Baseline symptom severity predicts serotonin transporter change during psychotherapy in patients with major depression.

AIMS: The role of the serotonin transporter (SERT) in the pathophysiology of depression is unclear and only a few follow-up studies exist. Our aim was to measure changes in SERT availability during psychodynamic psychotherapy in patients with major depression over a follow-up time of 12 or 18 months. METHODS: The patients were studied with iodine-123 labelled 2ß-carbomethoxy-3ß-(4-iodophenyl) serial single-photon emission tomography imaging and clinical rating scales of symptoms. RESULTS: Changes in SERT availability had no correlation with the change of symptoms, but the change of SERT availability during psychotherapy in the midbrain was predicted by the baseline severity of the clinical symptoms measured by the Symptom Checklist Depression Scale and the Symptom Checklist Global Severity Index. With cut-off values applied, it was found that SERT availabilities increased in patients with high baseline symptoms, and decreased in patients with low baseline symptoms. CONCLUSIONS: Together with our earlier finding of decreased SERT in patients with depression, these results indicate a state-dependent and possibly a compensatory role of decreased SERT availability in depression.

Optimisation of simultaneous tl-201/tc-99m dual isotope reconstruction with monte-carlo-based scatter correction.

Simultaneous Tl-201/Tc-99m dual isotope myocardial perfusion SPECT is seriously hampered by down-scatter from Tc-99m into the Tl-201 energy window. This paper presents and optimises the ordered-subsets-expectation-maximisation-(OS-EM-) based reconstruction algorithm, which corrects the down-scatter using an efficient Monte Carlo (MC) simulator. The algorithm starts by first reconstructing the Tc-99m image with attenuation, collimator response, and MC-based scatter correction. The reconstructed Tc-99m image is then used as an input for an efficient MC-based down-scatter simulation of Tc-99m photons into the Tl-201 window. This down-scatter estimate is finally used in the Tl-201 reconstruction to correct the crosstalk between the two isotopes. The mathematical 4D NCAT phantom and physical cardiac phantoms were used to optimise the number of OS-EM iterations where the scatter estimate is updated and the number of MC simulated photons. The results showed that two scatter update iterations and 10(5) simulated photons are enough for the Tc-99m and Tl-201 reconstructions, whereas 10(6) simulated photons are needed to generate good quality down-scatter estimates. With these parameters, the entire Tl-201/Tc-99m dual isotope reconstruction can be accomplished in less than 3 minutes.

Myocardial (123) I-metaiodobenzylguanidine washout and heart rate variability in asymptomatic subjects.

BACKGROUND: Myocardial (123) I-metaiodobenzylguanidine (MIBG) kinetics reflect the integrity and function of cardiac presynaptic sympathetic nerve terminals. Heart rate variability (HRV) is an indicator of cardiac sympatho-vagal balance. However, the function of cardiac sympathetic nerve terminals as a modulator of HRV in asymptomatic subjects has remained elusive. In addition, the physiological background for different components of HRV is not fully established. METHODS: We evaluated the relationship between myocardial MIBG washout and HRV in 30 asymptomatic subjects with familial risk of coronary artery disease (CAD). Early and delayed myocardial MIBG uptakes as well as MIBG washout between these two scans were assessed. Myocardial perfusion at rest and during bicycle exercise was evaluated with (99m) Tc-sestamibi (MIBI). HRV was measured from 24-hour ambulatory ECG recordings. RESULTS: Myocardial MIBG washout averaged 40 ± 8%. The mean heart rate at rest was 76 ± 14 beats/min. Standard deviation of all normal RR intervals (SDNN) was 94 ± 22 ms and very low frequency (VLF) was 1625 ± 958 ms(2) on average. Myocardial MIBG washout correlated inversely with SDNN (r =-0.390; P < 0.05) and with VLF (r =-0.459; P < 0.01) component of HRV but not with heart rate at rest (r = 0.207, P = ns). All subjects had normal myocardial perfusion at rest and during exercise. CONCLUSIONS: Increased cardiac presynaptic sympathetic nervous activity was related to reduced HRV in subjects with the risk of CAD but without evidence of myocardial ischemia or previous myocardial infarction. In addition, we found that VLF component of HRV includes information about sympathetic neural modulation of the heart rate.

Half-time myocardial perfusion SPECT imaging with attenuation and Monte Carlo-based scatter correction.

PURPOSE: To test the potential of a new reconstruction algorithm with Monte Carlo-based scatter correction in half-time myocardial perfusion single-photon emission computed tomography (SPECT). MATERIALS AND METHODS: The mathematical four-dimensional NURBS-based Cardiac-Torso phantom and the SIMIND Monte Carlo simulation package were used to simulate full-time and half-time SPECT projection data. The data were reconstructed using the standard ordered subset expectation maximization-based algorithm and the new Monte Carlo-based algorithm. Defect contrast, myocardium versus ventricle contrast and resolution were calculated. In addition to the simulation studies, full-time and half-time SPECT projection data of 30 patients were reconstructed with the standard and the new method. The patient data were qualitatively evaluated by four nuclear medicine experts on a scale from 1 (poor quality) to 5 (high quality). RESULTS: The new reconstruction method with half-time data produced higher contrast and better resolution in the simulations and also achieved higher qualitative scores in the patient study than the standard reconstruction with full-time data. CONCLUSION: Half-time myocardial perfusion imaging using the new reconstruction algorithm with Monte Carlo-based scatter correction produced images with superior quality when compared with full-time imaging with standard reconstruction.

Optimizing bioimpedance measurement configuration for dual-gated nuclear medicine imaging: a sensitivity study.

Motion artefacts due to respiration and cardiac contractions may deteriorate the quality of nuclear medicine imaging leading to incorrect diagnosis and inadequate treatment. Motion artefacts can be minimized by simultaneous respiratory and cardiac gating, dual-gating. Currently, only cardiac gating is often performed. In this study, an optimized bioimpedance measurement configuration was determined for simultaneous respiratory and cardiac gating signal acquisition. The optimized configuration was located on anterolateral upper thorax based on sensitivity simulations utilizing a simplified thorax model. The validity of the optimized configuration was studied with six healthy volunteers. In the peak-to-peak and frequency content analyses the optimized configuration showed consistently higher peak-to-peak values and frequency content than other studied measurement configurations. This study indicates that the bioimpedance method has potential for the dual-gating in nuclear medicine imaging. The method would minimize the need of additional equipment, is easy for the technologists to use and comfortable for the patients.

Reduction of collimator correction artefacts with bayesian reconstruction in spect.

Poor resolution of single photon emission computed tomography (SPECT) has degraded its use in clinical practice. Collimator correction has been shown to improve the reconstructed resolution, but the correction can generate ringing artefacts, which lower image quality. This paper investigates whether Bayesian reconstruction methods could reduce these artefacts. We have applied and tested three Bayesian reconstruction methods: smoothing prior, median root prior, and anatomical prior. To demonstrate the efficacy of these methods, we compared their physical and visual performance both in phantom and patient studies. All the three Bayesian reconstruction methods reduced the collimator correction artefacts. Images reconstructed using the smoothing prior and the median root prior had slightly lower contrast than the standard reconstruction with collimator correction, whereas the anatomical prior produced images with good resolution and contrast.

Brain derived neurotrophic factor and serotonin transporter binding as markers of clinical response to fluoxetine therapy in children with autism.

Fluoxetine, a selective serotonin reuptake inhibitor (SSRI), has shown favorable effects in some children with autism. There are no previous studies evaluating the connection between clinical outcome and markers of clinical response to fluoxetine treatment. We examined serum brain derived neurotrophic factor (BDNF) concentrations and serotonin transporter (SERT) binding in the medial frontal cortex and midbrain, measured by single photon emission computed tomography (SPECT) scanning, in a group of 13 autistic children and adolescents (12 males, one female; age 5-16 years), who were treated for six months with fluoxetine at a dose range of 10-40 mg/day. Clinical response was evaluated by the Autism Treatment Evaluation Checklist (ATEC). Serum concentrations of BDNF and SERT binding were measured at baseline and two months after termination of fluoxetine treatment. At baseline, before starting fluoxetine treatment, the serum concentration of BDNF had a bimodal distribution in the autism group with either a low concentration (n = 8, mean 1497 pg/mL) or a high concentration (n = 5, mean 14062 pg/mL) with respect to controls (n = 15, mean 9652 pg/mL), and SERT binding was uniformly low in the autistic subjects in medial frontal cortex and midbrain. Fluoxetine treatment led to positive effects in several aspects of communication, socialization and cognitive awareness, with 6 out 13 subjects being particularly good responders. These six also had a significant decrease in BDNF (p = 0.03) and minimal change in SERT binding after therapy. The other 7 subjects showed a trend towards an increase in BDNF and SERT binding. Our results indicate that fluoxetine may improve core autistic symptoms, and that this clinical response is linked to a decrease in serum BDNF.

Long-term epilepsy surgery outcomes in patients with MRI-negative temporal lobe epilepsy.

PURPOSE: The outcome of surgery in patients with temporal lobe epilepsy (TLE) and normal high-resolution magnetic resonance imaging (MRI) has been significantly worse than in patients with unilateral hippocampal damage upon MRI. The purpose of this study was to determine the long-term outcomes of consecutive true MRI-negative TLE patients who all underwent standardized preoperative evaluation with intracranial electroencephalography (EEG) electrodes. METHODS: In this study we present all adult MRI-negative TLE surgery candidates evaluated between January 1990 and December 2006 at Kuopio Epilepsy Center in Kuopio University Hospital, which provides a national center for epilepsy surgery in Finland. During this period altogether 146 TLE surgery candidates were evaluated with intracranial electrodes, of whom 64 patients with normal high-resolution MRI were included in this study. RESULTS: Among the 38 patients who finally underwent surgery, at the latest follow-up (mean 5.8 years), 15 (40%) were free of disabling seizures (Engel class I) and 6 (16%) were seizure-free (Engel class IA). Twenty-one (55%) of 38 patients had poor outcomes (Engel class III-IV). Outcomes did not change compared to 12-month follow-up. Histopathologic examination failed to reveal any focal pathology in 68% of our MR-negative cases. Only patients with noncongruent positron emission tomography (PET) results had worse outcomes (p = 0.044). DISCUSSION: Our results suggest that epilepsy surgery outcomes in MRI-negative TLE patients are comparable with extratemporal epilepsy surgery in general. Seizure outcomes in the long-term also remain stable. Modern imaging techniques could further improve the postsurgical seizure-free rate. However, these patients usually require chronic intracranial EEG evaluation to define epileptogenic areas.

Serotonin-transporter-linked promoter region polymorphism and serotonin transporter binding in drug-naïve patients with major depression.

AIMS: Both the serotonin transporter and its genetic regulation by the serotonin-transporter-linked polymorphic region have a role in the pathophysiology of depression. Most of the previous studies have found no influence of serotonin-transporter-linked polymorphic region allelic variation on serotonin transporter binding in healthy controls or patients with major depression. Due to the inconsistency of the previous findings, we compared single photon emission computed tomography imaging with the serotonin-transporter-linked polymorphic region genotype in patients with major depressive disorder. METHODS: A total of 23 drug-naïve patients with major depressive disorder were genotyped and brain imaged with ([123I])nor-beta-CIT single photon emission computed tomography. The severity of depression was evaluated with the 17-item Hamilton depression rating scale. RESULTS: Depressed patients homozygous for the short allele had lower ([123I])nor-beta-CIT binding in the medial prefrontal cortex, but not in the midbrain, compared with the other genotypes. CONCLUSION: The decreased medial prefrontal cortical serotonin transporter binding in the patients homozygous for the short allele may be linked to altered function of the serotonin-transporter-linked polymorphic region gene expressed in these patients, especially in the medial prefrontal cortex.

Extrapyramidal side-effects and dopamine D(2/3) receptor binding in substantia nigra.

BACKGROUND: The exact mechanisms for antipsychotic-induced extrapyramidal side-effects have remained obscure despite intensive research. Previous studies have highlighted a central role for nigral dopamine D(2) receptors in the control of motor functions. AIMS: The aim of the present study was to examine relationships between dopamine D(2) receptor binding in both substantia nigra and temporal cortex with extrapyramidal symptoms among antipsychotic-treated patients with schizophrenia. METHODS: Single-photon emission-computed tomography (SPECT) ligand [(123)I]epidepride was used to determine dopamine D(2/3) apparent binding potential in 13 antipsychotic-treated (seven with clozapine, four with olanzapine and two with haloperidol) patients with schizophrenia. Extrapyramidal symptoms were assessed with the Simpson and Angus Scale (SAS). RESULTS: A statistically significant correlation was observed between dopamine D(2/3) receptor apparent binding potential in the substantia nigra and extrapyramidal side-effects (r = -0.62, P = 0.024). No correlations were detected in the temporal cortex between dopamine D(2/3) receptor binding and extrapyramidal side-effects. CONCLUSIONS: These findings support the role of dopamine D(2) autoreceptors in substantia nigra regarding drug-induced movement disorders.

Brain electrical activity during food presentation in obese binge-eating women.

Binge-eating (BE) subjects have shown altered brain activity at frontal regions during food presentation. The aim of this study was to examine the frontal brain electrical activity in obese BE women (n = 12) and in obese women without BE (non-BE, n = 13). Brain electrical activity was measured using a quantitative electroencephalography during a resting state (eyes-closed) and when the subjects focused (eyes-open) their attention on a picture of a landscape (control experiment) or on a meal (food experiment). The BE showed greater frontal beta activity (14-20 Hz) than the non-BE in both the eyes-closed (on average 52%) and the eyes-open situations and independently of the stimulus (control experiment: 57% and food experiment: 71%). No significant differences between the groups were found in alpha, delta or theta amplitudes. Increased beta activity correlated positively with the disinhibition factor of the Three-Factor Eating Questionnaire. Thus, our results suggest that elevated frontal beta activity may be a marker of dysfunctional disinhibition-inhibition mechanism, which could make the obese BE women more vulnerable or sensitive to food and the environmental cues.

Dopamine transporter binding in females with panic disorder may vary with clinical status.

BACKGROUND: To date the involvement of dopamine system in neurobiology of panic disorder (PD) has been not investigated by imaging studies in humans. In this study, we evaluated the binding potential of dopamine transporter (DAT) in striatum of patients with PD. METHODS: Subjects comprised seven female patients with current PD, seven female PD patients in remission and seven female healthy controls, matched by age. Striatal DAT binding was evaluated using single-photon emission computed tomography and [(123)I]nor-beta-CIT tracer. RESULTS: Significantly higher DAT binding in striatum was detected in remitted PD females as compared with both currently ill PD and control females. The females with current PD demonstrated non-significant lowering in striatal DAT binding as compared with healthy controls. The correlation analysis in total sample of female patients showed significant and inverse relationship between striatal DAT binding characteristics and severity of panic symptoms. CONCLUSIONS: This is first report showing that DAT binding in striatum may depend on the clinical status in females with PD. Our data suggest that increased level of DAT may contribute to stability of remission; however, the exact involvement of dopamine system in PD pathogenesis requires further investigations. The preliminary results of current study should be confirmed by other independent studies and should also be extended to include male patients.

Perfusion differences on SPECT and PWI in patients with acute ischemic stroke.

INTRODUCTION: The purposes of the present study were to compare the flow defect volumes on perfusion-weighted magnetic resonance imaging (PWI) and (99m)Tc-labeled ethylcysteinate dimer ((99m)Tc-ECD) single photon emission computed tomography (SPECT) at acute and subacute stages of ischemic stroke and to analyze the relationship between the detected flow defects on the two methods and neurological status and clinical outcomes. METHODS: Perfusion defects on PWI and SPECT were measured within 48 h and on day 8 of the onset of stroke from 22 patients with their first-ever acute supratentorial ischemic stroke. The primary neurological status was evaluated prior to the imaging. Clinical outcome was assessed at 3 months after the onset of the stroke. RESULTS: The volumes of cerebral blood flow (CBF) defects did not differ between SPECT and PWI within the 48-h examinations. However, the volume of CBF defect was significantly larger on SPECT than on PWI on day 8 (p = 0.03). Within the 48-h examinations, the CBF defect volumes on SPECT and PWI were comparably related to the neurological status. On day 8, the CBF defect volume on SPECT showed higher correlation to the neurological status and more precisely predicted the clinical outcomes at 3 months than PWI. CONCLUSIONS: (99m)TC-ECD-SPECT and PWI both have ability to detect cerebral hypoperfusion in patients with ischemic stroke but with some differences. The value of SPECT is more accurate in terms of the delayed outcome, such as prognosis and rehabilitation planning.

Dopamine D2/3 receptor binding potential and occupancy in midbrain and temporal cortex by haloperidol, olanzapine and clozapine.

AIMS: Aberrant dopamine transmission in extrastriatal brain regions has been repeatedly illustrated among patients with schizophrenia. Differences between typical and second-generation antipsychotics in dopamine D(2) receptor modulation within various brain areas remain a topic for debate. The aim of the present study was therefore to investigate dopamine D(2/3) receptor apparent binding potential (BP(app)) and occupancy in midbrain and temporal cortex among clozapine-, olanzapine- and haloperidol-treated schizophrenia patients. METHODS: Dopamine D(2/3) binding was studied on single-photon emission computed tomography ligand [(123)I]epidepride in 13 schizophrenia patients treated with medication (two with haloperidol, four with olanzapine and seven with clozapine), six drug-naïve patients and seven healthy controls. RESULTS: Statistically significant differences in midbrain dopamine D(2/3) receptor BP(app) (P = 0.015) and occupancy (P = 0.016) were observed between the clozapine, olanzapine and haloperidol groups. The lowest occupancy was found in clozapine-treated patients (5%), followed by olanzapine-treated patients (28%), compared to haloperidol-treated patients (40%). No significant differences were observed in the temporal poles. Occupancy changed substantially depending on the comparison group used (either drug-naïve vs healthy controls) in the examined brain areas (P = 0.001), showing an overestimation with all antipsychotics when the healthy control group was used. CONCLUSION: Both typical and second-generation antipsychotics occupy cortical dopamine D(2/3) receptors, thus mediating therapeutic efficacy. Observed differences in midbrain dopamine D(2/3) occupancy between classical antipsychotics and second-generation antipsychotics may have clinical relevance by modulating altered nigrostriatal dopamine neurotransmission during the acute phase of schizophrenia.

Cardiac repolarization and striatal dopamine transporter function are interrelated.

OBJECTIVE: In Parkinson's disease, striatal dopamine transporter (DAT) binding and cardiac sympathetic function are disturbed. In addition, heart rate (HR)-corrected cardiac repolarisation time (QTc interval), which is partly under autonomic control, is prolonged. Whether there is physiological coupling between striatal DAT binding and QTc time (QTc-DAT relation) is not known. The purpose of this study is to evaluate QTc-DAT relation in healthy young adults. METHODS: Thirty-five participants (18 women, age 26.4+/-1.8 years; mean+/-SD) were studied with iodine-123 labelled 2beta-carbomethoxy-3beta-(4-iodophenyl) nortropane single photon emission tomography. Signal-averaged ECG was recorded at rest from each participant. QTc interval was computed with Bazett's correction and with the approach by Karjalainen, getting QTc and QTk intervals, respectively. RESULTS: Mean striatal DAT binding, as (striatum-cerebellum)/cerebellum, was 2.63+/-0.31. Mean HR, QT, QTc and QTk intervals were 66+/-9 bpm, 340+/-25 ms, 354+/-18 ms and 351+/-16 ms, respectively. HR-QT correlation was -0.63, P value of less than 0.001. HR was not related to striatal DAT binding. QTc-DAT and QTk-DAT relations were significant, r = -0.50, P = 0.004 and r = -0.59, P = 0.0002, respectively. In linear regression model, striatal DAT binding explained 35% of the variance of QTk interval (95% confidence interval: -46.9 to -13.0, P = 0.0002). CONCLUSION: This study suggests significant physiological QTc-DAT relation in young healthy adults. QTc interval measurements might carry diagnostically important information in clinical conditions, which have an effect on both striatal DAT binding and cardiac sympathetic function.

Differential hypometabolism patterns according to mild cognitive impairment subtypes.

AIMS: The present study investigated cerebral glucose metabolism and structural atrophy in controls and subjects with mild cognitive impairment (MCI). METHODS: The study included 13 controls, 7 MCI subjects considered as prodromal Alzheimer's disease (MCI of the Alzheimer type, aMCI) and 7 MCI subjects having cognitive decline due to other causes, established by clinical evaluation (MCI of the non-Alzheimer type, naMCI). Glucose metabolism in the frontal, parietal and posterior cingulate cortices, the hippocampus and parahippocampal gyrus was evaluated using Statistical Parametric Mapping 2 (SPM2). Structural analysis of the whole-brain grey matter was performed with voxel-based morphometry in SPM2. RESULTS: Significant hypometabolism was found in the medial temporal lobe in aMCI subjects compared to the controls and naMCI subjects. In addition, both the aMCI and naMCI patients had hypometabolism of the posterior cingulum relative to controls. The naMCI subjects showed atrophy of frontal and occipital areas compared to controls and aMCI patients, whereas the aMCI subjects did not show atrophy compared to the other groups. CONCLUSION: aMCI subjects have reduced glucose uptake levels, particularly in areas susceptible to pathological changes in Alzheimer's disease, and the changes are more pronounced in aMCI than naMCI subjects. Our results also suggest that functional changes may be more prominent than structural changes in MCI.

Serotonin and dopamine transporter binding in children with autism determined by SPECT.

Disturbances in the serotonergic system have been recognized in autism. To investigate the association between serotonin and dopamine transporters and autism, we studied 15 children (14 males, one female; mean age 8 y 8 mo [SD 3 y 10 mo]) with autism and 10 non-autistic comparison children (five males, five females; mean age 9 y 10 mo [SD 2 y 8 mo]) using single-photon emission computed tomography (SPECT) with [123 I] nor-beta-CIT. The children, with autism were studied during light sedation. They showed reduced serotonin transporter (SERT) binding capacity in the medial frontal cortex, midbrain, and temporal lobe areas. However, after correction due to the estimated effect of sedation, the difference remained significant only in the medial frontal cortex area (p=0.002). In the individuals with autism dopamine transporter (DAT) binding did not differ from that of the comparison group. The results indicate that SERT binding capacity is disturbed in autism. The reduction is more evident in adolescence than in earlier childhood. The low SERT binding reported here and the low serotonin synthesis capacity shown elsewhere may indicate maturation of a lesser number of serotonergic nerve terminals in individuals with autism.

Midbrain serotonin and striatum dopamine transporter binding in double depression: a one-year follow-up study.

Data on neurobiological differences between major depression (MD) and double depression (DD) are scarce. We examined the striatum dopamine (DAT) and midbrain serotonin transporter (SERT) binding of [123I] nor-beta-CIT in DD patients (n=8) and compared it to that in MD patients (n=11) and healthy controls (n=19). Drug-naïve patients and controls were imaged by single-photon emission computed tomography at baseline, and the patients also after one year of psychodynamic psychotherapy. Both DD and MD groups had lower midbrain [123I] nor-beta-CIT binding compared with the controls. Baseline 17-item Hamilton Depression Rating Scale (HAM-D-17) scores significantly decreased in both groups after one year of psychotherapy (DD: t=3.55, p=0.009; MD: t=5.86, p<0.001). No differences between the DD and MD groups were observed in age-adjusted baseline striatum or midbrain [123I] nor-beta-CIT binding or its change during psychotherapy. Age-adjusted baseline striatum [123I] nor-beta-CIT binding correlated inversely with the duration of both dysthymia (rho=-0.76, p=0.03) and MD (rho=-0.83, p=0.01) in the DD group. No such finding was observed in the MD group (rho=0.26, p=0.44). Baseline HAM-D-17 did not correlate with the change in striatum or midbrain [123I] nor-beta-CIT binding in either group. In conclusion, our findings suggest that when using midbrain [123I] nor-beta-CIT binding as a marker of SERT binding, no differences are detectable between patients with DD and MD. However, low striatum [123I] nor-beta-CIT binding, a marker of DAT binding, may be associated with a longer illness duration in dysthymia.

Temporal cortex dopamine D2/3 receptor binding in major depression.

The aim of this study was to assess the dopamine function of the temporal cortex in major depressive disorder using [(123)I]epidepride to image D(2/3) receptor binding sites. Ten major depressives and 10 healthy controls were selected from a general population sample for single-photon emission computed tomography imaging. Among the major depressives there was a strong bilateral correlation between the scores on the 21-item Hamilton Depression Rating Scale and D(2/3) receptor binding. Dopaminergic abnormalities may be present in the temporal cortices of major depressives.