Opposite Effects of High and Low Frequency rTMS on

Opposite Effects of High and Low Frequency rTMS on
Regional Brain Activity in Depressed Patients
Andrew M. Speer, Timothy A. Kimbrell, Eric M. Wassermann, Jennifer D. Repella,
Mark W. Willis, Peter Herscovitch, and Robert M. Post
Background: High (10 –20 Hz) and low frequency (1–5
Hz) repetitive transcranial magnetic stimulation (rTMS)
have been explored for possible therapeutic effects in the
treatment of neuropsychiatric disorders. As part of a
double-blind, placebo-controlled, crossover study evaluating the antidepressant effect of daily rTMS over the left
prefrontal cortex, we evaluated changes in absolute regional cerebral blood flow (rCBF) after treatment with 1and 20-Hz rTMS. Based on preclinical data, we postulated
that high frequency rTMS would increase and low frequency rTMS would decrease flow in frontal and related
subcortical circuits.
Methods: Ten medication-free, adult patients with major
depression (eight unipolar and two bipolar) were serially
imaged using 15O water and positron emission tomography to measure rCBF. Each patient was scanned at
baseline and 72 hours after 10 daily treatments with 20-Hz
rTMS and 10 daily treatments with 1 Hz rTMS given in a
randomized order. TMS was administered over the left
prefrontal cortex at 100% of motor threshold (MT).
Significant changes in rCBF from pretreatment baseline
were determined by paired t test.
Results: Twenty-hertz rTMS over the left prefrontal cortex
was associated only with increases in rCBF. Significant
increases in rCBF across the group of all 10 patients were
located in the prefrontal cortex (L ⬎ R), the cingulate
gyrus (L ⬎⬎ R), and the left amygdala, as well as bilateral
insula, basal ganglia, uncus, hippocampus, parahippocampus, thalamus, and cerebellum. In contrast, 1-Hz
rTMS was associated only with decreases in rCBF. Significant decreases in flow were noted in small areas of the
right prefrontal cortex, left medial temporal cortex, left
basal ganglia, and left amygdala. The changes in mood
following the two rTMS frequencies were inversely related
(r ⫽ ⫺.78, p ⬍ .005, n ⫽ 10) such that individuals who
improved with one frequency worsened with the other.
From Biological Psychiatry Branch, National Institute of Mental Health (AMS,
JDR, MWW, RMP), National Institute of Neurologic Disorders and Stroke
(EMW), and Positron Emission Tomography Department, National Institutes of
Health Clinical Center (PH), Bethesda, Maryland, and VA Medical Center,
North Little Rock, Arkansas (TAK).
Address reprint requests to Robert M. Post, M.D., NIH/NIMH/BPB, 10 Center
Drive, Room 3N212, Bethesda MD 20895.
Received February 17, 2000; revised September 13, 2000; accepted September 20,
2000.
© 2000 Society of Biological Psychiatry
Conclusions: These data indicate that 2 weeks of daily
20-Hz rTMS over the left prefrontal cortex at 100% MT
induce persistent increases in rCBF in bilateral frontal,
limbic, and paralimbic regions implicated in depression,
whereas 1-Hz rTMS produces more circumscribed decreases (including in the left amygdala). These data
demonstrate frequency-dependent, opposite effects of high
and low frequency rTMS on local and distant regional
brain activity that may have important implications for
clinical therapeutics in various neuropsychiatric disorders. Biol Psychiatry 2000;48:1133–1141 © 2000 Society of Biological Psychiatry
Key Words: Transcranial magnetic stimulation, regional
cerebral blood flow, depressed, high frequency (20 Hz),
low frequency (1 Hz), positron emission tomography
Introduction
R
epetitive transcranial magnetic stimulation (rTMS) is
a neurologic and psychiatric research tool that has
gained notable attention in recent years for its potential
application as a treatment for several neuropsychiatric
illnesses. It involves the use of a wire coil through which
brief pulses of electrical current are passed, leading to the
generation of magnetic fields that pass through the skull
(Barker et al 1985, 1987). Changes in neuronal activity in
the brain can thus be achieved when the coil is placed
close to the scalp. A figure eight coil allows for relatively
focal stimulation of the brain such that the hand or foot
area of the motor cortex can be selectively activated
(Cohen et al 1990; Wassermann et al 1992; Wilson et al
1993).
Transcranial magnetic stimulation results in a variety of
effects depending on the target area and stimulation
parameters, such as intensity and frequency. When applied
over the primary motor area, single-pulse TMS evokes
compound action potentials in contralateral muscles
(Rothwell et al 1991) followed by inhibition of cortical
motor output. Over the occipital cortex, single TMS pulses
can produce phosphenes (Marg and Rudiak 1994) and can
interrupt the perception of briefly presented visual stimuli
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(Amassian et al 1989). Repetitive transcranial magnetic
stimulation applied at high intensities near or over the
motor area for speech in the dominant hemisphere produces speech arrest (Epstein 1998; Epstein et al 1996;
Pascual-Leone et al 1991). Repetitive transcranial magnetic stimulation delivered over the motor cortex appears
to have different effects on cortical excitability depending
on the pulse frequency. Frequencies in the range of 5–20
Hz produce enhanced cortical responses, or facilitation,
which is demonstrated by a decreased motor-evoked
potential (MEP) threshold (Berardelli et al 1998; PascualLeone et al 1994). Repeated stimulation at frequencies of
about 1 Hz produces inhibition of subsequent cortical
responses (Chen et al 1997).
The initial application of high frequency (20 Hz) rTMS
over the left prefrontal cortex in depressed patients resulted in promising findings (George et al 1995). Subsequent controlled studies of daily left prefrontal rTMS
(10 –20 Hz) have demonstrated significant clinical improvement in depressed patients (George et al 1997;
Pascual-Leone et al 1996). Investigators are currently
attempting to determine the parameter settings of intensity,
frequency, laterality, location (Klein et al 1999), and
duration of stimulation optimal for the antidepressant
effects of rTMS, with the intent of finding alternatives to
electroconvulsive therapy (ECT) for at least a subgroup of
patients (Grunhaus et al 2000). In contrast to ECT, rTMS
would have the advantage of not requiring anesthesia and
of not inducing a seizure with its associated memory loss,
and would allow better control of stimulus frequency and
location (Post et al 1999). Other studies have explored the
potential use of rTMS to alleviate the symptoms of
obsessive– compulsive disorder (Greenberg et al 1997),
schizophrenia (Feinsod et al 1998; Geller et al 1997;
Hoffman et al 1999), and posttraumatic stress disorder
(McCann et al 1998).
Investigators have used various brain imaging procedures such as single photon emission computed tomography, functional magnetic resonance imaging (fMRI), and
positron emission tomography (PET) to examine how
brain activity (as reflected by cerebral glucose metabolism
and blood flow) is altered by rTMS during or shortly after
stimulation. Increases and decreases in blood flow or
metabolism have been found (Bohning et al 1999; Fox et
al 1997; Kimbrell et al 1999; Paus et al 1997, 1998)
depending on location and frequency of rTMS stimulation.
For example, T.A. Kimbrell et al (unpublished data) found
that, relative to the increases observed with sham, 20 min
of active 1-Hz rTMS in normal subjects produced global
and regional decreases in cerebral glucose metabolism.
The study of the long-term effects of brain stimulation
at different frequencies has in part derived from studies
exploring the models of long-term potentiation (LTP) and
long-term depression (LTD; Li et al 1998; Malenka 1994,
1995), as well as the concepts of kindling and quenching
(Post et al 1997; Weiss et al 1997). These models of
neuroplasticity have provided evidence that long-term
changes in neuronal excitability (depression and potentiation) can be achieved in vitro with low and high frequency
stimulation, respectively, in both hippocampal and amygdala slices. Whether or not analogous changes in more
global measures of neuronal excitability can be achieved
with rTMS in vivo remains uncertain.
The possibility of achieving differential long-term
changes in brain activity with rTMS is clinically important, as this may contribute to its potential therapeutic
value in neuropsychiatric disorders associated with cerebral hyper- or hypofunction. For example, our group has
examined the clinical effects of 2 weeks (10 daily or in
two groups of five daily sessions over 2 weeks) of rTMS
treatments at 1 Hz and 20 Hz administered at 80% of
motor threshold (MT) and found opposite effects on mood
(Kimbrell et al 1999). Preliminary evidence also suggested
differential clinical response as a function of baseline
metabolism within depressed patients; a response to 20-Hz
rTMS appeared to be associated with a pattern of baseline
hypometabolism, whereas response to 1-Hz rTMS appeared to be associated with baseline hypermetabolism
(Kimbrell et al 1999).
In this study we examined the effects of 1- and 20-Hz
rTMS at a higher intensity (100% MT) on regional
cerebral blood flow (rCBF). An 15O water PET procedure
to measure absolute rCBF was performed 72 hours after
each phase of active treatment. Using the preclinical data,
we predicted that 10 days of 1-Hz rTMS would decrease
rCBF, whereas 20 Hz rTMS would increase rCBF in a
sustained fashion.
Methods and Materials
Patients
Ten depressed patients meeting DSM-IV criteria for either
bipolar disorder, depressed phase (one woman and one man;
mean age ⫽ 46.0 ⫾ 1.4 [SD]), or unipolar major depression (five
women and three men; mean age ⫽ 44.4 ⫾ 7.6 [SD]) were
included. They were recruited from local as well as national
referrals to the Biological Psychiatry Branch, National Institute
of Mental Health (NIMH) inpatient unit (n ⫽ 6) or outpatient
clinic (n ⫽ 4) for participation in the rTMS and serial imaging
study. The study was approved by the Radiation Safety Committee of the National Institutes of Health (NIH) and by the
institutional review board of the NIMH. All patients gave written
consent for the rTMS and imaging procedures. Patients were
randomized to receive 2 weeks (10 daily or in two groups of five
daily sessions over 2 weeks) of rTMS treatments with 1-Hz or
20-Hz or sham rTMS. Those receiving sham first were then
assigned directly to 20 Hz, whereas those on active stimulation
Effects of rTMS on rCBF in Depression
were crossed over to the other frequency. The 10 patients
discussed in this article were the first patients to complete the
rTMS treatments with both frequencies and also to complete PET
scans at baseline and after each active treatment phase.
Ratings
Trained research assistants completed the 28-item Extended
Hamilton Psychiatric Rating for Depression (Ham E; Hamilton
1960) at baseline, at the end of each 5-day period of rTMS
treatment, and on the day of a PET procedure. The change from
baseline to after the rTMS session was calculated for each
frequency. The degree of improvement or worsening in mood
after high and low frequency rTMS treatments were established
by Pearson r.
rTMS
Repetitive transcranial magnetic stimulation was administered
using a Cadwell (Kennewick, WA) High Speed Magnetic Stimulator with a water-cooled figure-eight coil. Following an MRI
scan of the brain to exclude structural abnormalities, the active
MT was determined by placing the coil over the left primary
motor area and establishing the minimum amount of stimulator
output necessary to cause visible movement of the flexed right
thumb following at least five out of 10 single pulses. This
technique is highly correlated with the procedure using surface
electrodes to record the MEP (Pridmore et al 1998).
The left prefrontal cortex rTMS stimulation site was determined by measuring 5 cm anterior and in a parasagittal line from
the hand motor area. Ten daily rTMS treatments were administered over the left prefrontal cortex at 100% of MT with the coil
angled tangentially to the head. The sham condition was administered at 20 Hz with one wing of the figure-eight coil in contact
with the scalp and at a 45° angle with respect to the head. With
the coil held in this orientation over M1, TMS does not produce
MEPs but does produce sensations due to stimulation of scalp
nerves and muscles. This has been used as a sham in previous
studies (George et al 1997; Wassermann et al 1998; T.A.
Kimbrell et al, unpublished data). A visible twitch in the scalp
muscle was observed during these stimulations. Active high
frequency (20 Hz) stimulation was administered (2 sec on and 28
sec off) 40 times for a total of 1600 stimulations per 20-min
session. One-hertz rTMS was given in a continuous train of 1600
pulses over 26 min, 40 sec. Each patient had a minimum of 3
days between 1- and 20-Hz rTMS phases.
PET Imaging Procedures
Patients followed a low monoamine diet for a minimum of 4 days
and fasted 8 hours before each PET scan. Patients were imaged
at baseline while medication free for at least 2 weeks and then 3
days following the completion of their last (10th) rTMS treatment at each frequency. Scans were acquired with a GE (Waukesha, WI) Advance tomograph in the 3D mode (DeGrado et al
1994; Lewellen et al 1996). This scanner acquires 35 simultaneous slices with an interslice spacing of 4.25 mm and a
reconstructed transverse and axial resolution of 6 mm. Image
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2000;48:1133–1141
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reconstruction included corrections for attenuation, random
events, scatter, and dead time, and counts were converted to
nCi/mL. Subject preparation included insertion of an indwelling
radial artery catheter to permit measurement of the arterial input
function and insertion of an intravenous catheter in the other arm
for injection of 15O water. Scans were obtained in planes parallel
to the canthomeatal line with head movement minimized by a
thermoplastic face mask molded to each subject’s head and
attached to the scanner bed. A 10-min transmission scan was
obtained using two rotating Ge-68 sources to correct subsequent
emission scans for attenuation. Scans were performed while
subjects lay on the bed with eyes closed and ears unplugged in a
quiet, darkened environment. They were instructed to monitor
their mood state over the subsequent several minutes in an
attempt to provide more consistency and specificity of cognitive
processing during this resting state. Patients rated their level of
sadness, anxiety, and alertness on an ordinal scale from 0
(“none”) to 6 (“very severe”), before and immediately following
each of their five 2-min scans.
The patient’s pre- and postscan ratings did not significantly
change over the course of the scanning session, suggesting that
the task did not induce a transient change in mood state. None of
the ordinal measures changed significantly over this interval.
Each subject underwent five scans separated by 10 –12 min,
obtained after bolus intravenous injection of 10 mCi of 15O
water. Image acquisition began when the radiotracer arrived in
the head and continued for 60 sec. The arterial time–activity
curve was measured with an automated blood sampling and
counting system, and was used with an autoradiographic method
to produce quantitative images of rCBF (Herscovitch et al 1983;
Raichle et al 1983).
Imaging Analysis
Image analysis involved stereotactic normalization of scans
followed by rCBF analyses. It was performed on a Sun SPARCstation 2 workstation (Sun Microsystems, Mountain View, CA)
using Matlab (Mathworks, Sherborn, MA) with Statistical Parametric Mapping software (SPM, courtesy of MRC Cyclotron
Unit, Hammersmith Hospital, London, United Kingdom) (Friston et al 1991a) for stereonormalization and SPM95 for the group
analyses. ANALYZE (Mayo Foundation, Rochester, MN) and
NIH- and NIMH-developed software were also used in the
analysis and presentation. Global CBF (gCBF) comparisons were
performed on a Macintosh (Apple Computer, Cupertino, CA)
using StatView (Abacus Concepts, Berkeley, CA) and Microsoft
Excel.
Scans were visually inspected for artifacts. Stereotactic normalization consisted of interpolation to 43 slices, manual roll and
yaw correction, and application of a stereotactic normalization
algorithm (Friston et al 1991b) that reorients images along the
intercommisural plane (Friston et al 1989) and then nonlinearly
warps them into the standard space corresponding to the human
brain atlas of Talairach (Talairach and Tournoux 1988). These
images were then smoothed with a Gaussian low-pass filter of 10
mm in-plane and 6 mm axial full width at half maximum. The
resulting five sets of images for each scan session in each patient
were then averaged together to produce a single mean rCBF
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image representing an integration of blood flow over 10 min of
passive introspection. The rationale for working with these mean
images, as opposed to a set of five repeated measures for each
scan session, was the lack of a peer-reviewed method for treating
a random-effects analysis of variance design in SPM. These
mean images were used for all rCBF comparisons in this study.
Gray matter determination for the purposes of inclusion in SPM
analysis was carried out as follows: the background noise
threshold (above which a voxel is presumed to be within the
brain) was set at one eighth of the mean of the entire image
space, and whole-brain mean was calculated using only these
suprathreshold voxels. Voxels exceeding 80% of the whole-brain
mean were assumed to be in gray matter. Global CBF was
calculated from an average of the within-brain pixel values from
16 contiguous supratentorial slices of each patient’s scan. The
border of the brain for each PET slice was determined using a
semiautomated edge-finding program. The calculated gCBF
(mL/min/100 g tissue) represents the whole-brain mean CBF and
includes gray matter, white matter, and cerebrospinal fluid in
each slice.
To determine changes in rCBF during an rTMS treatment
period, a paired t test was performed in the group of 10 patients
comparing mean rCBF images immediately before and 72 hours
following the treatment phase in question. These paired t tests
resulted in Z maps corresponding to the raw probabilities in each
voxel of the null hypothesis of no change in rCBF. To correct for
multiple comparisons, the Z maps were then submitted to a
cluster analysis technique based on Gaussian random field theory
(Friston et al 1994) with a Z threshold of 1.96 (two-tailed p ⫽
.05) and a cluster probability threshold of p ⫽ .05. Cluster
analysis considers the smoothness of the Z map, which arises
from both low-pass filtering applied to the input images and
inherent spatial autocorrelation in the underlying brain functionality, in determining the effective independence of the multiple
comparisons made in the brain volume examined. Raw p values
are then displayed (for purposes of depicting the topography of
the changes) for all voxels falling within clusters deemed
significant by this analysis. The Talairach atlas (Talairach and
Tournoux 1988) was used to identify brain regions where blood
flow changes were observed.
Results
Global Changes in CBF following rTMS: Effects of
Frequency and Order
The differences from baseline in mean gCBF 72 hours
after the series of 10 treatments with 1- and 20-Hz rTMS
were consistent with predictions. Twenty-hertz rTMS
increased global blood flow significantly (paired t test,
p ⬍ .02), whereas 1-Hz rTMS did not significantly
alter global blood flow (paired t test, p ⬍ .37) relative to
the respective pre-rTMS treatment baseline (Figure 1).
The increases in gCBF following 20 Hz were observed
regardless of whether this was the first or second
treatment phase. However, there was a suggestion that
prior 20-Hz stimulation may have reduced the effect of
1 Hz in decreasing rCBF: five of six patients who received
1 Hz first showed decreases, whereas two of four patients
who received 1 Hz after the 20-Hz trial showed decreases.
Regional Changes in CBF
Relative to pre-rTMS treatment baseline, a PET scan 72
hours after the completion of 10 sessions of 20-Hz rTMS
over the left prefrontal cortex at 100% MT showed
widespread increases in rCBF. The following regions
demonstrated significant rCBF elevations: the prefrontal
cortex (L ⬎ R), cingulate gyrus (L ⬎⬎ R), and the left
amygdala, as well as bilateral insula, basal ganglia, uncus,
hippocampus, parahippocampus, thalamus, and cerebellum (Figure 2). Increases in rCBF were apparent over
almost the entire left cingulate area (Figure 2, lower left
corner), with only modest, scattered increases in the right
cingulate (Figure 2, lower right corner).
The same analysis was performed to evaluate the effects
of 10 daily sessions of 1-Hz rTMS on rCBF. The predicted
opposite effects for 1 Hz were observed, but they were less
dramatic in anatomic extent or statistical significance than
the increases observed with 20-Hz rTMS. There were
decreases in the following regions: small areas of the right
prefrontal cortex, left medial temporal cortex, left basal
ganglia, and left amygdala (Figure 3). In contrast to 20 Hz,
there were no areas of significant increases following 1-Hz
rTMS.
Relationship of Clinical Response to Change in
rCBF
The effects of 1- and 20-Hz rTMS on clinical antidepressant response in all patients were evaluated. Change in
Hamilton ratings in the same individuals following 10
rTMS treatments with 1 and 20 Hz were inversely correlated (r ⫽ ⫺.78, p ⬍ .005). Thus, each patient who
improved with 1-Hz rTMS tended to worsen with 20-Hz
rTMS, or vice versa. The mean change in Hamilton score
was not significant in either the 1-Hz (pre–Ham E, 28.8 ⫾
5.5, post–Ham E, 28.7 ⫾ 9.0) or 20-Hz (pre–Ham E,
29.1 ⫾ 9.1; post–Ham E, 26.8 ⫾ 5.0) rTMS phases.
Moreover, the degree of clinical response was not significantly correlated with change in blood flow in either the
1-Hz phase (r ⫽ ⫺.12, ns) or the 20-Hz phase (r ⫽ .32,
ns). In addition, when the changes in rCBF were covaried
for the degree of clinical improvement, the pattern of
findings in Figures 2 and 3 remained essentially unaltered
(data not illustrated).
Discussion
Our findings demonstrate that 10 daily treatments of
20-Hz rTMS at 100% MT over the left prefrontal cortex in
Effects of rTMS on rCBF in Depression
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2000;48:1133–1141
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Figure 1. Effects of repetitive transcranial magnetic stimulation (rTMS) frequency on absolute global cerebral blood flow (gCBF) in
depressed patients. Individual and mean gCBF values for all 10 patients are displayed before and 72 hours after completing a series
of 10 daily rTMS treatments at 20 Hz and 1 Hz given in a random order. Twenty-hertz stimulation significantly increased (p ⬍ .02),
whereas a 1-Hz stimulation nonsignificantly decreased (p ⬍ .37) mean gCBF across the group. A comparison of the change in mean
gCBF following 20 Hz and 1 Hz was also significant (p ⬍ .04).
depressed patients significantly increase rCBF in the
prefrontal cortex (L ⬎ R), the entire left cingulate gyrus,
and the left amygdala, as well as bilateral uncus, hippocampus, parahippocampus, thalamus, and cerebellum,
in a fashion that persists for at least 72 hours following the
last treatment. As predicted, the effects on rCBF following
10 daily treatments of 1-Hz rTMS were in the opposite
direction, but more circumscribed, with decreases in flow
in small areas of the right prefrontal cortex, left medial
temporal cortex, left basal ganglia, and left amygdala.
These opposite changes in rCBF were not correlated with
the degree of mood improvement in either phase.
One- and 20-Hz rTMS did have opposite effects on
mood in individual patients. Patients who improved with 2
weeks of rTMS on one frequency worsened on the other
(r ⫽ ⫺.78, p ⬍ .005, n ⫽ 10). These results at 100% MT
replicate those of Kimbrell et al (1999) at 80% MT, where
2 weeks of 1- versus 20-Hz rTMS also yielded opposite
effects on mood in individual depressed patients (r ⫽
⫺.80, p ⬍ .004, n ⫽ 10). The lack of cognitive impairment
in that study at 80% MT (Little et al 2000) was also
mirrored in the current study at 100% MT (A.M. Speer et
al, unpublished data).
Thus, high frequency stimulation over the left prefrontal
cortex leads to persistent increases in rCBF over widespread areas of the brain at a considerable distance from
the stimulation site. Since rTMS is thought to penetrate
about 1–2 cm into the brain, as revealed by the production
of MEPs at this depth (Epstein et al 1990; Marg and
Rudiak 1994), these remote changes in rCBF are likely
mediated transsynaptically. Consistent with this view is
the relative laterality of regional changes in blood flow,
with a predominance of alterations in the left versus the
right prefrontal cortex and cingulate, and bidirectional
changes in the left amygdala (ipsilateral) but not the right.
However, 20 Hz did increase rCBF in the frontal cortex
bilaterally, and surprisingly, 1-Hz rTMS decreased rCBF
only in the contralateral prefrontal cortex. It is possible
that the use of different rTMS parameters would lead to a
different pattern of changes. Although the observed
changes persisted for at least 3 days following the series of
10 rTMS treatments, the duration of the effect and whether
it could be magnified or extended are not known. How
these rTMS effects on rCBF relate to the current overview
of the literature suggesting a laterality–frequency interaction (i.e., high frequency rTMS over the left prefrontal
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A.M. Speer et al
Effects of rTMS on rCBF in Depression
Figure 2. Significant increases in absolute regional cerebral
blood flow (rCBF) 72 hours after 2 weeks of 20-Hz repetitive
transcranial magnetic stimulation (rTMS) over the left prefrontal
cortex at 100% of motor threshold relative to the pretreatment
baseline in the group of 10 depressed patients. A statistical
parametric map shows voxels that occur within significant
clusters and is color coded according to their raw p value.
Increases in rCBF are displayed with a red– orange–yellow color
scale, and there were no areas of decreases in rCBF displayed
with a dark–light blue color scale. Nonsignificant values are
displayed as gray on the positron emission tomography template.
The number in the top right corner of each horizontal section (top
two rows) indicates its position in mm with respect to the anterior
commissure (AC)–posterior commissure plane. Twenty-hertz
rTMS resulted in widespread increases in rCBF in the following
regions: prefrontal cortex (L ⬎ R), cingulate gyrus (L ⬎⬎ R),
bilateral insula, basal ganglia, uncus, hippocampus, parahippocampus, thalamus, cerebellum, and left amygdala. Note the
distal effects in bilateral cortical and subcortical structures
following stimulation over the left prefrontal cortex. Coronal
sections (middle, bottom row) are displayed at the AC and 4 mm
behind it to maximize visualization of the amygdala. Increases in
the left amygdala but not the right are best viewed in horizontal
sections at ⫺20, ⫺16, and ⫺12 mm, however. Sagittal sections
are 4 mm to the left and right of midline to illustrate the greater
increases in the left cingulate gyrus relative to the right. L, “left”
side of image.
4™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™
cortex [Post and Speer 2000] and low frequency over the
right [Klein et al 1999]) remains to be further delineated.
The long-lasting changes that we found in rCBF may be
partially analogous to the long-lasting changes in synaptic
excitability demonstrated in studies using in vitro slice
preparations. In hippocampal, cortical, and cerebellar slice
preparations, brief high frequency stimulation leads to
LTP in neural excitability in appropriate synaptic pathways. In contrast, low frequency stimulation (1 Hz)
administered for 15 min leads to LTD. One-hertz stimulation is able to reverse the effects of high frequency
stimulation and vice versa (Christie et al 1994; Linden
1994; Malenka 1994, 1995; O’Dell and Kandel 1994). The
bidirectional reversibility of LTP and LTD is less clear in
the amygdala slice preparation, where the baseline state of
neural excitability can affect the direction of long-term
4™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™
Figure 3. Significant decreases in absolute regional cerebral
blood flow (rCBF) 72 hours after 2 weeks of 1-Hz repetitive
transcranial magnetic stimulation (rTMS) over the left prefrontal
cortex at 100% of motor threshold relative to the pretreatment
baseline in the same group of 10 depressed patients. Horizontal,
sagittal, and coronal images are illustrated as in Figure 2. Focal
decreases in rCBF were present in the right prefrontal cortex
(horizontal sections ⫺4 to ⫹32 mm), left medial temporal cortex
(⫺20 to ⫺12 mm), left basal ganglia (14 to ⫹8 mm), and left
amygdala (⫺12 to ⫺8 mm). Note the opposite effect of rTMS
frequency on rCBF in the left amygdala (horizontal section ⫽
⫺12 mm) in Figure 2.
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1139
response to low frequency stimulation (Li et al 1998).
How these in vitro findings of differential excitability as a
function of frequency of stimulation are pertinent to the
much more widespread in vivo changes in neuronal
activity as reflected in rCBF we observed is not certain.
The effect of treatment order (whether 1-Hz phase preceded 20 Hz or vice versa) also warrants further examination. There is a suggestion of less consistent decreases in
gCBF with 1-Hz rTMS when it followed treatment with
20-Hz rTMS, as opposed to when it was administered first.
The more modest effects of 1-Hz rTMS in decreasing
rCBF (as compared to the more robust increases following
20-Hz rTMS) could be related to the order of high and low
frequency rTMS phases; the state of baseline hypoperfusion in depressed patients (i.e., a relative floor effect); or
the particular rTMS parameters utilized, including variability in placement of the coil over the prefrontal cortex.
This study has provided clear-cut evidence of the
differential effects of frequency of rTMS on the direction
of long-term adaptation in neural excitability as reflected
in rCBF in depressed patients. It raises the possibility of
eventual therapeutic applications of selectively activating
or inhibiting specific areas of the brain in different
neuropsychiatric syndromes by this noninvasive procedure. In keeping with the findings of this study, low or
high frequency rTMS may be differentially utilized in
attempting to reregulate dysfunctional circuits associated
with baseline hyperactivity or hypoactivity, respectively.
The authors thank the Theodore and Vada Stanley Foundation for their
generous support of this work, the National Institutes of Health (NIH)
PET technologists and cyclotron engineers for their expertise and
support, the Nursing staff and research assistants of the 3-West Clinical
Research Unit, National Institute of Mental Health, Nadine Demian for
her invaluable editorial assistance, and the NIH Anesthesiology Department for their expertise and support.
Interim analysis of this work was previously presented in abstract form
(Speer et al 1998, 1999).
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