Commentary on Frank et al., (2003): where does learning through motor imagery lie on the perceptual-motor continuum?

In this issue, Frank et al. (2023) propose that motor imagery provides a perceptual-cognitive scaffold allowing 'perceptual' learning to transfer into 'motor' learning. The present commentary explores the perspective that changes in perception itself are often critical to the development of motor skills. Motor imagery may therefore be most beneficial for developing motor skills with high perceptual demands, such as requiring rapid action selection. Potential challenges for the perceptual-cognitive scaffold approach are identified based on the possible involvement of mechanisms involved in motor learning through movement execution, and how they may be recruited through the use of motor imagery.

Inhibition, Shifting and Updating: Inter and intra-domain commonalities and differences from an executive functions activation likelihood estimation meta-analysis.

Executive functions are higher-order mental processes that support goal-directed behavior. Among these processes, Inhibition, Updating, and Shifting have been considered core executive domains. In this meta-analysis, we comprehensively investigate the neural networks of these executive domains and we synthesize for the first time the neural convergences and divergences among the most frequently used executive paradigms within those domains. A systematic search yielded 1055 published neuroimaging studies (including 26,191 participants in total). Our study revealed that a fronto-parietal network was shared by the three main domains. Furthermore, we executed conjunction analyses among the paradigms of the same domain to extract the core distinctive components of the main executive domains. This approach showed that Inhibition and Shifting are characterized by a strongly lateralized neural activation in the right and left hemisphere, respectively. In addition, both networks overlapped with the Updating network but not with each other. Remarkably, our study detected heterogeneity among the paradigms from the same domain. More specifically, analysis of Inhibition tasks revealed differing activations for Response Inhibition compared to Interference Control paradigms, suggesting that Inhibition encompasses relatively heterogeneous sub-functions. Shifting analyses revealed a bilateral overlap of the Wisconsin Card Sorting Task with the Updating network, but this pattern was absent for Rule Switching and Dual Task paradigms. Moreover, our Updating meta-analyses revealed the neural signatures associated with the specific modules of the Working Memory model from Baddeley and Hitch. To our knowledge, this is the most comprehensive meta-analysis of executive functions to date. Its paradigm-driven analyses provide a unique contribution to a better understanding of the neural convergences and divergences among executive processes that are relevant for clinical applications, such as cognitive enhancement and neurorehabilitation interventions.

Age-related increases in reaction time result from slower preparation, not delayed initiation.

Recent work indicates that healthy younger adults can prepare accurate responses faster than their voluntary reaction times would suggest, leaving a seemingly unnecessary delay of 80-100 ms before responding. Here, we examined how the preparation of movements, initiation of movements, and the delay between them are affected by aging. Participants made planar reaching movements in two conditions. The "free reaction time" condition assessed the voluntary reaction times with which participants responded to the appearance of a stimulus. The "forced reaction time" condition assessed the minimum time actually needed to prepare accurate movements by controlling the time allowed for movement preparation. The time taken to both initiate movements in the free reaction time and to prepare movements in the forced response condition increased with age. Notably, the time required to prepare accurate movements was significantly shorter than participants' self-selected initiation times; however, the delay between movement preparation and initiation remained consistent across the lifespan (∼90 ms). These results indicate that the slower reaction times of healthy older adults are not due to an increased hesitancy to respond, but can instead be attributed to changes in their ability to process stimuli and prepare movements accordingly, consistent with age-related changes in brain structure and function.NEW & NOTEWORTHY Previous research argues that older adults have slower response times because they hesitate to react, favoring accuracy over speed. The present results challenge this proposal. We found the delay between the minimum time required to prepare movements and the self-selected time at which they initiated remained consistent at ∼90 ms from ages 21 to 80. We therefore suggest older adults' slower response times can be attributed to changes in their ability to process stimuli and prepare movements.

Spatial scales in human movement between reservoirs of infection.

The life cycle of parasitic organisms that are the cause of much morbidity in humans often depend on reservoirs of infection for transmission into their hosts. Understanding the daily, monthly and yearly movement patterns of individuals between reservoirs is therefore of great importance to implementers of control policies seeking to eliminate various parasitic diseases as a public health problem. This is due to the fact that the underlying spatial extent of the reservoir of infection, which drives transmission, can be strongly affected by inputs from external sources, i.e., individuals who are not spatially attributed to the region defined by the reservoir itself can still migrate and contribute to it. In order to study the importance of these effects, we build and examine a novel theoretical model of human movement between spatially-distributed focal points for infection clustered into regions defined as 'reservoirs of infection'. Using our model, we vary the spatial scale of human moment defined around focal points and explicitly calculate how varying this definition can influence the temporal stability of the effective transmission dynamics - an effect which should strongly influence how control measures, e.g., mass drug administration (MDA), define evaluation units (EUs). Considering the helminth parasites as our main example, by varying the spatial scale of human movement, we demonstrate that a critical scale exists around infectious focal points at which the migration rate into their associated reservoir can be neglected for practical purposes. This scale varies by species and geographic region, but is generalisable as a concept to infectious reservoirs of varying spatial extents and shapes. Our model is designed to be applicable to a very general pattern of infectious disease transmission modified by the migration of infected individuals between clustered communities. In particular, it may be readily used to study the spatial structure of hosts for macroparasites with temporally stationary distributions of infectious focal point locations over the timescales of interest, which is viable for the soil-transmitted helminths and schistosomes. Additional developments will be necessary to consider diseases with moving reservoirs, such as vector-born filarial worm diseases.

Skill acquisition is enhanced by reducing trial-to-trial repetition.

Developing approaches to improve motor skill learning is of considerable interest across multiple disciplines. Previous research has typically shown that repeating the same action on consecutive trials enhances short-term performance but has detrimental effects on longer term skill acquisition. However, most prior research has contrasted the effects of repetition only at the block level; in the current study we examined the effects of repeating individual trials embedded in a larger randomized block, a feature that is often overlooked when random trial orders are generated in learning tasks. With 4 days of practice, a "Minimal Repeats" group, who rarely experienced repeating stimuli on consecutive trials during training, improved to a greater extent than a "Frequent Repeats" group, who were frequently presented with repeating stimuli on consecutive trials during training. Our results extend the previous finding of the beneficial effects of random compared with blocked practice on performance, showing that reduced trial-to-trial repetition during training is favorable with regard to skill learning. This research highlights that limiting the number of repeats on consecutive trials is a simple behavioral manipulation that can enhance the process of skill learning. Data/analysis code and Supplemental Material are available at https://osf.io/p3278/.NEW & NOTEWORTHY Numerous studies have shown that performing different subtasks across consecutive blocks of trials enhances learning. We examined whether the same effect would occur on a trial-to-trial level. Our Minimal Repeats group, who primarily responded to different stimuli on consecutive trials, learned more than our Frequent Repeats group, who frequently responded to the same stimulus on consecutive trials. This shows that minimizing trial-to-trial repetition is a simple and easily applicable manipulation that can enhance learning.

The 'breakpoint' of soil-transmitted helminths with infected human migration.

Building on past research, we here develop an analytic framework for describing the dynamics of the transmission of soil-transmitted helminth (STH) parasitic infections near the transmission breakpoint and equilibria of endemic infection and disease extinction, while allowing for perturbations in the infectious reservoir of the parasite within a defined location. This perturbation provides a model for the effect of infected human movement between villages with differing degrees of parasite control induced by mass drug administration (MDA). Analysing the dynamical behaviour around the unstable equilibrium, known as the transmission 'breakpoint', we illustrate how slowly-varying the dynamics are and develop an understanding of how discrete 'pulses' in the release of transmission stages (eggs or larvae, depending on the species of STH), due to infected human migration between villages, can lead to perturbations in the deterministic transmission dynamics. Such perturbations are found to have the potential to undermine targets for parasite elimination as a result of MDA and/or improvements in water and sanitation provision. We extend our analysis by developing a simple stochastic model and analytically investigate the uncertainty this induces in the dynamics. Where appropriate, all analytical results are supported by numerical analyses.

Reciprocal intralimb transfer of skilled isometric force production.

Motor control theories propose that the same motor plans can be employed by different effectors (e.g., the hand and arm). Skills learned with one effector can therefore "transfer" to others, which has potential applications in clinical situations. However, evidence from adaptation suggests this effect is not reciprocal; learning can be generalized from proximal to distal effectors (e.g., arm to hand), but not from distal to proximal effectors (e.g., hand to arm). We propose that skill learning may not follow the same pattern, because it relies on multiple learning processes beyond error detection and correction. Participants learned a skill task involving the production of isometric forces. We assessed their ability to perform the task with the hand and arm. One group then trained to perform the task using only their hand, whereas a second group trained using only their arm. In a final assessment, we found that participants who trained with either effector improved their skill in performing the task with both their hand and arm. There was no change in a control group that did not train between assessments, indicating that gains were related to the training, not the multiple assessments. These results indicate that in contrast to adaptation, motor skills can generalize from both proximal to distal effectors and from distal to proximal effectors. We propose this is due to differences in the processes underlying skill acquisition as compared with adaptation. NEW & NOTEWORTHY Prior research indicates that motor learning transfers from proximal to distal effectors, but not vice versa. However, this work focused on adapting existing behavior; we questioned whether different results would occur during learning of new motor skills. We found that the benefits of training on a skill task with either the hand or arm transferred across both effectors. This highlights important differences between adaptation and skill learning, and may allow therapeutic benefits for patients with impairments in specific effectors.

Resting state morphology predicts the effect of theta burst stimulation in false belief reasoning.

When required to represent a perspective that conflicts with one's own, functional magnetic resonance imaging (fMRI) suggests that the right ventrolateral prefrontal cortex (rvlPFC) supports the inhibition of that conflicting self-perspective. The present task dissociated inhibition of self-perspective from other executive control processes by contrasting belief reasoning-a cognitive state where the presence of conflicting perspectives was manipulated-with a conative desire state wherein no systematic conflict existed. Linear modeling was used to examine the effect of continuous theta burst stimulation (cTBS) to rvlPFC on participants' reaction times in belief and desire reasoning. It was anticipated that cTBS applied to rvlPFC would affect belief but not desire reasoning, by modulating activity in the Ventral Attention System (VAS). We further anticipated that this effect would be mediated by functional connectivity within this network, which was identified using resting state fMRI and an unbiased model-free approach. Simple reaction-time analysis failed to detect an effect of cTBS. However, by additionally modeling individual measures from within the stimulated network, the hypothesized effect of cTBS to belief (but, importantly, not desire) reasoning was demonstrated. Structural morphology within the stimulated region, rvlPFC, and right temporoparietal junction were demonstrated to underlie this effect. These data provide evidence that inconsistencies found with cTBS can be mediated by the composition of the functional network that is being stimulated. We suggest that the common claim that this network constitutes the VAS explains the effect of cTBS to this network on false belief reasoning. Hum Brain Mapp 37:3502-3514, 2016. © 2016 Wiley Periodicals, Inc.

Multimodal connectivity of motor learning-related dorsal premotor cortex.

The dorsal premotor cortex (dPMC) is a key region for motor learning and sensorimotor integration, yet we have limited understanding of its functional interactions with other regions. Previous work has started to examine functional connectivity in several brain areas using resting state functional connectivity (RSFC) and meta-analytical connectivity modelling (MACM). More recently, structural covariance (SC) has been proposed as a technique that may also allow delineation of functional connectivity. Here, we applied these three approaches to provide a comprehensive characterization of functional connectivity with a seed in the left dPMC that a previous meta-analysis of functional neuroimaging studies has identified as playing a key role in motor learning. Using data from two sources (the Rockland sample, containing resting state data and anatomical scans from 132 participants, and the BrainMap database, which contains peak activation foci from over 10,000 experiments), we conducted independent whole-brain functional connectivity mapping analyses of a dPMC seed. RSFC and MACM revealed similar connectivity maps spanning prefrontal, premotor, and parietal regions, while the SC map identified more widespread frontal regions. Analyses indicated a relatively consistent pattern of functional connectivity between RSFC and MACM that was distinct from that identified by SC. Notably, results indicate that the seed is functionally connected to areas involved in visuomotor control and executive functions, suggesting that the dPMC acts as an interface between motor control and cognition.

Evolutionary history of copy-number-variable locus for the low-affinity Fcγ receptor: mutation rate, autoimmune disease, and the legacy of helminth infection.

Both sequence variation and copy-number variation (CNV) of the genes encoding receptors for immunoglobulin G (Fcγ receptors) have been genetically and functionally associated with a number of autoimmune diseases. However, the molecular nature and evolutionary context of this variation is unknown. Here, we describe the structure of the CNV, estimate its mutation rate and diversity, and place it in the context of the known functional alloantigen variation of these genes. Deletion of Fcγ receptor IIIB, associated with systemic lupus erythematosus, is a result of independent nonallelic homologous recombination events with a frequency of approximately 0.1%. We also show that pathogen diversity, in particular helminth diversity, has played a critical role in shaping the functional variation at these genes both between mammalian species and between human populations. Positively selected amino acids are involved in the interaction with IgG and include some amino acids that are known polymorphic alloantigens in humans. This supports a genetic contribution to the hygiene hypothesis, which states that past evolution in the context of helminth diversity has left humans with an array of susceptibility alleles for autoimmune disease in the context of a helminth-free environment. This approach shows the link between pathogens and autoimmune disease at the genetic level and provides a strategy for interrogating the genetic variation underlying autoimmune-disease risk and infectious-disease susceptibility.

Haptoglobin (HP) and Haptoglobin-related protein (HPR) copy number variation, natural selection, and trypanosomiasis.

Haptoglobin, coded by the HP gene, is a plasma protein that acts as a scavenger for free heme, and haptoglobin-related protein (coded by the HPR gene) forms part of the trypanolytic factor TLF-1, together with apolipoprotein L1 (ApoL1). We analyse the polymorphic small intragenic duplication of the HP gene, with alleles Hp1 and Hp2, in 52 populations, and find no evidence for natural selection either from extended haplotype analysis or from correlation with pathogen richness matrices. Using fiber-FISH, the paralog ratio test, and array-CGH data, we also confirm that the HPR gene is copy number variable, with duplication of the whole HPR gene at polymorphic frequencies in west and central Africa, up to an allele frequency of 15 %. The geographical distribution of the HPR duplication allele overlaps the region where the pathogen causing chronic human African trypanosomiasis, Trypanosoma brucei gambiense, is endemic. The HPR duplication has occurred on one SNP haplotype, but there is no strong evidence of extended homozygosity, a characteristic of recent natural selection. The HPR duplication shows a slight, non-significant undertransmission to human African trypanosomiasis-affected children of unaffected parents in the Democratic Republic of Congo. However, taken together with alleles of APOL1, there is an overall significant undertransmission of putative protective alleles to human African trypanosomiasis-affected children.

Automated design of paralogue ratio test assays for the accurate and rapid typing of copy number variation.

MOTIVATION: Genomic copy number variation (CNV) can influence susceptibility to common diseases. High-throughput measurement of gene copy number on large numbers of samples is a challenging, yet critical, stage in confirming observations from sequencing or array Comparative Genome Hybridization (CGH). The paralogue ratio test (PRT) is a simple, cost-effective method of accurately determining copy number by quantifying the amplification ratio between a target and reference amplicon. PRT has been successfully applied to several studies analyzing common CNV. However, its use has not been widespread because of difficulties in assay design. RESULTS: We present PRTPrimer (www.prtprimer.org) software for automated PRT assay design. In addition to stand-alone software, the web site includes a database of pre-designed assays for the human genome at an average spacing of 6 kb and a web interface for custom assay design. Other reference genomes can also be analyzed through local installation of the software. The usefulness of PRTPrimer was tested within known CNV, and showed reproducible quantification. This software and database provide assays that can rapidly genotype CNV, cost-effectively, on a large number of samples and will enable the widespread adoption of PRT. AVAILABILITY: PRTPrimer is available in two forms: a Perl script (version 5.14 and higher) that can be run from the command line on Linux systems and as a service on the PRTPrimer web site (www.prtprimer.org).

Accelerometry as a tool for measuring the effects of transcranial magnetic stimulation.

OBJECTIVE: We predicted that accelerometry would be a viable alternative to electromyography (EMG) for assessing fundamental Transcranial Magnetic Stimulation (TMS) measurements (e.g. Resting Motor Threshold (RMT), recruitment curves, latencies). NEW METHOD: 21 participants were tested. TMS evoked responses were recorded with EMG on the First Dorsal Interosseus muscle and an accelerometer on the index fingertip. TMS was used to determine the (EMG-defined) RMT, then delivered at a range of intensities allowing determination of both the accelerometry-defined RMT and measurement of recruitment curves. RESULTS: RMT assessed by EMG was significantly lower than for accelerometry (t(19)=-3.84, p<.001, mean±SD EMG = 41.1±5.28% MSO (maximum stimulator output), Jerk = 44.55±5.82% MSO), though RMTs calculated for each technique were highly correlated (r(18)=.72, p<.001). EMG/Accelerometery recruitment curves were strongly correlated (r(14)=.98, p<.001), and Bayesian model comparison indicated they were equivalent (BF01>9). Latencies measured with EMG were lower and more consistent than those identified using accelerometry (χ2(1)=80.38, p<.001, mean±SD EMG=27.01±4.58 ms, Jerk=48.4±15.33 ms). COMPARISON WITH EXISTING METHODS: EMG is used as standard by research groups that study motor control and neurophysiology, but accelerometry has not yet been considered as a potential tool to assess measurements such as the overall magnitude and latency of the evoked response. CONCLUSIONS: While EMG provides more sensitive and reliable measurements of RMT and latency, accelerometry provides a reliable alternative to measure of the overall magnitude of TMS evoked responses.

Guidelines for reporting action simulation studies (GRASS): Proposals to improve reporting of research in motor imagery and action observation.

Researchers from multiple disciplines have studied the simulation of actions through motor imagery, action observation, or their combination. Procedures used in these studies vary considerably between research groups, and no standardized approach to reporting experimental protocols has been proposed. This has led to under-reporting of critical details, impairing the assessment, replication, synthesis, and potential clinical translation of effects. We provide an overview of issues related to the reporting of information in action simulation studies, and discuss the benefits of standardized reporting. We propose a series of checklists that identify key details of research protocols to include when reporting action simulation studies. Each checklist comprises A) essential methodological details, B) essential details that are relevant to a specific mode of action simulation, and C) further points that may be useful on a case-by-case basis. We anticipate that the use of these guidelines will improve the understanding, reproduction, and synthesis of studies using action simulation, and enhance the translation of research using motor imagery and action observation to applied and clinical settings.

A quantitative meta-analysis and review of motor learning in the human brain.

Neuroimaging studies have improved our understanding of which brain structures are involved in motor learning. Despite this, questions remain regarding the areas that contribute consistently across paradigms with different task demands. For instance, sensorimotor tasks focus on learning novel movement kinematics and dynamics, while serial response time task (SRTT) variants focus on sequence learning. These differing task demands are likely to elicit quantifiably different patterns of neural activity on top of a potentially consistent core network. The current study identified consistent activations across 70 motor learning experiments using activation likelihood estimation (ALE) meta-analysis. A global analysis of all tasks revealed a bilateral cortical-subcortical network consistently underlying motor learning across tasks. Converging activations were revealed in the dorsal premotor cortex, supplementary motor cortex, primary motor cortex, primary somatosensory cortex, superior parietal lobule, thalamus, putamen and cerebellum. These activations were broadly consistent across task specific analyses that separated sensorimotor tasks and SRTT variants. Contrast analysis indicated that activity in the basal ganglia and cerebellum was significantly stronger for sensorimotor tasks, while activity in cortical structures and the thalamus was significantly stronger for SRTT variants. Additional conjunction analyses then indicated that the left dorsal premotor cortex was activated across all analyses considered, even when controlling for potential motor confounds. The highly consistent activation of the left dorsal premotor cortex suggests it is a critical node in the motor learning network.

CCL3L1 copy number, HIV load, and immune reconstitution in sub-Saharan Africans.

BACKGROUND: The role of copy number variation of the CCL3L1 gene, encoding MIP1α, in contributing to the host variation in susceptibility and response to HIV infection is controversial. Here we analyse a sub-Saharan African cohort from Tanzania and Ethiopia, two countries with a high prevalence of HIV-1 and a high co-morbidity of HIV with tuberculosis. METHODS: We use a form of quantitative PCR called the paralogue ratio test to determine CCL3L1 gene copy number in 1134 individuals and validate our copy number typing using array comparative genomic hybridisation and fiber-FISH. RESULTS: We find no significant association of CCL3L1 gene copy number with HIV load in antiretroviral-naïve patients prior to initiation of combination highly active anti-retroviral therapy. However, we find a significant association of low CCL3L1 gene copy number with improved immune reconstitution following initiation of highly active anti-retroviral therapy (p = 0.012), replicating a previous study. CONCLUSIONS: Our work supports a role for CCL3L1 copy number in immune reconstitution following antiretroviral therapy in HIV, and suggests that the MIP1α -CCR5 axis might be targeted to aid immune reconstitution.

ß-defensin genomic copy number is associated with HIV load and immune reconstitution in sub-saharan Africans.

AIDS, caused by the retrovirus human immunodeficiency virus (HIV), is the leading cause of death of economically active people (age, 15-59 years) in sub-Saharan Africa. The host genetic variability of immune response to HIV and immune reconstitution following initiation of highly active antiretroviral therapy (HAART) is poorly understood. Here we focused on copy number variation of the ß-defensin genes, which have been shown to have anti-HIV activity, and are important chemoattractants for Th17 lymphocytes via the chemokine receptor CCR6. We determined ß-defensin gene copy number for 1002 Ethiopian and Tanzanian patients. We show that higher ß-defensin copy number variation is associated with increased HIV load prior to HAART (P=.005) and poor immune reconstitution following initiation of HAART (P=.003). We suggest a model where variable amounts of ß-defensin expression by mucosal cells, due to gene copy number variation, alters the efficacy of recruitment of Th17 lymphocytes to the site of infection, altering the dynamics of infection.

Transcranial magnetic stimulation reveals modulation of corticospinal excitability when observing actions with the intention to imitate.

Studies using transcranial magnetic stimulation have demonstrated that action observation can modulate the activity of the corticospinal system. This has been attributed to the activity of an 'action observation network', whereby premotor cortex activity influences corticospinal excitability. Neuroimaging studies have demonstrated that the context in which participants observe actions (i.e. whether they simply attend to an action, or observe it with the intention to imitate) modulates action observation network activity. The study presented here examined whether the context in which actions were observed revealed similar modulatory effects on corticospinal excitability. Eight human participants observed a baseline stimulus (a fixation cross), observed actions in order to attend to them, or observed the same actions with the intention to imitate them. Whereas motor evoked potentials elicited from the first dorsal interosseus muscle of the hand were facilitated by attending to actions, observing the same actions in an imitative capacity led to no facilitation effect. Furthermore, no motor facilitation effects occurred in a control muscle. Electromyographic data collected when participants physically imitated the observed actions revealed that the activity of the first dorsal interosseus muscle increased significantly during action execution compared with rest. These data suggest that an inhibitory mechanism acts on the corticospinal system to prevent the immediate overt imitation of observed actions. These data provide novel insight into the properties of the human action observation network, demonstrating for the first time that observing actions with the intention to imitate them can modulate the effects of action observation on corticospinal excitability.