Repetitive transcranial magnetic stimulation of the dorsolateral prefrontal cortex affects divided attention immediately after cessation of stimulation
Introduction
Transcranial magnetic stimulation (TMS) is a powerful tool to investigate the human brain non-invasively. By inducing an intracranial electrical current flow, TMS pulses lead to neuronal depolarization, and researchers can thus interfere with cortical processes in the stimulated region with high temporal and regional precision (George et al., 1999). Repetitive TMS with lower (up to 1 Hz) frequencies reduces, while rTMS with higher frequencies increases cortical excitability for up to some minutes. TMS thus provides a unique possibility to make reversible “lesions” in humans (Robertson et al., 2003).
Repetitive TMS has also been extensively studied for its use in the treatment of neuropsychiatric conditions, including mood disorders. While a recent meta-analysis concluded that the evidence to support the use of rTMS in the clinical treatment of major depression is insufficient yet (Martin et al., 2003), numerous studies pursue the refinement and clinical evaluation of this non-pharmacological treatment.
In light of the demonstrated statistically significant sustained antidepressant effects of rTMS (Gershon et al., 2003, Holtzheimer et al., 2001, Holtzheimer et al., 2004, Schlaepfer et al., 2003), it is important to establish potential mechanisms for those effects. Repetitive TMS of frontal brain regions has modulatory effects on several neurotransmitter systems. For instance, rTMS at 20 Hz has been found to increase the release of several monoamines in the hippocampus in rats (Keck et al., 2002), and to increase levels of dopamine by 50–100% both in the mesolimbic and the mesostriatal dopamine system for up to 2 h after cessation of stimulation (Keck et al., 2002). Completely line with this finding, Strafella et al. found that rTMS of the motor cortex increased striatal dopamine release, as detected by raclopride PET (Strafella et al., 2001). The antidepressant effect of rTMS found in some clinical studies is probably related to such neurochemical rTMS effects, which are similar to those brought about by other effective antidepressants like electroconvulsive therapy (Zyss et al., 1997), but other mechanisms including altered gene expression are also posited (Muller et al., 2000; Wassermann and Lisanby, 2001). These preclinical and PET data suggest that rTMS may affect neurotransmission for hours, which in turn could alter cognitive and emotional processes. Surprisingly little research has been done on cognitive effects of rTMS immediately after cessation of stimulation, possibly because cognitive neuroscientists are focussing on the immediate effects of TMS on cognition – which allows them to make ‘reversible lesions’ and the study of information processing with high temporal precision – while clinical researchers understandably explore longer term effects of rTMS on affect with a focus on therapeutic applications, with cognitive effects being only a treatment safety aspect.
Direct disruptive effects on cognitive functions were demonstrated for speech generation at high frequency (20 Hz) rTMS (Pascual-Leone et al., 1991) and for random number generation (Jahanshahi and Dirnberger, 1999). Safety studies convincingly suggest that rTMS does not result in long term cognitive impairments (Little et al., 2000; Schulze-Rauschenbach et al., 2005; Wassermann et al., 1996b). However, there are only few studies, which examined cognitive changes hours after the cessation of rTMS, in the very time window where neurochemical effects of rTMS, e.g. effects on dopamine release, have been reported. One study found that subjects stimulated at high intensity and at short interstimulus intervals showed impaired performance in the Wechsler memory test after cessation of the stimulation (Flitman et al., 1998). Some studies reported on acute mood effects of left prefrontal high-frequency rTMS, but the results remain inconclusive (Mosimann et al., 2000). Better knowledge about the effects of rTMS after cessation of the stimulation could also contribute to elucidate mechanisms of rTMS effects on affect.
We attempted to further explore this crucial time window of subacute rTMS effects on cognition by studying the impact of rTMS on executive functions. The time window of 20 min to 1 h has shown to be significant in previous studies measuring summation effects of many trains of pulses within one stimulation session (Dearing et al., 1997). We investigated executive and attentional functions after a single session of high frequency repetitive transcranial magnetic stimulation, with parameters typically used in clinical studies of rTMS in refractory major depression. The site of stimulation was the left dorsolateral prefrontal cortex, the region consistently chosen in depression treatment with rTMS (George et al., 1999) and in studies of induction of mood changes in healthy subjects (Mosimann et al., 2000). Clinical and neuroimaging studies identified the left dorsolateral prefrontal cortex as being involved in executive functions (categorizing, higher order functions, and dealing with interference) and attention (Berman et al., 1995).
In order to trace possible functional effects of rTMS lasting beyond the end of stimulation, we chose three well-established cognitive tasks tapping into frontal brain function, as evidenced by neuroimaging studies. The divided attention task used here has been found to activate the left prefrontal cortex (Loose et al., 2003). In contrast, the Stroop interference condition has frequently been found to activate the anterior cingulate gyrus (Pardo et al., 1990). The Wisconsin Card Sorting Task (WCST), activates a network of several frontal (including the DLPFC) as well as other brain regions (Berman et al., 1995).
Section snippets
Subjects/samples
Seventeen male students gave their written informed consent for the study, after the approval of the protocol by the local Ethical Committee.
Their mean age was 22.3 years (SD = 2.1, range: 19–26). All subjects were right-handed and were carefully screened for history of mental illness, substance abuse, head injury or physical illness. All subjects were screened for medical contra-indications to participating in an rTMS study according to safety guidelines for rTMS (Wassermann, 1998). Subjects
Results
All subjects tolerated the experimental procedure well, three reported mild headaches after the real stimulation procedure that resolved in all cases without treatment within 20 min. Not surprisingly, all subjects were able to correctly identify the real stimulation session after conclusion of their assessment.
Discussion
This study was designed to assess effects of left DLPFC rTMS stimulation on executive functions of healthy subjects after a time delay of 20 min to 1 h, a time window in which previous studies found strong neurochemical rTMS effects to occur.
In the Divided Attention Task, which requires simultaneous monitoring of visual and auditory stimuli and which has previously been shown to activate the DLPFC, we found significantly retarded visual reaction times after true rTMS as compared with sham rTMS.
Competing interests statement
None of the authors participating in this study has to report any financial arrangements or connections pertinent to the submitted manuscript.
Acknowledgements
This research was conducted with support from grants numbers 4038-044046 and 3231-044523 of the Swiss National Foundation to Dr. Schlaepfer.
References (36)
- et al.
Physiological activation of a cortical network during performance of the Wisconsin Card Sorting Test: a positron emission tomography study
Neuropsychologia
(1995) - et al.
High frequency repetitive transcranial magnetic stimulation (rTMS) of the left dorsolateral cortex: EEG topography during waking and subsequent sleep
Psychiatry Research – Neuroimaging
(2001) - et al.
Repetitive transcranial magnetic stimulation increases the release of dopamine in the mesolimbic and mesostriatal system
Neuropharmacology
(2002) - et al.
Acute left prefrontal transcranial magnetic stimulation in depressed patients is associated with immediately increased activity in prefrontal cortical as well as subcortical regions
Biological Psychiatry
(2004) - et al.
Mood effects of repetitive transcranial stimulation (rTMS) of left prefrontal cortex in healthy volunteers
Psychiatry Research
(2000) - et al.
Long-term repetitive transcranial magnetic stimulation increases the expression of brain-derived neurotrophic factor and cholecystokinin mRNA, but not neuropeptide tyrosine mRNA in specific areas of rat brain
Neuropsychopharmacology
(2000) - et al.
Repetitive transcranial magnetic stimulation (rTMS) in major depression. Relation between efficacy and stimulation intensity
Neuropsychopharmacology
(2002) Risk and safety of repetitive transcranial magnetic stimulation: report and suggested guidelines from the International Workshop on the Safety of Repetitive Transcranial Magnetic Stimulation, 5–7 June 1996
Electroencephalography and Clinical Neurophysiology
(1998)- et al.
Therapeutic application of repetitive transcranial magnetic stimulation: a review
Clinical Neurophysiology
(2001) - et al.
Seizures in healthy people with repeated “safe” trains of transcranial magnetic stimuli
Lancet
(1996)
Use and safety of a new repetitive transcranial magnetic stimulator
Electroencephalography and Clinical Neurophysiology
Repetitive transcranial magnetic stimulation of the dominant hemisphere can disrupt visual naming in temporal lobe epilepsy patients
Neuropsychologia
Preliminary comparison of behavioral and biochemical effects of chronic transcranial magnetic stimulation and electroconvulsive shock in the rat
Biological Psychiatry
Farbe Wort Interferenz Test (FWIT) (Color Word Interference Test). Psychologische Testsysteme
Mood effects of prefrontal repetitive high frequency transcranial magnetic stimulation (rTMS) in healthy volunteers
CNS Spectrums
Linguistic processing during repetitive transcranial magnetic stimulation
Neurology
Transcranial magnetic stimulation: applications in neuropsychiatry
Archives of General Psychiatry
Transcranial magnetic stimulation in the treatment of depression
American Journal of Psychiatry
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