RESUMEN
Fragile-X syndrome (FXS) and Neurofibromatosis of type 1 (NF-1) are two monogenic disorders sharing neurobehavioral symptoms and pathophysiological mechanisms. Namely, preclinical models of both conditions show overactivity of the mTOR signaling pathway as well as GABAergic alterations. However, despite its potential clinical relevance for these disorders, the GABAergic system has not been systematically studied in humans. In the present study, we used an extensive transcranial magnetic stimulation (TMS) assessment battery in combination with magnetic resonance spectroscopy (MRS) to provide a comprehensive picture of the main inhibitory neurotransmitter system in patients with FXS and NF1. Forty-three participants took part in the TMS session (15 FXS, 10 NF1, 18 controls) and 36 in the MRS session (11 FXS, 14 NF1, 11 controls). Results show that, in comparison to healthy control participants, individuals with FXS and NF1 display lower GABA concentration levels as measured with MRS. TMS result show that FXS patients present increased GABAB-mediated inhibition compared to controls and NF1 patients, and that GABAA-mediated intracortical inhibition was associated with increased excitability specifically in the FXS groups. In line with previous reports, correlational analyses between MRS and TMS measures did not show significant relationships between GABA-related metrics, but several TMS measures correlated with glutamate+glutamine (Glx) levels assessed with MRS. Overall, these results suggest a partial overlap in neurophysiological alterations involving the GABA system in NF1 and FXS, and support the hypothesis that MRS and TMS assess different aspects of the neurotransmitter systems.
Asunto(s)
Síndrome del Cromosoma X Frágil , Corteza Motora , Neurofibromatosis 1 , Humanos , Inhibición Neural/fisiología , Ácido gamma-Aminobutírico/metabolismo , Estimulación Magnética Transcraneal , Neurofibromatosis 1/metabolismoRESUMEN
It has been shown that when incentives are provided during movement preparation, activity in parieto-frontal regions reflects both expected value and motivational salience. Yet behavioral work suggests that the processing of rewards is faster than for punishments, raising the possibility that expected value and motivational salience manifest at different latencies during movement planning. Given the role of beta oscillations (13-30 Hz) in movement preparation and in communication within the reward circuit, this study investigated how beta activity is modulated by positive and negative monetary incentives during reach planning, and in particular whether it reflects expected value and motivational salience at different latencies. Electroencephalography was recorded while male and female humans performed a reaching task in which reward or punishment delivery depended on movement accuracy. Before a preparatory delay period, participants were informed of the consequences of hitting or missing the target, according to four experimental conditions: Neutral (hit/miss:+0/-0¢), Reward (hit/miss:+5/-0¢), Punish (hit/miss:+0/-5¢) and Mixed (hit/miss:+5/-5¢). Results revealed that beta power over parieto-frontal regions was strongly modulated by incentives during the delay period, with power positively correlating with movement times. Interestingly, beta power was selectively sensitive to potential rewards early in the delay period, after which it came to reflect motivational salience as movement onset neared. These results demonstrate that beta activity reflects expected value and motivational salience on different time scales during reach planning. They also provide support for models that link beta activity with basal ganglia and dopamine for the allocation of neural resources according to behavioral salience.SIGNIFICANCE STATEMENT The present work demonstrates that pre-movement parieto-frontal beta power is modulated by monetary incentives in a goal-directed reaching task. Specifically, beta power transiently scaled with the availability of rewards early in movement planning, before reflecting motivational salience as movement onset neared. Moreover, pre-movement beta activity correlated with the vigor of the upcoming movement. These findings suggest that beta oscillations reflect neural processes that mediate the invigorating effect of incentives on motor performance, possibly through dopamine-mediated interactions with the basal ganglia.
Asunto(s)
Ritmo beta/fisiología , Motivación/fisiología , Movimiento/fisiología , Desempeño Psicomotor/fisiología , Ganglios Basales/fisiología , Electroencefalografía , Femenino , Lóbulo Frontal/fisiología , Humanos , Masculino , Lóbulo Parietal/fisiología , Castigo , Tiempo de Reacción , Recompensa , Adulto JovenRESUMEN
Monetary rewards and punishments have been shown to respectively enhance retention of motor memories and short-term motor performance, but their underlying neural bases in the context of motor control tasks remain unclear. Using electroencephalography (EEG), the present study tested the hypothesis that monetary rewards and punishments are respectively reflected in post-feedback beta-band (20-30â¯Hz) and theta-band (3-8â¯Hz) oscillatory power. While participants performed upper limb reaching movements toward visual targets using their right hand, the delivery of monetary rewards and punishments was manipulated as well as their probability (i.e., by changing target size). Compared to unrewarded and unpunished trials, monetary rewards and the successful avoidance of punishments both entailed greater beta-band power at left central electrodes overlaying contralateral motor areas. In contrast, monetary punishments and reward omissions both entailed increased theta-band power at fronto-central scalp sites. Additional analyses revealed that beta-band power was further increased when rewards were lowly probable. In light of previous work demonstrating similar beta-band modulations in basal ganglia during reward processing, the present results may reflect functional communication of reward-related information between the basal ganglia and motor cortical regions. In turn, the increase in fronto-central theta-band power after monetary punishments may reflect an emphasized cognitive need for behavioral adjustments. Globally, the present work identifies possible neural substrates for the growing behavioral evidence showing beneficial effects of monetary feedback on motor learning and performance.
Asunto(s)
Ritmo beta/fisiología , Desempeño Psicomotor/fisiología , Recompensa , Ritmo Teta/fisiología , Femenino , Humanos , Aprendizaje/fisiología , Masculino , Adulto JovenRESUMEN
Fragile X syndrome (FXS) is a rare genetic disorder characterized by a deficit of the fragile X mental retardation protein (FMRP), encoded by the fragile X mental retardation gene (FMR1) on the X chromosome. It has been hypothesized that the absence of FRMP leads to higher levels of Insulin-like Growth Factor 1 (IGF-1) in the brain, possibly contributing to the intellectual impairment characteristic of the disorder. Preclinical studies have shown that metformin downregulates the insulin/IGF-1 signaling pathway, corrects dendritic defects, and improves repetitive behavior in Fmr1 knockout mice. Here, we conducted an open-label study to evaluate: (1) the safety of metformin in normoglycemic individuals with FXS; and (2) the efficacy of metformin to improve aberrant behavior, attention, and to modulate cortical functioning. Fifteen patients with FXS, aged from 17 to 44, received 500 mg of metformin twice/daily over a 9-week treatment period. The primary outcome measures were: (1) the incidence of adverse events (AE); (2) the decrease in IGF-1 levels; and (3) the global score of the Aberrant Behavior Checklist-Community, Fragile X. The secondary outcomes were: (1) the Test of Attentional Performance for children (KiTAP); and (2) the Transcranial Magnetic Stimulation (TMS) parameters measuring cortical excitability. The metformin treatment was well tolerated, with no significant related AE. The TMS data showed an increase in corticospinal inhibition mediated by GABAA and GABAB mechanisms. This study demonstrates the safety of metformin in normoglycemic patients with FXS, and suggests the potential of this medication in modifying GABA-mediated inhibition, a hallmark of FXS pathophysiology. Implications for future clinical trials are discussed.
Asunto(s)
Potenciales Evocados Motores/efectos de los fármacos , Síndrome del Cromosoma X Frágil/tratamiento farmacológico , Síndrome del Cromosoma X Frágil/fisiopatología , Hipoglucemiantes/uso terapéutico , Metformina/uso terapéutico , Estimulación Magnética Transcraneal/métodos , Adolescente , Adulto , Potenciales Evocados Motores/fisiología , Femenino , Síndrome del Cromosoma X Frágil/psicología , Humanos , Hipoglucemiantes/farmacología , Masculino , Metformina/farmacología , Corteza Motora/efectos de los fármacos , Corteza Motora/fisiología , Pruebas Neuropsicológicas , Resultado del Tratamiento , Adulto JovenRESUMEN
Fragile-X syndrome (FXS) is characterized by neurological and psychiatric problems symptomatic of cortical hyperexcitability. Recent animal studies identified deficient γ-aminobutyricacid (GABA) inhibition as a key mechanism for hyperexcitability in FXS, but the GABA system remains largely unexplored in humans with the disorder. The primary objective of this study was to assess GABA-mediated inhibition and its relationship with hyperexcitability in patients with FXS. Transcranial magnetic stimulation (TMS) was used to assess cortical and corticospinal inhibitory and excitatory mechanisms in 18 patients with a molecular diagnosis of FXS and 18 healthy controls. GABA-mediated inhibition was measured with short-interval intracortical inhibition (GABAA), long-interval intracortical inhibition (GABAB), and the corticospinal silent period (GABAA+B). Net intracortical facilitation involving glutamate was assessed with intracortical facilitation, and corticospinal excitability was measured with the resting motor threshold. Results showed that FXS patients had significantly reduced short-interval intracortical inhibition, increased long-interval intracortical inhibition, and increased intracortical facilitation compared to healthy controls. In the FXS group, reduced short-interval intracortical inhibition was associated with heightened intracortical facilitation. Taken together, these results suggest that reduced GABAA inhibition is a plausible mechanism underlying cortical hyperexcitability in patients with FXS. These findings closely match those observed in animal models, supporting the translational validity of these markers for clinical research.
Asunto(s)
Síndrome del Cromosoma X Frágil/fisiopatología , Corteza Motora/fisiopatología , Red Nerviosa/fisiopatología , Inhibición Neural , Adolescente , Adulto , Estudios de Casos y Controles , Femenino , Síndrome del Cromosoma X Frágil/diagnóstico , Humanos , Masculino , Estimulación Magnética Transcraneal , Adulto Joven , Ácido gamma-Aminobutírico/fisiologíaRESUMEN
Static magnetic fields (SMFs) are known to alter neural activity, but evidence of their ability to modify learning-related neuroplasticity is lacking. The present study tested the hypothesis that application of static magnetic stimulation (SMS), an SMF applied transcranially via a neodymium magnet, over the primary motor cortex (M1) would alter learning of a serial reaction time task (SRTT). Thirty-nine participants took part in two experimental sessions separated by 24 h where they had to learn the SRTT with their right hand. During the first session, two groups received SMS either over contralateral (i.e., left) or ipsilateral (i.e., right) M1 while a third group received sham stimulation. SMS was not applied during the second session. Results of the first session showed that application of SMS over contralateral M1 impaired online learning as compared to both ipsilateral and sham groups, which did not differ. Results further revealed that application of SMS did not impair offline learning or relearning. Overall, these results are in line with those obtained using other neuromodulatory techniques believed to reduce cortical excitability in the context of motor learning and suggest that the ability of SMS to alter learning-related neuroplasticity is temporally circumscribed to the duration of its application.