Elsevier

Biological Psychiatry

Volume 46, Issue 12, 15 December 1999, Pages 1603-1613
Biological Psychiatry

Priority Communication
Frequency dependence of antidepressant response to left prefrontal repetitive transcranial magnetic stimulation (rTMS) as a function of baseline cerebral glucose metabolism

https://doi.org/10.1016/S0006-3223(99)00195-XGet rights and content

Abstract

Background: Recent studies suggest that both high frequency (10–20 Hz) and low frequency (1 Hz) repetitive transcranial magnetic stimulation (rTMS) have an antidepressant effect in some individuals. Electrophysiologic data indicate that high frequency rTMS enhances neuronal firing efficacy and that low frequency rTMS has the opposite effect.

Methods: We investigated the antidepressant effects of 10 daily left prefrontal 1 Hz versus 20 Hz rTMS with the hypothesis that within a given subject, antidepressant response would differ by frequency and vary as a function of baseline cerebral glucose metabolism. After baseline PET scans utilizing [18F]-Fluorodeoxyglucose, thirteen subjects participated in a randomized crossover trial of 2 weeks of 20 Hz paired with 2 weeks 1 Hz or placebo rTMS.

Results: We found a negative correlation between degree of antidepressant response after 1 Hz compared to 20 Hz rTMS (r = −0.797, p < .004). Additionally, better response to 20 Hz was associated with the degree of baseline hypometabolism, whereas response to 1 Hz rTMS tended to be associated with baseline hypermetabolism.

Conclusions: These preliminary results suggest that antidepressant response to rTMS might vary as a function of stimulation frequency and may depend on pretreatment cerebral metabolism. Further studies combining rTMS and functional neuroimaging are needed.

Introduction

Repetitive transcranial magnetic stimulation (rTMS) is a procedure in which regional electrical activity in the brain is influenced by a pulsed magnetic field. The magnetic field is generated by passing current pulses through a conducting coil placed on the scalp. The rapidly changing magnetic field produces electrical currents thereby activating neurons Barker et al 1985, Barker et al 1986, Barker et al 1987. rTMS has generated interest as a probe and potential treatment in several neuropsychiatric disorders Belmaker and Fleischmann 1995, George 1997, George et al 1996a. Early reports of TMS’s effect in depressed patients used low frequency (0.3–1 Hz) stimuli over the cranial vertex that stimulates various regions Hoflich et al 1993, Kolbinger et al 1995. Subsequent open (George et al 1995) and randomized sham-controlled studies using high frequency stimuli (10–20 Hz) rTMS over the left prefrontal cortex George et al 1997b, Pascual-Leone et al 1996b have shown promising antidepressant effects. Additionally, Klein and colleagues recently reported that 1 Hz rTMS of the right prefrontal cortex has short-term antidepressant efficacy in a large, sham-controlled trial (Klein et al 1999).

Although the mechanisms of these behavioral effects are the subject of speculation Post et al 1997a, Post et al 1997b, Weiss et al 1997a, Weiss et al 1997b, studies of the effects of rTMS on the primary motor area (M1) and the corticospinal system have generated findings that may bear on this question. Experiments examining the size and threshold of motor evoked potentials (MEPs) to TMS test pulses before and after rTMS treatments suggest that the frequency of rTMS can influence corticospinal system excitability for as long as several minutes. Low frequency (1 Hz) stimulation decreases the amplitude of MEPs, indicating decreased excitability Chen et al 1997, Wassermann et al 1996, whereas treatment with higher frequencies, e.g., 10 Hz (Pascual-Leone et al 1994a) or 5 Hz (Berardelli et al 1998) seems to have the opposite effect, increasing MEP amplitude and lowering MEP threshold. It has been speculated that these changes are analogous to some extent to the differential effects of frequency of stimulation in vitro and in vivo respectively, where long-term synaptic depression (LTD) is associated with low frequency stimulation, while long-term potentiation (LTP) and kindling are associated with higher frequency stimulation Goddard et al 1969, Malenka 1994, Malenka and Nicoll 1997, Post et al 1997a, Post et al 1997b, Weiss et al 1997a.

Recently, investigators have begun to use functional neuroimaging in conjunction with rTMS to explore its effects Paus et al 1997, Wassermann et al 1998. These studies have indicated that rTMS is able to produce activation, not only at the site stimulated, but also in a network of interconnected areas, likely by means of transsynaptic spread. Paus and colleagues Paus et al (1997) stimulated the frontal eye fields with 10 Hz stimulation and reported increased cerebral blood flow (CBF) at the site of stimulation and in visual association cortex. We have recently found that 1 Hz left prefrontal rTMS significantly decreases global CMRglu in healthy controls compared to another group receiving sham condition (T.A. Kimbrell et al, unpublished data, 1999). These studies suggest that high frequency rTMS enhances cortical excitability and low frequency rTMS inhibits cortical excitability as measured by PET, although other studies that have combined rTMS and neuroimaging do not support this hypothesis Fox et al 1997, Paus et al 1998.

Functional neuroimaging studies in depression have most consistently reported decreased rCBF and rCMRglu in prefrontal, temporal, basal ganglia and anterior cingulate regions in patients as compared to healthy controls Baxter et al 1989, Bench et al 1995, Drevets et al 1997, George et al 1996b, Ketter et al 1996, Ketter et al 1997, Post et al 1987. It has been postulated that high frequency rTMS could activate these hypofunctional areas as a possible mechanism of its antidepressant effect. This has been preliminarily observed in individual cases in depression where successful treatment with 20 Hz rTMS was associated with reversal of prefrontal hypometabolism and hypoperfusion George et al 1995, Speer et al 1999.

Mood disorder patients, however, are heterogeneous in their presentation and likely also in pathophysiology. There are reports of increased cerebral activity as measured by PET in: familial pure depressive disorder (Drevets et al 1992); bipolar II patients with summer seasonal affective disorder (Goyer et al 1992); bipolar I depression (Ketter et al 1994); and depressed patients responsive to sleep deprivation Ebert et al 1991, Wu et al 1992, carbamazepine (Ketter et al 1996), and fluoxetine (Mayberg et al 1997). We have recently reported one Hz right prefrontal rTMS was associated with attenuation of frontal hypermetabolism and improvement in symptoms in two depressed patients with comorbid PTSD (McCann et al 1998). Together, this series of theoretical and empirical observations led us to explore the possible differential effects of 1 Hz versus 20 Hz stimulation of left frontal cortex at 80% of motor threshold in depressed patients.

Clinical studies done to date, electrophysiological studies, and some neuroimaging evidence thus suggest that high and low frequency rTMS may have differential effects in depression. Therefore, we decided to test the hypothesis that response to 20 Hz rTMS would be associated with a pattern of baseline cerebral hypometabolism and response to 1 Hz rTMS with baseline cerebral hypermetabolism.

Section snippets

Subjects

Thirteen subjects diagnosed by SCID interview and meeting DSM-IV criteria for major depression were enrolled in the study: 9 medication free unipolar patients; 1 bipolar II patient (on lithium); and 3 bipolar I patients (one on lithium and carbamazepine, one on lithium and lamotrigine, and one medication free). Patients gave oral and written consent for the procedures involved that were approved by the NIMH Intramural Review Board and the NIH. Bipolar patients who had relapsed during their

Clinical response

Individual patients showed differential responsivity to 1 Hz versus 20 Hz rTMS as evidenced by a significant negative correlation (r = −0.797, p < .004) between change in HAMD scores after treatment with each of the two frequencies (Figure 1). The most robust responders to one frequency tended to deteriorate during treatment with the other frequency. On average, the degree of improvement in HAMD tended to be greater (t = 2.23, p < .053) after 1 Hz treatment (−6.2 points) than after 20 Hz

Discussion

These results preliminarily suggest that there is a differential antidepressant response within individuals to 2 weeks of daily either 1 Hz or 20 Hz left prefrontal rTMS at 80% of motor threshold, and that response is associated with differential baseline cerebral CMRglu. That 1 Hz rTMS in this study tended to improve depression symptoms as measured by the HAMD, is in part consistent with reports that low frequency TMS improved mood Hoflich et al 1993, Kolbinger et al 1995. Although the

Acknowledgements

Special acknowledgment is given to Ted and Veda Stanley of the Stanley Foundation for the supporting the salaries of TAK, JTL, ALD, and MWM.

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      Changes in Glu and Gln volume observed following successful treatment suggest increased glucose utilization and upregulation of the tricarboxylic acid (TCA, or “Krebs”) cycle are key components of depression reduction (Fig. 2A; see (Bak et al., 2006; Flanagan et al., 2018) for details). Regional cerebral glucose metabolism (rCMRglu) and cerebral blood flow (rCBF) in the frontal cortex are altered in depression, indicating dysregulation in frontal utilization of glucose, a precursor for Glu and Gln (Baxter et al., 1989; Kimbrell et al., 2002; Bench et al., 1995; Hyder et al., 2006; Kimbrell et al., 1999; Conca et al., 2002; Li et al., 2010). Chronic unpredictable stress, which is associated with depression (Katz, 1982), decreases TCA cycle activity, thereby also reducing Glu and Gln synthesis (Kim et al., 2014; Rae, 2014).

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