Transcranial Direct Current Stimulation during Sleep Improves ...

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9988 • J. Neurosci., November 3, 2004 • 24(44):9985–9992 Marshall et al. • tDCS on Memory during SleepTable 1. Mean SEM number of correctly recalled word pairs on the PAL task and speed and accuracy of performance on the MT task before (Learning) and after (Recall)the retention intervalLearning (mean SEM) Recall (mean SEM) Retention (mean SEM) Significance (p)PALSleeptDCS 33.0 1.4 35.7 1.4 2.7 0.6 p 0.005Placebo 33.6 1.5 34.5 1.5 0.9 0.8WaketDCS 36.2 1.5 36.3 1.2 0.0 1.0 p 0.8Placebo 34.0 1.4 33.7 1.4 0.3 0.5MT draw time (in milliseconds)SleeptDCS 72.63 9.57 55.77 6.06 16.86 4.58 p 0.5Placebo 72.00 7.88 58.68 5.02 13.32 3.67WaketDCS 60.00 6.72 52.50 6.75 7.51 5.80 p 0.3Placebo 63.33 14.21 46.81 9.60 16.52 5.76MT error countSleeptDCS 7.1 1.4 5.4 1.3 1.8 0.6 p 0.8Placebo 6.6 1.6 4.5 1.4 1.9 0.7WaketDCS 14.6 3.5 8.7 1.5 5.9 1.7 p 0.5Placebo 12.7 3.1 8.8 1.2 3.9 2.3Retentionisdefinedbythedifferenceinretrievalperformancebeforeandaftertheretentioninterval.TheretentionintervalwasfilledwithSleeporwakefulness(Wake),duringwhicheithertDCSorplacebostimulationwasapplied.Therightcolumn indicates significant differences in retention, compared with the respective placebo condition. Corresponding performances during learning and recall did not differ significantly (see Results for details).Table 2. Sleep during the tDCS and placebo stimulation conditions of the SleepexperimenttDCS(mean SEM)Placebo(mean SEM)Awake % 6.0 2.5 5.7 1.3S1 % 9.3 1.7 9.6 2.5S2 % 46.9 4.4 48.9 3.6S3 % 18.4 2.1 16.6 1.6S4 % 16.6 4.1 17.5 4.2SWS % 35.0 4.2 34.1 4.4REM % 2.3 0.8 1.2 0.6Total time (in minutes) 96.1 4.9 88.6 3.7Latency toS2 (in minutes) 3.6 1.1 4.9 5.4SWS (in minutes) 25.4 6.3 22.9 3.7Percentage (%) of time spent in different sleep stages and latency to stage 2 sleep, SWS, and REM sleep (withreference to sleep onset) is shown. Total time defines the time from sleep onset until awakening. There were nosignificant differences between the conditions.S1–S4, Sleep stages 1–4.Figure 2. Memory performance on the PAL and MT tasks across retention periods of sleep(left) and wakefulness (right) during which either tDCS (hatched bar) or placebo stimulation(white bar) was applied. Recall after the retention interval is expressed as difference fromperformance at learning in number of words (for PAL) and in milliseconds for draw time (forMT).**p0.01,fordifferencesbetweentheeffectsoftDCSandplacebostimulation.Errorbarsrepresent SEM.tDCS, this decrease was smaller than in the placebo conditions(0.31 0.10 vs 0.60 0.11; p 0.05) regardless of sleep orwakefulness in the retention interval. Likewise, the EWL revealedthat after tDCS, subjects reported decreased feelings of “depression”(0.50 0.26), whereas in the placebo condition, suchfeelings increased across the retention intervals of sleep andwakefulness (0.37 0.32; p 0.05).Polysomnographic EEG recordings and sleep-associatedneuronal activityTable 2 summarizes the time spent asleep and in the differentsleep stages in the Sleep experiments for the tDCS and placeboconditions. There were no significant differences between the twoconditions, also when this analysis was restricted to a 45 mininterval beginning with the first appearance of SWS (i.e., withanodal stimulation in the tDCS condition). However, when thetime course for the mean sleep stage was determined (with sleepstage 1–4 given the values 1–4, respectively, and REM sleep thevalue 0) (Marshall et al., 1998), subjects toward the end of thetDCS stimulation and during the subsequent 15 min showeddeeper sleep than during the corresponding interval of the placebocondition, with this difference transiently reaching statisticalsignificance (Fig. 3). Power spectra determined separately forperiods of SWS and stage 2 sleep during the 30 min interval ofstimulation indicated that tDCS, compared with placebo, reducedpower in the lower frequency range (15–20 Hz) during
Marshall et al. • tDCS on Memory during Sleep J. Neurosci., November 3, 2004 • 24(44):9985–9992 • 9989Figure 3. Time course of mean sleep stage for tDCS (solid line) and placebo (dotted line)conditions of the Sleep experiment. Average sleep stages were determined by associating valuesof 1, 2, 3, and 4 to sleep stages 1–4 and 0 and 1 to REM sleep and wakefulness, respectively.Significant differences between the time courses are indicated at the bottom. The grayarea represents the stimulation interval.periods of stage 2 sleep. The effect was most pronounced at central(C3, C4) and parietal (P3, P4) electrode sites (Fig. 4). Duringperiods of SWS, tDCS suppressed frequencies around the andlower range (4–10 Hz) (Fig. 4). During the stimulation interval,visual spindle counts per sec in the tDCS versus placebo conditionwere 0.11 0.01 versus 0.13 0.01 ( p 0.05).The comparison of 15 sec epochs of acute anodal polarizationwith the intermittent epochs when stimulation was discontinuedindicated most consistent differences for the slow oscillatory and frequencies 3 Hz (Fig. 5). During acute anodal stimulation,power in this low frequency range was increased over the frontalcortex, most consistently 2 Hz, compared with intervals of discontinuedstimulation. At parietal sites, anodal stimulationacutely increased slow oscillatory activity 1 Hz (Fig. 5). Comparisonsof the time course of short-term effects across the 15 secepochs of acute anodal polarization versus intermittent epochsdid not yield consistent effects.HormonesAverage plasma levels of norepinephrine, cortisol, and growthhormone were not affected by tDCS (compared with placebo forboth sleep and wake experiments; p 0.4 for cortisol and growthhormone; p 0.1 for norepinephrine).DiscussionOur study examined the influence of anodaltDCS, inducing extracellular potentialsof negative polarity in underlying tissue,on processes of declarative memoryformation known to be enhanced duringperiods rich in SWS (Plihal and Born,1997, 1999). Results indicate that tDCS repeatedlyapplied during deep NonREMsleep improved declarative memory retention,whereas performance was unaffectedduring wakefulness. Retention of proceduralmemories, in contrast, was not affected bytDCS but was also not enhanced by sleep.Electrophysiological modification of thecortex by weak anodal polarization duringsleep consisted of an acute increase in slowoscillatory activity 3 Hz, accompanied bydiminished power in the faster , lower ,and lower EEG frequency bands across the30 min polarization period. The shift towardenhanced slow oscillatory activity during theperiod of tDCS expressed itself also as an increasein the depth of average sleep stage,which per se represents a mere descriptivemeasure that cannot account for enhancedretention performance. Duration of thestage SWS was not enhanced by tDCS. Finally,there were signs of improved moodafter tDCS in the Sleep and also in the Wakeexperiments, a finding that may have someimplications for treatment of mooddisorders.Figure4. AverageEEGpowerforperiodsofstage2sleepandSWSduringthe30minintervaloftDCS(hatchedbars)andacorrespondingintervalduringtheplacebocondition(whitebars)oftheSleepexperiments.(4–8Hz),lower(8–10Hz),andlower(15–20Hz)bandsareaveragedforfrontal(F7,Fz,F8),central(C3,Cz,C4),andparietal(P3,Pz,P4)electrodelocations.**p0.01;*p0.05; t p0.1,fordifferencesbetweentDCSandplacebo(stage2sleep,n14;SWS,n16).ErrorbarsrepresentSEM.Effects on memoryThe central effect of this study was the improvementin declarative memory forword pairs after tDCS during sleep. Thisimprovement is remarkable because it was
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