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Department of Psychiatry, National Centre Hospital for Mental, Nervous and Muscular Disorders, National Centre of Neurology and Psychiatry (NCNP), and Department of Neuropsychiatry, Keio University School of Medicine, Tokyo
Department of Psychiatry, National Centre Hospital for Mental, Nervous and Muscular Disorders, Tokyo
Department of Anaesthesiology, National Centre Hospital for Mental, Nervous and Muscular Disorders, NCNP, Tokyo, and Department of Anaesthesiology, Yokohama City University School of Medicine, Yokohama
Department of Radiology, National Centre Hospital for Mental, Nervous and Muscular Disorders, NCNP, Tokyo
Department of Neuropsychiatry, Keio University School of Medicine, Tokyo
Department of Radiology, National Centre Hospital for Mental, Nervous and Muscular Disorders, NCNP, Tokyo, Japan
Correspondence: Dr N. Motohashi, Department of Neuropsychiatry, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, 1110 Shimokato, Chuo City, Yamanashi 409-3898, Japan. Tel: +81 55 273 9847; fax: +81 55 273 6765; email: motohashi{at}yamanashi.ac.jp
Declaration of interest None. Funding detailed in Acknowledgements.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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Aims To investigate the time course of changes in cerebral blood flow during acute ECT.
Method Cerebral blood flow was quantified serially prior to, during and after acute ECT in six patients with depression under anaesthesia using [15O]H2O positron emission tomography (PET).
Results Cerebral blood flow during ECT increased particularly in the basal ganglia, brain-stem, diencephalon, amygdala, vermis and the frontal, temporal and parietal cortices compared with that before ECT. The flow increased in the thalamus and decreased in the anterior cingulate and medial frontal cortex soon after ECT compared with that before ECT.
Conclusions These results suggest a relationship between the centrencephalic system and seizure generalisation. Further, they suggestthat some neural mechanisms of action of ECT are mediated via brain regions including the anterior cingulate and medial frontal cortex and thalamus.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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METHOD |
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TOPABSTRACTINTRODUCTIONMETHODRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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All patients experienced clinical improvement after the ECT course (mean 8.5 sessions per patient, range 5–12); this was demonstrated by a reduced HRSD score (before ECT, mean=27.3, s.d.=9.8; after ECT, mean=14.5, s.d.=9.0; paired t-test, P=0.02).
Experimental procedure
A PET scan was performed on each patient during the first session of the
ECT course. On the day of the experiment the patients fasted and did not take
any medication after breakfast. The experiment began at 14.00 h, which was
more than 16 h after the last intake of medication. Electroencephalograms
(EEGs) were recorded from the disc electrodes placed at F3, F4, P3, P4, Fz, Cz
and Pz; the A1 and A2 electrodes were used as references. All inter-electrode
impedances were maintained below 10 k
. The EEG was amplified by a
multichannel EEG amplifier (Neurotop, Nihon Kohden, Tokyo, Japan) and filtered
using high-cut (low-pass) and low-cut (high-pass) filters with frequencies of
60 Hz and 0.53 Hz respectively. A venous line was inserted into the right
median antebrachial vein for transfusion and injecting a tracer, and an
arterial line was inserted into the left radial artery to measure the
radioactivity in the blood sample throughout the scanning period. The blood
pressure, pulse rate and arterial blood gas were monitored throughout the
experiment. Propofol (5 mg/kg per h) and vecuronium bromide (0.15 mg/kg
initially and 0.04 mg/kg later) were used for anaesthesia. A laryngeal mask
was inserted and the patient was kept under controlled ventilation with a
respirator (tidal volume 10 mL/kg; 8 times per min). The current was
administered through the bilateral temporal regions by means of a Thymatron
DGx with disposable electrodes (Somatics Inc., Lake Bluff, Illinois, USA). The
initial stimulus dose was 101.2 mC, and this was later increased in cases of
aborted seizures (no spike and wave complex observed on the EEG, i.e. there
was no seizure generalisation). In the case of complete seizures, the mean
duration of seizure activity on the EEG was 67.5 s (s.d.=26.1, range
50–120). A maximum of 12 intravenous injections of the radioisotope were
administered during relaxed wakefulness (3 injections), prior to ECT (3
injections), during ECT (1–3 injections) and after ECT (3 injections)
under anaesthesia. In order to perform a scan during ECT, the radioisotope was
injected just prior to the electrical stimulation. The interval between each
scan was approximately 10 min.
Scanning procedure
The PET images were acquired on a Siemens ECAT EXACT HR 961 scanner
(http://www.medical.siemens.com)
in the three-dimensional mode, as described in a previous report
(Kajimura et al,
1999). In brief, a camera with a 150 mm axial field of view was
used to acquire data simultaneously from 47 consecutive axial planes. An image
resolution of 3.8x3.8x4.7 mm was obtained after back projection
and filtering (Hanning filter; cut-off frequency 0.5 cycles per pixel). The
reconstructed image was displayed in a matrix of 128x128x47 voxel
format (voxel size 1.7x1.7x3.1 mm). Prior to the acquisition of
emission data, a 10 min transmission scan was carried out using a retractable
rotating 68Ga/68Ge source with three rods to correct for
tissue attenuation and background activity. For each scan, 259 MBq of
[15O]H2O was automatically flushed intravenously in a
bolus manner over a period of 15 s. The total radioactive dose per patient was
less than 1 mSv. The scanning was started manually 1 s after the initial
increase in head counts and was continued for 90 s. The arterial blood was
sampled automatically throughout the scanning period using a Pico-Count
flow-through radioactivity monitor (Bioscan Inc., Washington, DC, USA).
Absolute rCBF images were produced based on the arterial time activity data
obtained using an autoradiographic method
(Herscovitch et al,
1983; Raichle et al,
1983).
Data analysis
The PET images were analysed using the Statistical Parametric Mapping 2
(SPM2) software (Wellcome Department of Cognitive Neurology, London, UK;
http://www.fil.ion.ucl.ac.uk/spm)
implemented in MATLAB version 6.5 (MathWorks, Inc., Sherborn, Massachusetts,
USA) for Windows XP on a personal computer. Spatial normalisation was employed
to fit each individual brain to a standard template brain in a
three-dimensional space to correct for differences in the brain size and shape
and to facilitate inter-individual averaging. The stereotaxically normalised
scans contained 68 planes (voxel size 2x2x2 mm) and a final image
with a resolution of 17x17x20 mm was produced by smoothing with a
10 mm Gaussian kernel. Since SPM2 uses a standard brain from the Montreal
Neurological Institute, Canada, the precise anatomical localisations of
significant changes were indicated in accordance with the atlas of Talairach
& Tournoux (1988) using a
numerical transformation formula. Global cerebral blood flow (gCBF) was
calculated as the sum of the grey-matter blood flow, including that of the
region of interest after spatial normalisation. First, the absolute gCBF rates
during, before and after ECT as well as during wakefulness were analysed and
compared in this study; global normalisation with proportional scaling was
then used to compare the relative changes in the rCBF rate.
After specifying the appropriate design matrix, the condition of each voxel in each patient was assessed in accordance with the theory of Gaussian fields. The exact significance level of the difference between the conditions was characterised by the peak amplitude. In this study we focused on the cluster level to detect significantly different regions because our sample size was too small to be analysed by the random field theory, and such an analysis would lead to type II errors (false negative). Since we had some data on the neural mechanism of action of ECT (Bajc et al, 1989; Blumenfeld et al, 2003), we performed a priori studies. In general, the significance level was thresholded at P<0.05 with a false discovery rate correction (Genovese et al, 2002), and the minimum cluster size (k) was set at 100 voxels. Finally, the resulting T-values were converted to Z-scores for interpretation. In order to compare the physiological variables and the gCBF, one-way analysis of variance was performed followed by Bonferroni’s multiple comparison test.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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The physiological variables are listed in Table 1. The systolic blood pressure values increased during ECT compared with pre-ECT values (P=0.042). Other variables showed no significant change across the four different states (at rest, pre-ECT, during ECT and post-ECT).
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The gCBF decreased significantly when the patients were under propofol anaesthesia compared with when they were awake: mean 45.1 ml/100 g per min (s.d.=5.5) v. mean 20.5 ml/100 g per min (s.d.=4.8); P=0.0001. During ECT of generalised seizures, the gCBF value increased significantly compared with the baseline pre-ECT values: mean 37.5 ml/100 g per min (s.d.=8.9) during ECT; P=0.0001. Approximately 10–30 min post-ECT the gCBF value returned to the baseline pre-ECT values: mean 21.2 ml/100 g per min (s.d.=4.7); P=1.0. The averaged images obtained at each stage are shown in Fig. 1.
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Post-ECT, the rCBF increased in the thalamus and decreased in the anterior cingulate (Brodmann’s areas 24 and 32) and dorsolateral and medial frontal cortices (Brodmann’s areas 6, 8, 9, 10 and 11) compared with the pre-ECT rCBF (Fig. 3).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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Previous research
Thus far, the acute effects of ECT or generalised seizures on cerebral
blood flow have been examined in a limited number of human studies by using
the xenon-133 inhalation method, PET and SPECT
(Bajc et al, 1989;
Nobler et al, 1994;
Scott et al, 1994).
Previous reports have revealed that the cerebral blood flow or cerebral
glucose uptake increases during ECT or generalised seizures
(Engel et al, 1982;
Bajc et al, 1989;
Theodore et al, 1996)
and decreases after ECT (Nobler et
al, 1994; Scott et
al, 1994).
With regard to the regional distribution, blood flow increased in the frontal cortex, temporal cortex and basal ganglia and decreased in the parietal or occipital cortex during ECT (Bajc et al, 1989). Moreover, the rCBF decreased in the inferior anterior cingulate cortex 45 min after ECT (Scott et al, 1994). One PET study revealed that the global cerebral metabolic rate increased during an ECT-induced seizure and reduced post-ictally. The pattern of post-ictal hypometabolism was more prominent in the cortical structures than in the grey-matter structures (Engel et al, 1982). Further, only one group of researchers serially measured cerebral blood flow by using [15O]H2O PET in chemically induced seizures in people with epilepsy. They demonstrated that in two patients with generalised tonic–clonic seizures, the CBF increased, particularly in the thalamus (Theodore et al, 1996). More recently, Blumenfeld et al (2003) reported that the focal regions of the frontal and parietal association cortices show the greatest relative signal increase in SPECT during ECT.
Our finding of a significant increase in the gCBF during ECT and a decrease in the gCBF following ECT are in agreement with results reported previously (Engel et al, 1982; Bajc et al, 1989; Nobler et al, 1994; Blumenfeld et al, 2003). With regard to the regional distribution patterns, Bajc et al (1989) demonstrated relative increases in blood flow in the frontal and frontotemporal regions as well as in the basal ganglia in SPECT during ECT under anaesthesia. Our findings obtained during generalised ECT support these results. Further, the high-resolution PET used in our study facilitated the observation of the blood flow changes during ECT in the subcortical structures. In our study the generalised seizures increased the cerebral blood flow, particularly in the basal ganglia and reticular formation. These results are similar to those obtained in a recent SPECT study (Blumenfeld et al, 2003) and are in agreement with the viewpoint that the reticular formation is involved in the generalisation of seizure activity (Fromm, 1991).
Importance of the centrencephalic system during generalised ECT
Approximately 50 years ago, Penfield & Jasper
(1954) proposed that the
centrencephalic system is involved in seizure generalisation. In contrast to
the slow progression observed in the Jacksonian motor seizure, the sudden
rapid generalisation observed in grand mal seizures does not appear
to occur by the spread of excitation via the cortical circuits. These authors
defined the centrencephalic system as ‘the neuronal system in the higher
brain-stem that demonstrated a functional relationship with the two
hemispheres’ (Penfield & Jasper,
1954). Although this system has been theoretically defined, the
precise neural circuits of the centrencephalic system have not been clarified.
Thus, our study in humans further supports this centrencephalic theory of
seizure generalisation.
Since a chemically induced convulsion was also effective, generalised seizures of adequate duration appear to be closely related to the efficacy of ECT (Sackeim, 1994). Recent studies on deep brain stimulation and vagus nerve stimulation have demonstrated that the brain-stem structures are closely related to the pathophysiology of depression (Bejjani et al, 1999; Rush et al, 2000). Thus, further studies on the centrencephalic system, including the brain-stem, are required to elucidate the mechanisms of action of ECT.
Cerebral blood flow in the post-ECT state
In our study, the rCBF level remained elevated in the thalamus and
decreased in the anterior cingulate and medial frontal cortex following ECT.
These results are in agreement with those reported previously with regard to
the degree of rCBF after ECT or generalised tonic–clonic seizures in
humans (Nobler et al,
1994; Scott et al,
1994; Theodore et al,
1996). Both the anterior cingulate and medial frontal cortex have
long been thought to be involved in the pathophysiology of depression (see
Drevets, 2000, for review). In
particular, Nobler et al
(1994) demonstrated that
post-ictal blood flow reductions in anterior cortical regions were associated
with a positive clinical response. This finding was in line with the
hypothesis proposed by Sackeim
(1999) that diminished
activity in these regions might be a reflection of the anticonvulsant effect
of ECT – that is, triggering endogenous brain processes to terminate
generalised seizures. Furthermore, it is interesting to note that metabolic
activity decreased in the anterior cingulate cortex after treatment with
different classes of antidepressants (e.g. selective serotonin uptake
inhibitors) and interpersonal therapy
(Buchsbaum et al,
1997; Mayberg et al,
2000; Brody et al,
2001). In addition, we are inclined to speculate that the
increased blood flow in the thalamus following ECT may also be related to the
therapeutic effects of ECT because depression is characterised by symptoms of
diencephalic disturbances (Carney &
Sheffield, 1973; Abrams &
Taylor, 1976). Although repeated ECT is generally necessary for
ameliorating depressive symptoms, the antidepressant effects of ECT are
probably associated with changes in blood flow in the anterior cingulate and
medial frontal cortex and thalamus.
Study limitations
This study has several limitations, including the relatively small sample
size. In addition, the age range of our patients was wide, and they were not
all of the same gender. However, PET scans were obtained from each patient
prior to, during and following ECT, and we carefully noted the time course of
the changes in cerebral blood flow during ECT. Another limitation arises from
the fact that the patients were receiving some medication. The effects of the
medication on cerebral blood flow cannot be ruled out, although the patients
had fasted for more than 16 h between the last intake of medication and the
time of the experiment. Moreover, we think that there is a relationship
between muscle tone and blood pressure, although vecuronium (a muscle
relaxant) was used to minimise changes in muscle tone, and the blood pressure
would not be directly influenced owing to the mechanism of autoregulation in
the brain.
In conclusion, to our knowledge this is the first PET study that has serially measured cerebral blood flow during acute ECT. Our results suggest that acute ECT increases cerebral blood flow, particularly in the centrencephalic system, and one of the mechanisms of action of ECT may be related to the brain regions that include the anterior cingulate and medial frontal cortex and the thalamus.
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ACKNOWLEDGMENTS |
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TOPABSTRACTINTRODUCTIONMETHODRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMETHODRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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Received for publication February 6, 2006. Revision received July 5, 2006. Accepted for publication September 1, 2006.
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