Faculty Bibliography

The reliability of transcranial magnetic stimulation (TMS) measures in healthy older adults and stroke patients has been insufficiently characterized. We determined whether common TMS measures could reliably evaluate change in individuals and in groups using the smallest detectable change (SDC), or could tell subjects apart using the intraclass correlation coefficient (ICC). We used a single-rater test-retest design in older healthy, subacute stroke, and chronic stroke subjects. At twice daily sessions on two consecutive days, we recorded resting motor threshold, test stimulus intensity, recruitment curves, short-interval intracortical inhibition, and facilitation, and long-interval intracortical inhibition. Using variances estimated from a random effects model, we calculated the SDC and ICC for each TMS measure. For all TMS measures in all groups, SDCs for single subjects were large; only with modest group sizes did the SDCs become low. Thus, while these TMS measures cannot be reliably used as a biomarker to detect individual change, they can reliably detect change exceeding measurement noise in moderate-sized groups. For several of the TMS measures, ICCs were universally high, suggesting that they can reliably discriminate between subjects. TMS measures should be used based on their reliability in particular contexts. More work establishing their validity, responsiveness, and clinical relevance is still needed.

Transcranial Direct Current Stimulation (tDCS) is a method of non-invasive brain stimulation that has been frequently used in experimental and clinical pain studies. However, the molecular mechanisms underlying tDCS-mediated pain control, and most important its placebo component, are not completely established. In this pilot study, we investigated in vivo the involvement of the endogenous mu-opioid system in the global tDCS-analgesia experience. Nine healthy volunteers went through positron emission tomography (PET) scans with [11C]carfentanil, a selective mu-opioid receptor (MOR) radiotracer, to measure the central MOR activity during tDCS in vivo (non-displaceable binding potential, BPND)--one of the main analgesic mechanisms in the brain. Placebo and real anodal primary motor cortex (M1/2mA) tDCS were delivered sequentially for 20 minutes each during the PET scan. The initial placebo tDCS phase induced a decrease in MOR BPND in the periaqueductal gray matter (PAG), precuneus, and thalamus, indicating activation of endogenous mu-opioid neurotransmission, even before the active tDCS. The subsequent real tDCS also induced MOR activation in the PAG and precuneus, which were positively correlated to the changes observed with placebo tDCS. Nonetheless, real tDCS had an additional MOR activation in the left prefrontal cortex. Although significant changes in the MOR BPND occurred with both placebo and real tDCS, significant analgesic effects, measured by improvements in the heat and cold pain thresholds, were only observed after real tDCS, not the placebo tDCS. This study gives preliminary evidence that the analgesic effects reported with M1-tDCS, can be in part related to the recruitment of the same endogenous MOR mechanisms induced by placebo, and that such effects can be purposely optimized by real tDCS.

Convergent findings point to a left-sided specialization for the representation of learned actions in right-handed humans, but it is unknown whether analogous hemispheric specialization exists for motor skill learning. In the present study, we explored this question by comparing the effects of anodal transcranial direct current stimulation (tDCS) over either left or right motor cortex (M1) on motor skill learning in either hand, using a tDCS montage to better isolate stimulation to one hemisphere. Results were compared with those previously found with a montage more commonly used in the field. Six groups trained for three sessions on a visually guided sequential pinch force modulation task with their right or left hand and received right M1, left M1, or sham tDCS. A linear mixed-model analysis for motor skill showed a significant main effect for stimulation group (left M1, right M1, sham) but not for hand (right, left) or their interaction. Left M1 tDCS induced significantly greater skill learning than sham when hand data were combined, a result consistent not only with the hypothesized left hemisphere specialization for motor skill learning but also with possible increased left M1 responsiveness to tDCS. The unihemispheric montage effect size was one-half that of the more common montage, and subsequent power analysis indicated that 75 subjects per group would be needed to detect differences seen with only 12 subjects with the customary bihemispheric montage.

In humans, training in which good performance is rewarded or bad performance punished results in transient behavioral improvements. The relative effects of reward and punishment on consolidation and long-term retention, critical behavioral stages for successful learning, are not known. Here, we investigated the effects of reward and punishment on these different stages of human motor skill learning. We studied healthy subjects who trained on a motor task under rewarded, punished, or neutral control conditions. Performance was tested before and immediately, 6 hr, 24 hr, and 30 days after training in the absence of reward or punishment. Performance improvements immediately after training were comparable in the three groups. At 6 hr, the rewarded group maintained performance gains, whereas the other two groups experienced significant forgetting. At 24 hr, the reward group showed significant offline (posttraining) improvements, whereas the other two groups did not. At 30 days, the rewarded group retained the gains identified at 24 hr, whereas the other two groups experienced significant forgetting. We conclude that training under rewarded conditions is more effective than training under punished or neutral conditions in eliciting lasting motor learning, an advantage driven by offline memory gains that persist over time.

Despite its increasing use in experimental and clinical settings, the cellular and molecular mechanisms underlying transcranial direct current stimulation (tDCS) remain unknown. Anodal tDCS applied to the human motor cortex (M1) improves motor skill learning. Here, we demonstrate in mouse M1 slices that DCS induces a long-lasting synaptic potentiation (DCS-LTP), which is polarity specific, NMDA receptor dependent, and requires coupling of DCS with repetitive low-frequency synaptic activation (LFS). Combined DCS and LFS enhance BDNF-secretion and TrkB activation, and DCS-LTP is absent in BDNF and TrkB mutant mice, suggesting that BDNF is a key mediator of this phenomenon. Moreover, the BDNF val66met polymorphism known to partially affect activity-dependent BDNF secretion impairs motor skill acquisition in humans and mice. Motor learning is enhanced by anodal tDCS, as long as activity-dependent BDNF secretion is in place. We propose that tDCS may improve motor skill learning through augmentation of synaptic plasticity that requires BDNF secretion and TrkB activation within M1.

Motor skills can take weeks to months to acquire and can diminish over time in the absence of continued practice. Thus, strategies that enhance skill acquisition or retention are of great scientific and practical interest. Here we investigated the effect of noninvasive cortical stimulation on the extended time course of learning a novel and challenging motor skill task. A skill measure was chosen to reflect shifts in the task's speed-accuracy tradeoff function (SAF), which prevented us from falsely interpreting variations in position along an unchanged SAF as a change in skill. Subjects practiced over 5 consecutive days while receiving transcranial direct current stimulation (tDCS) over the primary motor cortex (M1). Using the skill measure, we assessed the impact of anodal (relative to sham) tDCS on both within-day (online) and between-day (offline) effects and on the rate of forgetting during a 3-month follow-up (long-term retention). There was greater total (online plus offline) skill acquisition with anodal tDCS compared to sham, which was mediated through a selective enhancement of offline effects. Anodal tDCS did not change the rate of forgetting relative to sham across the 3-month follow-up period, and consequently the skill measure remained greater with anodal tDCS at 3 months. This prolonged enhancement may hold promise for the rehabilitation of brain injury. Furthermore, these findings support the existence of a consolidation mechanism, susceptible to anodal tDCS, which contributes to offline effects but not to online effects or long-term retention.

Reversible posterior leukoencephalopathy syndrome (RPLS) is characterized radiographically by magnetic resonance imaging as white matter hyperintensities, which reflect cerebral edema. These changes are typically restricted to the parietal and occipital lobes, and are usually quite symmetric. We report a case of asymmetric RPLS involving only one frontal lobe in a patient with severe hypertension, chronic internal carotid artery stenosis, and ipsilateral vasogenic edema.

OBJECTIVE: Previous studies demonstrated that single-pulse transcranial magnetic stimulation (TMS) of one motor cortex (M1) exerts a brief inhibitory effect on the contralateral M1. The purpose of this study was to test the hypothesis that 30min of 1Hz TMS of M1 will result in a lasting increase in excitability in the contralateral M1. METHODS: Healthy volunteers were tested on 2 separate days, before (baseline) and after one of two interventions: (a) stimulation of M1 with 1Hz TMS for 30min at 115% of resting motor threshold, and (b) sham stimulation. Recruitment curves to TMS, pinch force, and simple reaction time were assessed in the hand contralateral to the unstimulated motor cortex. RESULTS: The main finding of this study was that 30min of 1Hz significantly increased recruitment curves in the contralateral motor cortex in the real stimulation condition relative to sham (P<0.005, factorial analysis of variance (ANOVA)). This change outlasted the stimulation period for at least 15min and occurred in the absence of changes in pinch force or reaction time. CONCLUSIONS: These results raise the potential for inducing lasting modulation of excitability in M1 by 1Hz TMS of the other M1, a phenomenon possibly reflecting modulation of interhemispheric interactions. SIGNIFICANCE: It is conceivable that 1Hz TMS applied to M1 may be used to modulate excitability in the opposite motor cortex for therapeutic purposes.