Article
Left dorso-lateral repetitive transcranial magnetic stimulation affects cortical excitability and functional connectivity, but does not impair cognition in major depression

https://doi.org/10.1016/S0278-5846(02)00210-5Get rights and content

Abstract

Purpose: Transcranial magnetic stimulation (TMS) has been used for over a decade to investigate cortical function. More recently, it has been employed to treat conditions such as major depression. This study was designed to explore the effects of differential treatment parameters, such as stimulation frequency. In addition, the data were examined to determine whether a change in connectivity occurred following TMS. Method: Fifteen patients with major depression were entered into a combined imaging and treatment experiment with single photon emission computed tomography (SPECT) and repetitive transcranial magnetic stimulation (rTMS) over left dorso-lateral prefrontal cortex (DLPFC). Brain perfusion during a verbal fluency task was compared between pre- and poststimulation conditions. Patients were then treated with 80% of motor threshold for a total of 10 days, using 5000 stimuli at 5, 10 or 20 Hz. Tests of cortical excitability and neuropsychological tests were done throughout the trial. Findings: Patients generally improved with treatment. There was no perceptible difference between stimulation frequencies, which may have reflected low study power. An increase in rostral anterior cingulate activation after the first treatment day was associated with increased functional connectivity in the dorso-lateral frontal loop on the left and the limbic loop on both sides. No noticeable deterioration in neuropsychological function was observed. Conclusion: TMS at the stimulation frequencies used seems to be safe over a course of 5000 stimuli. It appears to have an activating effect in anterior limbic structures and increase functional connectivity in the neuroanatomical networks under the stimulation coil within an hour of stimulation.

Introduction

Transcranial magnetic stimulation (TMS) is currently under investigation worldwide as a potential treatment for major depression (George et al., 1999a). A modest antidepressant response appears to be a fairly robust finding, although a recent controlled trial showed no difference from placebo (Loo et al., 1999). One reason for this may be that the optimal stimulation parameters for an antidepressant response are still unknown. Possible parameters include the site of stimulation, stimulation intensity, its frequency, the duration of stimulus trains and the total number of stimuli administered.

In order to begin to understand the possible effects of different treatment parameters, it will be necessary to run a number of pilot studies, with relatively small numbers of subjects, but using intensive assessments to predict the parameters most likely to lead to successful treatment effects. Such studies will, by necessity, be underpowered compared with standard antidepressant treatment studies. In addition, intensive investigations, such as imaging, electrophysiology or neuropsychology, may increase our knowledge of the mechanisms of TMS action on the brain.

Stimulation frequency is without doubt one of the important parameters of TMS: Chen et al. (1997) reported that low-frequency TMS with 0.9 Hz decreased motor cortex excitability in healthy volunteers. Higher-frequency TMS was, for example, found to stimulate the motor cortex in patients with Parkinson's disease and resulted in improvement of specific motor tasks (Pascual-Leone et al., 1994). This study is, therefore, designed to test the following specific hypotheses: (1) higher-frequency (10 and 20 Hz) stimulation is relatively more excitatory than lower frequencies (5 Hz), as measured by TMS and single photon emission computed tomography (SPECT); (2) there will be functional connectivity changes before and after TMS, detectable during a “prefrontal task,” caused by “driving” the left dorso-lateral prefrontal cortex (DLPFC) with different stimulus frequencies, which result in a variety of responses. Finally, by including a number of neuropsychological measures, we hoped to add a degree of certainty that 5000 repetitive left dorso-lateral prefrontal TMS do not result in cognitive deterioration. It is important to note that in a study with three frequency groups, five patients in each group, any effect sizes comparing these groups will have to be large to detect any significant clinical differences. The power to detect physiological or even neuropsychological effects maybe greater, particularly if there is a smaller measurement error compared with clinical measures. Because our first objective was to compare stimulation frequencies in a parallel design, we did not include a placebo condition.

Section snippets

Patients

Fifteen patients with a DSM-IV (American Psychiatric Association, 1994) diagnosis of major depressive episode (all unipolar) were recruited from in- and outpatient facilities of the Royal Edinburgh and other local hospitals after written consent for participation. A diagnosis of a major depressive episode was confirmed by detailed clinical interview and examination of the case records. Patients were excluded if they had any history of physical illness likely to affect brain physiology, head

Results

Table 2 gives demographic and clinical details of the patients. There were more male patients in the 5-Hz group, and the 10-Hz group had patients with a longer duration of current illness. More patients in the 20-Hz group took benzodiazepines. However, across the groups, there were no statistically significant differences. All patients tolerated the TMS procedure without significant adverse effects. In particular, no seizures were induced, and headaches, if experienced, were mild and responded

Motor excitability

Of the initial hypotheses, the authors were able to demonstrate (even with the small numbers of subjects involved in the task) that stimulation at 5 Hz over motor cortex subsequently reduces the response amplitudes and, implicitly, cortical excitability. Any change after 10 and 20 Hz, if it occurs, is clearly more discrete and not detectable with our design. It is important to remember that (a) the measurement of excitability over motor cortex may not be representative for DLPFC, which is one

Conclusions

In summary, we found no evidence of negative cognitive effects in 15 depressed patients over a course of 5000 TMS stimuli given at 5, 10 or 20 Hz over LDLPF cortex. Although any changes may be masked by the cognitive improvement that goes with recovery from depression, the magnitude of any possible negative effect must be small. Because of the absence of a control group and no difference in rate of improvement among the three frequency groups, there is no direct evidence from this study that

Acknowledgements

We would like to thank Dr. Julia Lappin, Carol A. Swanson and Catherine Murray for clinical support, and the Medical Research Council (UK) and Gordon Small Charitable Trust (K.A.) for funding.

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