Paired - pulse transcranial magnetic stimulation during preparation for 1 simple and choice reaction time tasks 2 3 4 5 6 7

39 Motor preparation for execution of both simple and choice reaction time tasks (SRT and 40 CRT) involves enhancement of corticospinal excitability (CE). However, motor preparation 41 implies also changes in inhibitory control that have been much less studied so far. Short 42 interval intracortical inhibition (SICI) has been shown to decrease before CE increase. 43 Therefore, we reasoned that, if SICI contributes to inhibitory control of voluntary movement 44 during the preparatory phase it would be larger in CRT than in SRT, because of the need to 45 keep the movement unreleased until the uncertainty resolves on which task is required. We 46 measured changes in SICI and in CE at different time points preceding motor reaction in 47 normal subjects. Single-pulse transcranial magnetic stimulation (spTMS) and paired-pulse 48 transcranial magnetic stimulation (ppTMS) produced time-dependent changes in both SRT 49 and CRT, with shortening when applied close to the presentation of the imperative signal 50 (‘early’), and lengthening when applied near the expected reaction (‘late’). In addition, at all 51 stimulation time points, reaction time was shorter with ppTMS than with spTMS, but there 52 was no consistent association between the amount of SICI and reaction time changes. At early 53 stimulation time points, CE was reduced in CRT but not in SRT. However, SICI in CRT was 54 not different from SICI in SRT. At late stimulation time points, SICI decreased just before 55 enhancement of CE. Our findings indicate that inhibitory circuits other than SICI are 56 responsible for setting the level of CE at earlier parts of the reaction time period. Although the 57 decrease in SICI may contribute to the increase in CE at the last part of the premotor period, 58 the two phenomena are not dependent on each other. 59 60 61 62 63 64 65 66 67 68 69 70 71 Paired-pulse TMS in simple and choice reaction time tasks 3 INTRODUCTION 72 Preparation for execution of a motor task requires setting a motor plan, which 73 comprises all the intentions, expectations, rules, and strategies that apply to a defined 74 behavioral context. This includes an appropriate balance between excitation and 75 inhibition of structures implied in task execution (Ridderinkhof, 2002). In reaction time 76 tasks, where the subjects are prepared to react to an imperative signal (IS), the amount 77 of online inhibitory control might modulate the amount of excitation. However, the 78 balance between excitation and inhibition might differ according to the reaction time 79 paradigm. Indeed, inhibition should contribute more to choice reaction time (CRT), in 80 which erroneous outcome has to be avoided (Hasbroucq et al., 1997, 1999b; Vidal et al., 81 2003; Carbonnell et al., 2004; Burle et al., 2004; Davranche et al., 2007), than to simple 82 reaction time (SRT), in which the stimulus drives an overlearned response (Luce, 1986; 83 Henderson and Dittrich, 1998). 84 The excitability of the motor pathway can be examined using transcranial magnetic 85 stimulation (TMS). It is known that, in ballistic movements, corticospinal excitability 86 (CE), measured with subthreshold or suprathreshold single-pulse TMS (spTMS), shows 87 a progressive increase beginning at approximately 100 ms preceding movement onset 88 (Rossini et al., 1988; Starr et al., 1988; Pascual-Leone et al., 1992c; Hoshiyama et al., 89 1996; Hoshiyama et al., 1997; Chen et al., 1998; Leocani et al., 2000; Burle et al., 2002; 90 McMillan et al., 2004). The inhibitory aspect of motor preparation has received 91 relatively less attention. However, Reynolds and Ashby (1999) reported a decrease in 92 short-latency intracortical inhibition (SICI), examined with paired-pulse TMS (ppTMS) 93 according to the technique described by Kujirai et al. (1993), preceding the increase of 94 CE in SRT. This suggests that SICI might be actively suppressing unwanted motor 95 cortical output in the premotor time and needs to be removed before the arrival of the 96 excitatory drive to the motor cortex (Floeter and Rothwell, 1999). 97 A study of the changes in the motor evoked potential with reaction time paradigms 98 cannot be separated from that of the effects induced by TMS on reaction time. 99 Suprathreshold spTMS causes a lengthening of reaction time, which is more marked 100 with stimuli applied closer to the expected onset of electromyographic activity (Day et 101 al., 1989; Rothwell et al., 1989; Pascual-Leone et al., 1992a; Priori et al., 1993; 102 Berardelli et al., 1994; Romaiguere et al., 1997; Ziemann et al., 1997; Leocani et al., 103 2000; Burle et al., 2002). On the contrary, subthreshold or slightly suprathreshold 104 spTMS causes the opposite effect, i.e., reaction time shortening, when applied together 105 Paired-pulse TMS in simple and choice reaction time tasks 4 with IS or at a short interval afterwards (Hallett et al., 1991; Pascual-Leone et al., 106 1992a,b; Pascual-Leone et al., 1994; Romaiguere et al., 1997; Terao et al., 1997; 107 Ziemann et al., 1997; Leocani et al., 2000; Molinuevo et al., 2000; Burle et al., 2002; 108 Hashimoto et al., 2004). Because SICI modifies motor cortical excitability, we 109 considered the possibility that SICI circuits contribute to modulation of reaction time by 110 TMS. 111 We carried out the present study under a double aim: First, we wanted to know if 112 SICI is responsible for inhibitory control during movement preparation in reaction time 113 paradigms. If this is the case, we would expect SICI to be larger in CRT than in SRT 114 tasks because of more inhibitory control required in the former than in the later. Second, 115 we hypothesized that some of the effects of TMS on reaction time may be mediated by 116 activation of intracortical inhibitory circuits. If this is the case, we would expect SICI to 117 vary in parallel with reaction time (i.e., larger SICI in trials with reaction time delay and 118 viceversa). Both hypotheses were tested using spTMS and ppTMS during SRT and 119 CRT paradigms. 120