Elsevier

Biological Psychiatry

Volume 45, Issue 11, 1 June 1999, Pages 1440-1446
Biological Psychiatry

Original Articles
Effects of left frontal transcranial magnetic stimulation on depressed mood, cognition, and corticomotor threshold

https://doi.org/10.1016/S0006-3223(99)00031-1Get rights and content

Abstract

Background: The pathophysiology of depression may include synaptic hypoactivity of left prefrontal cortex. Several groups of investigators have described improved mood associated with rapid transcranial magnetic stimulation (rTMS) but have not looked for possible cognitive side effects associated with left prefrontal magnetic stimulation.

Methods: We measured the effects of left prefrontal rTMS on mood, cognition, and motor evoked potential threshold in 10 patients with medication-resistant major depression.

Results: In a 2-week open trial of left prefrontal rTMS off antidepressant medications, scores on the Hamilton Rating Scale for Depression and the Beck Depression Inventory decreased by 41% and 40%, respectively. After resuming pre-rTMS antidepressant medication, improvement in mood was still significant at 1 and 3 months later. rTMS had no adverse effects on neuropsychological performance. rTMS treatments were associated with significant decreases in motor evoked potential threshold in the 9 of 10 patients who remained off psychotropic medications during the 2-week treatment period.

Conclusions: These preliminary data suggest that left prefrontal rTMS is safe and improves mood in patients with medication-resistant major depression. Changes in motor evoked potential threshold suggest that prefrontal rTMS may alter brain activity at sites remote from the stimulation. Double-blind, sham-controlled studies are needed.

Introduction

Several lines of evidence implicate hypoactivity of left prefrontal cortex in the pathophysiology of depression. A number of functional imaging studies have shown left prefrontal synaptic hypoactivity in depressed patients Bench et al 1992, Bench et al 1993, George et al 1993. Recovery from depression is associated with normalization of regional cerebral blood flow in left prefrontal cortex (Bench et al 1995). Furthermore, depression is associated with left, but not right hemisphere lesions Goldstein 1948, Gainotti 1972, Gasparrini et al 1978, particularly with lesions in proximity to the left frontal pole (Starkstein et al 1987). These observations suggest that activation of left prefrontal cortex might ameliorate depression.

The cerebral cortex can be stimulated noninvasively using time-varying magnetic fields, a technique known as transcranial magnetic stimulation (TMS) Barker et al 1985, Rothwell et al 1991. In contrast to the direct transcranial electrical currents used in electroconvulsive therapy, magnetic fields are unaffected by the high impedance of the skull. Thus, TMS can stimulate the cerebral cortex relatively painlessly in awake patients. Early studies using TMS centered over the scalp vertex obtained promising but inconclusive evidence of improved mood in patients with severe depression Hoflich et al 1993, Grisaru et al 1994, Kolbinger et al 1995. These studies may have been limited by the rate at which high-voltage capacitors could be recharged, limiting stimulation to rates < 1 Hz, and by the use of large, nonfocal stimulating coils. However, commercially available magnetic stimulators are now capable of maintaining stimulation rates as high as 25 Hz (Pascual-Leone et al 1994). With the development of rapid-rate transcranial magnetic stimulation (rTMS), several groups of investigators have described improved mood associated with focal left prefrontal cortex rTMS in patients with medication-resistant major depression George et al 1995, Pascual-Leone 1996, Epstein et al 1998.

Based on these results, we conducted an open trial of left prefrontal rTMS in depressed patients. In addition to examining the efficacy of rTMS treatment, we also wanted to evaluate possible cognitive side effects of left-prefrontal rTMS. Previous investigators concluded that left prefrontal rTMS in depression appears to be safe; based largely on the absence of seizures associated with treatments George et al 1995, George et al 1997, Pascual-Leone 1996, Epstein et al 1998 and because treated patients have not reported cognitive side effects (Epstein et al 1998). However, subjective reports of memory loss after electroconvulsive therapy are unrelated to objective measures of cognitive dysfunction (Weiner et al 1986). rTMS-induced cognitive side effects are possible (Green et al 1997), and previous studies have not looked for subtle or long-term cognitive side effects associated with left prefrontal rTMS.

We also wished to evaluate the mechanism of action of left prefrontal rTMS in major depression. Conventional thinking is that the effects of TMS are highly local, confined to the cortex immediately beneath the magnetic coil, in this case, in the left dorsolateral prefrontal cortex. Decades of study of the dorsolateral prefrontal cortex (Stuss and Benson 1986) implicate this region of the brain in the formulation of behavioral plans in novel tasks in which successive responses are modified by sensory feedback. The left dorsolateral prefrontal cortex has also been implicated in depression by some functional imaging studies Bench et al 1992, Bench et al 1993, George et al 1993 and some studies of post-stroke depression Goldstein 1948, Gainotti 1972, Gasparrini et al 1978, Starkstein et al 1987. However, these findings still lack a satisfactory scientific explanation and are at odds with the extensive neuropsychological and primate data on this region. From a purely theoretical point of view, depression as a particular state of emotional tone, is most likely to represent a pathologic functional state involving the limbic system and linked orbitofrontal cortices. Some functional imaging studies provide some empirical support for this hypothesis (Mayberg 1997). Even if this hypothesis is correct, the question remains as to how rTMS could modify the function of this spatially distant system if the effects of left prefrontal rTMS were strictly local. In the first reported study of left prefrontal rTMS in depression, George and co-workers (1995) observed that rTMS appeared to increase brain activity at sites remote from the stimulation. We decided to look at another system, also spatially distant from the dorsolateral prefrontal cortex, the motor system, whose function is readily measurable, to determine whether rTMS was exerting distant effects in our subjects, and therefore, whether even more distant effects on the limbic and orbitofrontal systems were plausible. Dorsolateral prefrontal cortex is linked by multisynaptic pathways to both motor systems (area 6) and orbitofrontal cortex (via frontopolar connections). We therefore postulated that left prefrontal rTMS might increase the excitability of the motor system in depressed patients.

Section snippets

Methods and materials

The subjects of this investigation were 10 patients (5 men) between 30 and 74 (mean 52) years of age. All patients were screened with a psychiatric interview and met DSM-IV criteria for major depression. None of the patients were bipolar. All had failed at least two separate 4-week trials of antidepressant medications. All patients had scores greater than 18 on a 24-item version of the Hamilton Rating Scale for Depression (HAM-D) (Hamilton 1967). Mean HAM-D score prior to rTMS treatment was 37

Results

rTMS treatment was associated with significant improvement in mood Figure 1, Figure 2, including a 41% mean reduction in the 24 item HAM-D (37 ± 8 pre-rTMS vs. 22 ± 11 day 10 rTMS) and a 40% mean reduction in BDI scores (32 ± 8 pre-rTMS vs. 19 ± 11 day 10 rTMS). Five of the 10 patients could be classified as treatment responders, defined by at least a 50% reduction in HAM-D scores by the completion of the rTMS treatment period. Post-rTMS HAM-D scores in these 5 patients were 10, 14, 18, 19,

Discussion

This study confirms previous reports George et al 1995, George et al 1997, Pascual-Leone 1996, Epstein et al 1998 suggesting that left prefrontal rTMS improves mood in patients with medication-resistant major depression. However, there are important limitations to this research. First, our study, and two prior studies George et al 1995, Epstein et al 1998, have been open trials, and therefore placebo responses cannot be excluded. Furthermore, although two previously published controlled studies

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