Alzheimer disease and neuroplasticity

Alzheimer's disease (AD) is considered the most harmful form of dementia in the elderly population. At present, there are no effective treatments and this is likely due to the incomplete understanding of the pathophysiology. Recent data indicate that synaptic dysfunction could be a central element of AD pathophysiology. It was found that a synaptic breakdown is an early event that heralds neuronal degeneration. Transcranial magnetic stimulation (TMS) has been recently introduced as a novel approach to identify the early signatures of synaptic dysfunction characterizing AD pathophysiology. In this chapter, we review the new neurophysiologic signatures of AD that have been emphasized by TMS studies. We show how TMS measurement of neuroplasticity identified long-term potentiation (LTP)-like cortical plasticity as a key element of AD synaptic dysfunction. These measurements are useful to increase the accuracy of differential diagnosis, predict disease progression, and anticipate response to therapy. Moreover, enhancing neuroplasticity holds as a promising therapeutic approach to improve cognition in AD. In recent years, studies showed treatments with multiple sessions of rTMS can influence cognition in people with neurodegenerative diseases. In the second part of this chapter, we also consider novel therapeutic approaches based on the clinical use of rTMS

Understanding the physiological role of the cerebellum and motor cortex on human motor learning

Many of our daily life activities, such using a new computer or playing sports rely on the acquisition and retention of specific movement patterns. Our ability to learn these patterns depends on multiple behavioral and neuronal processes. While animal research has described learning-related plastic changes within the cerebellum and primary motor cortex (M1), little is known how these changes relate to learning different types of human behavior. In this dissertation, we used non-invasive brain stimulation to assess neural excitability in these brain regions following motor adaptation and skill learning. In chapter 2, we investigated whether excitability changes occurring in the cerebellum are somatotopy-specific in the presence or absence of adaptive motor learning. We used transcranial magnetic stimulation (TMS) to assess cerebellar excitability and found that learning elicited changes for not only a trained effector, but also for an uninvolved effector, likely related to inter-effector transfer of learning. However, when assessing excitability during movement preparation, where no learning occurs, we found modulation was effector-specific, indicating that learning-related changes in cerebellar excitability follow a somatotopy specific rule. Subsequently we studied whether this cerebellar physiological mechanism also extends learning a skill, a behavior known to induce long-term plasticity (LTP) changes in M1. In chapter 3, we used both TMS and transcranial direct current stimulation to explore cerebellar and M1 mechanisms during different stages of motor skill learning. We found a reduction in cerebellar excitability early in skill learning, but not late. On the other hand, changes in M1 long-term potentiation (LTP)-like plasticity only occurred after a significant amount of training had taken place. While this hints towards an important temporal interaction in the physiological role of the cerebellum and M1 when learning a novel skill, it remained unclear if this result was related to acquiring distinct motor components that constitute the skill. The motor skill participants learned involved integrating how to interact with a new device and environment (sensorimotor map), along with a sequence movements. In chapter 4, we deconstructed the skill task to identify distinct physiological contributions of the cerebellum and M1 associated to learning each skill component. We found that learning the sensorimotor map, reflecting the dynamics of the skill, only elicited changes in cerebellar excitability, whereas learning the sequence of movements resulted in both cerebellar excitability and M1 LTP-like plasticity changes. These results indicate that learning the different components that constitute a motor skill engages the cerebellum and motor cortex in a concerted manner

Modulating Motor Learning through Transcranial Direct-Current Stimulation: An Integrative View

Motor learning consists of the ability to improve motor actions through practice playing a major role in the acquisition of skills required for high-performance sports or motor function recovery after brain lesions. During the last decades, it has been reported that transcranial direct-current stimulation (tDCS), consisting in applying weak direct current through the scalp, is able of inducing polarity-specific changes in the excitability of cortical neurons. This low-cost, painless and well-tolerated portable technique has found a wide-spread use in the motor learning domain where it has been successfully applied to enhance motor learning in healthy individuals and for motor recovery after brain lesion as well as in pathological states associated to motor deficits. The main objective of this mini-review is to offer an integrative view about the potential use of tDCS for human motor learning modulation. Furthermore, we introduce the basic mechanisms underlying immediate and long-term effects associated to tDCS along with important considerations about its limitations and progression in recent years

Motor potentials evoked by transcranial magnetic stimulation: interpreting a simple measure of a complex system

Transcranial magnetic stimulation (TMS) is a non‐invasive technique that is increasingly used to study the human brain. One of the principal outcome measures is the motor‐evoked potential (MEP) elicited in a muscle following TMS over the primary motor cortex (M1), where it is used to estimate changes in corticospinal excitability. However, multiple elements play a role in MEP generation, so even apparently simple measures such as peak‐to‐peak amplitude have a complex interpretation. Here, we summarize what is currently known regarding the neural pathways and circuits that contribute to the MEP and discuss the factors that should be considered when interpreting MEP amplitude measured at rest in the context of motor processing and patients with neurological conditions. In the last part of this work, we also discuss how emerging technological approaches can be combined with TMS to improve our understanding of neural substrates that can influence MEPs. Overall, this review aims to highlight the capabilities and limitations of TMS that are important to recognize when attempting to disentangle sources that contribute to the physiological state‐related changes in corticomotor excitability

SICI during changing brain states: Differences in methodology can lead to different conclusions

Background Short-latency intracortical inhibition (SICI) is extensively used to probe GABAergic inhibitory mechanisms in M1. Task-related changes in SICI are presumed to reflect changes in the central excitability of GABAergic pathways. Usually, the level of SICI is evaluated using a single intensity of conditioning stimulus so that inhibition can be compared in different brain states. Objective Here, we show that this approach may sometimes be inadequate since distinct conclusions can be drawn if a different CS intensity is used. Methods We measured SICI using a range of CS intensities at rest and during a warned simple reaction time task. Conclusions Our results show that SICI changes that occurred during the task could be either larger or smaller than at rest depending on the intensity of the CS. These findings indicate that careful interpretation of results are needed when a single intensity of CS is used to measure task-related physiological changes

Cerebellar Transcranial Magnetic Stimulation: The Role of Coil Type from Distinct Manufacturers

Background Stimulating the cerebellum with transcranial magnetic stimulation is often perceived as uncomfortable. No study has systematically tested which coil design can effectively trigger a cerebellar response with the least discomfort. Objective To determine the relationship between perceived discomfort and effectiveness of cerebellar stimulation using different coils: MagStim (70 mm, 110 mm-coated, 110-uncoated), MagVenture and Deymed. Methods Using the cerebellar-brain inhibition (CBI) protocol, we conducted a CBI recruitment curve with respect to each participant’s maximum tolerated-stimulus intensity (MTI) to assess how effective each coil was at activating the cerebellum. Results Only the Deymed double-cone coil elicited CBI at low intensities (−20% MTI). At the MTI, the MagStim (110 mm coated/uncoated) and Deymed coils produced reliable CBI, whereas no CBI was found with the MagVenture coil. Conclusions: The Deymed double-cone coil was most effective at cerebellar stimulation at tolerable intensities. These results can guide coil selection and stimulation parameters when designing cerebellar TMS studies

Comparing the effects of focal and conventional tDCS on motor skill learning: A proof of principle study

Transcranial direct current stimulation (tDCS) has emerged as a promising intervention in clinical and behavioral neuroscience; however, the response variability to this technique has limited its impact, partly due to the widespread of current flow with conventional methods. Here, we investigate whether a more targeted, focal approach over the primary motor cortex (M1) is advantageous for motor learning and targeting specific neuronal populations. Our preliminary results show that focal stimulation leads to enhanced skill learning and differentially recruits distinct pathways to M1. This finding suggests that focal tDCS approaches may improve the outcomes of future studies aiming to enhance behavior

Experimental Protocol to Test Explicit Motor Learning–Cerebellar Theta Burst Stimulation

Implicit and explicit motor learning processes work interactively in everyday life to promote the creation of highly automatized motor behaviors. The cerebellum is crucial for motor sequence learning and adaptation, as it contributes to the error correction and to sensorimotor integration of on-going actions. A non-invasive cerebellar stimulation has been demonstrated to modulate implicit motor learning and adaptation. The present study aimed to explore the potential role of cerebellar theta burst stimulation (TBS) in modulating explicit motor learning and adaptation, in healthy subjects. Cerebellar TBS will be applied immediately before the learning phase of a computerized task based on a modified Serial Reaction Time Task (SRTT) paradigm. Here, we present a study protocol aimed at evaluating the behavioral effects of continuous (cTBS), intermittent TBS (iTBS), or sham Theta Burst Stimulation (TBS) on four different conditions: learning, adaptation, delayed recall and re-adaptation of SRTT. We are confident to find modulation of SRTT performance induced by cerebellar TBS, in particular, processing acceleration and reduction of error in all the conditions induced by cerebellar iTBS, as already known for implicit processes. On the other hand, we expect that cerebellar cTBS could induce opposite effects. Results from this protocol are supposed to advance the knowledge about the role of non-invasive cerebellar modulation in neurorehabilitation, providing clinicians with useful data for further exploiting this technique in different clinical conditions

Reply to: "Reflecting the causes of variability of EEG responses elicited by cerebellar TMS"

In their commentary on our recently published paper about electroencephalographic responses induced by cerebellar transcranial magnetic stimulation (Fong et al., 2023), Gassmann and colleagues (Gassmann et al., 2023b) try to explain the differences between our results and their own previous work on the same topic. We agree with them that many of the differences arise from our use of a different magnetic stimulation coil. However, two unresolved questions remain. (1) Which method is most likely to achieve optimal activation of cerebellar output? (2) To what extent are the evoked cerebellar responses contaminated by concomitant sensory input? We highlight the role of careful experimental design and of combining electrophysiological and behavioural data to obtain reliable TMS-EEG data

Reply to: "Reflecting the causes of variability of EEG responses elicited by cerebellar TMS"

In their commentary on our recently published paper about electroencephalographic responses induced by cerebellar transcranial magnetic stimulation (Fong et al., 2023), Gassmann and colleagues (Gassmann et al., 2023b) try to explain the differences between our results and their own previous work on the same topic. We agree with them that many of the differences arise from our use of a different magnetic stimulation coil. However, two unresolved questions remain. (1) Which method is most likely to achieve optimal activation of cerebellar output? (2) To what extent are the evoked cerebellar responses contaminated by concomitant sensory input? We highlight the role of careful experimental design and of combining electrophysiological and behavioural data to obtain reliable TMS-EEG data