L3,4Dihydroxy6F18fluorophenylalanine ... - Wiley Online Library

Psychiatry and Clinical Neurosciences 2014; 68: 292–298

doi:10.1111/pcn.12139

Regular Article

L-3,4-Dihydroxy-6-[F-18]fluorophenylalanine positron emission tomography demonstrating dopaminergic system abnormality in the brains of obsessive–compulsive disorder patients Hung-Jen Hsieh, MD,1,5† Kun-Han Lue, MSc,6† Hsin-Chi Tsai, Shin-Yuan Chen, MD, MSc4 and Pan-Fu Kao, MD, MSc7,8*

MD,2

Chau-Chin Lee,

MD,3

Departments of 1Nuclear Medicine, 2Psychiatry, 3Radiology, 4Neuro-Medical Scientific Center, Buddhist Tzu Chi General Hospital, 5Department of Radiological Technology, Tzu Chi College of Technology, Hualien, 6Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu, 7School of Medicine, Chung Shan Medical University, and 8Department of Nuclear Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan

Aim: Obsessive–compulsive disorder (OCD) is a chronic disabling neuropsychiatric disorder. Current treatment modalities, such as pharmacological and behavioral methods, are sometimes unsatisfactory. The mesolimbic dopaminergic pathway is supposed to have a role in the pathogenesis of OCD. In this study, L-3,4-Dihydroxy-6-[F-18]fluorophenylalanine (F-18 FDOPA) positron emission tomography (PET) is exploited to investigate the possible abnormality of dopaminergic neuronal circuits in the brains of OCD patients in vivo. Methods: The study subjects were recruited after psychological assessment and gave written informed consent to participate. The F-18 FDOPA PET scans were performed on five OCD patients and six healthy volunteers at 120 min after 185 MBq of F-18 FDOPA intravenous injection. The PET results were analyzed with the Statistical Parametric Mapping tool.

BSESSIVE–COMPULSIVE DISORDER (OCD) is a relatively common chronic neuropsychiatric disorder, with a lifetime prevalence of 2–3%.1,2 The victims are bothered by intrusive thoughts which impel unnecessary and meaning-

O

Results: Compared to the healthy subjects, the OCD brains showed increased dopaminergic metabolism in the left frontal premotor cortex (P < 0.001), along with trends toward an increase in the left posterior cingulate gyrus, the left cuneus, the left lingual gyrus, the right cuneus and precuneus, the right lingual gyrus, the right middle temporal gyrus, the left cerebellum, and the right cerebellum (P < 0.01). Conclusion: Our observations suggest that the increased dopaminergic neuronal function in these brain areas may be implicated in the pathogenesis of OCD. Key words: L-3,4-Dihydroxy-6-[F-18]fluorophenylalanine, obsessive–compulsive disorder, positron emission tomography.

less repetitive behaviors, recognized by the patients themselves (disease insight). In severe cases, daily life activities may be disarranged, threatening the patients with a loss of social and working abilities.

*Correspondence: Pan-Fu Kao, MD, MSc, Department of Nuclear Medicine, Chung Shan Medical University Hospital, 110, Sec. 1, Jianguo North Rd, Taichung 40201, Taiwan. Email: [email protected] † Authors with equal contributions. Received 9 January 2013; revised 29 July 2013; accepted 16 October 2013.

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© 2014 The Authors Psychiatry and Clinical Neurosciences © 2014 Japanese Society of Psychiatry and Neurology


F-18 FDOPA in brains of OCD patients 293

OCD tends to be underdiagnosed and undertreated. OCD patients may spend more than 9 years seeking a correct diagnosis, and it takes 17 years from disease onset to obtain an optimal treatment.3 Furthermore, the outcomes of current treatment modalities with pharmacological selective serotonin inhibitors therapy, cognitive-behavioral therapy, and support group therapy are sometimes unsatisfactory. A subset of refractory patients must undergo invasive neurosurgical interventions, of which the mechanisms of action and long-term benefits still need to be clarified.4 The cause of OCD is not clear. A dominant trait of transmission of OCD is noted.5 Dysfunction of the cortico-striato-thalamo-cortical (CSTC) loop has been suggested for the pathogenesis of OCD. Previous 2-Deoxy-2- [F-18]fluoroglucose (F-18 FDG) positron emission tomography (PET) or O-15 H2O PET studies have shown inconsistently increased metabolism in some brain areas of OCD patients, including the orbital frontal cortex, the premotor cortex, the caudate nucleus, and the anterior cingulum.6–9 Magnetic resonance imaging (MRI) has also shown disease correlation in some regions of the frontalstriatal circuitry and limbic system.10,11 Among all of the aforementioned findings, the ventral CSTC circuit seems to play a crucial role. Dopamine, an important neurotransmitter in this mesolimbic pathway, is believed to be implicated in the pathogenesis of OCD.12–14 In this study, we applied L-3,4-Dihydroxy6-[F-18]fluorophenylalanine (F-18 FDOPA) PET to clarify the possible abnormality of dopaminergic neuronal function in the brains of OCD patients.

brain tumor; brain vessel disease; a history of epilepsy or encephalitis, or increased intracranial pressure; and other conditions evaluated as unsuitable to undergo this study. Five OCD patients (four men and one woman; 33.2 ± 11.2 years old) were enrolled for the study. Clinically, these patients exhibited similar predominant themes, for example, demanding reassurance, worrying about and checking whether things were orderly or in the right place, and cleaning in response to fears of contamination. Psychiatric medications were withheld 5–7 days before the study. Six subjects with a Y-BOCS test score of zero and who gave witnessed written informed consent were recruited from volunteers as the normal control group for the study. All subjects fasted for 4–6 h before the FDOPA PET studies. Oral administration of 100 mg of Carbidopa was given 1 h before the F-18 FDOPA injection. A mean dose of 185 MBq (5 mCi) of F-18 FDOPA was given intravenously. During the 120-min period of radiotracer uptake time, the patients were kept in a quiet, dim room and were instructed to close their eyes. The 30-min brain scans were gained with an integrated PET/computed tomography (CT) scanner (Discovery ST, GE Medical Systems, Waukesha, WI, USA). The system produced 47 contiguous slices, 3.27 mm per slice thickness images, with an axial resolution of 2.14 mm by full width at half maximum in the center of the field of view. The raw data were reconstructed into a 128 × 128 matrix using the built-in algorithms from a 3-D iterative reconstruction method. The emission images were attenuation-corrected with CT-based translation. The PET images from the five OCD patients were compared to a normal database from the six young, healthy subjects (four men and two women; 22.8 ± 1.2 years old, Y-BOCS of each = 0) on a voxelby-voxel basis using the Statistical Parametric Mapping (SPM) software package (Wellcome Department of Cognitive Neurology, London, UK). The individual PET images were registered to the corresponding MRI images by use of the mutual information algorithm.15 The individual MRI images were then spatially normalized to the Montreal Neurological Institute (MNI) MRI template, and the resulting transformation parameters were applied to the co-registered PET images. This normalization procedure incorporates the anatomical detail and high spatial resolution from the MRI to provide accurate spatial normalizations.16 The spatial normalization used 16 non-linear iterations, and medium non-linear

METHODS The study was approved by the ethics committee of the hospital. All patients gave witnessed written informed consent before the study. During an 18-month period, all the patients who met the OCD criteria of the DSM-IV were enrolled from the psychiatric department of a medical center. Clinical disease severity was assessed using the Yale–Brown Obsessive Compulsive Scale (Y-BOCS), the Hamilton Depression Rating Scale (HAM-D), and the Global Assessment of Functioning (GAF) score. Patients with the following conditions were excluded from the study: older than 60 years and younger than 20 years; pregnant or lactating women; those exhibiting delusions, hallucinations, or alcohol or substance abuse; previous brain surgery; clips or implants in the brain;


294 H.-J. Hsieh et al.


Table 1. Patient profiles: Demographic features and clinical characteristics Patient no.

Sex

Age (years)

Y-BOCS

HAMD

HAMA

GAF

1 2 3 4 5

F M M M M

45 21 25 45 30

22 35 16 29 23

36 13 18 25 13

33 22 12 31 3

41∼50 31∼40 61∼70 51∼60 61∼70

GAF, Global Assessment of Functioning Scale; HAMA, Hamilton Anxiety Rating Scale; HAMD, Hamilton Depression Rating Scale; Y-BOCS, Yale–Brown Obsessive Compulsive Scale.

regularization. Transformed images were written with a voxel size of 2 × 2 × 2 mm using trilinear interpolation. Smoothing was performed with an isotropic kernel of 12 mm. The proportional scaling and analysis threshold was set to a value of 50 and of 80%, respectively. To evaluate significant differences, the height threshold (T = 2.82, P = 0.01) and the extent threshold (k = 10 voxels) were set. The results were converted to the Talairach coordinates using the MNIto-Talairach conversion tool.17 To compare the differences between the OCD patients and the normal control group, a 2-sample t-test was performed. All processing was performed using SPM2 under MATLAB 6.5 (The Mathworks, Natick, MA, USA).

RESULTS Five OCD patients (four men and one woman; 33.2 ± 11.2 years old) were enrolled from the psychi-

atric department of a medical center. The clinical disease severity of these five OCD patients, who were assessed using the Y-BOCS, the HAM-D, and the GAF score, is listed in Table 1. Six young, healthy subjects (four men and two women; 22.8 ± 1.2 years old) were recruited as the normal control group for the study. The results are summarized and listed in Table 2. Compared to the control group, the OCD patients showed increased FDOPA metabolism in the left frontal premotor cortex (Brodmann area 6, BA 6) (peak MNI coordinates, x,y,z = −16,−8,72, P < 0.001). Trends toward increased metabolism (P < 0.01) were observed for the left posterior cingulate gyrus (peak MNI coordinates, x,y,z = −26,−62,14), the right subcortical white matter (peak MNI coordinates, x,y,z = 24,−6,30), the left cuneus (peak MNI coordinates, x,y,z = −22,−76,30), the left lingual gyrus (peak MNI coordinates, x,y,z = −26,−62,−4), the right

Table 2. Increased FDOPA metabolism in OCD patients’ brains compared to normal control group subjects Cluster level

Voxel level

Pcorrected

kE

Puncorrected

PFWE-corr

PFDR-corr

T-score

Z-score

Puncorrected

x,y,z (mm)

Brain area

0.999 0.974 0.855

106 311 567

0.531 0.273 0.144

0.956

370

0.233

1.000 1.000 1.000 1.000

74 11 13 19

0.607 0.869 0.855 0.818

0.844 0.998 0.998 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000

0.317 0.317 0.317 0.317 0.317 0.317 0.317 0.317 0.317 0.317 0.317 0.317

5.28 3.83 3.77 3.16 2.98 3.50 3.48 3.32 3.19 3.00 3.00 2.87

3.48 2.88 2.85 2.53 2.42 2.71 2.70 2.62 2.54 2.43 2.43 2.36

0.000 0.002 0.002 0.006 0.008 0.003 0.003 0.004 0.005 0.007 0.007 0.009

−16,−8,72 24,−6,30 −26,−62,14 −22,−76,30 −26,−62,−4 28,−70,−50 18,−64,−50 −6,−60,−24 6,−84,20 20,−72,54 48,−76,18 16,−88,−8

Left frontal lobe, BA6 Right subcortical white matter Left posterior cingulate gyrus Left cuneus Left lingual gyrus Right cerebellum Right cerebellum Left cerebellum Right cuneus Right precuneus Right middle temporal gyrus Right lingual gyrus

OCD, obsessive–compulsive disorder.



SPM{T9}

SPM results: D:/120min Height threshold T = 2.82 Extent threshold k = 10 voxels

Figure 1. SPM analysis (P < 0.01, voxel threshold = 10). Compared to the healthy subjects, the obsessive–compulsive disorder (OCD) patients showed increased dopaminergic activity in the left frontal premotor cortex (BA 6), the left posterior cingulate gyrus, the left cuneus, the left lingual gyrus, the right cuneus and precuneus, the right lingual gyrus, the right middle temporal gyrus, the left cerebellum, and the right cerebellum.

cuneus (peak MNI coordinates, x,y,z = 6,−84,20), the right precuneus (peak MNI coordinates, x,y,z = 20,−72,54), the right lingual gyrus (peak MNI coordinates, x,y,z = 16,−88,−8), the right middle temporal gyrus (peak MNI coordinates, x,y,z = 48,−76,18), the left cerebellum (peak MNI coordinates, x,y,z = −6,−60,−24), and the right cerebellum (peak MNI coordinates, x,y,z = 28,−70,−50). The differences in FDOPA metabolism mentioned above are illustrated in Figure 1.

DISCUSSION The possible role of the ventral CSTC circuit in the pathogenesis of OCD has received investigative attention in recent years. One neurotransmitter that might be of crucial importance in the mediation of OCD through the CSTC loop is dopamine.18 The results of our F-18 FDOPA PET study showed an abnormal increase in dopamine metabolism in certain areas of the OCD brains (see Table 2). Many of these areas are located outside the striatum, which is known to contain the most abundant radiotracer accumulation of F-18 FDOPA. In the CSTC loop, dopamine exerts a key modulatory action through the ventral striatum/nucleus accumbens (NAc), the midbrain ventral tegmental area (VTA), the orbitofrontal cortex, and the prefrontal cortex (PFC), as well as the cingulate gurus and the


temporolimbic cortex.13,19 These areas were shown to have abnormal functional connections in OCD patients compared to the control subjects, which is also supported by some functional MRI studies.20,21 In fact, some observations have suggested that dopaminergic projections from the brain stem (VTA) reach nearly all regions of the neocortex, with a rostral to caudal gradient of decreasing concentration.22,23 Brown et al. demonstrated the highest dopamine concentration in the prefrontal and temporal regions and the lowest concentration in the occipital cortex.22 A few years later, D1 and D2 dopaminergic receptors were found in the sensorimotor cortex.24 In addition to its immediate effects on neuron excitability or on inhibitory interneurons, dopamine is also involved in the formation of long-term potentiation in different brain areas, for example, the PFC, the striatum, and the NAc. Dopamine in the PFC has an important role in reward-driven learning, working memory formation, and behavior flexibility in response to environmental changes.25 Similarly, it is considered that the dopaminergic projection to the motor cortex is implicated in the formation of motor memories. In the human PET studies measuring dopamine antagonist raclopride, dopamine is increased in the supplementary motor area and is reduced in the globus pallidus internus during finger sequence learning.26 Dopaminergic signals to the motor cortex are not simply optimizing motor skill learning, but are a requirement.27 Destroying VTA dopaminergic neurons prevents improvements in novel forearm reaching skills.28 Stimulations of the VTA-to-M1 dopaminergic pathway induce expressions of immediate early gene (IEG), for example, c-fos, in the primary motor cortex, which represents a first step in the cascade of cellular events leading to synaptic plasticity and so-called motor skill learning.29,30 These findings suggest that the dopaminergic neurons originating in the VTA contribute to premotor and motor cortex plasticity, relaying reward information that supports the encoding of successful motor skills within these areas. A high, sustained background dopaminergic tone in the premotor cortex is associated with faster implicit sequence learning in a task-dependant manner. Our study also shows increased dopamine metabolism in the premotor cortex. This may be linked to the disease characteristics of OCD that patients usually show, such as a lower gating threshold for intrusive thoughts or sensorimotor stimuli,




uncontrolled anxiety or fear, and compelling strategy sequences of ritualistic behaviors and stereotype actions. The cerebellum, in coordination with the CSTC circuit, has long been considered to be involved in the pathogenesis of OCD.13 Some imaging studies have shown supportive results, for example, increased gray matter volume in the bilateral anterior cerebellum in OCD patients.21 Correspondingly, our study shows increased dopamine metabolism in the bilateral cerebellar hemispheres. Abnormalities in the insulo-opercular region, including the cuneus cortex, were also observed in the study by Pujol et al.21 In comparison, our study shows increased dopamine metabolism in the bilateral cuneus. Moreover, our study shows increased dopamine metabolism in the left posterior cingulate gyrus, the right precuneus, the bilateral cuneus, and the bilateral lingual gyri. The posterior cingulate gyrus, the cuneus, and the precuneus are among the least understood functional areas in the brain. The precuneus is considered one of the recently expanded parts of the brain and is among the last regions to myelinate.31 These functional areas have been implicated in the aspects of conscious awareness, selfreflection, attention shifting between different tasks, episodic memory retrieval, and the processing of working memory.32,33 These functional areas, together with the lingual gyrus, joined with the occipital pole and the tentorial surface of the temporal lobe (parahippocampal and entorhinal cortex), are an important part of the mesolimbic dopaminergic pathways. The interacting role of these areas and its final effect on the possible disease mechanism of OCD still need systemic investigations. Depression is commonly comorbid in OCD. Two of our patients (no. 1 and no. 4) with depression symptoms to some extent were not excluded from the study, considering depression is presently a syndrome (cluster of symptoms and signs)-based diagnosis rather than an etiological one, and depression itself overlaps with or constitutes part of the disease spectrum of many neuropsychological disorders.34,35 In addition, depression yields incoherent results across neuroimaging studies with its lack of consistency. Possible relevant brain regions include the prefrontal cortex, the ventral striatum, the basal ganglia, the thalamus, and the limbic system, such as the amygdala.36–38 Our preliminary study shows no definite abnormal FDOPA metabolism in these suspected areas. Potential confounding conditions

include the fact that clinical depression scales contain items regarding many aspects of the disease. In upcoming studies where more OCD patients could be included, those with extreme depression symptoms might be specified and subgrouped when performing FDOPA PET image analysis to illuminate this characteristic. Our study is limited by the low number of enrolled subjects. The statistical significances of the findings described above need to be validated by more largescale studies. Our normal control template comes from a group consisting of young, healthy volunteers not perfectly age-matched. There is evidence showing that in the brains of healthy subjects, no significant change of FDOPA uptake was detected on PET coupled with the aging effect.39 Age-related declines in brain dopaminergic activity in the frontal and anterior cingulate regions suggested by some other authors were not observed in our study.40 Studies with ideal age-matched control subjects may further clarify this aspect. In conclusion, OCD is a common, chronic disabling disorder, which is often under-recognized and undertreated. A more thorough understanding of the disease mechanism is needed. Our FDOPA PET preliminary study results showed increased dopamine metabolism in selective brain areas, which may implicate the potential pathogenesis of OCD.

ACKNOWLEDGMENTS The authors sincerely thank Professor Guo-Fang Tseng at Tzu Chi University for providing neuroanatomical consultation. The study was supported by Tzu-Chi General Hospital (grant TCRD 99-10). No other potential conflict of interest relevant to this article was reported.

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