ORIGINAL ARTICLE
Time course of cerebral blood flow changes following
electroconvulsive therapy in depressive patients-measured at 3time points using single photon emission computed tomography
Harumasa Takano, Motoichiro Kato, Ataru Inagaki, Koichiro Watanabe,and Haruo Kashima

Department of Neuropsychiatry, School of Medicine, Keio University, Tokyo, Japan(Received for publication on June 30, 2006)(Revised for publication on September 1, 2006)(Accepted for publication on September 21, 2006)

Abstract. Although electroconvulsive therapy (ECT) has been employed for treating depression for more than 60 years, its mechanisms of action are yet unknown. To clarify the
ECT effects on brain function, we examined cerebral blood flow (CBF) using single photon
emission computed tomography at 3 time points-few days before an ECT course (Pre) andapproximately 5 days (Post 1) and 1 month (Post 2) after the last ECT session. Eight depressive patients completed the study. In all the patients, the depressive symptoms improved
after the ECT course, and major cognitive impairment was not observed at any time point.
At Pre, the regional CBF (rCBF) in the widespread areas in the frontal lobe and limbic regions including cingulate cortex and parahippocampal gyrus was lower in the patients thanin the normal controls. At Post 1 and Post 2, the rCBF in the frontal and limbic regions continued to be lower in the patients than in the controls although the successive recovery ofdecreased rCBF in the frontal region was observed. Regarding the time course among thepatients, the rCBF in the right medial frontal region significantly increased (toward normal)
at Post 2, not at Post 1. These findings suggest that depressive patients have decreased CBF
in the frontal and limbic regions, and the medial frontal region plays a crucial role in ECTand recovery from depression. Further, patients who have undergone ECT treatment for depression should be carefully observed because brain functions continue to change even after
a successful ECT course. (Keio J Med 55 (4) : 153 －160, December 2006)
Key words: depression, electroconvulsive therapy (ECT), single photon emission computed tomography (SPECT), brain mapping

Introduction
Depression is one of the most common mental disorders and is mainly characterized by depressive mood andloss of interest or pleasure. It has been reported as one of
the most burdensome diseases worldwide1 and could frequently be fatal due to acts of suicide committed by thedepressive patients. While depression can be effectively
treated in the majority of patients by administering either
antidepressant medication or some types of psychotherapy, up to 20% of the patients fail to respond to these

therapies.2
On the other hand, electroconvulsive therapy (ECT)
has been employed in the treatment of depression for
more than 60 years. The safety of this therapy has been
improved with the introduction of some techniquessuch as succinylcholine-induced muscle relaxation,
barbiturate-induced anesthesia, oxygenation, and briefpulse stimulation. It is estimated that every year, morethan 1 million patients receive ECT worldwide.3 ECT
has been clearly mentioned in the therapeutic guidelines
for depression,4 and a recent meta-analysis reconfirmed

Reprint requests to: Harumasa Takano, M.D., Department of Neuropsychiatry, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo
160-8582, Japan, E-mail: hrtakano@dj9.so-net.ne.jp
153

Takano H, et al: Cerebral blood flow changes following ECT

154

its efficacy and safety.5 Despite its established utility, themechanisms of action of ECT remain to be clarified.
Functional neuroimaging techniques such as positronemission tomography (PET) and single photon emission
computed tomography (SPECT) have revealed a biological basis underlying depression. Most of these studies
have indicated decreased frontal activity in the depressive state under resting conditions.6, 7 Most importantly,
the medial frontal region that includes the anterior cingulate cortex was of particular concern because considerable data support the involvement of this area in moodregulation and depression. However, previous reports onchanges in the cerebral blood flow (CBF) and metabolism following an ECT course (short-term; within several
days to 1 week after the last session) have presented conflicting results.8 Although most reports have suggested
the involvement of the frontal areas of the brain, some
reports have indicated an increase in the frontal activity, 9-1 1 some have indicated a decrease,1 2-1 4 whereas a
few reports have showed no change.1 5, 1 6 Furthermore,
although short-term follow-up findings after an ECTcourse have been widely studied, there are only a few
studies that have analyzed the mid-term or long-term
follow-up observations.
In this study, aiming to clarify the time course of ECT
effects on the brain function, we investigated changes in
the clinical symptoms and measured the CBF by using
SPECT at 3 time points-before a course of ECT, approximately 5 days after the course, and 1 month after
the last ECT session.

to 6 months prior to the study were excluded from thestudy. All the patients underwent brain magnetic resonance imaging (MRI) or computed tomography (CT); theresults of these investigations were normal, except forthe observation of minimum cerebral atrophy.
Clinical assessments were performed at 3 time
points-few days (2.8 ± 2.4 days) before the first ECT(Pre), approximately 5 days (4.8 ± 1.5 days) after thecompletion of the treatment course (Post 1), and 1 month(31.9 ± 3.2 days) after the last ECT session (Post 2).
The severity of depressive symptoms was rated on the
17-item Hamilton Depression Scale (HAM-D),1 8 andMini-Mental State Examination (MMSE)1 9 was performed in order to examine the general mental status.
Concurrently, the regional CBF (rCBF) was measured by
SPECT.
All patients received a few psychotropic drugs, including antidepressants. The medications remained unchanged
from the first (Pre) to the last (Post 2) assessment, i.e.,during the entire study period; however, benzodiazepines
or neuroleptics were provided for insomnia and anxiety, as
required. Table 1 shows the demographics of the patients.
Regarding the SPECT images for CBF, 12 healthy subjects (6 males and 6 females; age 55.9 ± 5.6 years) served
as normal controls (no significant difference was observedin the age between the patients and normal controls by unpaired t-test at p < 0.05). This study was approved by the
ethical committee of the hospital.

Subjects and Methods

ECT was generally administered in accordance withthe guidelines of the American Psychiatric Association.20
The patients were treated with bifrontotemporal ECT using a brief-pulse square-wave ECT device (Thymatronsystem IV device; Somatics, Inc., Lake Bluff, IL, USA).
ECT treatments were performed 3 times a week, andthey were continued until a stable response was obtained.
General anesthesia was induced by intravenous administration of sodium thiopental (4 mg/kg), and succinylcholine (1 mg/kg) was used to induce muscle relaxation.
Electroencephalogram (EEG) seizure manifestations
were monitored to ensure adequate seizure duration. The
titration method20 was applied for determining the stimulus intensity of the first ECT session. The patients were
restimulated at a higher intensity when the seizure duration was less than 25 seconds.

Subjects
Patients who fulfilled the criteria for a major depressive disorder according to the Diagnostic and Statistical
Manual of Mental Disorders (4th ed.)1 7 were selected
for this study on the basis of careful clinical diagnostic
examinations. Each patient provided a written informed
consent prior to the participation in the study. Of the
10 patients who first agreed to participate, 8 inpatients(5 males and 3 females, mean age ± standard deviation(SD): 48.9 ± 16.2 years) completed the study. Of the 2drop-out subjects, 1 patient showed no improvement after several ECT treatments and refused to continue withthe therapy. The other patient responded to ECT once;
however, this patient’s condition was aggravated during
the follow-up period, and he refused to undergo further
examination. Patients were referred to the Keio University Hospital for ECT because they showed an inadequate
response to their previous therapies. All patients wereright-handed; those who had a history of major medical
illnesses, cognitive disorders, psychoactive substanceabuse or dependence, or those who had received ECT up

Electroconvulsive therapy

Single photon emission computed tomography
Patients were injected with 740 MBq of Tc-99mhexamethyl propyleneamine oxime ( 9 9mTc-HMPAO;
Nihon Mediphysics, Tokyo, Japan), and SPECT imaging
was performed 30 minutes after administering the injection. A 3-headed rotating gamma camera (Toshiba GCA-

Keio J Med 2006; 55 (4): 153 －160

155

Table 1 Characteristics of the Patients
Patient

Age

Sex

No EpisoDur

Psycho Antidepressants taken (mg/day)

HAM-D
Pre

Post 1

Post 2

1

27

F

2

2

amoxapine (100)

17

10

7

2

33

M

1

30

nortriptyline (100)

20

5

6

3

40

M

3

3

clomipramine (50)

26

9

7

4

41

M

5

12

amoxapine (100), mianserin (30)

20

7

9

5

53

F

3

38

trazodone (100)

23

4

3

6

58

M

3

1

amoxapine (100), mianserin (30)

24

7

9

7

68

F

2

2

milnacipran (105), trazodone (100)

39

12

13

8

71

M

2

21

clomipramine (25)

21

6

8

+

Abbreviations: No Episo: the number of depressive episodes, Dur: duration of the current episode and duration of medication in the current
episode, Psycho: with psychotic features, HAM-D: Hamilton Depression Scale, Pre: at several days before electroconvulsive therapy, Post 1: at
approximately 5 days after the last electroconvulsive therapy session, Post 2: at 1 month after the last electroconvulsive therapy session, F: female,
M: male9300A/DI; Toshiba Corporation, Tokyo, Japan) mountedwith ultra high-resolution fanbeam collimators was used
for data acquisition, and a medical image processor(GMS5500; Toshiba Corporation, Tokyo, Japan) was
employed for image processing. The energy window foracquisition was set at 140 keV with a width of 20%. The
gamma camera was rotated continuously for 16 minutes,
and SPECT data were arranged into 90 projections over
360°. Images were reconstructed in a 128 × 128 matrix
using a ramp filter after the data was processed with a
Butterworth filter (order 8, 0.11 cycles/pixel).
Image analyses
Image analyses were carried out using a three-dimensional stereotactic surface projection (3D-SSP) method.21 In brief, all CBF images were globally normalized
and transformed to correspond to the size and shape ofthe standard brain22 by linear and nonlinear parameters.
Maximum cortical activity was extracted to the adjacentpredefined surface pixels on a pixel-by-pixel basis. In order to compare the CBF between the patients and normal
controls, pixel-by-pixel Z scores were used. Here, the Zscores were defined as follows:
Z = (mean counts per pixel of the patients - mean
counts per pixel of the normal controls)/SD of normal
controls.
Moreover, in order to evaluate the relative rCBF values, the mean counts for each gyrus level classification
were calculated by the stereotactic extraction estimation(SEE) method,2 3 and the mean value of the counts per
pixel of the whole brain was adjusted to 50.

Data analyses
Statistical analyses were carried out by using the SPSS
software, version 14.0 J (SPSS Inc, Tokyo, Japan). Repeated measures of analysis of variance (ANOVA) wereused for the analysis of data over time, and Bonferroni
correction was used for multiple comparisons; significance was set at a level of 0.05.
Results
Clinical evaluations
ECT was performed 7.3 ± 1.2 times (range: 5-10
times) for each patient. As shown in Table 1, one patient
had psychotic features and responded well to ECT, but
her depressive symptoms did not remit when remission was defined as a total HAM-D score of less than 8
points. The total HAM-D score changed significantly between the 3 time points (repeated measures of ANOVA,
p = 0.000). Post-hoc analysis by Bonferroni correction
revealed significant differences between the Pre and Post
1 observations as well as the Pre and Post 2 observations. Compared to the HAM-D scores at Pre, the scoresat Post 2 were reduced by more than 50% in all the patients. This finding is indicative of the clinical efficacyof the treatment and the sustained improvement. Furthermore, no significant correlations were observed between
the ratio of HAM-D at Post 1/at Pre and the clinical variables on depression including the number of depressive
episodes, the duration of the current episode, and theduration of medication in the current episode (Pearson’s coefficient, p < 0.05). In contrast, as shown in Table 2,
the total MMSE score was at least 25 in all the patients,
and repeated measures of ANOVA demonstrated no sig-

Takano H, et al: Cerebral blood flow changes following ECT

156
Table 2 Results of the Mini-Mental State Examination
Pre

Post 1

Post 228.3 ± 1.7

28.3 ± 1.4

29.3 ± 0.9(25-30)(26-30)(28-30)MMSE

Upper rows: Data are presented as mean ± standard deviation.
Lower rows: the numbers denote the range of the total score

nificant changes in MMSE before and after ECT.
CBF measured by SPECT
1. Comparison between the patients and normal controls
At Pre, the relative rCBF in the widespread areas in
the frontal lobe and limbic regions, including the anterior and posterior cingulate cortices, parahippocampal
gyrus, thalamus, and uncus, was lower in the depressive
patients than in the normal controls (Fig. 1; A). On theother hand, the relative rCBF in the widespread areas in
the occipital, parietal, posterior temporal lobes, and the
cerebellum was higher in the depressive patients than in
the normal controls. At Post 1 and Post 2, the rCBF in
the frontal areas (particularly the inferior frontal area)
and the limbic regions (the anterior and posterior cingu-

late cortices and thalamus) in the patients continued to
be lower than that in the normal controls, although thesuccessive recovery of decreased rCBF in the frontal region was observed during 1 month after ECT. (Fig. 1; B,C).
2. Time course of changes in the rCBF in the patients
Table 3 represents the mean counts per pixel in eachregion as obtained by the SEE method; these counts
would reflect the relative rCBF values in the cerebral
regions. Repeated measures of ANOVA revealed significant changes in the rCBF (mean counts) in the right medial frontal gyrus (p = 0.012), right cuneus (p = 0.015),
and right parahippocampal gyrus (p = 0.048).
Post-hoc multiple comparisons using Bonferroni correction demonstrated a significant increase in the rCBF
in the right medial frontal region at Post 2 compared tothat at Pre (p = 0.045). It also showed a tendency forincrease in the rCBF in the right medial frontal region at
Post 2 compared to that at Post 1 (p = 0.061). Post hoc
analysis also showed a trend of increase in the rCBF in theright parahippocampal gyrus at Post 1 compared to thatat Pre (p = 0.076), whereas significant decreases wereobserved in rCBF in the right cuneus at Post 1 comparedto that at Pre (p = 0.025).
Furthermore, due to the wide age range of our patientsand the gender differences, we performed 2-way factori-

Fig. 1 Areas showing relative increases (red) and relative decreases (blue) in the regional cerebral blood flow (rCBF) in the patientscompared to those in the normal controls. From left to right: right lateral view, left lateral view, right midline view, left midline view,
and inferior view. L indicates left and R indicates right.
Color bars on the right side represent the Z scores. INC indicates relative increases in the rCBF in the patients in comparison with thenormal controls, and DEC indicates relative decreases in the rCBF in the patients in comparison with the normal controls.
A) Observations at Pre (several days before electroconvulsive therapy (ECT)) in patients vs normal controlsB) Observations at Post 1 (approximately 5 days after the last ECT session) in patients vs normal controlsC) Observations at Post 2 (1 month after the last ECT session) in patients vs normal controls

Keio J Med 2006; 55 (4): 153 －160

157

Table 3 Relative Rates of the Mean Counts per Pixel in Each Brain Region\
Superior frontal gyrus
Middle frontal gyrus
Inferior frontal gyrus
Medial frontal gyrus
Orbital gyrus*

Rectal gyrus
Paracentral lobule
Precentral gyrus
Subcallosal gyrus
Superior parietal lobule
Inferior parietal lobule
Angular gyrus
Postcentral gyrus
Precuneus
Supramarginal gyrus
Superior temporal gyrus
Middle temporal gyrus
Inferior temporal gyrus
Transverse temporal gyrus
Superior occipital gyrus
Middle occipital gyrus
Inferior occipital gyrus
Cuneus
Fusiform gyrus*

Lingual gyrus
ThalamusCingulate gyrus
Parahippocampal gyrus
Anterior cingulate cortex
Posterior cingulate
Uncus

*

L
R
L
R
L
R
L
R
L
R
L
R
L
R
L
R
L
R
L
R
L
R
L
R
L
R
L
R
L
R
L
R
L
R
L
R
L
R
L
R
L
R
L
R
L
R
L
R
L
R
L
R
L
R
L
R
L
R
L
R
L
R

47.9
48.3
48.9
49.3
46.8
48.1
48.7
48.3
50.6
48.3
46.8
46.3
49.2
48.7
49.1
48.8
43.0
42.3
49.1
49.7
51.0
51.1
52.2
52.4
49.5
49.6
53.2
53.5
54.1
51.5
49.9
49.6
52.2
49.3
49.1
49.6
53.4
51.8
52.6
53.8
52.8
54.0
51.2
51.5
55.2
56.1
50.1
50.1
56.8
55.8
54.7
56.9
47.4
47.5
44.7
45.0
44.3
44.0
48.6
50.4
43.6
44.4

Pre
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±

1.8
1.8
1.5
1.2
0.8
1.3
1.2
1.3
2.1
3.5
2.9
1.9
2.4
2.8
1.9
1.5
2.9
2.2
2.3
2.4
1.7
2.2
2.3
2.3
1.7
1.9
0.9
2.0
2.8
1.5
1.5
1.3
1.5
1.2
1.3
0.9
3.2
2.4
3.9
4.3
3.4
3.2
3.1
3.5
3.4
3.3
1.3
1.5
3.0
3.9
5.1
5.2
1.5
0.9
2.5
2.9
2.4
2.1
2.6
2.3
2.4
1.6

48.3
48.6
49.3
50.1
47.3
48.8
48.8
48.6
49.9
47.6
47.4
46.5
48.7
49.1
49.0
49.5
42.9
41.1
50.2
50.5
51.7
52.4
50.9
52.3
50.1
50.4
53.4
53.1
54.0
52.8
49.8
50.0
52.1
50.1
49.1
49.3
52.8
51.7
52.9
53.6
52.9
53.9
52.0
51.7
54.5
54.7
50.2
50.3
55.6
54.6
55.3
52.9
47.1
47.2
45.1
47.6
44.4
44.2
48.5
49.5
45.2
46.3

Post 1
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±

1.2
1.4
1.0
1.0
1.5
0.9
1.3
1.4
2.8
3.0
2.2
3.7
2.9
2.6
1.6
1.8
2.3
4.1
1.9
2.0
2.3
2.1
3.2
2.4
1.7
2.6
2.0
2.1
2.4
2.0
1.5
1.8
1.9
1.0
1.9
1.3
3.3
4.0
3.3
4.4
3.1
3.0
2.7
2.5
3.3
3.1
1.8
1.4
4.2
3.5
4.6
4.2
2.2
2.6
2.0
2.5
2.4
3.1
1.9
1.4
2.3
3.0

48.6
48.9
49.4
49.9
47.7
48.4
49.1
49.6
48.7
49.6
46.0
46.3
49.2
48.3
49.1
49.8
42.9
41.6
50.7
50.2
52.1
51.6
50.9
51.6
50.0
49.6
53.8
53.2
54.2
51.9
49.7
50.1
51.8
49.9
47.7
48.5
53.8
52.7
52.3
52.6
52.4
53.0
51.0
51.8
54.6
54.6
48.9
49.6
55.3
55.4
54.1
54.2
47.7
47.9
45.8
46.8
45.0
44.6
48.5
49.1
44.7
44.8

Post 2
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±

1.7
1.6
1.8
1.5
1.7
1.7
2.2
1.6
2.9
2.7
2.7
2.0
3.4
4.0
1.4
1.6
1.7
2.8
2.3
2.4
1.9
2.4
2.1
3.1
1.9
2.2
2.2
2.3
2.6
1.4
1.3
1.0
1.6
1.5
0.9
1.4
3.6
2.8
4.4
3.6
2.7
2.7
1.7
3.4
2.5
2.9
0.9
1.8
2.5
2.6
3.6
3.2
1.6
1.6
2.2
3.1
3.2
3.5
2.4
2.5
2.5
1.8

*Represents statistical significance at p < 0.05 by repeated measures of analysis of variance.
Abbreviations: R: right, L: left, Pre: at few days before electroconvulsive therapy, Post 1: at approximately 5 days after the last electroconvulsive
therapy session, Post 2: at 1 month after the last electroconvulsive therapy session

Takano H, et al: Cerebral blood flow changes following ECT

158

al ANOVA for comparing young (patients 1-4: age 35.3
± 6.6 years) and old (patients 5-8: age 62.5 ± 8.4 years)
patients as well as male and female patients (5 and 3, respectively). However, no significant change in the rCBF
was observed in each region between young and old patients as well as between male and female patients.
Discussion
In the present study, the depressive symptoms of ourpatients improved after a course of ECT treatment, andthis improvement was observed even at 1-month followup. In contrast, MMSE showed neither abnormality nor
evident exacerbation; this suggests the safety of the treatment.
Compared to the normal controls, the depressive patients showed a reduction in the rCBF in the frontal partof the brain and limbic regions, particularly the medial
frontal areas that include the anterior cingulate cortex
before ECT treatment. These findings are in agreementwith that of previous studies,6, 7 and these regions of thebrain have been known to play a crucial role in moodregulation.
Regarding the changes in the rCBF before and after the
ECT course, in the present study, the rCBF in the right
medial frontal area showed no significant change at Post
1; however, it remarkably increased at Post 2, that is, 1month after ECT. On the other hand, the rCBF remained
lower in some frontal regions in the patients than in thenormal controls at Post 1 and 2. To date, several studies
have reported the changes in the CBF and cerebral metabolic rate for glucose (CMRglc) before and after an ECTcourse; however, the results of these studies were contradictory.8 Although most studies indicated the involvement of the frontal lobe and anterior cingulate cortex,
some studies reported an increased brain activity in theseareas,9-11 others reported a reduction,12-14 whereas a few
reports showed no change.15, 16 For example, Bonne et alreported increases in the rCBF in the anterior cingulate
cortex only in patients responding to ECT 5-8 days after
the last session.9 This study was similar to our study inthat the rCBF increased in the frontal area after recovery
from depression and it was measured using9 9 mTc-HMPAO SPECT; however, in our study, the scanning was
performed twice after the ECT course. In sharp contrast,
by using fluorodeoxy-glucose (FDG) PET, Nobler et al
demonstrated that the post-ECT reductions in CMRglc,
particularly in the frontal and parietal cortices and theanterior and posterior cingulate gyri, were identified approximately 5 days after the ECT course.1 3 Further, byusing 1 3 3Xe inhalation technique, they also showed thepost-ECT reductions in the frontal areas of the brain 10
years before the abovementioned study was conducted.12
The discrepancy between these results could be due toseveral factors.

One possible explanation for the difference would be
the diverse modalities used to measure the brain function, such as CBF measurement by 1 3 3Xe inhalation1 2
and9 9m Tc-HMPAO SPECT 9-1 1 and the measurementof metabolism by FDG-PET.1 3, 1 4 The1 3 3 Xe inhalation
technique has a relatively low resolution; therefore, inearlier studies that used this technique, it was difficult to
examine specific brain regions.
The second possible reason for the differences in the
results could be the various methods of image analysis
used. Recent advances in 3D brain image analysis methods, such as the introduction of statistical parametricmapping (SPM)2 4 and 3D-SSP, enable us to conduct
accurate investigations. Earlier studies were performed
using manually drawn regions of interest (ROI) andcerebellar uptake normalization;9-1 1, 1 6 they may not be
objective or reproducible. In particular, it could affectthe results if the cerebellar uptake differs between scans.
The 3D-SSP and SEE methods used in this study are automated, user independent with regard to data extraction;
therefore, they are objective and reliable. These methods
are also considered appropriate for use in cases of brain
atrophy;2 5 thus, using them in our study was advantageous because some of our elderly patients had mild cerebral atrophy.
Another possible reason for the difference would be thetime lapsed after the final treatment because the effectsof ECT change dramatically with time. Pevious reports,
which were conducted at post-ECT subacute state, thatis, within hours to several days post-ECT, consistently
indicated that the rCBF in the anterior region of the brain
was reduced post-ECT, while the present study revealed
the increased rCBF in the frontal lobes at 1 month after
ECT.
In subacute phase after ECT, Scott et al detected a
post-ECT reduction in the rCBF only in the inferior
anterior cingulate cortex 45 minutes after the ECT treatment.26 Volkow et al performed FDG-PET 24 hours after the ECT session and observed a decreased uptake inthe frontal cortex bilaterally.27 These results in subacuteperiod were in agreement with the hypothesis proposedby Sackeim et al that ECT caused postictal suppressionof brain activity, and that the degree of suppression iscorrelated with the clinical outcome; the hypothesis further stated that one of the mechanisms of action of ECT
was due to this anticonvulsant effect (ECT triggers an
endogenous process that terminates the seizure and results in enhanced suppression of the postictal functional
brain activity).28
However, only a few studies have reported mid-termor long-term follow-up observations of CBF or CMRglc
after an ECT course. Awata et al reported that the meanrCBF reduction with cerebellar normalization in latelife depression before ECT was increased (normalized) 2
and 12 weeks after ECT.29 However, persistent anterior

Keio J Med 2006; 55 (4): 153 －160

paralimbic hypoperfusion was observed even 12 weeks
after ECT. Another study that used FDG-PET reported
that hypometabolism in various frontal regions did not
resolve at 1-month follow-up.3 0 Although these studies
were not controlled with regard to the patients’ medication status, the results were similar to those of our study.
Recently, Navarro et al demonstrated that in both the
medication-treatment and ECT-treatment groups who
showed remission for more than 12 months, the frontal
hypoperfusion on SPECT at baseline was observed tonormalize on follow-up SPECT that was conducted ina drug-free state (medications had been washed out 2
weeks before the examination).31
To summarize the results mentioned above, it may besuggested that the rCBF in the frontal region decreases
immediately after a successful ECT treatment course(within hours to several days post-ECT), and then increases and tends to recover gradually. In other words,
brain changes after ECT continue even after an improvement in the depressive symptoms.
One feature that requires further discussion is that asignificant change in the rCBF in the cuneus of patientswas also found in the study. It is difficult to explain its
precise mechanism, because we did not quantify theabsolute values of the rCBF, i.e., we only observed therelative changes (distribution) in the rCBF; however,from this way of measurement, it might be possible thatthe rCBF change in the cuneus might be secondary andinduced by the primary change in the right medial frontal
area. Additionally, we observed significant rCBF changes only in the right side of the brain. There has been noclear consensus on the laterality in the rCBF with regard
to depression7 as well as the change induced by ECT8;
however, Drevets et al 6 demonstrated that right, but notleft subgenual prefrontal cortex activity was associatedwith the severity of depression, and this observation appears to be consistent with our results.
The present study has several limitations, including
the small sample size and variations in terms of patients’age and gender. However, no significant difference wasobserved in the rCBF changes in any region between theyoung and old patients as well as the gender difference.
Moreover, our depression patients voluntarily participated in this study after giving informed consent; therefore, we cannot completely exclude the possibility of a
selection bias in sampling subjects. In addition, although
we maintained an almost uniform medication status during the entire study period, the patients concomitantly
received some psychotropics. This was because it is extremely difficult to maintain a drug-free state after ECT
for a long period due to ethical reasons, and after ECT
treatment, almost all patients require antidepressant medications to prevent a relapse. Further follow-up studies
with larger sample size are required to serially observe
the post-ECT state or trait abnormalities in the brain.
Finally, it is important that ECT should be recognized159

as a scientific treatment. Its efficacy and safety should
be assessed by performing objective measurements suchas clinical evaluation scales and CBF changes, and be
confirmed by evaluating both the effect of ECT on brain
itself and the degree of recovery from depression. Thus,
elucidating the mechanisms of action of ECT would help
us to obtain a better understanding of the neurobiology
of depression.
Acknowledgements: A part of this work was supported by research
grants from the Welfide Medical Research Foundation, Japan.

References
1.

World Health Organization: The World Health Report 2001:
Mental Health: New Understanding, New Hope, World HealthOrganization, 2001
2. Keller MB, Lavori PW, Mueller TI, Endicott J, Coryell W,
Hirschfeld RM, Shea T: Time to recovery, chronicity, and levelsof psychopathology in major depression. A 5-year prospective
follow-up of 431 subjects. Arch Gen Psychiatry 1992; 49: 809－
816
3. Abrams R: Electroconvulsive therapy, New York, Oxford University Press, 2002
4. American Psychiatric Association: Practice guideline for the treatment of patients with major depressive disorder (revision). Am J
Psychiatry 2000; 157: 1－45
5. The UK ECT Review Group: Efficacy and safety of electroconvulsive therapy in depressive disorders: a systematic review andmeta-analysis. Lancet 2003; 361: 799－808
6. Drevets WC: Functional anatomical abnormalities in limbic andprefrontal cortical structures in major depression. Prog Brain Res
2000; 126: 413－431
7. Mayberg HS: Depression. In: Mazziottam JC, Toga AW, Frackowiak RSJ, eds, Brain Mapping: The Disorders, San Diego, Academic Press, 2000; 485－507
8. Motohashi N, Takano H, Uema T, Ogawa K, Nishikawa M, Ohnishi T, Matsuda H: Mechanisms of action of electroconvulsive
therapy: investigations with PET and SPECT. In: Okuma T, Kanba S, Inoue Y, eds, Recent Advances in the Research of Affective
Disorder in Japan, Tokyo, Elsevier Science, 2002; 185－194
9. Bonne O, Krausz Y, Shapira B, Bocher M, Karger H, Gorfine M,
Chisin R, Lerer B: Increased cerebral blood flow in depressed patients responding to electroconvulsive therapy. J Nucl Med 1996;
37: 1075－1080
10. Vangu MD, Esser JD, Boyd IH, Berk M: Effects of electroconvulsive therapy on regional cerebral blood flow measured by
99mtechnetium HMPAO SPECT. Prog Neuropsychopharmacol
Biol Psychiatry 2003; 27: 15－19
11. Milo TJ, Kaufman GE, Barnes WE, Konopka LM, Crayton JW,
Ringelstein JG, Shirazi PH: Changes in regional cerebral bloodflow after electroconvulsive therapy for depression. J Ect 2001;
17: 15－21
12. Nobler MS, Sackeim HA, Prohovnik I, Moeller JR, Mukherjee S,
Schnur DB, Prudic J, Devanand DP: Regional cerebral blood flow
in mood disorders, III. Treatment and clinical response. Arch Gen
Psychiatry 1994; 51: 884－897
13. Nobler MS, Oquendo MA, Kegeles LS, Malone KM, Campbell
CC, Sackeim HA, Mann JJ: Decreased regional brain metabolism
after ect. Am J Psychiatry 2001; 158: 305－308
14. Henry ME, Schmidt ME, Matochik JA, Stoddard EP, Potter WZ:
The effects of ECT on brain glucose: a pilot FDG PET study. J
Ect 2001; 17: 33－40
15. Yatham LN, Clark CC, Zis AP: A preliminary study of the effects
of electroconvulsive therapy on regional brain glucose metabo-

160
lism in patients with major depression. J Ect 2000; 16: 171－176
16. Mervaala E, Kononen M, Fohr J, Husso-Saastamoinen M,
Valkonen-Korhonen M, Kuikka JT, Viinamaki H, Tammi AK,
Tiihonen J, Partanen J, Lehtonen J: SPECT and neuropsychological performance in severe depression treated with ECT. J Affect
Disord 2001; 66: 47－58
17. American Psychiatric Association: Diagnostic and statistical manual of mental disorders, Washington DC, American PsychiatricPress, 1994
18. Hamilton M: A rating scale for depression. J Neurol Neurosurg
Psychiatry 1960; 23: 56－62
19. Folstein MF, Folstein SE, McHugh PR: “Mini-mental state”. A
practical method for grading the cognitive state of patients for theclinician. J Psychiatr Res 1975; 12: 189－198
20. American Psychiatric Association Committee on Electroconvulsive Therapy: The practice of electroconvulsive therapy, Washington DC, American Psychiatric Association, 2001
21. Minoshima S, Frey KA, Koeppe RA, Foster NL, Kuhl DE: A diagnostic approach in Alzheimer’s disease using three-dimensional
stereotactic surface projections of fluorine-18-FDG PET. J Nucl
Med 1995; 36: 1238－1248
22. Talairach J, Tournoux P: Co-planar stereotaxic atlas of the humanbrain, Stuttgart, Thieme, 1988
23. Mizumura S, Kumita S, Cho K, Ishihara M, Nakajo H, Toba M,
Kumazaki T: Development of quantitative analysis method forstereotactic brain image: assessment of reduced accumulationin extent and severity using anatomical segmentation. Ann Nucl
Med 2003; 17: 289－295
24. Friston KJ: Statistical parametric mapping and other analyses offunctional imaging data. In: Toga AW, Mazziotta JC, eds, Brain
Mapping: The Methods, San Diego, Academic Press, 1996; 363－

Takano H, et al: Cerebral blood flow changes following ECT
386
25. Ishii K, Willoch F, Minoshima S, Drzezga A, Ficaro EP, Cross
DJ, Kuhl DE, Schwaiger M: Statistical brain mapping of 18FFDG PET in Alzheimer’s disease: validation of anatomic standardization for atrophied brains. J Nucl Med 2001; 42: 548－557
26. Scott AI, Dougall N, Ross M, O’Carroll RE, Riddle W, Ebmeier
KP, Goodwin GM: Short-term effects of electroconvulsive treatment on the uptake of 99mTc-exametazime into brain in major
depression shown with single photon emission tomography. J Affect Disord 1994; 30: 27－34
27. Volkow ND, Bellar S, Mullani N, Jould L, Dewey S: Effects ofelectroconvulsive therapy on brain glucose metabolism: a preliminary study. Convuls Ther 1988; 4: 199－205
28. Sackeim HA: The anticonvulsant hypothesis of the mechanismsof action of ECT: current status. J Ect 1999; 15: 5－26
29. Awata S, Konno M, Kawashima R, Suzuki K, Sato T, Matsuoka
H, Fukuda H, Sato M: Changes in regional cerebral blood flow
abnormalities in late-life depression following response to electroconvulsive therapy. Psychiatry Clin Neurosci 2002; 56: 31－40
30. Yuuki N, Ida I, Oshima A, Kumano H, Takahashi K, Fukuda M,
Oriuchi N, Endo K, Matsuda H, Mikuni M: HPA axis normalization, estimated by DEX/CRH test, but less alteration on cerebral
glucose metabolism in depressed patients receiving ECT after
medication treatment failures. Acta Psychiatr Scand 2005; 112:257－265
31. Navarro V, Gasto C, Lomena F, Mateos JJ, Portella MJ, Massana
G, Bernardo M, Marcos T: Frontal cerebral perfusion after antidepressant drug treatment versus ECT in elderly patients with major
depression: a 12-month follow-up control study. J Clin Psychiatry
2004; 65: 656－661