Resumen de Combined transcranial magnetic stimulation to potentiate motor and memory performance
Transcranial magnetic stimulation (TMS) has demonstrated to non-invasively stimulate the human brain and induce synaptic plasticity when its application follows specific stimulation protocols. In recent years, paired associative stimulation (PAS) has emerged as a promising stimulation protocol for the neuromodulation of cortico-spinal excitability and motor performance. PAS is based on the principles postulated by Donald Hebb, which describe that when two axons of different neurons are close enough to each other and repeatedly one participates in the activation of the other, metabolic and growth changes occur between them. Therefore, these plastic changes called spike timing-dependent plasticity (STDP) are associative and related to the space and time in which neurons are activated. To induce STDP in humans, a PAS protocol is followed which consist on synchronizing TMS with a second stimulation. The neuronal activations derived from both stimulations converge in the same brain region, commonly in the primary motor cortex (M1).
PAS has resulted in different protocols, depending on the nature of the stimulus that is paired with the TMS. TMS can be combined with a peripheral electrical stimulus or with another TMS pulse, and, moreover, it can also be combined with the endogenous activation of the M1 cortex, which is triggered by performing movement in a motor task. This latter combination, the task-related combined stimulation, has demonstrate the capacity to neuromodulate corticospinal excitability and motor performance. In addition, it has two main advantages: 1. TMS is paired with an endogenous activity evoked by a task that the participant performs, therefore, any brain region that can be activated by TMS and a task can be targeted; 2. The inclusion of a task in the protocol causes that the neurons activated during the task can be the target of the stimulation and consequently, the function performed by these neurons could also be enhanced. Despite the possibilities this technique offers and its demonstrated effects, task-related combined stimulation has been little explored compared to the total literature of TMS protocols. Furthermore, it has been exclusively related to simple motor tasks and M1 location.
However, we consider that both motor functions of complex movements and cognitive functions related to memory (outside of M1) are critical targets that could be enhanced with task-related combined stimulation. In the clinical field, the facilitation of motor and memory functions would significantly help patients with impaired activities of daily living (ADL).
Therefore, the hypothesis of this PhD thesis is that task-related combined stimulation can improve functions related to ADLs. Thus, the main objective is to investigate this hypothesis by designing and applying combined-stimuli protocols focused on facilitating targeted functions. The specific aims are to design two task-related combined-stimuli protocols to test their effects on complex motor performance and working memory (WM). In this way, the development of protocols that induce plasticity and promote critical functions in ADLs could significantly impact clinical therapy in the future.
First, we designed and tested a protocol that synchronizes TMS over the M1 with a movement-related dynamic task (MRDT). In 22 healthy subjects, we measured time-accuracy, trajectory-accuracy, and object-directed motor function, and assessed the recruitment curve of motor evoked potentials (MEPs) to evaluate motor corticospinal excitability in Abductor Pollicis Brevis (APV) and Abductor Digiti Minimi (ADM) hand muscles. MEPs and motor outcome measures were collected before, immediately after, and 30 minutes after combined stimulation in an active versus sham experimental design. Second, we designed and tested a protocol that combined TMS directed to the hippocampus with endogenous hippocampal activity during a WM task. In 96 volunteers randomized across one experimental group and three parallel groups (motor cortex stimulation, sham stimulation, and no stimulation), we measured the hit items in the WM task before, immediately after, and 30 minutes after the combined stimulation. WM capacity measured by hit items was compared across groups, times, and baseline memorization levels. In addition, we compared the M1 and hippocampal depths on individual MRIs to analyze the feasibility of hippocampal stimulation. Moreover, we characterized the learning derivate by solely playing the task (without active or sham stimulation) to contextualize the results.
On the one hand, MRDT combined stimulation improved time-accuracy motor performance defined by reaction times (RTs), and motor corticospinal excitability was modulated, reflected as a significant MEP amplitude change at 110% of resting motor threshold (RMT) intensity in the ADM and at 130% of RMT intensity in the APB muscle. RTs and ADM MEP amplitudes correlated positively in specific time and intensity assessments. On the other hand, memory-related combined stimulation resulted in increased memorization capacity in the WM task, which was dependent on the stimulated brain location and subjects basal memorization level. Low baseline (LB) participants in the motor cortex stimulation group and medium baseline (MB) participants in the hippocampal stimulation group showed significantly improved memorization capacity. High baseline (HB) subjects did not show any significant change in WM. In addition, when comparing M1 and hippocampal depths, we estimated that the intensity that triggered foot M1 activation was likely to activate hippocampal neurons. Moreover, WM task practice by itself significantly increased WM capacity. Despite this, memory-related combined stimulation had a facilitation effect.
Thus, MRDT combined stimulation induced an immediate shift in time-accuracy performance, indicating a short-term improvement effect, although excitability enhancement was not apparent in the MEP, probably due to the contribution of muscular fatigue. The trajectory-accuracy and object-directed performance were not significantly affected, suggesting that this intervention have specifically improved the function of the stimulated brain location. Memory-related combined stimulation also facilitated WM function, which was brain location and basal level specific. This could also be related to the specificity of brain location stimulation. The results might suggest that the potentiation of WM is significant when the stimulation is over the cortical area that has a function required at a particular level of memorization capacity and a ceiling effect if the capacity is at the highest level.
Overall, the results showed that task-related combined stimulation is facilitatory of the targeted task performance, likely depending on the function of the stimulated brain area. However, revealing whether our results correspond to the specificity of the function of the neuronal population that is stimulated will require research that controls this variable in the future. Furthermore, more research on muscle fatigue and direct hippocampal stimulation is needed to develop an optimal protocol in the clinical field. Despite this, the contribution of this doctoral thesis is relevant due to the application of the technique to a new neuronal location, and enables its use to promote additional functions that are critical for future clinical research, taking into account the burden it represents for patients when these functions are affected.
