Pascual-Leone, Alvaro

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Pascual-Leone, Alvaro

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Pascual-Leone

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Alvaro

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Pascual-Leone, Alvaro

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Adaptability and reproducibility of a memory disruption rTMS protocol in the PharmaCog IMI European project
(Nature Publishing Group UK, 2018) Martin-Trias, Pablo; Lanteaume, Laura; Solana, Elisabeth; Cassé-Perrot, Catherine; Fernández-Cabello, Sara; Babiloni, Claudio; Marzano, Nicola; Junqué, Carme; Rossini, Paolo Maria; Micallef, Joëlle; Truillet, Romain; Charles, Estelle; Jouve, Elisabeth; Bordet, Régis; Santamaria, Joan; Jovicich, Jorge; Rossi, Simone; Pascual-Leone, Alvaro; Blin, Olivier; Richardson, Jill; Bartrés-Faz, David
Transcranial magnetic stimulation (TMS) can interfere with cognitive processes, such as transiently impairing memory. As part of a multi-center European project, we investigated the adaptability and reproducibility of a previously published TMS memory interfering protocol in two centers using EEG or fMRI scenarios. Participants were invited to attend three experimental sessions on different days, with sham repetitive TMS (rTMS) applied on day 1 and real rTMS on days 2 and 3. Sixty-eight healthy young men were included. On each experimental day, volunteers were instructed to remember visual pictures while receiving neuronavigated rTMS trains (20 Hz, 900 ms) during picture encoding at the left dorsolateral prefrontal cortex (L-DLPFC) and the vertex. Mixed ANOVA model analyses were performed. rTMS to the L-DLPFC significantly disrupted recognition memory on experimental day 2. No differences were found between centers or between fMRI and EEG recordings. Subjects with lower baseline memory performances were more susceptible to TMS disruption. No stability of TMS-induced memory interference could be demonstrated on day 3. Our data suggests that adapted cognitive rTMS protocols can be implemented in multi-center studies incorporating standardized experimental procedures. However, our center and modality effects analyses lacked sufficient statistical power, hence highlighting the need to conduct further studies with larger samples. In addition, inter and intra-subject variability in response to TMS might limit its application in crossover or longitudinal studies.
Reproducibility of Single-Pulse, Paired-Pulse, and Intermittent Theta-Burst TMS Measures in Healthy Aging, Type-2 Diabetes, and Alzheimer’s Disease
(Frontiers Media S.A., 2017) Fried, Peter; Jannati, Ali; Davila-Pérez, Paula; Pascual-Leone, Alvaro
Background: Transcranial magnetic stimulation (TMS) can be used to assess neurophysiology and the mechanisms of cortical brain plasticity in humans in vivo. As the use of these measures in specific populations (e.g., Alzheimer’s disease; AD) increases, it is critical to understand their reproducibility (i.e., test–retest reliability) in the populations of interest. Objective: Reproducibility of TMS measures was evaluated in older adults, including healthy, AD, and Type-2 diabetes mellitus (T2DM) groups. Methods: Participants received two identical neurophysiological assessments within a year including motor thresholds, baseline motor evoked potentials (MEPs), short- and long-interval intracortical inhibition (SICI, LICI) and intracortical facilitation (ICF), and MEP changes following intermittent theta-burst stimulation (iTBS). Cronbach’s α coefficients were calculated to assess reproducibility. Multiple linear regression analyses were used to investigate factors related to intraindividual variability. Results: Reproducibility was highest for motor thresholds, followed by baseline MEPs, SICI and LICI, and was lowest for ICF and iTBS aftereffects. The AD group tended to show higher reproducibility than T2DM or controls. Intraindividual variability of baseline MEPs was related to age and variability of RMT, while the intraindividual variability in post-iTBS measures was related to baseline MEP variability, intervisit duration, and Brain-derived neurotrophic factor (BDNF) polymorphism. Conclusion: Increased reproducibility in AD may reflect pathophysiological declines in the efficacy of neuroplastic mechanisms. Reproducibility of iTBS aftereffects can be improved by keeping baseline MEPs consistent, controlling for BDNF genotype, and waiting at least a week between visits. Significance: These findings provide the first direct assessment of reproducibility of TMS measures in older clinical populations. Reproducibility coefficients may be used to adjust effect- and sample size calculations for future studies.
Novel Therapeutic Approaches to the Treatment of Chronic Abdominal Visceral Pain
(TheScientificWorldJOURNAL, 2006) Patrizi, Franca; Freedman, Steven; Pascual-Leone, Alvaro; Fregni, Felipe
Chronic abdominal visceral pain (CAVP) has a significant clinical impact and represents one of the most frequent and debilitating disorders in the general population. It also leads to a significant economic burden due to workdays lost, reduced productivity, and long-term use of medications with their associated side effects. Despite the availability of several therapeutic options, the management of patients with CAVP is often inadequate, resulting in frustration for both patients and physicians. This may in part be explained by the lack of understanding of the mechanisms underlying chronic pain; in contrast with acute pain in which the pathophysiology is relatively well known and has several satisfactory therapeutic options. Recently, the development of tools for brain investigation, such as functional magnetic resonance imaging, has provided new insights on the pathophysiology of chronic pain. These new data have shown that plastic changes in the central and peripheral nervous system might play an important role in the maintenance of chronic pain. Therefore, approaches aimed at the modulation of the nervous system, rather than the ones interfering with the inflammatory pathways, may be more effective for chronic pain treatment. We propose that noninvasive central nervous system stimulation, with transcranial magnetic stimulation (TMS), might be a novel therapeutic option for CAVP. This paper will present an overview of the pathophysiology and the available therapies for CAVP, focusing on the recent advances in the treatment of this pathology.
Meaning in life: resilience beyond reserve
(BioMed Central, 2018) Bartrés-Faz, David; Cattaneo, Gabriele; Solana, Javier; Tormos, Josep M.; Pascual-Leone, Alvaro
Background: The contribution of psychological factors to brain health and resilience remains poorly investigated. Furthermore, their possible interaction with ‘classical’ cognitive reserve (CR) estimates in predicting perceived mental health and cognitive status has not been specifically addressed. Methods: We obtained data from 1081 adults responding to questionnaires on the three meaning in life (MiL) dimensions: purpose in life (PiL), sense of coherence (SoC), and engagement with life (EwL). A questionnaire on CR variables was also administered. The outcome measures were self-reported cognitive function and affective status (depression, stress, and anxiety). Multiple linear regression analyses were used to evaluate the association between sociodemographic variables, MiL dimensions, and CR with the two selected outcomes. Mediation analyses, adjusted for age and gender, were applied to determine whether the MiL dimensions mediated the putative effects of CR on self-reported mental and cognitive health. Results: All three MiL components, but not CR estimates, correlated with the self-reported affective status of the participants. Higher CR, PiL, and SoC (but not EwL) scores significantly correlated with higher perceived cognitive function. Notably, the observed association between the CR measures and self-reported cognitive function was mediated by PiL and SoC. Conclusions: Psychological MiL dimensions mediate the association between classic CR estimates and self-perceived cognitive function. Further studies on CR could consider including formal measures of such psychological factors to better understand their unique or synergistic contributions, as well as investigate the associated mechanisms maintaining brain function at older ages. Electronic supplementary material The online version of this article (10.1186/s13195-018-0381-z) contains supplementary material, which is available to authorized users.
Differential effects of motor cortical excitability and plasticity in young and old individuals: a Transcranial Magnetic Stimulation (TMS) study
(Frontiers Media S.A., 2014) Bashir, Shahid; Perez, Jennifer M.; Horvath, Jared C.; Pena-Gomez, Cleofe; Vernet, Marine; Capia, Anuhya; Alonso-Alonso, Miguel; Pascual-Leone, Alvaro
Aging is associated with changes in the motor system that, over time, can lead to functional impairments and contribute negatively to the ability to recover after brain damage. Unfortunately, there are still many questions surrounding the physiological mechanisms underlying these impairments. We examined cortico-spinal excitability and plasticity in a young cohort (age range: 19–31) and an elderly cohort (age range: 47–73) of healthy right-handed individuals using navigated transcranial magnetic stimulation (nTMS). Subjects were evaluated with a combination of physiological [motor evoked potentials (MEPs), motor threshold (MT), intracortical inhibition (ICI), intracortical facilitation (ICF), and silent period (SP)] and behavioral [reaction time (RT), pinch force, 9 hole peg task (HPT)] measures at baseline and following one session of low-frequency (1 Hz) navigated repetitive TMS (rTMS) to the right (non-dominant) hemisphere. In the young cohort, the inhibitory effect of 1 Hz rTMS was significantly in the right hemisphere and a significant facilitatory effect was noted in the unstimulated hemisphere. Conversely, in the elderly cohort, we report only a trend toward a facilitatory effect in the unstimulated hemisphere, suggesting reduced cortical plasticity and interhemispheric communication. To this effect, we show that significant differences in hemispheric cortico-spinal excitability were present in the elderly cohort at baseline, with significantly reduced cortico-spinal excitability in the right hemisphere as compared to the left hemisphere. A correlation analysis revealed no significant relationship between cortical thickness of the selected region of interest (ROI) and MEPs in either young or old subjects prior to and following rTMS. When combined with our preliminary results, further research into this topic could lead to the development of neurophysiological markers pertinent to the diagnosis, prognosis, and treatment of neurological diseases characterized by monohemispheric damage and lateralized motor deficits.
The compensatory dynamic of inter-hemispheric interactions in visuospatial attention revealed using rTMS and fMRI
(Frontiers Media S.A., 2014) Plow, Ela B.; Cattaneo, Zaira; Carlson, Thomas A.; Alvarez, George; Pascual-Leone, Alvaro; Battelli, Lorella
A balance of mutual tonic inhibition between bi-hemispheric posterior parietal cortices is believed to play an important role in bilateral visual attention. However, experimental support for this notion has been mainly drawn from clinical models of unilateral damage. We have previously shown that low-frequency repetitive TMS (rTMS) over the intraparietal sulcus (IPS) generates a contralateral attentional deficit in bilateral visual tracking. Here, we used functional magnetic resonance imaging (fMRI) to study whether rTMS temporarily disrupts the inter-hemispheric balance between bilateral IPS in visual attention. Following application of 1 Hz rTMS over the left IPS, subjects performed a bilateral visual tracking task while their brain activity was recorded using fMRI. Behaviorally, tracking accuracy was reduced immediately following rTMS. Areas ventro-lateral to left IPS, including inferior parietal lobule (IPL), lateral IPS (LIPS), and middle occipital gyrus (MoG), showed decreased activity following rTMS, while dorsomedial areas, such as Superior Parietal Lobule (SPL), Superior occipital gyrus (SoG), and lingual gyrus, as well as middle temporal areas (MT+), showed higher activity. The brain activity of the homologues of these regions in the un-stimulated, right hemisphere was reversed. Interestingly, the evolution of network-wide activation related to attentional behavior following rTMS showed that activation of most occipital synergists adaptively compensated for contralateral and ipsilateral decrement after rTMS, while activation of parietal synergists, and SoG remained competing. This pattern of ipsilateral and contralateral activations empirically supports the hypothesized loss of inter-hemispheric balance that underlies clinical manifestation of visual attentional extinction.
Differential Pharmacological Effects on Brain Reactivity and Plasticity in Alzheimer’s Disease
(Frontiers Media S.A., 2013) Brem, Anna-Katharine; Atkinson, Natasha J.; Seligson, Erica E.; Pascual-Leone, Alvaro
Acetylcholinesterase inhibitors (AChEIs) are the most commonly prescribed monotherapeutic medications for Alzheimer’s disease (AD). However, their underlying neurophysiological effects remain largely unknown. We investigated the effects of monotherapy (AChEI) and combination therapy (AChEI and memantine) on brain reactivity and plasticity. Patients treated with monotherapy (AChEI) (N = 7) were compared to patients receiving combination therapy (COM) (N = 9) and a group of age-matched, healthy controls (HCs) (N = 13). Cortical reactivity and plasticity of the motor cortex were examined using transcranial magnetic stimulation. Cognitive functions were assessed with the cognitive subscale of the Alzheimer Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), activities of daily living (ADLs) with the ADCS-ADL. In addition we assessed the degree of brain atrophy by measuring brain-scalp distances in seven different brain areas. Patient groups differed in resting motor threshold and brain atrophy, with COM showing a lower motor threshold but less atrophy than AChEI. COM showed similar plasticity effects as the HC group, while plasticity was reduced in AChEI. Long-interval intracortical inhibition (LICI) was impaired in both patient groups when compared to HC. ADAS-Cog scores were positively correlated with LICI measures and with brain atrophy, specifically in the left inferior parietal cortex. AD patients treated with mono- or combination-therapy show distinct neurophysiological patterns. Further studies should investigate whether these measures might serve as biomarkers of treatment response and whether they could guide other therapeutic interventions.
Risk Taking in Hospitalized Patients with Acute and Severe Traumatic Brain Injury
(Public Library of Science, 2013) Fecteau, Shirley; Levasseur-Moreau, Jean; García-Molina, Alberto; Kumru, Hatiche; Vergara, Raúl Pelayo; Bernabeu, Monste; Roig, Teresa; Pascual-Leone, Alvaro; Tormos, José Maria
Rehabilitation can improve cognitive deficits observed in patients with traumatic brain injury (TBI). However, despite rehabilitation, the ability of making a choice often remains impaired. Risk taking is a daily activity involving numerous cognitive processes subserved by a complex neural network. In this work we investigated risk taking using the Balloon Analogue Risk Task (BART) in patients with acute TBI and healthy controls. We hypothesized that individuals with TBI will take less risk at the BART as compared to healthy individuals. We also predicted that within the TBI group factors such as the number of days since the injury, severity of the injury, and sites of the lesion will play a role in risk taking as assessed with the BART. Main findings revealed that participants with TBI displayed abnormally cautious risk taking at the BART as compared to healthy subjects. Moreover, healthy individuals showed increased risk taking throughout the task which is in line with previous work. However, individuals with TBI did not show this increased risk taking during the task. We also investigated the influence of three patients’ characteristics on their performance at the BART: Number of days post injury, Severity of the head injury, and Status of the frontal lobe. Results indicate that performance at the BART was influenced by the number of days post injury and the status of the frontal lobe, but not by the severity of the head injury. Reported findings are encouraging for risk taking seems to naturally improve with time postinjury. They support the need of conducting longitudinal prospective studies to ultimately identify impaired and intact cognitive skills that should be trained postinjury.
TMS affects moral judgment, showing the role of DLPFC and TPJ in cognitive and emotional processing
(Frontiers Media S.A., 2014) Jeurissen, Danique; Sack, Alexander T.; Roebroeck, Alard; Russ, Brian E.; Pascual-Leone, Alvaro
Decision-making involves a complex interplay of emotional responses and reasoning processes. In this study, we use TMS to explore the neurobiological substrates of moral decisions in humans. To examining the effects of TMS on the outcome of a moral-decision, we compare the decision outcome of moral-personal and moral-impersonal dilemmas to each other and examine the differential effects of applying TMS over the right DLPFC or right TPJ. In this comparison, we find that the TMS-induced disruption of the DLPFC during the decision process, affects the outcome of the moral-personal judgment, while TMS-induced disruption of TPJ affects only moral-impersonal conditions. In other words, we find a double-dissociation between DLPFC and TPJ in the outcome of a moral decision. Furthermore, we find that TMS-induced disruption of the DLPFC during non-moral, moral-impersonal, and moral-personal decisions lead to lower ratings of regret about the decision. Our results are in line with the dual-process theory and suggest a role for both the emotional response and cognitive reasoning process in moral judgment. Both the emotional and cognitive processes were shown to be involved in the decision outcome.
Suppression of Motor Cortical Excitability in Anesthetized Rats by Low Frequency Repetitive Transcranial Magnetic Stimulation
(Public Library of Science, 2014) Muller, Paul A.; Dhamne, Sameer C.; Vahabzadeh-Hagh, Andrew M.; Pascual-Leone, Alvaro; Jensen, Frances E.; Rotenberg, Alexander
Repetitive transcranial magnetic stimulation (rTMS) is a widely-used method for modulating cortical excitability in humans, by mechanisms thought to involve use-dependent synaptic plasticity. For example, when low frequency rTMS (LF rTMS) is applied over the motor cortex, in humans, it predictably leads to a suppression of the motor evoked potential (MEP), presumably reflecting long-term depression (LTD) – like mechanisms. Yet how closely such rTMS effects actually match LTD is unknown. We therefore sought to (1) reproduce cortico-spinal depression by LF rTMS in rats, (2) establish a reliable animal model for rTMS effects that may enable mechanistic studies, and (3) test whether LTD-like properties are evident in the rat LF rTMS setup. Lateralized MEPs were obtained from anesthetized Long-Evans rats. To test frequency-dependence of LF rTMS, rats underwent rTMS at one of three frequencies, 0.25, 0.5, or 1 Hz. We next tested the dependence of rTMS effects on N-methyl-D-aspartate glutamate receptor (NMDAR), by application of two NMDAR antagonists. We find that 1 Hz rTMS preferentially depresses unilateral MEP in rats, and that this LTD-like effect is blocked by NMDAR antagonists. These are the first electrophysiological data showing depression of cortical excitability following LF rTMS in rats, and the first to demonstrate dependence of this form of cortical plasticity on the NMDAR. We also note that our report is the first to show that the capacity for LTD-type cortical suppression by rTMS is present under barbiturate anesthesia, suggesting that future neuromodulatory rTMS applications under anesthesia may be considered.