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Wright, D. L.

Publications and source records attributed to Wright, D. L..

11 recordsLinked to original sources

Characterizing bilateral M1 excitability changes after learning a novel spatiotemporal coordination pattern

Bimanual coordination is essential for many skilled everyday actions and requires maintaining specific spatiotemporal relationships between the two hands according to task demands. However, the contribution of the primary motor cortices (M1s) to learning such relationships is only partially understood. Conventional bimanual tasks necessarily engage both M1s in controlling the moving hands, making learning-related changes difficult to distinguish from those associated with movement execution. To reduce this effector-related confound, we used a unimanual and bimanual rhythmic coordination paradigm in which participants learned the same novel 90-degree relative-phase relationship by coordinating either hand with a virtual partner and compared these conditions with conventional bimanual practice. In three experiments, performance accuracy and stability improved during practice and improved further after a 6-h retention interval with comparable time-dependent changes across unimanual and bimanual trained groups. In Experiment 2, motor-evoked potentials measured before and after training revealed an overall increase in corticospinal excitability across both M1s under unimanual and bimanual training. In Experiment 3, bidirectional dual-site paired-pulse stimulation revealed effector-dependent changes in interhemispheric inhibition, in which bimanual practice produced no reliable directional modulation, whereas unimanual practice produced asymmetric changes that depended on the trained hand. Neither corticospinal excitability nor interhemispheric inhibition showed a consistent relationship with behavioral improvement. Together, these findings demonstrate comparable behavioral learning of a novel spatiotemporal coordination relationship across bimanual and unimanual contexts, while showing that behavioral improvement is not straightforwardly reflected in M1 neurophysiological changes. Causal intervention studies are therefore needed to determine whether and when M1 contributes directly to acquisition of novel coordination relationships.

neuroscience↗

A Causal Role for the Hippocampus in Gating Rapid Motor Memory Consolidation

How humans acquire motor skills is a fundamental biological question. Early learning involves rapid gains during practice and brief rest, yet the causal contribution of the hippocampus remains unclear. Here, we applied individualized, MRI-guided transcranial ultrasound stimulation (TUS) to modulate the posterior hippocampus in healthy adults. To establish a physiological benchmark, we first showed that this TUS protocol produced a sustained reduction in corticospinal excitability when applied to the primary motor cortex. When applied to the posterior hippocampus, electroencephalography revealed reduced frontocentral gamma-band activity, providing physiological evidence of hippocampal-frontal network modulation. Behaviorally, TUS altered the temporal dynamics of skill acquisition. Compared with sham, hippocampal TUS attenuated micro-offline gains during rest while increasing performance improvements during active practice. This shift from offline to online learning was replicated in an independent cohort with comparable baseline motor performance. Importantly, hippocampal TUS enhanced overall performance during learning, and this higher level of performance remained evident 24 hours later. Together, these findings provide causal evidence that the human hippocampus contributes to how motor learning is distributed between active practice and brief rest, showing that this temporal organization of learning can be altered by non-invasive neuromodulation.

neuroscience↗

Connectivity between supplementary motor complex and primary motor cortex: a dual-coil paired-pulse TMS study

In recent years, dual-coil paired-pulse transcranial magnetic stimulation (ppTMS) has garnered interest for its potential in elucidating neural circuit dynamics. In this study, the dual-coil ppTMS was utilized to assess the effective connectivity between the supplementary motor complex (SMC) and the primary motor cortex (M1) in humans. A robust facilitatory connection between the SMC and M1 was observed, manifested as a 19% increase in mean peak-to-peak motor-evoked potentials following preconditioning of SMC 7 ms prior to M1 stimulation. Importantly, the facilitatory influence of SMC only occurred when the preconditioning stimulation was administered 4 cm anterior to Cz but not when applied at 5-cm, 6-cm, or 7-cm distance. While previous work has focused on demonstrating important temporal dynamics for SMC-M1 plasticity, the present findings highlight a critical contribution of spatial specificity for modulation of SMC-M1 circuitry. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/610643v1_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@12fb447org.highwire.dtl.DTLVardef@e4bfacorg.highwire.dtl.DTLVardef@1e3d262org.highwire.dtl.DTLVardef@93984_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIThe conditioned stimulus induced larger MEPs compared to the unconditioned stimulus C_LIO_LIThe connectivity between SMC and M1 diminished when the SMC coil was moved forward C_LIO_LIFindings highlight the importance of spatial specificity for modulation of SMC-M1 circuitry C_LI

neuroscience↗

A cup of coffee can boost your motor performance: Enhanced motor sequence learning with caffeine

Caffeine is consumed in various beverages, such as coffee, energy drinks, soda, and tea. The effects of caffeine have been shown to manifest in various ways across different studies. Some studies suggest that caffeine can enhance motor performance. Despite this, numerous motor learning studies do not control for participants caffeine intake or do not record whether participants consumed caffeine. The purpose of this study was to compare the motor learning performance (i.e., online improvement) of individuals who consumed caffeine and those who did not before practice with a novel motor sequence task. Sixty-five right-handed healthy undergraduate students participated in this study. Individuals reported their caffeine consumption through a pre-experiment questionnaire prior to performing an eight-item serial reaction time task. The participants who consumed caffeine reported drinking one cup of coffee on average 158.8 minutes before performing the sequential task. The motor performance of individuals who consumed caffeine was compared to those who did not, with the caffeine-consuming group (n = 13) exhibiting faster response times during online learning than the non-caffeine group (n = 52). The findings of this study suggest that caffeine should be controlled for in future motor learning research.

neuroscience↗

Combined effects of pharmacological interventions and intermittent theta-burst stimulation on motor sequence learning

Drugs that modulate N-methyl-D-aspartate (NMDA) or {gamma}-Aminobutyric acid type A (GABAA) receptors can shed light on their role in synaptic plasticity mechanisms underlying the effects of non-invasive brain stimulation. However, research on the combined effects of these drugs and exogenous stimulation on motor learning is limited. This study aimed to investigate the effects of pharmacological interventions combined with intermittent theta-burst stimulation (iTBS) on human motor learning. Nine right-handed healthy subjects (mean age {+/-} SD: 31.56 {+/-} 12.96 years; 6 females) participated in this double-blind crossover study. All participants were assigned to four drug conditions in a randomized order: (1) D-cycloserine (partial NMDA receptor agonist), (2) D-cycloserine + dextromethorphan (NMDA receptor agonist + antagonist), (3) lorazepam (GABAA receptor agonist), and (4) placebo (identical microcrystalline cellulose capsule). After drug intake, participants practiced the 12-item keyboard sequential task as a baseline measure. Two hours after drug intake, iTBS was administered at the primary motor cortex. Following iTBS, the retention test was performed in the same manner as the baseline measure. Our findings revealed that lorazepam combined with iTBS impaired motor learning during the retention test. Future studies are still needed for a better understanding of the mechanisms through which TMS may influence human motor learning.

neuroscience↗

Generalization in motor learning: learning bimanual coordination with one hand

The ability to coordinate movements between the hands is crucial for many daily tasks. However, the precise mechanisms governing the storage and utilization of bimanual movement and the distinct contributions of each limb in this process are currently not fully understood. Two key questions persist: 1) How is the neural representation of bimanual coordination stored in the brain, and 2) How is the information governing bimanual coordination shared between hemispheres? In this investigation, we used a virtual partner (VP) to systematically address these issues by allowing the same coordination pattern (CP) to be acquired with unimanual and bimanual movements. More specifically, we used four experimental groups: unimanual (left, right) VP, bimanual, and control conditions. For each condition, retention and transfer tests were administered immediately and 6 hours after the initial practice. The control condition employed the same protocol as unimanual conditions without practice. As anticipated, performance after practice and during retention sessions indicated that all groups learned to perform the target CP. Furthermore, generalization from unimanual to bimanual occurred when the same type of visual feedback (VF) was provided. Interestingly, the absence of VF impaired motor generalization from unimanual to bimanual condition unless the participants initially practiced the task bimanually. Taken together, our results demonstrated that both limbs could access the memory representation of the CP. However, this globally shared representation appeared to be encoded in the visual-spatial domain. The conditions without VF underscored the importance of proprioception in forming a motor representation in intrinsic coordinates. NEW & NOTEWORTHYConventional views on acquiring bimanual skills stress the need for simultaneous engagement of both hands. However, our study challenges this notion by demonstrating that the coordination pattern learned in unimanual conditions significantly boosts subsequent bimanual coordination--a novel approach to skill acquisition. Yet, this advantage diminishes without visual feedback, resulting in a breakdown of the intended bimanual coordination, highlighting the limitations of relying solely on unimanual practice.

neuroscience↗

M1 recruitment during interleaved practice is important for encoding, not just consolidation, of novel skill memory

Primary motor cortex (M1) plays a major role in motor memory acquisition and retention in humans, but its role in interleaved practice (as opposed to repetitive practice) remains unknown. We anticipated that the improved retention typically associated with interleaved practice depends on M1, and thus cathodal transcranial direct current (ctDCS) stimulation to M1 during training would disrupt this improved retention. The benefits of interleaved practice have been reported to occur from more effective consolidation, manifested as rapid skill memory stabilization followed by more long-term enhancement. While we observed the expected decline in retention performance following interleaved practice paired with ctDCS, this reduced retention resulted from more modest encoding of novel skill memory during acquisition rather than from disruption of offline consolidation processes. These data highlight the broad role played by motor cortex for both encoding and retention of novel skill memory.

neuroscience↗

C3 in the 10-20 system may not be the best target for the motor hand area

The C3 region in the international 10-20 system for electroencephalography (EEG) recording is assumed to represent the right motor hand area. Therefore, in the absence of transcranial magnetic stimulation (TMS) or a neuronavigational system, neuromodulation methods, such as transcranial direct current stimulation, target C3 or C4, based on the international 10-20 system, to influence the cortical excitability of the right and left hand, respectively. The purpose of this study is to compare the peak-to-peak motor evoked potential (MEP) amplitudes of the right first dorsal interosseus (FDI) muscle after single-pulse TMS at C3, C3h, and C1. Using an intensity of 110% of the resting motor threshold, 15 individual MEPs from each of C3, C3h, C1, and hotspots were randomly recorded from FDI for sixteen right-handed undergraduate students. Average MEPs were greatest at C3h and C1, with both being larger than those recorded at C3. These data are congruent with recent findings using topographic analysis of individual MRIs that revealed poor correspondence between C3/C4 and the respective hand knob. Implications for the use of scalp locations determined using the 10-20 system for localizing the hand area are highlighted. HighlightsO_LIMEPs recorded at C3h and C1 were larger than those recorded at C3. C_LIO_LIScalp locations other than C3 offer a more accurate estimation of human hand area. C_LI

neuroscience↗

Timing of Transcranial Direct Current Stimulation at M1 Does Not Affect Motor Sequence Learning

Administering anodal tDCS at the primary motor cortex (M1) at various temporal loci relative to motor training is reported to affect subsequent performance gains. Stimulation administered in conjunction with motor training appears to offer the most robust benefit that emerges during offline epochs. This conclusion is made, however, based on between-experiment comparisons that involved varied methodologies. The present experiment addressed this shortcoming by administering the same 15-minute dose of anodal tDCS at M1 before, during, or after practice of a serial reaction time task (SRTT). It was anticipated that exogenous stimulation during practice with a novel SRTT would facilitate offline gains. Ninety participants were randomly assigned to one of four groups: tDCS before practice, tDCS during practice, tDCS after practice, or no tDCS. Each participant was exposed to 15 minutes of 2 mA of tDCS and motor training of an eight-element SRTT. The anode was placed at right M1 with the cathode at left M1, and the left hand was used to execute the SRTT. Test blocks were administered 1 and 24 hours after practice concluded. The results revealed significant offline gain for all conditions at the 1-hour and 24-hour test blocks. Importantly, exposure to anodal tDCS at M1 at any point before, during, or after motor training failed to change the trajectory of skill development as compared to the no stimulation control condition. These data add to the growing body of evidence questioning the efficacy of exogenous stimulation as an adjunct to motor training for fostering skill learning. HighlightsO_LITime-dependent consolidation of a novel motor skill occurred within 1 hour after the first practice block C_LIO_LIFurther consolidation of this memory still occurred 24 hours after practice C_LIO_LItDCS at M1 before, during, or after the initial bout of practice did not modify online or offline performance gains C_LI

neuroscience↗

Chiral evasion and stereospecific antifolate resistance in Staphylococcus aureus

Antimicrobial resistance is a health care crisis. The resistance-conferring mutation F98Y in Staphylococcus aureus dihydrofolate reductase (SaDHFR) reduces effectiveness of antifolates, e.g., trimethoprim (TMP). Although propargyl-linked antifolates (PLAs) are much more resilient than TMP towards F98Y, this substitution still vitiates their inhibition potency. Surprisingly, differences in the enantiomeric configuration at the stereogenic center of PLAs influence the isomeric state of NADPH cofactor. Is resistance correlated with chiral evasion? A mechanism of action underpinning this coupling is unknown. To understand the molecular basis of F98Y-mediated resistance and how PLAs inhibition drives NADPH isomeric states, we used OSPREY to analyze a comprehensive suite of structural, biophysical, biochemical, and computational data. We present a model showing how F98Y SaDHFR exploits a different anomeric configuration of NADPH to evade certain PLAs inhibition, while other PLAs remain resilient to resistance. Our model should enable general design of inhibitors that are resilient to chiral evasion.

biochemistry↗

Toward Broad Spectrum DHFR inhibitors Targeting Trimethoprim Resistant Enzymes Identified in Clinical Isolates of Methicillin-Resistant Staphylococcus aureus

The spread of plasmid borne resistance enzymes in clinical Staphylococcus aureus isolates is rendering trimethoprim and iclaprim, both inhibitors of dihydrofolate reductase (DHFR), ineffective. Continued exploitation of these targets will require compounds that can broadly inhibit these resistance-confering isoforms. Using a structure-based approach, we have developed a novel class of ionized non-classical antifolates (INCAs) that capture the molecular interactions that have been exclusive to classical antifolates. These modifications allow for a greatly expanded spectrum of activity across these pathogenic DHFR isoforms, while maintaining the ability to penetrate the bacterial cell wall. Using biochemical, structural and computational methods, we are able to optimize these inhibitors to the conserved active sites of the endogenous and trimethoprim resistant DHFR enzymes. Here, we report a series of INCA compounds that exhibit low nanomolar enzymatic activity and potent cellular activity with human selectivity against a panel of clinically relevant TMPR MRSA isolates.

biochemistry↗