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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2006-0573
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The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 12 4786-4791
Copyright © 2006 by The Endocrine Society

Positron Emission Tomography Reveals Correlations between Brain Metabolism and Mood Changes in Hyperthyroidism

M. F. Schreckenberger, U. T. Egle, S. Drecker, H. G. Buchholz, M. M. Weber, P. Bartenstein and G. J. Kahaly

Departments of Nuclear Medicine (M.F.S., S.D., H.G.B, P.B.) and Medicine I (M.M.W., G.J.K.), Gutenberg University Hospital, 55131 Mainz, Germany; and Kinzigtal Hospital for Psychosomatic Medicine and Psychotherapy (U.T.E.), 77723 Gengenbach, Germany

Address all correspondence and requests for reprints to: Mathias F. Schreckenberger, M.D., Department of Nuclear Medicine, Gutenberg University Hospital, Langenbeckstrasse 1, 55131 Mainz, Germany. E-mail: schreckenberger{at}nuklear.klinik.uni-mainz.de; or George J. Kahaly, Thyroid Research Laboratory, Department of Medicine I, Gutenberg University Hospital, Langenbeckstrasse 1, 55131 Mainz, Germany. E-mail: gkahaly{at}mail.uni-mainz.de.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Context: Hyperthyroidism is frequently associated with emotional distress. The underlying cerebral processes of the endocrine-induced mood changes are unclear.

Objective: The objective of this study was to investigate, for the first time, the neuronal correlates of thyrotoxicosis-associated psychic symptoms using positron emission tomography (PET).

Design: The study was designed as a cross-sectional trial.

Setting: The study was performed at joint nuclear medicine and thyroid clinics.

Patients: Twelve patients with untreated Graves’ hyperthyroidism were evaluated.

Methods: Levels of emotional distress were self-rated by means of the Hospital Anxiety and Depression Scale. Both patients and 20 age- and gender-matched euthyroid controls underwent a brain fluorodeoxyglucose PET scan. Subsequently, the functional relationship between brain metabolism and the psychometric scores was analyzed.

Results: Compared with controls and visualized by fluorodeoxyglucose PET, hyperthyroid patients showed a decreased (P < 0.0001) glucose metabolism in the limbic system (uncus and inferior temporal gyrus). Activation foci in the posterior cingulate and in the inferior parietal lobe were correlated with both anxiety and depression scales (P < 0.001). Compared with patients with normal anxiety levels, those with increased anxiety yielded an enhanced glucose metabolism (P < 0.001) in the bilateral sensory association cortex. Serum free T3/free T4 levels negatively correlated with regional glucose metabolism in the medial posterior cingulate.

Conclusions: Thyrotoxicosis and associated psychic symptoms are correlated to regional metabolic changes in the main structures of the limbic/paralimbic system.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
THYROID DYSFUNCTION IS frequently associated with mood disorders, e.g. emotional distress, for which different neuroendocrine mechanisms may be discussed: TRH acting as a neurotransmitter with antidepressant properties, interactions between TSH and 5-hydroxy tyramine activity (1), and alterations of the hypothalamic-pituitary-thyroid axis (2). Due to the clinical relevance of thyroid-associated mood changes, a combination of endocrine and psychological testing as well as functional brain imaging by means of positron emission tomography (PET) may provide further insight into the underlying mechanisms of the functional neuroendocrine relationships. To date, there are very few studies on regional cerebral metabolism dealing with hypothyroidism-associated changes (3, 4, 5) and which prevailingly report global reductions of cerebral blood flow and glucose metabolism. Investigations with 31P nuclear magnetic-resonance spectroscopy of the frontal lobe in hypothyroidism showed reversible alterations with an increased cerebral metabolism after hormone replacement therapy (6).

Also, thyrotoxicosis induces a wide range of cognitive and affective-emotional impairments (7) and is considered one common cause of emotional distress (8). However, the functional relationship between thyroid metabolism, psychopathology, and regional brain metabolism remains unclear. There is one report only on a thyrotoxic patient with a reduced bilateral temporal-parietal perfusion that was partially reversible after antithyroid therapy (9). Thus, it was the purpose of this pilot study to investigate both changes of regional cerebral metabolic activity measured by fluorodeoxyglucose PET, a surrogate marker of neuronal activity, in hyperthyroid patients as well as correlations between thyroid hormones, emotional distress, and regional brain metabolism in those subjects.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Twelve consecutive patients with newly diagnosed and untreated Graves’ hyperthyroidism [median age 35.5 yr, range: 23–76, 10 females, median TSH < 0.03 mU/liter, free T3 (FT3) 8.2 pg/ml, free T4 (FT4) 2.3 ng/dl, TSH-R antibodies 15 mU/liter] were included. All patients complained about nervousness, irritability, increased heart rate and perspiration, easy fatigability, heat intolerance, and weight loss. The trial was carried out following the Helsinki Declaration and was approved by the local ethics committee. All subjects gave informed consent. Patients had neither previous history of relevant physical illness or psychiatric disorders, nor family history of psychiatric disorders, nor were they taking psychotropic medication. Before entering the study, all subjects were screened and clinically examined by the two senior investigators (M.F.S., G.J.K.). Before the PET investigation, patients were asked to fast for 8 h but had free access to water. An indwelling cannula was placed in a lower arm vein for blood drawing and subsequent tracer injection. Patients’ PET data sets were compared with those of 20 age- and gender-matched healthy euthyroid volunteers. Before enrollment, these control subjects were also extensively (clinically, psychologically, and biochemically) screened. Serum free FT3 and FT4, baseline TSH, thyroglobulin, thyroid peroxidase, and TSH-receptor autoantibodies were measured on the same investigation day with the help of commercially available kits (Roche Diagnostics, Mannheim, Germany).

Psychometric tests

The level of emotional distress was self-rated by the German version (10) of the Hospital Anxiety and Depression Scale (HADS). The HADS consists of 14 items. Seven of these items assess anxiety and seven assess depression, respectively. In comparison with other questionnaires, the main advantage of the HADS is that items covering somatic symptoms not necessarily due to anxiety or depression are not integrated. By the use of cut-off values, the HADS is able to give information on the severity of anxiety and depression: 0–7 normal, 8–10 mild, 11–14 moderate, and 15–21 severe. The HADS has been extensively evaluated, showing good sensitivity, specificity, and reliability for diagnosing anxiety and affective disorders (11, 12, 13, 14, 15).

The German Giessen questionnaire ("Giessener Beschwerdebogen") as a second applied psychometric test, measures four domains of physical complaints by means of 67 items given on a five-point Likert scale (heart complaints, fatigue, stomach troubles, pain in legs and arms, and an overall index). Reference values representative for the German population are available, and the patients’ scores can be compared with those of several thousand healthy persons (16, 17)

PET investigation and image reconstruction

Within 1 wk after screening, all PET investigations were performed at the same daytime (morning) to minimize influences by circadian endocrine variability. Subsequently, all patients received methimazole. PET was performed using an ECAT Exact PET Scanner (Siemens/CTI, Knoxville, TN). The emission scan started 30 min after iv injection of 152 ± 30 MBq F18-fluorine-deoxyglucose (18-FDG) and continued for 20 min in a three-dimensional acquisition mode, being performed in one bed position because the PET scanner has an axial field of view of 16.2 cm. Attenuation correction was performed using a computerized threshold limit routine to define an isodensity contour for the maximum cerebral activity/pixel. The exact position of these isodensity contours was controlled visually slice-by-slice and eventually corrected manually. Next, 47 transverse slices (slice thickness 3.375 mm) were reconstructed using a 4-mm Hamming filter. The transaxial full width at half maximum was 6.0 mm. PET images were realigned and stereotactically normalized into the standard anatomical space (18) by means of linear and nonlinear transformation (19). Subsequently, the normalized images were smoothed with a three-dimensional Gaussian filter using a 12-mm full width at half maximum kernel. The effect of the two different conditions (hyperthyroid patients/euthyroid controls) on regional cerebral 18-FDG activity was estimated according to the general linear model (20).

Statistical analysis

PET data sets were analyzed using Statistical Parametric Mapping software (SPM 99, Wellcome Department of Cognitive Neurology, London, UK). After proportional scaling of all PET scans to a mean global cerebral activity (21), t-statistical parametric maps (SPM {t}) were calculated. For the categorical comparison, hyperthyroidism vs. euthyroidism, the t-values of the scans were calculated on a voxel-by-voxel basis and then transformed to Z-scores. A statistical threshold of P < 0.0001 (22) was applied for hyperthyroidism-associated changes of regional cerebral glucose metabolism. For the correlation analysis of the levels of anxiety and depression, respectively, and the regional cerebral glucose metabolism, only activation foci that reached a threshold of P < 0.001 or better were considered significant as reported in previous studies using similar approaches of data analysis (23, 24, 25). To reduce the {alpha}-error and to increase statistical power, clusters of at least 50 contiguous voxels only passing the predefined statistical thresholds were regarded as significant (correction on cluster level).


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
Thyroid-related hormones and autoantibodies of the Graves’ patients are shown in Table 1Go. The HADS revealed a mean score for anxiety of 9.08 (SD 4.81, median 11.00, range 2–15). Seven patients showed elevated scores higher than 10 indicating an anxiety spectrum disorder. Mean score for depression was 7.08 (SD 4.85, median 6.5, 0–18). Also, two patients had an increased score higher than 10. Both subjects had enhanced anxiety, too. In contrast, all euthyroid controls showed normal values (<8) for both anxiety and depression. Also and compared with controls, the Giessen questionnaire showed significantly increased physical complaints, most especially heart complaints, dyspnea, and fatigue.


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  		TABLE 1. Thyroid laboratory values and psychometric scores (HADS) of the patient group

 
PET findings

The categorical comparison of hyperthyroid patients vs. euthyroid controls revealed no significant increases of regional cerebral glucose metabolism passing the given threshold of P < 0.0001. In contrast, hyperthyroid patients showed a significantly decreased metabolism in the right-hemispheric limbic system: mainly in the right uncus and inferior temporal gyrus including Brodmann areas (BA) 20 and 36 (Z = 4.66). Smaller regions of significantly reduced glucose metabolism were also found in homologous structures of the left hemisphere: the left uncus and inferior temporal gyrus including BA 20 and 36 (Z = 4.04, Table 2Go and Fig. 1Go). Serum FT3 and FT4 negatively correlated with the regional cerebral glucose metabolism in the medial posterior cingulate (BA 23). In contrast, no correlations with thyroid-related autoantibodies were noted.


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  		TABLE 2. Brain regions where glucose metabolism was reduced in the hyperthyroid patients (P < 0.0001)

 

Figure 1
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  		FIG. 1. Decreased glucose metabolism (in blue) in the bilateral temporal lobe of hyperthyroid patients vs. euthyroid controls. Also see Table 2Go.

 
The correlation analysis between anxiety scores and regional cerebral glucose metabolism yielded a significant positive correlation (P < 0.001) between the level of anxiety in the HADS and the metabolic activity in the bilateral posterior cingulate (right posterior cingulate: Z = 4.33; left posterior cingulate: Z = 3.49) and the left inferior parietal lobule including BA 40 (Z = 3.67, Table 3Go and Fig. 2Go).


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  		TABLE 3. Brain regions where glucose metabolism was positively correlated to the level of anxiety in the HADS (P < 0.001)

 

Figure 2
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  		FIG. 2. Positive correlation between the level of anxiety and the metabolic activity (in red-orange) in the bilateral posterior cingulate cortex. Also see Table 3Go.

 
Also, the correlation analysis between depression scores and regional cerebral glucose metabolism revealed a similar result to the one between anxiety and brain metabolism (P < 0.001). The level of depression was exclusively correlated to the metabolic activity of the bilateral posterior cingulate (right posterior cingulate: Z = 4.33; left posterior cingulate: Z = 4.42, Table 4Go and Fig. 3Go).


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  		TABLE 4. Brain regions where glucose metabolism was positively correlated to the level of depression in the HADS (P < 0.001)

 

Figure 3
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  		FIG. 3. Positive correlation between the level of depression and the metabolic activity (in red-orange) in the bilateral posterior cingulate cortex. Also see Table 4Go.

 
The subsequent categorical comparison of the hyperthyroid patients with increased scores of anxiety (n = 7) vs. those with anxiety levels within the normal range yielded an increased metabolism (P < 0.001) in the bilateral parietal lobe mainly in the sensory association cortex. There was no significant decrease of regional cerebral glucose metabolism (Table 5Go and Fig. 4Go).


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  		TABLE 5. Brain regions where glucose metabolism was increased in hyperthyroid patients with increased levels of anxiety in the HADS compared to the patients with normal anxiety levels (P < 0.0001)

 

Figure 4
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  		FIG. 4. Increased glucose metabolism (in red-orange) in the bilateral sensory association cortex of those hyperthyroid patients with increased levels of anxiety compared with the patients with normal anxiety levels. Also see Table 5Go.

 
After reaching biochemical euthyroidism, FDG-PET was again performed in two subjects. Compared with the baseline findings in the hyperthyroid state, the two patients now showed a complete normalization of their brain metabolism.


   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
This is the first functional brain imaging study on the cerebral metabolic changes in thyrotoxicosis. This cross-sectional study has showed that, compared with euthyroid controls, the cerebral glucose metabolism in the limbic system (hippocampus and functionally associated medial cingulate) is affected in hyperthyroid patients. It has further revealed activation in the posterior cingulate and in the inferior parietal lobe, highly correlated with both anxiety and depression scales.

The effects of hyperthyroidism on cerebral activity were first reported by Sokoloff et al. (26), who described an increased cerebral blood flow but normal oxygen consumption. This was surprising because cerebral blood flow and oxidative glucose metabolism usually are correlated positively under physiological conditions. Thus, these findings were interpreted as secondary effects due to a decreased vascular resistance rather than changes of cerebral neuronal activity. On the other hand, there is one case report only dealing with PET in dementia and thyrotoxicosis (9). In a patient with impairments of attention, memory, and constructive skills, reduced blood flow of the bilateral temporal-parietal cortex was shown. After methimazole treatment, the memory and constructive abilities were considerably improved while the temporal-parietal perfusion deficits were gradually normalized. Also, in our study, hyperthyroidism-associated cortical hypometabolism was noted.

The effects of thyroid hormones on cerebral neuronal activity/metabolism might be mediated via different mechanisms. Animal studies have revealed that the distribution of nuclear T3 receptors in the mature brain is not homogenous but does show relevant regional differences (27). The highest concentrations of receptors were found in limbic brain structures, the amygdala and the hippocampus, whereas the lowest concentrations were observed in the brain stem and the cerebellum. Thyroid hormones also modulate (age-dependent) the expression of the cerebral glucose transporter GLUT-1, because the 55-kDa GLUT-1 isoform was reduced in both hyperthyroid and hypothyroid young rats (28). The GLUT-1 isoform located at the blood-brain barrier is essential for glucose uptake, and a hyperthyroidism-induced lowered expression of this isoform might explain the cortical hypometabolism noted in thyrotoxic patients.

In euthyroid patients with major depression or bipolar disorder, an inverse correlation between TSH and cerebral blood flow (O15-water PET) and glucose metabolism (18-FDG PET), respectively, was reported (29), without significant correlations for T3 or T4. In our thyrotoxic patients, a correlation between TSH levels and cerebral blood flow could not be evaluated because all patients had endogenous TSH suppression. However, it is worth discussing if the observed correlations to the cingulate metabolism are directly induced by the elevated thyroid hormone concentrations or are a secondary epiphenomenon due to thyrotoxicosis-associated mood changes. In experimentally generated anxiety by means of autobiographical memory scripts in healthy volunteers (30), there was a specific deactivation of the mesial and inferior temporal cortex including the BA 20 and 37, resembling the results in the hyperthyroid patients. In this context, our finding of a close relationship between posterior cingulate metabolism and the levels of anxiety and depression in hyperthyroidism is in accordance with functional imaging studies emphasizing the role of the posterior cingulate cortex for encoding emotional stimuli and memory-related functions (31). Performing factor analysis of depressive symptoms in patients with major depression, the posterior cingulate cortex activity (measured as regional cerebral blood flow) correlated to a factor with high loadings for anxiety (32). Compared with the metabolic changes in limbic areas of euthyroid subjects with psychogenic emotional distress, our hyperthyroid patients with somatic anxiety showed similar patterns of brain metabolism. Therefore, it is a novel and remarkable finding that both psychogenic as well as organic-induced anxieties seem to involve identical brain regions.

The relevance of the posterior cingulate for encoding emotional stimuli was also shown (33) using functional MRI. The auditory presentation of threat-related words (compared with emotionally neutral words) specifically activated the posterior cingulate cortex. The functional relationship between thyroid hormones, posterior cingulate and mood disorder was also shown in euthyroid depressive patients (34). The posterior cingulate cortex was activated before patients responded to a supraphysiological levothyroxine therapy, and the improved mood was accompanied by a decrease of the posterior cingulate activity.

In our study, the hyperthyroid patients with elevated anxiety levels additionally showed an increased metabolism of the bilateral sensory association cortex. Although we cannot validate this statement, activation may be the cerebral correlate of a changed body self-perception of these patients, because they characteristically reported pathologically increased perceptions of normal body reactions with subsequently aggravated anxiety. Also, we are aware of the limitations of this study, e.g. the relatively small number of subjects and the absence of direct comparison with euthyroid patients who were either anxious or depressed. Hence our findings may not be specific to hyperthyroidism. This is why, at our institution, we do actually extend this pilot trial to further elucidate if the observed metabolic changes of limbic structures are reversible after remission and if there are differences in cerebral metabolism between toxic goiter and Graves’ disease, Graves’ patients frequently showing "accentuated" personality traits. In conclusion, in this pilot cross-sectional study, thyrotoxicosis and associated psychic symptoms were correlated to regional metabolic changes of limbic structures.


   Footnotes
 
Data in this article are partly derived from the thesis of S. Drecker, Medical Faculty, Gutenberg University, Mainz, Germany.

Author disclosure summary: The authors M.F.S., S.D., H.G.B., P.B., and G.J.K. have nothing to declare. The authors U.T.E. and M.M.W. received lecture fees.

First Published Online September 12, 2006

Abbreviations: BA, Brodmann area; 18-FDG, F18-fluorine-deoxyglucose; FT3, free T3; FT4, free T4; HADS, Hospital Anxiety and Depression Scale; PET, positron emission tomography.

Received March 14, 2006.

Accepted September 5, 2006.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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