Cortical reorganization and plasticity In the healthy brain

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Background: Cortical reorganization occurs in the adult central nervous system, especially during motor skill acquisition. This plasticity contributes to various forms of human behavior including skill learning and memory formation, consolidation, reconsolidation and short- and long-term retention. It is very important to understand the role of these different behavioral processes and of the mechanisms underlying these various forms of human plasticity during skill acquisition to improve skill learning and memory in healthy adults. Findings this year: Many fine motor skills are composed of sequences of individual actions performed with very precise timing (e.g. playing a piece of music on a piano). On occasion, errors may occur. In the real word, such skill errors may have serious consequences (e.g. - when an airline pilot is attempting to manually land a plane). In these types of situations, the ability to predict a skill error before it occurs would clearly be advantageous. In a study conducted over the past year, we asked whether it is possible to use real-time human brain activity and finger movement measurements to predict future errors in a motor sequence skill 1. We employed a task designed to assess learning of a motor skill that is analogous to learning a short piece of piano music. We found that prolonged keypress transition times, reflecting slower speed, and anomalous delta-band oscillations embedded within cingulate-entorhinal-precuneus brain network activity consistently appear before upcoming skill errors. A machine learning classifier combining anomalous low-frequency activity and prolonged keypress transition times predicted up to 70% of future errors, with the decoding strength (posterior probability of error) progressively increasing leading up to the error event. This exciting finding demonstrates for the first time, that it is possible to predict individual future errors in a sequential motor skill by monitoring anomalous behavior and brain activity features that indicate an impending error is about to occur. Signals predictive of upcoming errors could theoretically be used in real-time feedback applications to warn individuals and allow them to arrest or correct erroneous actions before they occur. For example, in the context of clinical neurorehabilitation, advanced warning signals, if delivered sufficiently early, could allow stroke patients undergoing gait rehabilitation therapy to be warned of an impending bad step and prevent a fall. In FY2023 we also successfully concluded an international collaboration with research groups at the University of Tel Aviv (Israel) and University of Leipzig (Germany), with the work published in the journal, Scientific Reports 2. The University of Tel Aviv group, led by Dr. Nitzan Censor, has previously shown that same amount of skill learning can be achieved with relatively very little practice (i.e. only a handful of practice trials compared to hundreds) if the practice trials reactivate memories at critical time-points. This finding has important implications for performance enhancement strategies and neurorehabilitation interventions. This collaborative research project was aimed at understanding whether consolidated memories, which are susceptible to modifications following their reactivation hours or days after formation, display this same susceptibility to modification during early learning of the skill (i.e. - seconds and minutes after the onset of initial skill training). This project is a continuation of our research program that has repeatedly shown that motor skills display rapid consolidation during the first several minutes of training. Remarkably, almost all of the skill performance improvements during this early learning stage are expressed as sharp jumps in performance following short rest periods interspersed with practice of the skill, as opposed to steady increases that occur during the actual practice. We conducted a set of two online experiments using crowdsourced research platform 3 where we tested whether interference or performance enhancement occurs following brief memory reactivations in the early stage of skill learning. Results of the two experiments showed that memories forming during early learning are not susceptible to interference nor to enhancement within a rapid reactivation-induced time window, relative to control conditions. This set of evidence suggests that reactivation-induced motor skill memory modulation might be dependent on consolidation at the macro-timescale level, requiring hours or days to occur. Finally, in collaboration with a biomedical engineering research team at the City College of New York in Manhattan, we successfully published findings in the journal, Brain Stimulation 4. The study investigated the effects of transcranial direct current stimulation (tDCS) delivered at an intensity of 4 milliamperes (4mA) on enhancement of motor skill learning. This intensity is a factor of two greater than previous investigations (2mA), which had produced mixed efficacy results. Using a single-blinded design, a total of 108 healthy adult participants were randomly assigned to three groups. Each group received either (A) anodal (n = 36) or (B) cathodal (n = 36) tDCS delivered at an intensity of 4mA total, or (C) no stimulation (n = 36). The stimulation was applied while participants practiced a motor sequence skill learning task over a period of 12 minutes. Anodal stimulation was delivered across four electrode pairs (1 mA each), with anode electrodes located above the right parietal cortex and cathode electrodes located above the right frontal cortex. The group receiving cathodal stimulation, which included the same spatial electrode montage but with reversed polarities, served as an active control for sensation associated with the stimulation. The group receiving no-stimulation was used to compare baseline performance with the stimulation groups. Functional MRI data obtained in 10 subjects was used to model current flows associated with electrode placement that optimized maximal field intensity within the primary motor cortex. A single optimal electrode montage was then selected and used for all participants in the study. We observed a significant skill learning enhancement in participants receiving anodal stimulation compared to cathodal (Cohen's d = 0.71) or no stimulation (d = 0.56). This enhanced skill learning effect persisted for at least 1 h, and even generalized to subsequent learning for new sequences practiced on the same or opposite hand. Sensation ratings were comparable in the active groups and indicated that the higher intensity stimulation was tolerated well, and comparable to previous studies conducted with 2mA intensities. Futhermore, our current flow modeling indicates that the optimal electrode montage used in this study induces stronger motor cortex polarization than alternative montages used previously, further enhancing the intensity effect. This finding represents an important step forward in realizing stronger efficacy of non-invasive brain stimulation techniques that can be applied to clinical interventions in the future.