What I look at everyday!

Surgery

Today, I went into MUSC and collected behavioral data and watched the beginning of rat brain surgery. It ended up being really interesting. Dr. Adkins and her assistant, had the rat set up on his own operating table, under special anesthesia. I got to watch Zack make a few incisions to start the process, but then I had to leave. Overall, it was yet another success!

Article

This week Dr. Adkins was absent, so I saw the c-section and read a hefty article. The article talked about neural plasticity. Neural plasticity is the ability the brain has to adopt after a traumatic injury; basically, it's how the brain fixes itself. There were about 10 principles of experience-dependent plasticity in the article. The first principle talked about how if something isn't used, it will go away. For example, if someone doesn't walk for a year, their muscles will deteriorate. Or if someone is in a coma, they might wake up and no longer be able to swallow because that neuron in their brain wouldn't have been used for an extended period of time. In addition, it talks about how something controlled by the motor cortex must be improved and also repeated. Next, when studying the motor behaviors of the post stroke organism, one must take time into account. For instance, if one looks at a rat right after his stroke, he will be extremely, but if one waits for 72 hours, the rat will be more responsive and less sluggish. Lastly, age is another big factor we must take into account. The older the rat is, the harder the rehab and the younger, the easier the rehab. Thus, after this article, I gained a better understanding of the entire stroke and post stroke process.

C-section

Yesterday, I watched a c-section in the morning. It went moderately well. The baby didn't really want to come out so the doctors had to do some pretty hard pushing on the patient's stomach. Thus, it made it especially exciting when the baby came out. Overall, it was yet another success.

End of the week

Today, I had another exciting day. I got to run around the university with Dr. Adkins meeting other doctors, touring different labs, and looking at the rat MRI machines. In conclusion to my interesting day, I got word from Dr. Adkins' lab manager saying that I would be receiving my badge (so I can open doors and get into labs) when I return to work next Monday! Lastly, I was able to get in contact with Roper Labor and Delivery and I am scheduled to see a c-section on Monday at 8 am and work in the ER on Tuesday!

Full Week

Last week, I think I finally mastered collecting the data for the rat behaviors. At first, I completely butchered and I felt stupid and embarrassed, but now I feel like I have it down to a science (pun intended (:). Anyways, this week, I will be looking at rats that are post op and I will be getting my badge!!! I'm so so so excited to get my badge. It has been quite a process to be able to get it. I just finished the series of OSHA quizzes that will now permit me to acquire the door opening badge (literally I will be able to open doors). But that's about it for now. I have another exciting week ahead of me at MUSC with more adventures to come. After this week, I will be back in Roper again while Dr. Adkins is out so I'll be getting to do be with patients and all the awesome nurses. Can't wait!!!

Weekend Events

Over the weekend, I worked in both the ER and Labor and Delivery at Roper for 4 hours shifts. While at Roper, I saw various patients with differing stories. Some of the most interesting would be breast feeding issues, a baby needing a nicotine patch, an injection given to a man who needed to have a lower heart rate to help with a heart attack, a sick cancer patient, an MRI, severe stomach issues, urinal breakdowns, a pelvic exam, bladder issues causing an elderly woman to have to use a "pamper" (aka a diaper), and so on. All of these were fascinating and exciting to see, but I was especially interested by all the urine work. I never knew how much one could learn just by simply running test on urine. The nurse explained to me that just by looking at urine, one can learn about every bodily system; it literally tells one everything!!!

Now to Catch Up!

Last week, for 5 days straight, I worked vigorously doing a variety of task. Tuesday- Friday, I watched the rat videos, recorded and analyzed data. Then, to conclude the week, I had the privilege of actually watching the rat test where the rat reached for the pellets after he had had a stroke. Each time the rat got better and better, the doctor would take one away until the procedure became routine. To go along with my work, I read the article below.

Zimerman et al

Enhancing Skill Acquisition After Stroke 2187

sions, different phenomena occur with an either increased mainte- nance or deterioration of motor performance defined as “offline effects.”26
Additionally, we examined factors that might potentially influence motor learning such as attention level, perception of fatigue, and discomfort/pain due to the stimulation; they were assessed for both interventions in each session using visual analog scale question- naires. After the completion of TRAIN-tDCS, patients were asked to identify whether they had received “real” or “placebo” stimulation.
Transcranial Direct Current Stimulation
The initial TRAIN-tDCS session was performed at the time of receiving cathodal tDCS or sham stimulation (Figure 1). tDCS was delivered through 2 sponge electrodes embedded in a saline-soaked solution; the surface of each electrode was 25 cm2 (Eldith, DC- stimulator; Neuroconn). The cathode was positioned on the proj- ection of the hand knob area of the cM1 on the subject’s scalp, whereas the anode was placed on the contralateral supraorbital region.11 The hand knob area of the motor cortex was identified in each patient by single-pulse TMS (70-mm figure-8 coil; Magstim, Dyfed, UK) by standardized procedures.27 tDCS was applied for 20 minutes; the current was initially increased in a ramp-like fashion over several seconds (8 seconds) until reaching 1 mA (current density of 0.04 mA/cm2) as described in previous studies.10,11 During sham, just like during real tDCS, stimulation was started in a ramp-like fashion but faded out slowly after 30 seconds, a procedure demonstrated to warrant successful blinding.10 In this crossover design, each subject performed the experiment with each stimulation type in a pseudorandomized order. The participants and the examiner were blind for the type of stimulation.
Motor Cortical Excitability Determined by TMS
In a separate experiment, changes in corticospinal excitability and short interval intracortical inhibition (SICI) after cathodal tDCS application to the cM1 were evaluated in both hemispheres during rest with well-established single and paired-pulse TMS protocols.28 TMS was performed as follows: before tDCS (baseline); immedi- ately; 30 minutes; 60 minutes and 90 minutes after offset of tDCS. The rationale of the present design was to determine the neurophys- iological effects of cathodal tDCS in patients with stroke over both contralesional and ipsilesional M1. Seven of the 12 patients com-

Figure 1. Experimental design. A, After baseline (BASE), patients attended a training composed of 5 blocks (B1–B5) combined with tDCS or sham (TRAIN- tDCS) 90 minutes and 24 hours after the effects were re-evaluated in a testing block followed by 4 blocks of practice (POST-90 and POST-24). VAS question- naires were recorded before and after each session. Online and offline effects were analyzed (see “Methods”). The dia- gram illustrates the position of the tDCS electrodes with the cathode placed over the projection of cM1. B, In a different experiment, MEP and SICI were mea- sured before and after tDCS in both hemispheres in a counterbalanced order. tDCS indicates transcranial direct current stimulation; VAS, visual analog scale; cM1, contralesional motor cortex; MEP, motor-evoked potential; SICI, short inter- val intracortical inhibition.
pleted this experiment (for a detailed description, see the online-only Data Supplement Methods).
Data Acquisition and Analysis
Patients’ motor performance was recorded with an ergonomic 4-button electronic keyboard connected to a computer using Presen- tation software (Version 0.61; Neurobehavioral System, Albany, CA). For further analysis, we used a custom-made software routine using Matlab (Version 7.1.0.246; The MathWorks, Natick, MA) to automatically record the number of overall and correct sequences in each block. Normal distribution of the data was assessed by Kolmogorov–Smirnov tests. Repeated-measure analyses of variance were used to evaluate: (1) the level of attention and perception of fatigue toward the task with the factors INTERVENTION and VAS-TIME; (2) the effects of INTERVENTION on behavioral measurement during TRAIN-tDCS; and (3) the effects of INTERVENTION on Re-TEST. Online gains were calculated between the last and first block of each session (eg, Train-tDCSB5/Train-tDCSBase) and offline effects were assessed by contrasting the first block of the following and the last block of the previous session (eg, Test-90B1/Train-tDCSB5).16 Be- cause of the small sample size, the effects of tDCS on TMS-TIME were assessed separately in each hemisphere by nonparametric Friedman analysis of variance and Wilcoxon signed-rank test for post hoc comparisons. All calculations with repeated-measure anal- ysis of variance were Greenhouse-Geisser-corrected; post hoc testing was corrected for multiple comparisons if necessary. All statistical analyses were conducted with SPSS 15.0 (SPSS for Windows 15.0; SPSS, Chicago, IL). The level of significance was set at P􏰁0.05.
Results
All patients completed the study; none of them reported any adverse effects with tDCS or TMS. All data were normally distributed as evaluated by Kolmogorov-Smirnov goodness- of-fit tests. There was no difference in pain or discomfort perception between sham and tDCS stimulation (t[11]􏰀0.84, P􏰀0.41); neither did the type of stimulation or session influence attention, fatigue, or hand tiredness (for statistics, see online-only Data Supplement Table I). Moreover, none of the patients were able to distinguish between tDCS and sham stimulation.

2188 Stroke August 2012

Carryover Effect Between Arms
Baseline comparisons revealed comparable performance for the 2 experimental stimulation conditions for correct sequences (BasetDCS􏰀43.4􏰃7.6, BaseSham􏰀45.7􏰃7.9; t[11]􏰀1.2, P􏰀0.26) and overall sequences (BasetDCS􏰀60.2􏰃8.6, BaseSham􏰀63.4􏰃 8.9; t[11]􏰀1.2, P􏰀0.22). Additionally, the order of the sequence (Sequence A versus Sequence B) did not have any impact on the baseline performance in correct sequences (Base1st􏰀43.1􏰃7.5, Base2nd􏰀46.3􏰃8.2; t[11]􏰀1.4, P􏰀0.17) nor in overall sequences (Base1st􏰀60.2􏰃8.1, Base2nd􏰀64.2􏰃9.5; t[11]􏰀1.7, P􏰀0.11), consistent with the absence of relevant carryover effects.
Effects of Simulation on Retention
The analysis of the retest blocks at follow-up sessions revealed a significant effect of INTERVENTION (F[1,11]􏰀5.1, P􏰀0.04) and TEST (F[2,22]􏰀29.9, P􏰁0.01) in the number of correct sequences; furthermore, there was a significant INTERVENTION by TEST interaction (F[2,22]􏰀4.2, P􏰀0.02). Post hoc Scheffe ́ test demonstrated that Test-90 and Test-24 were significantly different between tDCS and sham at 5% level (tDCSTest-90􏰀68.8􏰃9.1 and shamTest-90􏰀56.1􏰃 6.4; tDCSTest-24􏰀76.4􏰃9.2, shamTest-24􏰀63.5􏰃9.1). Tempo- ral components of skill acquisition (online and offline effects) in the follow-up periods demonstrated no differences in late online learning for both conditions in POST-90 (t[11]􏰀0.26, P􏰀nonsignificant) nor in POST-24 (t[11]􏰀1.3, P􏰀nonsignificant; Figure 2) in correct sequences. Furthermore, offline changes did not differ between the interventions for POST-90 (t[11]􏰀􏰄0.3, P􏰀nonsignificant) and for POST-24 (t[11]􏰀2.3, P􏰀nonsignificant). Nonparametric Wilcoxon test revealed no significant difference between the correct sequences per- formed within INTERVENTION at the 3-month follow-up (tDCSTest-3m􏰀49.1􏰃9.2, shamTest-3m􏰀47.4􏰃9.3, Z􏰀0.9, P􏰀0.3).
Effects of Stimulation on the TRAIN-tDCS Session
Repeated-measure analysis of variance revealed a significant improvement in the number of correct sequences with cath- odal tDCS compared with sham stimulation demonstrated by the factor INTERVENTION (F[1,11]􏰀4.7, P􏰀0.04); there was also a significant effect on BLOCKS (F[5,55]􏰀10.9, P􏰁0.01); and more importantly, there was a significant INTERVEN- TION by BLOCKS (F[5,55]􏰀3.9, P􏰀0.01) interaction. Post

Figure 2. Follow-up sessions. A, The bar graph shows the number of correct sequences evaluated at Test-90 and Test-24; the percentages of improve- ment for tDCS compared with sham stimulation are included in the graph for both test blocks (*Scheffe ́ post hoc P􏰁0.05). B, Practice sessions performed at Post-90 minutes and Post-24 (late online learning) hours did not show fur- ther behavioral improvement (error bars􏰀SEM). tDCS indicates transcranial direct current stimulation.
hoc analysis demonstrated that, relative to sham treatment, tDCS facilitated the training effect to a larger extent at the second, fourth, and fifth blocks of training. A significant difference between the 2 stimulation conditions was apparent for the correct sequence (tDCSonline􏰀1.7􏰃0.2, shamonline􏰀 1.3􏰃0.1, t[11]􏰀2.2, P􏰀0.04) as well as the overall sequences (tDCSonline􏰀1.5􏰃0.1, shamonline􏰀1.2􏰃0.1, t[11]􏰀3.4, P􏰁0.01) in the early online learning period (B5/Base). The increase in correct sequences with tDCS could potentially be driven by a change in the speed–accuracy relationship toward reduced speed and enhanced accuracy. To evaluate this question we conducted the same analysis for the overall sequences; here, too, we found a trend toward an increase in overall sequences for the factor INTERVENTION (F[1,11]􏰀3.9, P􏰀0.06) with a significant effect on BLOCKS (F[5,55]􏰀15.2, P􏰁0.01) and an INTERVENTION by BLOCKS (F[5,55]􏰀3.6, P􏰀0.03) inter- action. Furthermore, the success rate did not decrease signif- icantly with tDCS making a relevant change in the speed– accuracy–relation unlikely.
Effects of tDCS on Cortical Excitability
Motor-Evoked Potential
The resting motor threshold was 58.4%􏰃6.4% in the cM1 and 64.6%􏰃7.2% in the stroke M1 (P􏰀0.09). Mean motor- evoked potential (MEP) amplitudes were 1.18􏰃0.1 mV and 0.91􏰃0.2 mV respectively for the baseline condition (Z􏰀􏰄1.6, P􏰀0.11) and the power intensities were 66.2%􏰃2.6% in the cM1 and 77.8%􏰃3.8% in the lesioned M1 (P􏰀0.03). After cathodal tDCS, a significant reduction in the MEPs over the unaffected motor cortex was demonstrated using a nonparametric Friedman analysis of variance test (􏰇2[4]􏰀10.61, P􏰀0.03). Post hoc analysis revealed a trend for MEP reduction at Post30 (from 1.18􏰃0.1 to 0.89􏰃0.1 mV, P􏰀0.06) and a significant effect at Post0 (from 1.18􏰃0.1 to 0.84􏰃0.1 mV, P􏰀0.02) and Post60 (from 1.18􏰃0.1 to 0.77􏰃0.1 mV, P􏰁0.01) with a normalization of the values at Post90. On the other hand, there was no modification of the MEPs in the lesioned hemisphere (􏰇2[4]􏰀1.1, P􏰀0.8).
Short Interval Intracortical Inhibition
No significant differences were observed between SICI in both M1 during baseline (Z􏰀􏰄1.6, P􏰀0.1). tDCS resulted

Zimerman et al Enhancing Skill Acquisition After Stroke 2189

Figure 3. Early training session (TRAIN-tDCS). A, The number of correct sequences achieved in each block is displayed for cathodal tDCS and sham; the baselines blocks were not different between conditions (BASE). B, A significant improvement with tDCS compared with sham stimulation during the early training session was observed (early online learning). C, Relationship between tDCS-induced behavioral improvement and cortical excitability changes; the abscissa displays the online effects; the ordinate displays tDCS-induced decrease of SICI (Post0/baseline). tDCS indicates transcranial direct current stimulation; SICI, short interval intracortical inhibition.

in an increase (more inhibition) of SICI in the cM1 (􏰇2[4]􏰀11.08, P􏰀0.02). In contrast, a reduction of SICI (less inhibition) was demonstrated in the stroke hemisphere (􏰇2[4]􏰀9.37, P􏰀0.05). Post hoc testing showed that disinhi- bition in the lesioned M1 was restricted to Post0 at the 0.0125 level of significance (from 43.8%􏰃5.9% at baseline to 65.7%􏰃7.3% of unconditioned MEP). All other comparisons were not significant (for more details, see the online-only Data Supplement).
Relationship Between Skill Acquisition and Cortical Excitability Changes
A significant correlation was observed between the tDCS- induced improvement during TRAIN-tDCS and the tDCS- induced modulation of SICI (reduced inhibition􏰀disinhibition) in the stroke M1 (y􏰀0.84x􏰅0.54, R2􏰀0.63, P􏰀0.03; Figure 3C). Behavioral improvement was not correlated with the tDCS-induced changes of excitability within the cM1 deter- mined by MEP amplitudes (r2􏰀0.08, P􏰀0.5) or SICI
(r2􏰀0.13, P􏰀0.8).
Discussion
The main findings of the present study were that (1) the application of inhibitory tDCS to the cM1 concurrent with training can facilitate the effects of training yielding to subsequent improvement of the early online learning period; (2) this improvement translated into better performance for at least 24 hours; and (3) revealed an association between an intervention-induced decrease of SICI (less inhibition) within M1 of the lesioned hemisphere and a tDCS-induced enhance- ment of skill acquisition. Taken together, these findings support the beneficial effects of NIBS techniques in patients with stroke with mild motor impairment not only to enhance motor functions, as suggested previously,3,5,11,15 but also to boost the acquisition and potentially retention of complex motor functions with the paretic hand, a concept that might provide a basis for the improvement of longer-lasting func- tional recovery processes after stroke.

Clearly, acquisition of motor skills is essential to almost every daily life activity we perform from writing to driving a car or using a cell phone. Reacquisition of skills resulting in improved or more accurate motor performance is paramount to recovery of function after a brain lesion. Despite the structural changes and the abnormal patterns of neural acti- vation during the execution of motor tasks in patients with stroke, robust evidence has been provided that acquisition of motor skills is not abolished.29 In this context, NIBS tech- niques have the ability to enhance lasting changes in neuro- plasticity with the opportunity to modify behavior and inter- act beneficially with learning processes.6,8,11,30
Previous imaging and dual-pulse TMS studies demon- strated a deleterious contribution of the contralesional hemi- sphere in recovery of motor function after stroke.31,32 This abnormal and imbalanced interhemispheric interaction is 1 favorite model that underlies the experimental therapeutic strategies based on NIBS.33 Previous studies have shown the positive effect of NIBS targeting the healthy cM1 to tran- siently facilitate performance of activities of daily living (eg, Jebsen Taylor Hand function test),11,34 peak pinch accelera- tion,35 grasping,36 or simple and choice reaction times.37 However, in most of these studies, NIBS techniques were applied after patients reached stable levels of the task (eg, Jebsen Taylor Hand function test), likely reflecting a tDCS- induced performance improvement. It is not known if appli- cation of NIBS during an early acquisition period, before performance reaches an asymptotic level, could potentiate or even speed up the learning process of a novel procedural task with consecutive better retention.
Recently it was demonstrated that consecutive sessions of anodal tDCS over M1 can help healthy subjects to learn an isometric pinch task through an effect of consolidation.16 In the present design, the combined approach of tDCS with a skill acquisition task revealed a consistent improvement during the first training period, in line with a previous study performed with high-frequency repetitive TMS over the lesioned M1.38 Strikingly, in the present study, a longer- lasting improvement, beyond the pure effect of stimulation,

2190 Stroke August 2012

could be demonstrated. Even after successive sessions of practice, the performance levels achieved with tDCS could not be reached after sham stimulation. How long will the effects of tDCS on retention last? This important question could not be sufficiently answered within the present study design. However, a 3-month follow-up session no longer revealed group differences between the 2 conditions probably due to the small subsample of 5 patients.
In the past decade, considerable evidence has accumulated regarding the plasticity of the human M1 as a function of motor learning. M1 is not only crucial to the execution, but also to acquisition and consolidation of novel motor skills. Motor practice is associated with an increase in excitability of the sensorimotor cortex, promoting plastic changes even in the chronic stage after a stroke.39 During acquisition of a novel motor skill, rewiring processes in M1 occur, consistent with rapid formation and stabilization of dendritic spines.40 These processes are most likely based on unmasking of pre-existing connections within the cortex, allowing rapid changes in sensorimotor representations by reducing the activity of existing inhibitory connections.41 Recent studies in humans using MR spectroscopy demonstrated that 30 min- utes of motor learning generated a short-term and rapid reduction of the mean 􏰆-aminobutyric acid concentration within the M1.42 Further pharmacological evidence support- ing the notion that plasticity of the human sensorimotor cortex is modulated by changes in local 􏰆-aminobutyric acid concentration comes from the observation that lorazepam, a 􏰆-aminobutyric acid-A receptor agonist, might suppress use- dependent plasticity in healthy subjects.43 In this context, the decrease of SICI, a physiological measure hypothesized to reflect intracortical 􏰆-aminobutyric acid-A neuronal activ- ity,9,44 after tDCS, and its positive correlation with the tDCS-induced behavioral improvement during training might, at least in part, explain the behavioral benefits by modulation of intracortical inhibition. Thus, one possible conjecture is that the ongoing state of the cortex at the time of stimulation can reinforce the long-term effects induced by motor practice. If so, tDCS influences the ability of the affected M1 to undergo plastic modifications by preparing the “cortical ground” for successful plastic changes due to motor training. Currently this notion is still speculative in nature; however, it is consistent with recent studies conducted with animals and healthy humans.8,16,45
Limitations of the Study
In the present study, tDCS was applied to the contralesional M1; however, due to the size of the direct current electrodes (25 cm2), the spatial resolution is rather low. Thus, it is conceivable that the stimulation effects are not entirely restricted to M1, but also might have spread to adjacent structures like the premotor cortex.46 As recently discussed,47 the notion that the unaffected hemisphere has a nonbeneficial effect on the lesioned hemisphere and consecutive behavior does not apply to all groups of patients. This fact might relevantly depend on lesion location, time after stroke, and size and integrity of the corticospinal pathway among other factors, hypotheses, which are addressed in upcoming stud- ies.13,14 Finally, it is important to keep in mind that the present

results might only apply to this homogenic and selected subgroup of patients with subcortical lesions and mild im- pairment. Indeed, it is not yet known whether this interven- tion will have comparable beneficial effects in patients with more severe deficits who have experienced extensive cortical and subcortical lesions. We might even speculate that such an intervention might not prove to be beneficial for this sub- group.47 Upcoming studies designed to address these aspects are definitely needed to provide the basis for more patient- individualized therapeutic interventions.
In summary, noninvasive transcranial brain stimulation combined with motor training did enhance the acquisition of a novel skill with the paretic hand and led to a persistent enhancement of function in well-recovered patients with chronic stroke. The intervention dominantly influenced the early phase of online learning leading to behavioral improve- ments still apparent during the retention 24 hours after intervention. Thus, the present findings further support the potential of noninvasive brain stimulation in the treatment of functional deficits to enhance skill reacquisition and long- term functional recovery after brain lesions.
Sources of Funding
This research was supported by a grant from the German Academic Exchange Service to M.Z. (A/07/95990), the Alexander von Hum- boldt Foundation (Feodor-Lynen) to F.C.H., the Forschungsfo ̈rder- ungsfonds Medizin of the University of Hamburg to F.C.H. (NWF- 04/07) and to M.Z. (NWF-11/09), the Kompetenznetz Schlaganfall to C.G., and the German Research Foundation (SFB 936-C4) to F.C.H.

None.

Disclosures
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