Department of Neurology, University Hospital Zurich, CH-8091 Zurich, Switzerland
Address correspondence to Daria Knoch, Department of Neurology, University Hospital Zurich, Frauenklinikstrasse 26, CH-8091 Zurich, Switzerland. Email: daria.knoch{at}usz.ch.
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Abstract |
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Key Words: dorsolateral prefrontal cortex pulse frequency random number generation response suppression transcranial magnetic stimulation
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Introduction |
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rTMS is widely employed as a research tool in cognitive neuroscience. Extent and type of a neurophysiologic response can be altered differentially by rTMS frequency. Slow (1 Hz) rTMS over the motor cortex decreased the excitability and resulted in a long-lasting depression of motor evoked potentials (Chen et al., 1997
). Conversely, fast (
5 Hz) rTMS increased cortical excitability (Pascual-Leone et al., 1994
). Given these frequency-dependent effects of rTMS on motor cortex, it seems reasonable to assume analogously opposite effects of slow and fast rTMS on cognitive functioning (Robertson et al., 2003
). This assumption has not, however, been empirically tested. We set out to investigate the effects of slow and fast rTMS on cognition by employing an RNG paradigm.
RNG requires subjects to generate numbers in a random fashion for a number of trials. Previous studies have provided evidence that humans are poor at random generation, and that, compared with computer-generated random series, produce characteristic biases, i.e. too few repetitions (e.g. 55) and too much counting in steps of one (e.g. 56, 32) (Brugger, 1997). This latter bias reflects interference by over-learned and highly automatized rules, i.e. forward and backward counting. Thus, for successful task performance individuals must overcome over-learned routines, whose control is typically assigned to the prefrontal cortex. Specifically, Jahanshahi and collaborators suggested that the left dorsolateral prefrontal cortex (DLPFC) exerts a controller function over an associative network, suppressing most habitual responses, i.e. those adjacent in natural order and represented, in neighboring nodes of the network (for number generation, see Jahanshahi et al., 1998
; for letter generation, see Jahanshahi and Dirnberger, 1999
). Support for the critical role of the DLPFC for the monitoring of habitual responses was provided by both neuroimaging (Daniels et al., 2003
; Jahanshahi et al., 2000
) and electrophysiological studies (Joppich et al., 2004
). Of special importance in the present context is the observation that high frequency (20 Hz) rTMS over the left, but not right, DLPFC increased counting bias in an RNG task (Jahanshahi et al., 1998
). This was interpreted as a breakdown in the controlling function of the DLPFC, whose already limited capacity in suppressing habitual responses would be further compromised.
In the present study we applied slow and fast rTMS over the left and right DLPFC immediately before subjects performed an RNG task (off-line paradigm). We predicted (i) a TMS effect on counting bias and not on other prominent sequential response stereotypies (e.g, repetition avoidance); (ii) a lateralization of stimulation effects to the left hemisphere; and, crucially, (iii) opposite effects of fast and slow rTMS on the magnitude of counting bias specifically, an increase with 10 Hz and a decrease with 1 Hz stimulation trains.
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Materials and Methods |
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Results |
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In contrast, in the sequences of those subjects stimulated over the right DLPFC (Fig. 1b, right panel) there was no frequency-dependent effect for counting in steps of one [F(2,16) = 0.23, P = 0.98]. All sequences showed the well-known excess of counting (compared with pseudorandom sequences all t-values > 3.51, all P-values < 0.001, two-tailed).
As expected, there was no significant difference in the number of counts between the two no-stimulation control conditions [F(1,16) = 0.58, P = 0.46). Also, neither the number of repetitions nor that of any other responses pairing of non-adjacent numbers was affected by side of stimulation nor by frequency of stimulation [all F(2,16) 0.06, all P-values
0.94).
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Discussion |
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TMS studies of cognition using an off-line paradigm usually stimulate with low frequencies for a duration of 515 min (for a review, see Robertson et al., 2003). This type of stimulation is expected to transiently disrupt the cortical function by inducing a depression of excitability that outlasts the duration of the rTMS train itself (Chen et al., 1997
; Maeda et al., 2000
). However, since the present experiment aimed to compare the effects of slow rTMS with those of high rTMS and since longer trains at high stimulation frequencies are increasingly risky with respect to seizure induction (Pascual-Leone et al., 1994
), we stimulated for a duration of only 1 min. This procedural step renders difficult a direct comparison with previously employed low-frequency off-line paradigms.
The physiological mechanisms of the observed frequency-dependent behavior changes remain unclear. One prominent notion, derived from motor cortex stimulation, is that fast rTMS induces neuronal excitation and slow rTMS neuronal inhibition of the target region. If equally applicable to stimulation of the DLPFC, this hypothesis would predict fast rTMS to reduce counting bias (by activating this structure's known function of habitual response suppression) and slow rTMS to enhance this bias (by disrupting its inhibitory function). Both predictions are opposite to what was found in the present experiment (and, with respect to fast rTMS, in the study by Jahanshahi et al., 1998). This may indicate that findings regarding frequency-dependent TMS effects on motor cortex functions may not readily be extrapolated to predict frequency-dependent TMS effects over the DLPFC. In fact, recent research has provided evidence for excitatory effects of slow rTMS if high stimulation intensities are applied. Nahas et al. (2001)
, studying acute rTMS effects by fMRI, found DLPFC activations after 1 Hz rTMS at 100% MT and 120% MT. As we also focused on acute stimulation effects (although immediately after and not during stimulation), it appears highly conceivable that, in our experiment, suprathreshold 1 Hz rTMS abolished any counting bias by boosting the inhibitory function of the DLPFC.
As a final note, we mention that the effects of rTMS are not necessarily limited to the stimulated area, but are also observed at remote sites (e.g. Nahas et al., 2001; Paus et al., 2001
; Strafella et al., 2001
; Li et al., 2004
). It remains to be established whether potential remote rTMS effects influence the number associative network, supposedly localized in the superior temporal cortex (Jahanshahi et al., 1998
) in a frequency-dependent manner.
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Acknowledgments |
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References |
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