BACKGROUND:Repeated sub-concussive head impacts are a growing brain health concern, but their possible biomarkers remain elusive. One impediment is the lack of a randomised controlled human experimental model to study their effects on the human brain. OBJECTIVES:This work had two objectives. The first one was to provide a randomised controlled human experimental model to study the acute effects of head impacts on brain functions. To achieve this, this work's second objective was to investigate if head impacts from heading footballs acutely alter brain excitability by increasing corticospinal inhibition as compared to a control group. METHODS:In practised and unpractised young healthy adults, transcranial magnetic stimulation was used to assess corticospinal silent period (CSP) duration and corticospinal excitability (CSE) before and immediately after performing headings by returning 20 hand-thrown balls directed to the head (Headings; n = 30) or the dominant foot (Control; n = 30). Moreover, the Rivermead Post-Concussion Questionnaire (RPQ) was used to assess the symptoms of head impacts. Head acceleration was also assessed in subgroups of participants. RESULTS:The intervention lengthened CSP duration in both the Headings (6.4 ± 7.5%) and Control groups (4.6 ± 2.6%), with no difference in lengthening between the two groups. Moreover, CSE was not altered by the intervention and did not differ between groups. However, performing headings increased headaches and dizziness symptoms and resulted in greater head acceleration upon each football throw (12.5 ± 1.9g) as compared to the control intervention (5.5 ± 1.3g). CONCLUSIONS:The results suggest that head impacts from football headings do not acutely alter brain excitability as compared to a control intervention. However, the results also suggest that the present protocol can be used as an experimental model to investigate the acute effects of head impacts on the human brain.

Motor sequence learning gradually quickens reaction time, suggesting that sequence learning alters motor preparation processes. Interestingly, evidence has shown that preparing sequence movements decreases short intracortical inhibition (SICI) in the contralateral motor cortex (M1), but also that sequence learning alters motor preparation processes in both the contralateral and ipsilateral M1s. Therefore, one possibility is that sequence learning alters the SICI decreases occurring during motor preparation in bilateral M1s. To examine this, two novel hypotheses were tested: unilateral sequence preparation would decrease SICI in bilateral M1s, and sequence learning would alter such bilateral SICI responses. Paired-pulse transcranial magnetic stimulation was delivered over the contralateral and ipsilateral M1s to assess SICI in an index finger muscle during the preparation of sequences initiated by either the right index or little finger. In the absence of sequence learning, SICI decreased in both the contralateral and ipsilateral M1s during the preparation of sequences initiated by the right index finger, suggesting that SICI decreases in bilateral M1s during unilateral motor preparation. As sequence learning progressed, SICI decreased in the contralateral M1 whilst it increased in the ipsilateral M1. Moreover, these bilateral SICI responses were observed at the onset of motor preparation, suggesting that sequence learning altered baseline SICI levels rather than the SICI decreases occurring during motor preparation per se. Altogether, these results suggest that SICI responses in bilateral M1s reflect two motor processes: an acute decrease of inhibition during motor preparation, and a cooperative but bidirectional shift of baseline inhibition levels as sequence learning progresses.

The ingestion of dietary cocoa flavanols acutely alters functions of the cerebral endothelium, but whether the effects of flavanols permeate beyond this to alter other brain functions remains unclear. Based on converging evidence, this work tested the hypothesis that cocoa flavanols would alter brain excitability in young healthy adults. In a randomised, cross-over, double-blinded, placebo-controlled design, transcranial magnetic stimulation was used to assess corticospinal and intracortical excitability before as well as 1 and 2 h post-ingestion of a beverage containing either high (695 mg flavanols, 150 mg (−)-epicatechin) or low levels (5 mg flavanols, 0 mg (−)-epicatechin) of cocoa flavanols. In addition to this acute intervention, the effects of a short-term chronic intervention where the same cocoa flavanol doses were ingested once a day for 5 consecutive days were also investigated. For both the acute and chronic interventions, the results revealed no robust alteration in corticospinal or intracortical excitability. One possibility is that cocoa flavanols yield no net effect on brain excitability, but predominantly alter functions of the cerebral endothelium in young healthy adults. Future studies should increase intervention durations to maximize the acute and chronic accumulation of flavanols in the brain, and further investigate if cocoa flavanols would be more effective at altering brain excitability in older adults and clinical populations than in younger adults.

Monetary rewards and punishments enhance motor performance and are associated with corticospinal excitability (CSE) increases within the motor cortex (M1) during movement preparation. However, such CSE changes have unclear origins. Based on converging evidence, one possibility is that they stem from increased glutamatergic (GLUTergic) facilitation and/or decreased type A gamma-aminobutyric acid (GABAA)-mediated inhibition within M1. To investigate this, paired-pulse transcranial magnetic stimulation was used over the left M1 to evaluate intracortical facilitation (ICF) and short intracortical inhibition (SICI), indirect assays of GLUTergic activity and GABAA-mediated inhibition, in an index finger muscle during the preparation of sequences initiated by either the right index or little finger. Behaviourally, rewards and punishments enhanced both reaction and movement time. During movement preparation, regardless of rewards or punishments, ICF increased when the index finger initiated sequences, whereas SICI decreased when both the index and little fingers initiated sequences. This finding suggests that GLUTergic activity increases in a finger-specific manner whilst GABAA-mediated inhibition decreases in a finger-unspecific manner during preparation. In parallel, both rewards and punishments non-specifically increased ICF, but only rewards non-specifically decreased SICI as compared to neutral. This suggests that to enhance performance rewards both increase GLUTergic activity and decrease GABAA-mediated inhibition, whereas punishments selectively increase GLUTergic activity. A control experiment revealed that such changes were not observed post-movement as participants processed reward and punishment feedback, indicating they were selective to movement preparation. Collectively, these results map the intracortical excitability changes in M1 by which incentives enhance motor performance.

Classically interpreted as a competition between opposite memories (A vs B), anterograde interference (AI) also emerges in the absence of competing memories (A vs A), suggesting that mechanisms other than those involved in memory competition contribute to AI. To investigate this, we tested the hypothesis that extending motor practice would enhance a first memory, but come at the cost of reduced learning capabilities when subsequently exposed to a second learning session of the same task. Based on converging biological evidence, AI was expected to depend upon the degree of extended practice of the initial exposure. During a first Session, four conditions were carried out where participants (n = 24) adapted to a gradually introduced - 20 degrees visual deviation while the extent of the initial exposure was manipulated by varying the duration or type of the performance asymptote. Specifically, the performance asymptote at - 20 degrees was either Short (40 trials), Moderate (160 trials), Long (320 trials), or absent due to continuously changing perturbations around the mean of - 20 degrees (Jagged; 160 trials). After a 2-min interval, participants re-adapted to the same (-20 degrees) visual deviation, which was meant to probe the effect of extended practice in the first Session on the learning capabilities of a second identical memory (A vs A). The results first confirmed that the duration of exposure in the first Session enhanced immediate aftereffects in the Moderate, Long, and Jagged conditions as compared to the Short condition, suggesting that extended practice enhanced retention of the first memory. When comparing the second Session to the first one, results revealed a different pattern of re-adaptation depending on the duration of initial exposure: in the Short condition, there was evidence for facilitated re-adaptation and similar aftereffects. However, in the Moderate, Long and Jagged conditions, re-adaptation was similar and aftereffects were impaired, suggestive of AI. This suggests that extended practice initially enhances memory formation, but comes at the cost of reduced subsequent learning capabilities. One possibility is that AI occurs because extended practice induces the emergence of networkspecific homeostatic constraints, which limit subsequent neuroplastic and learning capabilities in the same neural network.

We report the occurrence of a TMS-related seizure in a healthy 19-year-old man with no history of neurological or psychiatric disorder. The participant had no family history of epilepsy, febrile seizures, or close head injury. After the episode, the participant reported past occurrences of loss of consciousness in the context of orthopaedic injuries. On the day of the event, the participant did not have additional risk factors; he did not take any medication at the moment of testing nor in the prior days and his sleep pattern did not change. He reported no illicit drug use, substance abuse, or taking high doses of caffeine. There was no unusual event in the preceding days. This was his first session of TMS. The event occurred in a research lab at the Research Center of Sherbrooke University Hospital. The session involved 30 minutes of static magnetic stimulation (SMS), tracking of corticospinal excitability (CSE) with single-pulse TMS, and repetitive TMS (rTMS). The session started with the measure of the resting motor threshold (RMT) assessed with electromyography from the first dorsal interosseus using the 5 out of 10 motor evoked potentials (MEPs) of >50μV criterion. Thirty single-pulse evoked MEPs were acquired with an intensity of 120% of RMT at baseline. SMS was performed using a nickel-plated neodymium disc magnet (N52, 50mm diameter, 25mm thickness, axially magnetized) placed for 30 minutes over the left primary motor cortex (M1) while the participant was at rest, a procedure presumed to reduce cortical excitability and hence, seizure susceptibility. The magnet was then removed, and thirty MEPs induced by single-pulse TMS at 120% of RMT were acquired at eight-minute intervals for 40 minutes, with interstimulus intervals varying between 5 and 7 seconds. At that point, the participant had received 210 single pulses of TMS; he was feeling well and did not report any side effects. The seizure occurred subsequently, while rTMS was being applied to the left M1 with a figure-of-eight coil oriented at 45o of midline and connected to a Rapid-2 stimulator (MagStim, Whitland, UK ®). The current was biphasic, and the stimulation parameters were the following: 15 Hz trains for 2 seconds (30 pulses), separated by an inter-train interval of 18.6 seconds, with an intensity set at 130% of RMT. The subject was sitting in a reclining chair (70o), and the experimenter was standing behind him. The seizure started during the second or third train of stimulation; a clonic movement appeared in the right hand, and gradually extended to the forearm, bicep, and shoulder, propagated to the contralateral side, and generalized into symmetric tonic-clonic activity. The patient convulsed for approximately 3 min before the seizure self-terminated. Oxygen saturation level and blood pressure could be measured, and the experimenter could not confirm the presence of eye deviation or head turning. There was no tongue biting or incontinence, but the patient suffered from a small scalp laceration during the convulsive episode. Postictal confusion lasted approximately 15 minutes and the patient had no recollection of the event. Close-by medical staff were immediately called in, and the patient was quickly transferred to the emergency room. A brain computerized tomography (CT) scan revealed no anomaly, and the patient was discharged 2 h after his admission. Five days after the event, the patient was seen by a neurologist who performed a complete neurological exam and awake electroencephalography recordings. No abnormality was noted. The clinical diagnosis of this event was TMS-induced focal to bilateral tonic-clonic seizure (secondary generalized seizure). The clinical presentation with regards to the site of onset and propagation pattern of the clonic movements, the duration of generalized convulsions, and the presence of postictal confusion strongly support this hypothesis over alternative diagnoses such as a syncopal episode or psychogenic non-epileptic seizure. This is the first report of the event, and it has not been listed elsewhere. Of note, the use of rTMS as reported here was an infringement of the approved study protocol. This ethical breach and the details of the event were communicated to the institution's review board within 24h. We obtained informed consent from the participant to publish this specific event as part of a scientific communication. A unique feature of this case is the presence of CSE measurements over an extensive period preceding the seizure. A close examination of the single pulse MEPs collected suggests that the application of SMS at the beginning of the session did not alter durably CSE, but that rTMS was applied during a period of enhanced excitability (Fig. 1). There is at least one report of seizures induced by high frequency rTMS during a situation of increased cortical excitability [[1]Edwardson M. Fetz E.E. Avery D.H. Seizure produced by 20Hz transcranial magnetic stimulation during isometric muscle contraction in a healthy subject.Clin Neurophysiol. 2011; 122: 2326-2327https://doi.org/10.1016/j.clinph.2011.04.005Crossref PubMed Scopus (11) Google Scholar], where 20Hz rTMS (90% RMT) was applied to the M1 during the performance of an isometric contraction, provoking a generalized seizure in a healthy participant without known risk factors. The authors postulated that the increase in CSE induced by the muscle contraction may have contributed to the cortical spread and lowering of the seizure threshold. Whether the presence of enhanced excitability played a determinant role in the present case is uncertain, as the intensity and train duration used could have been sufficient to induce a seizure in themselves. Nonetheless, researchers should be cautious when combining high frequency rTMS with interventions believed to increase cortical excitability. TMS studies conducted in these circumstances – or in any novel stimulation protocol – should use EMG to monitor the spread of excitation and afterdischarges in proximal muscles in order to interrupt stimulation when such manifestations occur [[2]Rossi S. Antal A. Bestmann S. Bikson M. Brewer C. Brockmöller J. et al.Safety and recommendations for TMS use in healthy subjects and patient populations, with updates on training, ethical and regulatory issues: expert Guidelines.Clin Neurophysiol. 2021; 132 (Wassermann E, Cohen L, Flitman S): 269-306https://doi.org/10.1016/j.clinph.2020.10.003Crossref PubMed Scopus (279) Google Scholar]. To our knowledge, 15 Hz rTMS with intensities above the RMT induced seizures in at least two other instances in individuals without known risk factors (105% and 120% RMT; >2.5-s trains) [[3]Chen R. Hallett M. Seizures in healthy people with repeated “safe” trains of transcranial magnetic stimuli.Lancet. 1996; 347: 825-826https://doi.org/10.5555/uri:pii:S0140673696908983Abstract Google Scholar,[4]Wassermann E.M. Risk and safety of repetitive transcranial magnetic stimulation: report and suggested guidelines from the international workshop on the safety of repetitive transcranial magnetic stimulation, june 5-7, 1996.Electroencephalogr Clin Neurophysiol. 1998; 108: 1-16https://doi.org/10.1016/s0168-5597(97)00096-8Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar], and in one individual with major depression that was sleep deprived [[5]Prikryl R. Kucerova H. Occurrence of epileptic paroxysm during repetitive transcranial magnetic stimulation treatment.J Psychopharmacol. 2005; 19: 313https://doi.org/10.1177/0269881105051545Crossref PubMed Scopus (18) Google Scholar] (110% RMT; 10-s trains). While current guidelines do not address specifically the safe settings for 15 Hz stimulation (1, 5, 10, 20, and 25Hz are discussed) [[2]Rossi S. Antal A. Bestmann S. Bikson M. Brewer C. Brockmöller J. et al.Safety and recommendations for TMS use in healthy subjects and patient populations, with updates on training, ethical and regulatory issues: expert Guidelines.Clin Neurophysiol. 2021; 132 (Wassermann E, Cohen L, Flitman S): 269-306https://doi.org/10.1016/j.clinph.2020.10.003Crossref PubMed Scopus (279) Google Scholar], we would like to note that all reported seizures using 15 Hz occurred when using settings exceeding the safety guidelines for 10 Hz stimulation. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Monetary rewards and punishments enhance motor performance and are associated with corticospinal excitability (CSE) increases within the motor cortex (M1) during movement preparation. However, such CSE changes have unclear origins; they could stem from increased glutamatergic (GLUTergic) facilitation and/or decreased type A gamma-aminobutyric acid (GABA A )-mediated inhibition within M1. To investigate this, paired-pulse transcranial magnetic stimulation was used to assess GLUTergic facilitation and GABA A inhibition within M1 whilst participants prepared to execute 4-element finger-press sequences. Behaviourally, rewards and punishments enhanced both reaction and movement times. Neurochemically, regardless of rewards or punishments, a digit- specific increase in GLUTergic facilitation and digit- unspecific decrease in GABA A inhibition occurred during preparation as movement onset approached. In parallel, both rewards and punishments non-specifically increased GLUTergic facilitation, but only rewards non-specifically decreased GABA A inhibition during preparation. This suggests that, to enhance performance, rewards both increase GLUTergic facilitation and decrease GABA A inhibition whilst punishments selectively increase GLUTergic facilitation. A control experiment revealed that such changes were not observed post-movement as participants processed reward and punishment feedback, indicating they were selective to movement preparation. Collectively, these results map the neurochemical changes in M1 by which incentives enhance motor performance.

The ingestion of alcohol yields acute biphasic subjective effects: stimulation before sedation. Despite their predictive relevance to the development of alcohol use disorders (AUD), the neurobiological markers accounting for the biphasic effects of alcohol remain poorly understood in humans. Informed by converging lines of evidence, this study tested the hypothesis that alcohol ingestion acutely increases gamma-aminobutyric acid (GABA)-mediated inhibition, which would positively and negatively predict the feeling of stimulation and sedation, respectively. To do so, healthy participants (n = 20) ingested a single dose of 94% ABV alcohol (males: 1.0 ml/kg; females: 0.85 ml/kg) in a randomized placebo-controlled cross-over design. The alcohol's biphasic effects were assessed with the Brief-Biphasic Alcohol Effects Scale, and non-invasive neurobiological markers were measured with transcranial magnetic stimulation, before and every 30 min (up to 120 min) after the complete ingestion of the beverage. Results showed that acute alcohol ingestion selectively increased the duration of the cortical silent period (CSP) as compared to placebo, suggesting that alcohol increases non-specific GABAergic inhibition. Importantly, CSP duration positively and negatively predicted increases in the feeling of stimulation and sedation, respectively, suggesting that stimulation emerges as GABAergic inhibition increases and that sedation emerges as GABAergic inhibition returns to baseline values. Overall, these results suggest that modulations of GABAergic inhibition are central to the acute biphasic subjective effects of alcohol, providing a potential preventive target to curb the progression of at-risk individuals to AUD.

The neurochemical mechanisms underlying motor memory consolidation remain largely unknown. Based on converging work showing that ethyl alcohol retrogradely enhances declarative memory consolidation, this work tested the hypothesis that post-learning alcohol ingestion would enhance motor memory consolidation. In a within-subject and fully counterbalanced design, participants (n = 24; 12M; 12F) adapted to a gradually introduced visual deviation and ingested, immediately after adaptation, a placebo (PBO), a medium (MED) or high (HIGH) dose of alcohol. The alcohol doses were bodyweight- and gender-controlled to yield peak breath alcohol concentrations of 0.00% in the PBO, ~0.05% in the MED and ~0.095% in the HIGH condition. Retention was evaluated 24 h later through reach aftereffects when participants were sober. The results revealed that retention levels were neither significantly nor meaningfully different in both the MED and HIGH conditions as compared to PBO (all absolute Cohen's dz values < ~0.2; small to negligible effects), indicating that post-learning alcohol ingestion did not alter motor memory consolidation. Given alcohol's known pharmacological GABAergic agonist and NMDA antagonist properties, one possibility is that these neurochemical mechanisms do not decisively contribute to motor memory consolidation. As converging work demonstrated alcohol's retrograde enhancement of declarative memory, the present results suggest that distinct neurochemical mechanisms underlie declarative and motor memory consolidation. Elucidating the neurochemical mechanisms underlying the consolidation of different memory systems may yield insights into the effects of over-the-counter drugs on everyday learning and memory but also inform the development of pharmacological interventions seeking to alter human memory consolidation.

Anterograde interference emerges when two opposite (B -> A) or identical tasks (A -> A) are learned in close temporal succession, suggesting that interference cannot be fully accounted for by competing memories. Informed by neurobiological evidence, this work tested the hypothesis that interference depends upon the degree of overlap between the neural networks involved in the learning of two tasks. In a fully within-subject and counterbalanced design, participants (n = 24) took part in two learning sessions where the putative overlap between learning-specific neural networks was behaviourally manipulated across four conditions by modifying reach direction and the effector used during gradual visuomotor adaptation. The results showed that anterograde interference emerged regardless of memory competition-that is, to a similar extent in the B -> A and A -> A conditions-and along a gradient as a function of the tasks' similarity. Specifically, learning under similar reaching conditions generated more anterograde interference than learning under dissimilar reaching conditions, suggesting that putatively overlapping neural networks are required to generate interference. Overall, these results indicate that competing memories are not the sole contributor to anterograde interference and suggest that overlapping neural networks between two learning sessions are required to trigger interference. One discussed possibility is that initial learning modifies the properties of its neural networks to constrain further plasticity induction and learning capabilities, therefore causing anterograde interference in a network-dependent manner. One implication is that learning-specific neural networks must be maximally dissociated to minimize the interfering influences of previous learning on subsequent learning.

While the effects of rewards on memory appear well documented, the effects of punishments remain uncertain. Based on neuroimaging data, this study tested the hypothesis that, as compared to a neutral condition, a context allowing successful punishment avoidance would enhance memory to a similar extent as rewards. In a fully within-subject and counter-balanced design, participants (n = 18) took part in 3 distinct learning sessions during which the delivery of performance-contingent monetary punishments and rewards was manipulated. Specifically, participants had to reach towards visual targets while compensating for a gradually introduced visual deviation. Accuracy at achieving targets was either punished (Hit: "+0$"; Miss: "- 0.5$), rewarded (Hit: "+0.5$"; Miss: "- 0$"), or associated with neutral binary feedback (Hit: "Hit"; Miss: "Miss"). Retention was assessed through reach aftereffects both immediately and 24 h after initial acquisition. The results disconfirmed the hypothesis by showing that the punishment and reward learning sessions both impaired retention as compared to the neutral session, suggesting that both types of incentives similarly impaired memory formation and consolidation. Two alternative but complementary interpretations are discussed. One interpretation is that the presence of punishments and rewards induced a negative learning context, which - based on neurobiological data - could have been sufficient to interfere with memory formation and consolidation. Another interpretation is that punishments and rewards emphasized the disrupting effects of target hits on implicit learning processes, therefore yielding retention impairments. Altogether, these results suggest that incentives can have counterproductive effects on memory.

Anterograde interference emerges when two differing tasks are learned in close temporal proximity, an effect repeatedly attributed to a competition between differing task memories. However, recent development alternatively suggests that initial learning may trigger a refractory period that occludes neuroplasticity and impairs subsequent learning, consequently mediating interference independently of memory competition. Accordingly, this study tested the hypothesis that interference can emerge when the same motor task is being learned twice, that is when competition between memories is prevented. In a first experiment, the inter-session interval (ISI) between two identical motor learning sessions was manipulated to be 2 min, 1 h or 24 h. Results revealed that retention of the second session was impaired as compared to the first one when the ISI was 2 min but not when it was 1 h or 24 h, indicating a time-dependent process. Results from a second experiment replicated those of the first one and revealed that adding a third motor learning session with a 2 min ISI further impaired retention, indicating a dose-dependent process. Results from a third experiment revealed that the retention impairments did not take place when a learning session was preceded by simple rehearsal of the motor task without concurrent learning, thus ruling out fatigue and confirming that retention is impaired specifically when preceded by a learning session. Altogether, the present results suggest that competing memories is not the sole mechanism mediating anterograde interference and introduce the possibility that a time- and dose-dependent refractory period—independent of fatigue—also contributes to its emergence. One possibility is that learning transiently perturbs the homeostasis of learning-related neuronal substrates. Introducing additional learning when homeostasis is still perturbed may not only impair performance improvements, but also memory formation.

Evidence-based therapeutic options for children with developmental coordination disorder (DCD) are scarce. This work explored the effects of cerebellar anodal transcranial direct current stimulation (atDCS) on three 48 h-apart motor sequence learning and upper limb coordination sessions in children with DCD. The results revealed that, as compared to a Sham intervention (n = 10), cerebellar atDCS (n = 10) did not meaningfully improve execution speed but tended to reduce the number of execution errors during motor sequence learning. However, cerebellar atDCS did neither meaningfully influence offline learning nor upper limb coordination, suggesting that atDCS' effects are circumscribed to its application duration. These results suggest that cerebellar atDCS could have beneficial effects as a complementary therapeutic tool for children with DCD.

Overlearning (i.e. extending practice at asymptote) is known to enhance retention (Postman, 1962). Shibata et al., (2017) examined the effect of overlearning on subsequent learning and found it leading to an increased inhibitory state and anterograde interference (i.e. detrimental effect of prior learning on future learning; A-B). Recent work from our laboratory (Hamel et al., 2021) showed that, if constrained into a close temporal window, learning twice the same task (A-A) also leads to anterograde interference. These findings dispute the assumption that exposure to a perturbation necessarily leads to faster re-adaptation the second time (i.e. savings; Krakauer, 2009). The objective of this work was to test whether increasing the duration of practice would increase the degree of anterograde interference. In a fully within-subject and counterbalanced design, four conditions were carried out where participants (n = 24) adapted to 20° gradual visual deviation while the length or type of the performance asymptote was manipulated. The performance asymptote at 20° was either Short (40 trials), Moderate (160 trials), Long (320 trials), or kept changing around 20° for 160 trials (Jagged). Following a 2-minute break, participants were re-exposed to the same visual deviation and practiced at performance asymptote for 40 trials. Namely, increasing the duration of asymptote (Short to Moderate) increased anterograde interference. Surprisingly, no further increase was detected (Moderate to Long), suggesting the presence of a ceiling effect. One interpretation is that the increased inhibitory state is prompted by the accumulation of adenosine due to the energy-consuming metaplasticity of sensorimotor adaptation.

We read with great interest the letter recently published by Hamel et al. reporting “no influence of static magnetic field stimulation applied for 30 minutes over the human M1 on corticospinal excitability” [[1]Hamel R. De La Fontaine É. Bernier P.M. Lepage J.F. Letter to the editor: No influence of static magnetic stimulation applied for 30 minutes over the human M1 on corticospinal excitability.Brain Stimul. 2020; 13: 594-596Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar], as measured by motor evoked potentials (MEPs) elicited by single-pulse transcranial magnetic stimulation (TMS). First of all, we would like to thank the authors for their attempt to replicate some of our findings on the long-lasting effects of transcranial static magnetic field stimulation (tSMS) [2Dileone M. Mordillo-Mateos L. Oliviero A. Foffani G. Long-lasting effects of transcranial static magnetic field stimulation on motor cortex excitability.Brain Stimul. 2018; 11: 676-688Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar, 6Pineda-Pardo J.A. Obeso I. Guida P. Dileone M. Strange B.A. Obeso J.A. et al.Static magnetic field stimulation of the supplementary motor area modulates resting-state activity and motor behavior.Commun Biol. 2019; 2: 397https://doi.org/10.1038/s42003-019-0643-8Crossref PubMed Scopus (16) Google Scholar]. In their previous tSMS paper, the authors showed that tSMS applied for 30 minutes over M1 significantly impairs online sequence learning [[3]Lacroix A. Proulx-Bégin L. Hamel R. De Beaumont L. Bernier P.M. Lepage J.F. Static magnetic stimulation of the primary motor cortex impairs online but not offline motor sequence learning.Sci Rep. 2019; 9: 9886Crossref PubMed Scopus (10) Google Scholar]. Using the exact same tSMS protocol, they now seem to fail to induce the expected reduction of MEP amplitude [[2]Dileone M. Mordillo-Mateos L. Oliviero A. Foffani G. Long-lasting effects of transcranial static magnetic field stimulation on motor cortex excitability.Brain Stimul. 2018; 11: 676-688Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar]. Thank to the full transparency of the authors, we could look carefully at their MEP data, which are available online [[1]Hamel R. De La Fontaine É. Bernier P.M. Lepage J.F. Letter to the editor: No influence of static magnetic stimulation applied for 30 minutes over the human M1 on corticospinal excitability.Brain Stimul. 2020; 13: 594-596Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar]. In 18 healthy subjects, they measured the average MEP amplitudes at baseline and at 6 time points within 1h after 30min of tSMS delivered to the left motor cortex. Their original Figure 1 suggests that the average MEP amplitudes of individual subjects displayed a relatively high variability across time points, which seems in contrast with the high within-session reliability of average MEP amplitudes reported in the literature [[4]Cavaleri R. Schabrun S.M. Chipchase L.S. The number of stimuli required to reliably assess corticomotor excitability and primary motor cortical representations using transcranial magnetic stimulation (TMS): a systematic review and meta-analysis.Syst Rev. 2017; 6: 48Crossref PubMed Scopus (59) Google Scholar,[5]Goldsworthy M.R. Hordacre B. Ridding M.C. Minimum number of trials required for within- and between-session reliability of TMS measures of corticospinal excitability.Neuroscience. 2016; 320: 205-209Crossref PubMed Scopus (105) Google Scholar]. To quantify this temporal variability, we measured the Pearson correlations between the average MEP amplitudes pre tSMS and the average MEP amplitudes at each of the 6 time points post tSMS (pre-post1: r = 0.22; pre-post2: r = 0.63; pre-post3: r = 0.19; pre-post4: r = 0.61; pre-post5: r = 0.54; pre-post6: r = 0.37). These correlations are markedly lower than the correlations observed in our study (pre-post MEP correlations ranged between 0.71 and 0.97, see Table 1 in Ref. [[2]Dileone M. Mordillo-Mateos L. Oliviero A. Foffani G. Long-lasting effects of transcranial static magnetic field stimulation on motor cortex excitability.Brain Stimul. 2018; 11: 676-688Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar]). Higher temporal variability implies lower statistical power to detect possible effects induced by an intervention. Temporal variability can be mitigated by aggregating data over time. We thus reasoned that by aggregating MEP amplitudes over the six time-points post-tSMS available in the authors’ data, sufficient statistical power might be reached to uncover a significant effect of tSMS. To reduce the impact of possible outliers, we aggregated the average MEP data across time points using the median. Data were then averaged across subjects and reported as mean ± standard deviation (n = 18). We observed that the post1-post6 median MEP amplitude (1.09 ± 0.38 mV) was significantly smaller than the baseline MEP amplitude pre-tSMS (1.28 ± 0.34 mV; paired t-test: p = 0.026). A slightly more significant difference was obtained with the Log-transformed (i.e. Log(x+1)) median MEP amplitude (p = 0.016), or the median of the Log-transformed MEP amplitude (p = 0.015). The post1-post6 median normalized MEP amplitude (0.867 ± 0.259) was also significantly smaller than 1 (one sample t-test: p = 0.043), suggesting a reduction compared to pre-tSMS. Further studies are certainly warranted to clarify what are the methodological and/or biological factors that may contribute to the variability of tSMS neurophysiological effects. Nonetheless, the authors’ data do support a significant “influence of static magnetic field stimulation applied for 30 minutes over the human M1 on corticospinal excitability”. A.O. and G.F. are cofounders of the company Neurek SL, which is a spinoff of the Foundation of the Hospital Nacional de Parapléjicos. L.M-M., A.O. and G.F. are inventors listed on the following patents: P201030610 and PCT/ES2011/070290 (patent abandoned). The research of the authors is funded by the Department of Economy, Industry and Competitiveness, Spain, and co-financed by the European Union (FEDER) “A way to make Europe” (SAF2016-80647-R and SAF2017-86246-R). Response to significant influence of static magnetic stimulation applied for 30 minutes over the human M1 on corticospinal excitabilityBrain Stimulation: Basic, Translational, and Clinical Research in NeuromodulationVol. 13Issue 5PreviewWe are pleased that our recent attempt to replicate the methods and results from Dileone et al. [1] has garnered attention from the authors of the original findings. Briefly, despite having a ∼99% probability of replicating the results from Dileone et al. [1], our results revealed that transcranial static magnetic stimulation (tSMS) yielded neither significant (all uncorrected p values > 0.101) nor meaningful (effect size values below medium-sized benchmark values; all Cohen’s dz < 0.408) depression of corticospinal excitability (CSE) [2], a finding also reported by another group using a smaller sample [3]. Full-Text PDF Open Access

The combination of behavioral experiences that enhance long‐term retention remains largely unknown. Informed by neurophysiological lines of work, this study tested the hypothesis that performance‐contingent monetary rewards potentiate repetition‐dependent forms of learning, as induced by extensive practice at asymptote, to enhance long‐term retention of motor memories. To this end, six groups of 14 participants ( n = 84) acquired novel motor behaviors by adapting to a gradual visuomotor rotation while these factors were manipulated. Retention was assessed 24 h later. While all groups similarly acquired the novel motor behaviors, results from the retention session revealed an interaction indicating that rewards enhanced long‐term retention, but only when practice was extended to asymptote. Specifically, the interaction indicated that this effect selectively occurred when rewards were intermittently available (i.e., 50%), but not when they were absent (i.e., 0%) or continuously available (i.e., 100%) during acquisition. This suggests that the influence of rewards on extensive practice and long‐term retention is nonlinear, as continuous rewards did not further enhance retention as compared with intermittent rewards. One possibility is that rewards’ intermittent availability allows to maintain their subjective value during acquisition, which may be key to potentiate long‐term retention.

Learning rarely occurs in isolation from previous experiences. In fact, the brain's response to an ongoing event depends on its previous history of activity. Namely, neurobiological evidence indicates that previous learning, by disrupting the brain's homeostatic state, can transiently saturate neuroplastic capacity, thus potentially impairing subsequent retention capacities. The objective of the present work was to test this hypothesis. Three distinct experiments were conducted in which participants (n = 124) adapted twice to the same gradually introduced 21° visuomotor rotation over two separate sessions. Retention was assessed through extinction of adapted behaviors upon removal of the rotation immediately after adaptation. Globally, results revealed that when the two sessions were interleaved with 2 or 12min, but not with 1 or 24h, retention of the second session was impaired as compared to the first one, suggesting a temporally graded saturation of retention capacities by previous learning. Furthermore, putatively inhibitory and excitatory repetitive transcranial magnetic stimulation (rTMS) protocols were applied over M1 during the 12min inter-session interval to modify the history of brain activity with the objective of restoring subsequent retention. Although the rTMS protocols effectively modulated M1 activity, they failed to alter subsequent retention capacities, suggesting that previous learning-induced homeostatic state disruption may be refractory to the effects of rTMS over M1. Globally, the present results indicate that the brain's retention capacities can be impaired by its previous history of learning of the same task and that the passage of time may remain, yet, the best way to restore retention capacities.

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.

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 STATEMENTThe 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.

It is generally conceived that the amount of practice trials and the delivery of performance-contingent monetary rewards are key drivers of long-term retention of motor memories. While these two factors likely interact to promote retention, this possibility has never been tested. Here, we tested this hypothesis by using a gradual visuomotor adaptation paradigm where the amount of practice trials (i.e., either 400 or 800) as well as the delivery of performance-contingent monetary rewards (i.e., either rewards or no reward) were manipulated. Participants took part in two experimental sessions separated by a 24-hour interval. During initial acquisition, performance and short-term retention were assessed via vision and no-vision catch trials, respectively. Long-term retention was measured the following day by using no vision trials. Expectedly, results revealed that performance-contingent rewards enhanced performance during the first 400 acquisition trials. Counter-intuitively, although performance remained similar between groups, levels of short-term retention were lower in the rewarded as compared to the unrewarded group during the last 400 acquisition trials. Unexpectedly, practicing for 800 trials with performance-contingent rewards impaired long-term retention as compared to when rewards were not delivered. Anticipatedly, practicing for 800 trials led to better long-term retention than practicing for 400 trials. The present results suggest that extrinsic rewards can undermine the formation of long-term motor memories, an idea that finds support in cellular/molecular studies, as well as work stemming from experimental psychology. Overall, these findings challenge classic reinforcement learning theories by showing that long-term retention does not always benefit from reward delivery during acquisition.