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Departments of Psychiatry (E.L.C., A.S.), Neurology (A.I.), Radiology (G.C.), and Endocrinology (C.D.) and Positron Tomography Laboratory (A.G.D.V., A.B., D.L., J.M.), Université Catholique de Louvain, B-1200 Bruxelles, Belgium
Address all correspondence and requests for reprints to: E. L. Constant, M.D., Department of Psychiatry, Unité 21, Université Catholique de Louvain, Cliniques Universitaires Saint-Luc, Avenue Hippocrate 10, B-1200 Bruxelles, Belgium. E-mail: constanteric{at}hotmail.com
Abstract
Hypothyroidism is often associated with defective memory, psychomotor slowing, and depression. However, the relationship between thyroid status and cognitive or psychiatric disturbances remains unclear. Using psychometric scales, 10 patients who had undergone total thyroidectomy for thyroid carcinoma were evaluated for depression, anxiety, and psychomotor slowing; they were examined both when euthyroid and hypothyroid after thyroid hormone withdrawal. Positron emission tomography was used, with oxygen-15-labeled water and fluorine-18F-labeled 2-deoxy-2fluoro-D-glucose as the tracers, to correlate the regional cerebral blood flow and cerebral glucose metabolism with the mental state in patients. Two different image analysis techniques (regions of interest and statistical parametric maps) were applied. In hypothyroidism, there was a generalized decrease in regional cerebral blood flow (23.4%, P < 0.001) and in cerebral glucose metabolism (12.1%, P < 0.001) and there were no specific local defects. Patients were also significantly more depressed (P < 0.001), anxious (P < 0.001) and psychomotor slowed (P < 0.005) in hypo than in euthyroid status. These results indicate that the brain activity was globally reduced in severe hypothyroidism of short duration without the regional modifications usually observed in primary depression.
THE THYROID HORMONE is important both for the functional development and maturation of the central nervous system and for its proper functioning throughout life. Whereas the association between the absence of thyroid hormone in congenital hypothyroidism and profound mental retardation is well documented (1), adult onset hypothyroidism may have a variety of somatic, neuropsychological and psychiatric symptoms such as inattentiveness (2), inability to concentrate (2), deficits in memory (2), psychomotor slowing (1) but also depressive mood state (2), anxiety, and sometimes persecutive delusions (2, 3). In addition, the pathophysiological processes relating thyroid activity to these symptoms remain unclear in adult onset hypothyroidism.
Regional cerebral blood flow (rCBF) and measures of regional brain metabolic activity such as cerebral glucose metabolism (rCMRGlc) and ratio of phosphocreatinine to inorganic phosphate have been measured in patients with adult onset hypothyroidism. Three groups reported that CBF was decreased in hypothyroidism (4, 5, 6), and two groups hypothesized that increased vascular resistance caused the CBF reduction and not decreased brain activity (6, 7). Marangell et al. (8) observed that peripheral TSH was inversely related to global and regional CBF and CMRGlc in affectively ill patients. However, these patients were not clinically in hypothyroidism. Using phosphorus-31 nuclear magnetic resonance spectroscopy, Smith and Ain (9) reported a relatively increased ratio of frontal phosphocreatine to inorganic phosphate in response to treatment of hypothyroidism, suggesting increased metabolism in the frontal lobe during hypothyroid treatment.
To elucidate the relationship between regional CBF and regional CMRGlc, both were measured in this study in patients who had been thyroidectomized for thyroid carcinoma. The patients were studied during both euthyroidism and hypothyroidism. In addition, the mental state of each patient was quantified at the time of the study and compared with the CBF/CMRGlc coupling to look for possible correlations.
Materials and Methods
Subjects
We studied 10 patients who underwent thyroidectomy for thyroid carcinoma (8 females and 2 males; mean age, 44 yr; range, 27–65 yr) in euthyroidism and after withdrawal of thyroid hormones. Patients were right-handed and neurologically normal. There was no previous history of psychiatric illness and only one patient was taking a psychotropic medication in both conditions (patient 2 took 10 mg citalopram as antidepressant). It is also worth noting that patient 4 was already significantly depressed and anxious during euthyroidism.
All patients gave their informed consent before undergoing the positron emission tomography (PET) studies, the protocol of which has been approved by the Medical Ethics Committee of the School of Medicine at the Université Catholique de Louvain.
Schedule and clinical tests
A severe hypothyroidism status of short duration (4–5 wk) was
induced in these patients to perform an [131I
total body] scintigraphy. The PET acquisition in hypothyroidism took
place 2–3 d before the ingestion of 131I. Using
this schedule excluded any interference with the emission of 
rays
by the 131I tablet that had to be ingested 5
d before the scintigraphy. The PET acquisition in euthyroidism took
place 8 wk before or after the time period of hypothyroidism. The two
PET acquisitions were performed in alternative order between patients,
so that alterations due to any familiarization to the PET procedure
could be eliminated.
Serum thyroid indices (i.e. TSH, total and free T3, total and free T4) were measured by RIA in blood samples collected on the morning of the day of the PET session. Normal values were of 0.2–3.5 µU/ml for TSH and of 0.8–2.0 ng/dl for free T4 (FT4).
In the euthyroid condition, all patients were clinically euthyroid. However, they were not all biologically strictly euthyroid. Patients 1, 6, 7, and 8 were biologically in euthyroidism (normal FT4 and TSH). Patients 2 and 9 were in subclinical hypothyroidism (normal FT4 and TSH >3.5 µU/ml), and patients 3, 4, 5, and 10 were in subclinical hyperthyroidism (normal FT4 and TSH < 0.2 µU/ml).
The mental state of the patient was evaluated for depression [Montgomery and Asberg Rating Scale (MADRS) (10)], for anxiety [Hamilton Anxiety Scale (HAM-A) (11)], and for psychomotor retardation [Widlöcher Retardation Scale (WRS) (12)] just after each PET procedure. These scales were assessed by the same investigator (E.L.C.) throughout the study. Patients were considered as significantly depressed if MADRS more than 15, anxious if HAM-A more than 20, and psychomotor retarded if WRS more than 16.
PET acquisition
Each PET acquisition took place in the morning. The patient fasted for at least two hours and was studied at rest in a quiet environment with reduced auditory stimuli. Before the PET acquisition, blood glucose levels were always measured. PET measurements were performed using a whole-body, high resolution tomograph (ECAT EXACT-HR, CTI/Siemens). This tomograph allows simultaneous imaging of 47 transaxial slices in three-dimentional mode (septa retracted), with an effective resolution of 8 mm full width-at-half-maximum (13) and a slice thickness of 3.125 mm. All images were reconstructed using standard software including scatter correction, with both transaxial Hanning filter (cutoff frequency of 0.30) and axial Hanning filter (cutoff frequency of 0.50). Positioning of the subject in the gantry was accomplished by aligning two sets of low power laser beams with the canthomeatal line and the sagittal line, respectively. Head-restraining adhesive bands were used. A 22-gauge catheter was then placed in the antecubital vein of one arm for radiotracer injection. A 24-gauge catheter (Abbocath) was inserted in the other arm in a radial artery under local anesthesia with bipuvacaïne to allow input function determination.
Before tracer administration, each subject underwent a 15-min
transmission scan performed with retractable germanium-68 rotating rod
sources, allowing the subsequent correction of emission images for
attenuation. Transmission scans were acquired with the rod-windowing
technique (14), producing scatter-free attenuation maps.
CBF measurements were then performed using a 20-sec bolus of
oxygen-15-labeled water (8 mCi, 296 MBq). Beginning 10 sec after the
start of the injection, 8 serial images were acquired for 100 sec
(7 x 10 sec and 1 x 30 sec). Fifteen minutes after the CBF
study, measurement of glucose metabolism (CMRGlc) was performed using 4
mCi (148 MBq) 18F-labeled 2-deoxy-2-fluoro-D-glucose (FDG)
(15) injected as a slow bolus over 30 sec. Brain scanning
was started immediately and emission data were collected in dynamic
mode for 1 h (10 x 1 min and 5 x 10 min). Throughout
these two studies, arterial blood sampling was performed for input
curve measurement. Whole blood and plasma radioactivity were counted in
a well counter cross-calibrated against the PET tomograph. The
plasma glucose levels were measured with a Beckman glucose analyzer
(Beckman Coulter, Inc. Instruments, Fullerton, CA).
For each subject, three-dimensional magnetic resonance images (MRIs) were also obtained on a 1.5 Tesla unit (Signa, General Electric) using the Spoiled Grass technique. T-1 weighted anatomical images (TR = 25 ms, TE = 6 ms, flip angle = 25 degrees, slice thickness = 1.5 mm) were obtained in the bicommissural (AC-PC) orientation.
Data analysis
Zero to 15 water studies were first analyzed by fitting the global brain time-activity curves with the classical one tissue compartment model, allowing the estimation of both the delay between the radial arterial and the true cerebral input and the dispersion of the input curve. CBF parametric images were then generated from a 40-sec integral image, using the estimated delay and dispersion values and assuming a fixed value of 0.84 ml/g for the partition coefficient of water (16).
Sequential FDG concentration images, covering the period from 30–50 min after tracer injection, were summed and converted into maps of glucose utilization according to the autoradiographic method of Phelps et al. (17) with the following rate constants: k1 = 0.092 min-1; k2 = 0.14 min-1; k3 = 0.075 min-1; k4 = 0.0056 min-1; and the lumped constant (LC): LC = 0.42 (18).
Two different image analysis techniques were applied. First, CBF and CMRGlc parametric images from the two different conditions for the same patient were realigned and co-registered with the subject’s MRI using Automated Image Registration 3.0 (19). Using an image analysis program (Mediman (20), irregular regions of interest were delineated by taking in consideration the activity on the glucose utilization parametric image (21) and the anatomical landmarks on the MRI. A total of 46 volumes of interest (VOIs) were defined by summing the planar regions related to anatomical structures that were present on adjacent planes. Because of the limited precision in VOI definition, only well-defined areas were considered for analysis. The 46 VOIs were subsequently replicated on the blood flow parametric images. Mean regional values of blood flow and metabolism were computed, on a voxel basis, into these VOIs and were separately compared between eu- and hypothyroidism, using an ANOVA (with F tests) with two fixed cross factors for VOI and condition (thyroid status).
Second, the co-registered matching brain images (MRI and PET) were spatially normalized, using SPM 96 (Wellcome Dept. Cognitive Neurology), in the Talairach and Tournoux (22) coordinate system, with a cubic (2 x 2 x 2 mm) voxel size. The PET data were further smoothed with a 15-mm Gaussian filter to account for residual intersubject differences and were corrected for differences in global activity by proportional scaling. Statistical parametric maps were computed separately for CBF and CMRGlc on a voxel-by-voxel basis, using the general linear model (23). A multisubject –different conditions design was used, which generates Z maps testing the main effect of the condition. Statistical inference on the SPM {Z} was corrected for multiple comparisons using the theory of Gaussian fields (23). Only regions significantly activated at P < 0.05 (corrected for multiple comparisons) and P < 0.001 (uncorrected for multiple comparisons) were considered.
Results
Results of clinical tests
TSH, FT4, and blood glucose levels are shown
in Table 1
. The mean TSH was 1.49 ±
2.35 µU/ml (mean ± SD) and mean
FT4 was 1.8 ± 0.2 ng/dl in euthyroid
patients. Patients (2, 9) had TSH values slightly above
normal but were clinically euthyroid with normal
FT4 values. In hypothyroidism, the mean TSH was
109.83 ± 40.25 µU/ml and mean FT4 was
0.15 ± 0.07 ng/dl. Mean blood glucose levels were similar in
euthyroidism (93.9 ± 15.7 mg/dl) and hypothyroidism (83.5 ±
16.6 mg/dl).
|
. All the patients were significantly
more depressed (paired-samples t test, P <
0.001), anxious (P < 0.001), and psychomotor slowed
(P < 0.005) in hypo than in euthyroid status. No
patient exhibited any sign of depression or anxiety in euthyroidism,
except patient 4.
|
The VOIs analysis demonstrated a significant decrease both in rCBF
values (P < 0.001) and in rCMRGlc values
(P < 0.001) during the hypothyroidism compared with
euthyroidism (ANOVA, condition effect). No interaction was found
between the thyroid condition and the regional pattern of
blood flow or metabolism (ANOVA, interaction VOI*condition,
P > 0.05). Regional values (Figs. 1 and 2)
demonstrate a global effect of thyroid status without regional effect.
All VOIs were further averaged to provide a global CBF and CMRGlc
measure for each patient and each condition (Figs. 3 and 4).
In euthyroidism, mean CBF and CMRGlc values were 44.3 ± 11.5
ml/(100 g·min) and 40.8 ± 9.7 µmol/(100 g·min),
respectively, whereas in hypothyroidism these values averaged 33.9
± 9.4 ml/(100 g.min) and 35.9 ± 7.7 µmoles/(100 g.min)
respectively. Therefore, the mean CBF and CMRGlc decrease related to
hypothyroidism compared with euthyroidism were 23.4% and 12.1%,
respectively, for the entire patient group. Eight of the 10 patients
presented a reduced CBF and brain metabolism in hypothyroidism.
However, 2 of the 10 patients presented divergent results. Patients 4
and 5 presented a reduced CBF with a slight, but not statistically
significant, increased cerebral glucose metabolism in the same
hypothyroidism condition. In these two patients, the effect was also
global rather than regional.
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Discussion
In this study, CBF and CMRGlc are significantly (23.4% and 12.1%) and proportionally reduced in severe hypothyroidism of short duration. This effect is global and not regional.
Methodological issues
The limitations of the autoradiographic PET/FDG method and its application to pathological cases have been extensively discussed elsewhere (24), and the actual values of both the rate and lumped constants in hypothyroidism are unknown. However, previous reports have shown that glucose metabolism assessed by both the autoradiographic and dynamic methods (where individual rate constants are estimated) are largely consistent, which would validate the use of the autoradiographic method with standard rate constants (18, 24, 25). In hypothyroidism, the value of the LC, which takes into account the different behavior of FDG and glucose, may hypothetically differ from that in euthyroidism. Animal studies, however, have failed to find any significant difference in LC regional distribution, except in extreme conditions like hypoglycemia (26). Therefore, the differences between hypothyroidism and control state, in terms of absolute and relative glucose metabolic rates, are unlikely to be due to inappropriate LC or rate constants. The glycemia was similar in both conditions (hypo and euthyroidism). Patients were randomly studied. Half of the patients who had the PET acquisition in eu- followed by hypothyroidism showed similar results as the other half (hypo followed by euthyroidism). This indicates that a metabolic effect due to familiarization with the PET acquisition technique is excluded. In addition, the observed CBF and CMRGlc decrease (23.4% and 12.1%, respectively) for all VOIs are too large to be attributed to a second test session effect because previous data (27) have shown a percent change for CMRGlc between two PET sessions of 1–8%. The present study involves 10 patients. The majority of PET studies investigating regional changes usually involve a few number of patients. If a regional effect is present, it is generally observed in such a small population.
Effect of thyroid status on brain metabolism
Neuropsychological and psychiatric disturbances in hypothyroidism such as psychomotor slowing (1), depression (3), or anxiety (3) are well documented. Cognitive changes with alterations in attention, concentration, perception, and speed of thought seem to be the most common of the clinical manifestations (2). Nevertheless, the pathophysiological mechanisms involved in these disturbances remain unclear. The observation of a decreased CBF in hypothyroidism (4, 5, 6) was previously interpreted as a consequence of increased vascular resistance in hypothyroidism rather than a simultaneous brain hypoactivity.
In 1950, Scheinberg et al. (5) observed in hypothyroidism a low cardiac output per square meter of body surface with a normal or elevated mean arterial pressure, indicating that the total vascular resistance of the body was increased in hypothyroidism. Nevertheless, using the nitrous oxide technique and Nelson’s modification of Somogyi’s method, he also found a reduction in global CBF (38%) and cerebral oxygen and glucose consumption (27%) from normal values when patients were in hypothyroidism. In this study, no regional analysis was performed. Cerebral vascular resistance showed a 91% increase. The finding of a normal arterial-internal jugular oxygen difference with a reduced CBF in that study is compatible with the interpretation that, in hypothyroidism, there is a decreased demand for oxygen and glucose reflecting a reduced neural activity in neural tissues.
On the other hand, in untreated hyperthyroid patients, Sokoloff et al. (7) found moderate elevation of CBF but with cerebral oxygen consumption entirely normal. He concluded that the gross energy metabolism of the brain, as reflected by the oxygen utilization, may be independent of the action of the thyroid hormone.
More recently, two different studies (8, 9) have investigated the relationships between hypothyroidism or subclinical hypothyroidism and brain metabolism in adults. In their PET study, Marangell et al. (8) observed that serum TSH was inversely related to both global and regional CBF and cerebral glucose metabolism in affectively ill patients. However, patients were divided into low and high TSH subgroups but were not biologically in hypothyroidism (FT4 was 1.27 ng/dl for the CBF study and 1.33 ng/dl for the cerebral glucose metabolism study (8)), so that a definite effect of hypothyroidism could not be concluded. The present study is the first one to examine both the CBF and CMRGlc in the same patients examined under the two conditions (hypo and euthyroidism) and to correlate the metabolic status with the mental state.
In the present study, all but two patients disclosed both reduced CBF and CMRGlc values in hypothyroidism compared with euthyroidism. The fact that all the patients were not exactly in the same biological condition in euthyroidism (strict euthyroidism, subclinical hypothyroidism, subclinical hyperthyroidism) had no consequence on the general tendency of the results. Two of the 10 patients presented divergent results. Patients 4 and 5 presented a slight, but not statistically significant, hypermetabolism in hypothyroidism with a reduced CBF. However, patient 4 also showed atypical psychometric results because this subject was already significantly anxious and depressed in euthyroidism and did not show the usual psychomotor slowing in hypothyroidism. There might be a link between these unusual psychometric results and the atypical imaging findings. It is interesting to note that patient 5 presented a particularly high glycemia (128 mg/dl) in euthyroidism.
These results tend to confirm the work of Smith and Ain (9) who reported a relatively increased ratio of frontal phosphocreatine to inorganic phosphate in response to treatment of hypothyroidism using phosphorus-31 nuclear magnetic resonance spectroscopy, suggesting increased metabolism on the frontal lobe during hypothyroid treatment.
Our results indicate that there is a globally reduced neural activity in hypothyroidism which cannot be explained by an increased vascular resistance alone as not only CBF but also CMRGlc are reduced in hypothyroidism. It is noteworthy that, in this study as well as in the study of Scheinberg et al. (5), the reduction in CBF was more important than the one in cerebral glucose metabolism. This may be explained by a possible contribution of an increased vascular resistance. Another possible explanation is the higher sensitivity of the CBF method to detect neural activity changes. This characteristic is used for activation studies (28). However, the reduced cerebral glucose metabolism can also be interpretated as resulting from deficiency in thyroid hormone, under which circumstances the brain cells apparently do not extract sufficient quantities of oxygen and glucose from the blood. These findings are compatible with the mental state changes observed in hypothyroidism described below.
Effect of thyroid status on mental state
The underlying hypothesis of this study was that, in hypothyroidism, patients would be more depressed as compared with euthyroidism. Therefore, a global effect as well as regional modifications in rCBF and rCMRGlc were expected, according to previous reports in depression (29). Previous reports indicate that depression induces brain metabolic changes, ranging from hypometabolism in discrete frontal lobe regions, in particular the anterolateral prefrontal cortex (30), to widespread decline in rCMRGlc involving subcortical regions such as the caudate nucleus (29) and the cerebellum (31). Concerning the CBF, a reduction in rCBF in the left anterior cingulate and left dorsolateral prefrontal cortex was previously described in depressed patients (32). There is an emerging consensus that the prefrontal and limbic areas constitute an anatomical network that may be functionally abnormal in major depression.
In the present study, patients were significantly more depressed (P < 0.001), anxious (P < 0.001), and psychomotor slowed (P < 0.005) in hypo than in euthyroidism. We observed in hypothyroidism a significant decrease in global CBF (P < 0.001) and in CMRGlc (P < 0.001) with no interaction between the thyroid condition and the regional pattern. In particular, there was no reduction of rCBF and rCMRGlc in the prefrontal and limbic cortices, even at a very low statistical threshold (P = 0.05, uncorrected), although these changes are usually described in depressed patients. One possible explanation to this discrepant obervation is the fact that, in the present study, the induced hypothyroid status is sudden and massive which would lead to a global effect rather than to regional changes. In this study, patients in hypothyroidism were also more psychomotor slowed than depressed and their depressed status was mild or moderate but not severe.
It is well known that T4 and T3 hormones regulate the cellular function in most organs including the brain. T3 nuclear receptors are prominent in brain tissue, particularly in neurons, and they are regionally distributed: high concentrations are found in the amygdala and hippocampus whereas low concentrations are observed in the brain stem and cerebellum (33). We could thus predict that, in hypothyroidism, we would observe a decreased regional cerebral metabolism in the amygdala and hippocampus. Our results did not confirm this prediction.
Although nonsignificant at P < 0.001 (uncorrected for multiple comparisons), the observation of reduced rCBF in the left cuneus, using SPM, is interesting to note. In his study, Marangell et al. (8) found that in the contralateral homonym region (right cuneus, Talairach 6, -94,8) regional cerebral glucose metabolism had maximal inverse correlations with TSH (r= -0-57, df = 27, one-tailed P < 0.001, not corrected for multiple comparisons).
Conclusion
This is the first study that shows evidence of significant and proportional decrease in rCBF (23.4%; P < 0.001) and in rCMRGlc (12.1%; P < 0.001) in severe hypothyroidism of short duration, without any regional effect (P > 0.05, two-way ANOVA and SPM analysis).
This coupled hypoperfusion/hypometabolism is evenly distributed among all brain regions. It seems to reflect a direct effect of thyroid status on the overall brain activity, which represents a distinctive pattern from the regional dysfunction usually found in classical depression.
Additional studies are needed to examine whether the results of the present study are applicable to other types of hypothyroidism.
Acknowledgments
We thank the patients who participated in the study, C. Semal for help in isotope preparation, M. Sibomana from the computer science staff, and R. Bausart for technical assistance. Thanks are also due to the clinical laboratory at the Cliniques Universitaires St. Luc, Brussels, for RIA analyses. A.G.D.V. is research associate at the National Funds for Scientific Research (Belgium).
Footnotes
This abstract was accepted for oral presentation at the 12th International Thyroid Congress, Kyoto, Japan, October 2000.
Abbreviations: FDG, 18F-labeled 2-deoxy-2-fluoro-D-glucose; FT3, free T3; FT4, free T4; HAM-A, Hamilton Anxiety Scale; LC, lumped constan; MADRS, Montgomery and Asberg Rating Scale; MRI, magnetic resonance imaging; rCBF, regional cerebral blood flow; rCMRGlc, regional cerebral glucose metabolism; PET, positron emission tomography; VOI, volumes of interest; WRS, Widlöcher Retardation Scale.
Received September 29, 2000.
Accepted April 18, 2001.
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