvement, MIS of 7.25 ± 3.77, sustained during Hiatus 7.00 ± 4.90 and Taper 4.63 ± 2.39 Phases compared to baseline. For the three participants that underwent EEG, a decreased theta/gamma ratio in AG was observed. Conversely, participants did not show improvement in the MoCA, 1.13 ± 3.80 after the Acute Phase, and there was a modest decrease during the Hiatus −0.64 ± 3.28 and Taper −2.56 ± 5.03 Phases.ConclusionThis pilot study shows that the home-based, remotely-supervised, study companion administered, multi-channel tACS protocol for older adults with AD was feasible and safe. Further, targeting the left AG, memory in this sample was improved. These are preliminary results that warrant larger more definite trials to further elucidate tolerability and efficacy of the HB-tACS intervention. NCT04783350.Clinical trial registrationhttps://clinicaltrials.gov/ct2/show/NCT04783350?term=NCT04783350&draw=2&rank=1, identifier NCT04783350

Spontaneous and perturbation-based electroencephalographic markers of brain health

[eng] INTRODUCTION: Brain health is the optimal state of brain functioning that allows the individual to reach their maximum potential throughout life, regardless of the presence or absence of diseases. In order to promote and preserve brain health in the face of disease, it is essential to discover its brain determinants. Some of the main challenges to brain health are mental disorders and neurodegenerative diseases, the most prevalent of which are mood disorders, schizophrenia, and Alzheimer's disease. From a pathophysiological point of view, these diseases share dysfunctions in synaptic transmission, rooted in inhibitory and excitatory processes, which could be detectable by electroencephalography and potentially modifiable by non-invasive brain stimulation techniques. Therefore, in this thesis we have investigated candidate biomarkers of brain health that could be neurophysiologically relevant in the context of common diseases that challenge it, and, more importantly, that are potentially modifiable. HYPOTHESIS: The general hypotheses are: 1) candidate biomarkers of brain health are detectable by non-invasive and potentially scalable methods, and 2) reveal relevant mechanisms for diseases that present dysfunctions in synaptic transmission, rooted in excitatory and inhibitory processes. The specific hypotheses for each of the three studies in this thesis are: 1) A "toy model" of brain resilience can be constructed using a controlled brain disturbance to simulate the stressor and assess brain reactivity as an indicator of the organism's response. This integrated model will identify a distinctive signature of brain resilience in the face of the anticipated impact of psychosocial stressors associated with the COVID-19 pandemic. 2) Inhibitory abnormalities of patients with schizophrenia during a visual working memory task are detectable and can be deepened using an interpretable machine learning model, in order to differentiate patients from controls using only electroencephalography (EEG) data. 3) higher cortical excitability correlates with higher concentrations of phosphorylated tau secreted in plasma, while no association was observed with the concentration of passive secretion 'neurofilament light'. OBJECTIVES: The main objective of this thesis is to investigate candidate biomarkers of brain health that are potentially translational and modifiable in the context of some of its most prevalent challenges. The specific objectives of each of the three studies are: 1) to build a "toy model" of brain resilience and use it in the context of psychosocial stressors associated with the COVID-19 pandemic. 2) implement an interpretable machine learning algorithm that can differentiate patients from controls based solely on EEG data, while revealing the specific neurophysiological mechanisms that led to the classification. 3) to establish the relationship between cortical excitability and proteins involved in the pathophysiology of Alzheimer's disease using non-invasive methods.[cat] INTRODUCCIÓ: La salut cerebral és l'estat òptim del funcionament cerebral que permet a l’individu assolir el seu màxim potencial al llarg de la vida, independentment de la presència o absència de malalties. Per poder promoure i preservar la salut cerebral enfront de la malaltia, és fonamental descobrir els seus determinants cerebrals. Alguns dels principals reptes per a la salut cerebral són els trastorns mentals i les malalties neurodegeneratives, els més prevalents dels quals són els trastorns de l'estat d'ànim, l'esquizofrènia i la malaltia d'Alzheimer. Des del punt de vista fisiopatològic, aquestes malalties comparteixen disfuncions en la transmissió sinàptica, arrelades en processos inhibitoris i excitatoris, que podrien ser detectables mitjançant l'electroencefalografia i potencialment modificables mitjançant tècniques d’estimulació cerebral no invasives. Per tant, en aquesta tesi hem investigat biomarcadors candidats de la salut cerebral que podrien ser neurofisiològicament rellevants en el context de malalties comunes que la desafien, i, el que és més important, que són potencialment modificables. HIPÒTESIS: Les hipòtesis generals són: 1) els biomarcadors candidats de la salut cerebral són detectables mitjançant mètodes no invasius i potencialment escalables, i 2) revelen mecanismes rellevants per a malalties que presenten disfuncions en la transmissió sinàptica , arrelades en processos excitatoris i inhibitoris. Les hipòtesis específiques per a cadascun dels tres estudis d'aquesta tesi són: 1) Es pot construir un "model de joguina" de la resiliència cerebral utilitzant una pertorbació cerebral controlada per simular l'estressor i avaluar la reactivitat cerebral com a indicador de la resposta de l'organisme. Aquest model integrat permetrà identificar una signatura distintiva de la resiliència cerebral davant de l’impacte anticipat dels estressors psicosocials associats a la pandèmia de la COVID-19. 2) Les anomalies inhibitòries dels pacients amb esquizofrènia durant una tasca de memòria de treball visual són detectables i es poden aprofundir mitjançant un model interpretable d'aprenentatge automàtic, per tal de diferenciar pacients de controls utilitzant només dades d'electroencefalografia (EEG). 3) l'excitabilitat cortical més elevada es correlaciona amb concentracions més altes de tau fosforilada secretada en plasma, mentre que no s'observà cap associació amb la concentració de ‘neurofilament light’ de secreció passiva. OBJECTIUS: L'objectiu principal d'aquesta tesi és investigar biomarcadors candidats de la salut cerebral que siguin potencialment translacionals i modificables en el context d'alguns dels seus reptes més prevalents. Els objectius específics de cadascun dels tres estudis són: 1) construir un "model de joguina" de la resiliència cerebral i emprar-lo en el context dels estressors psicosocials associats a la pandèmia de la COVID-19. 2) implementar un algoritme interpretable d'aprenentatge automàtic que pugui diferenciar pacients de controls basant-se únicament en dades d'EEG, alhora que reveli els mecanismes neurofisiològiques específics que donat lloc a la classificació. 3) establir la relació entre l'excitabilitat cortical i les proteïnes implicades en la fisiopatologia de la malaltia d'Alzheimer utilitzant mètodes no invasius

Corticospinal and transcallosal modulation of unilateral and bilateral contractions of lower limbs

Purpose Interhemispheric inhibition may play a role in the expression of bilateral deficit in force (BLD). This study investigated whether the degree of BLD is reflected in the nature of interhemispheric interaction during unilateral and bilateral contractions. Methods Subjects divided into three groups, ‘bilateral’ (n = 7), ‘unilateral’ (n = 5) and ‘control’ (n = 8), performed unilateral and bilateral maximal voluntary isometric knee extensions while receiving electrical stimulation, and transcranial magnetic stimulation of the target and ipsilateral muscles. Main variables of interest included peak force for subsequent calculation of bilateral index, voluntary activation level (VAL), motor evoked potential amplitudes (MEPs) and silent period durations (SPs). Results BLD was noted only for the whole sample (p = 0.009), but not for any of the groups. VAL was significantly higher during bilateral compared to unilateral contractions (~97 vs. 92 %, p = 0.023), with no differences between groups. MEPs of target and ipsilateral muscles were significantly bigger during bilateral contractions (p = 0.042 and p = 0.022, respectively), with no differences between groups. No differences in SPs were observed. Conclusions Higher values of MEPs and VAL during bilateral contractions, in conjunction with unaltered SPs, do not support the concept of inhibition related to BLD, but rather suggest the possibility of cortical facilitation. Based on the existing literature, this behavior may be specific to the lower limb musculature, but the possibility of sub-cortical or higher-order neural alterations cannot be excluded

Dense attention network identifies EEG abnormalities during working memory performance of patients with schizophrenia

Introduction: Patients with schizophrenia typically exhibit deficits in working memory (WM) associated with abnormalities in brain activity. Alterations in the encoding, maintenance and retrieval phases of sequential WM tasks are well established. However, due to the heterogeneity of symptoms and complexity of its neurophysiological underpinnings, differential diagnosis remains a challenge. We conducted an electroencephalographic (EEG) study during a visual WM task in fifteen schizophrenia patients and fifteen healthy controls. We hypothesized that EEG abnormalities during the task could be identified, and patients successfully classified by an interpretable machine learning algorithm. Methods: We tested a custom dense attention network (DAN) machine learning model to discriminate patients from control subjects and compared its performance with simpler and more commonly used machine learning models. Additionally, we analyzed behavioral performance, event-related EEG potentials, and time-frequency representations of the evoked responses to further characterize abnormalities in patients during WM. Results: The DAN model was significantly accurate in discriminating patients from healthy controls, ACC = 0.69, SD = 0.05. There were no significant differences between groups, conditions, or their interaction in behavioral performance or event-related potentials. However, patients showed significantly lower alpha suppression in the task preparation, memory encoding, maintenance, and retrieval phases F(1,28) = 5.93, p = 0.022, η2 = 0.149. Further analysis revealed that the two highest peaks in the attention value vector of the DAN model overlapped in time with the preparation and memory retrieval phases, as well as with two of the four significant time-frequency ROIs. Discussion: These results highlight the potential utility of interpretable machine learning algorithms as an aid in diagnosis of schizophrenia and other psychiatric disorders presenting oscillatory abnormalities

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

Disease‑modifying agents to counteract cognitive impairment in older age remain elusive. Hence, identifying modifiable factors promoting resilience, as the capacity of the brain to maintain cognition and function with aging and disease, is paramount. In Alzheimer’s disease (AD), education and occupation are typical cognitive reserve proxies. However, the importance of psychological factors is being increasingly recognized, as their operating biological mechanisms are elucidated. Purpose in life (PiL), one of the pillars of psychological well‑being, has previously been found to reduce the deleterious effects of AD‑related pathological changes on cognition. However, whether PiL operates as a resilience factor in middle‑aged individuals and what are the underlying neural mechanisms remain unknown.Medicin