Alterations in resting-state functional activity and connectivity for major depressive disorder appetite and weight disturbance phenotypes.

BACKGROUND: Major depressive disorder (MDD) is often accompanied by changes in appetite and weight. Prior task-based functional magnetic resonance imaging (fMRI) findings suggest these MDD phenotypes are associated with altered reward and interoceptive processing. METHODS: Using resting-state fMRI data, we compared the fractional amplitude of low-frequency fluctuations (fALFF) and seed-based connectivity (SBC) among hyperphagic (n = 77), hypophagic (n = 66), and euphagic (n = 42) MDD groups and a healthy comparison group (n = 38). We examined fALFF and SBC in a mask restricted to reward [nucleus accumbens (NAcc), putamen, caudate, ventral pallidum, and orbitofrontal cortex (OFC)] and interoceptive (anterior insula and hypothalamus) regions and also performed exploratory whole-brain analyses. SBC analyses included as seeds the NAcc and also regions demonstrating group differences in fALFF (i.e. right lateral OFC and right anterior insula). All analyses used threshold-free cluster enhancement. RESULTS: Mask-restricted analyses revealed stronger fALFF in the right lateral OFC, and weaker fALFF in the right anterior insula, for hyperphagic MDD v. healthy comparison. We also found weaker SBC between the right lateral OFC and left anterior insula for hyperphagic MDD v. healthy comparison. Whole-brain analyses revealed weaker fALFF in the right anterior insula, and stronger SBC between the right lateral OFC and left precentral gyrus, for hyperphagic MDD v. healthy comparison. Findings were no longer significant after controlling for body mass index, which was higher for hyperphagic MDD. CONCLUSIONS: Our results suggest hyperphagic MDD may be associated with altered activity in and connectivity between interoceptive and reward regions.

Does the change in glutamate to GABA ratio correlate with change in depression severity? A randomized, double-blind clinical trial.

Previous proton magnetic resonance spectroscopy (1H-MRS) studies suggest a perturbation in glutamate and/or GABA in Major Depressive Disorder (MDD). However, no studies examine the ratio of glutamate and glutamine (Glx) to GABA (Glx/GABA) as it relates to depressive symptoms, which may be more sensitive than either single metabolite. Using a within-subject design, we hypothesized that reduction in depressive symptoms correlates with reduction in Glx/GABA in the anterior cingulate cortex (ACC). The present trial is a randomized clinical trial that utilized 1H-MRS to examine Glx/GABA before and after 8 weeks of escitalopram or placebo. Participants completed the 17-item Hamilton Depression Rating Scale (HDRS17) and underwent magnetic resonance spectroscopy before and after treatment. Two GABA-edited MEGA-PRESS acquisitions were interleaved with a water unsuppressed reference scan. GABA and Glx were quantified from the average difference spectrum, with preprocessing using Gannet and spectral fitting using TARQUIN. Linear mixed models were utilized to evaluate relationships between change in HDRS17 and change in Glx/GABA using a univariate linear regression model, multiple linear regression incorporating treatment type as a covariate, and Bayes Factor (BF) hypothesis testing to examine strength of evidence. No significant relationship was detected between percent change in Glx, GABA, or Glx/GABA and percent change in HDRS17, regardless of treatment type. Further, MDD severity before/after treatment did not correlate with ACC Glx/GABA. In light of variable findings in the literature and lack of association in our investigation, future directions should include evaluating glutamate and glutamine individually to shed light on the underpinnings of MDD severity. Advancing Personalized Antidepressant Treatment Using PET/MRI, ClinicalTrials.gov, NCT02623205.

Discovery and replication of cerebral blood flow differences in major depressive disorder.

Major depressive disorder (MDD) is a serious, heterogeneous disorder accompanied by brain-related changes, many of which are still to be discovered or refined. Arterial spin labeling (ASL) is a neuroimaging technique used to measure cerebral blood flow (CBF; perfusion) to understand brain function and detect differences among groups. CBF differences have been detected in MDD, and may reveal biosignatures of disease-state. The current work aimed to discover and replicate differences in CBF between MDD participants and healthy controls (HC) as part of the EMBARC study. Participants underwent neuroimaging at baseline, prior to starting study medication, to investigate biosignatures in MDD. Relative CBF (rCBF) was calculated and compared between 106 MDD and 36 HC EMBARC participants (whole-brain Discovery); and 58 MDD EMBARC participants and 58 HC from the DLBS study (region-of-interest Replication). Both analyses revealed reduced rCBF in the right parahippocampus, thalamus, fusiform and middle temporal gyri, as well as the left and right insula, for those with MDD relative to HC. Both samples also revealed increased rCBF in MDD relative to HC in both the left and right inferior parietal lobule, including the supramarginal and angular gyri. Cingulate and prefrontal regions did not fully replicate. Lastly, significant associations were detected between rCBF in replicated regions and clinical measures of MDD chronicity. These results (1) provide reliable evidence for ASL in detecting differences in perfusion for multiple brain regions thought to be important in MDD, and (2) highlight the potential role of using perfusion as a biosignature of MDD.

Examining the underpinnings of loudness dependence of auditory evoked potentials with positron emission tomography.

Loudness dependence of auditory evoked potentials (LDAEP) has long been considered to reflect central basal serotonin transmission. However, the relationship between LDAEP and individual serotonin receptors and transporters has not been fully explored in humans and may involve other neurotransmitter systems. To examine LDAEP's relationship with the serotonin system, we performed PET using serotonin-1A (5-HT1A) imaging via [11C]CUMI-101 and serotonin transporter (5-HTT) imaging via [11C]DASB on a mixed sample of healthy controls (n â€‹= â€‹4: 4 females, 0 males), patients with unipolar (MDD, n â€‹= â€‹11: 4 females, 7 males) and bipolar depression (BD, n â€‹= â€‹8: 4 females, 4 males). On these same participants, we also performed electroencephalography (EEG) within a week of PET scanning, using 1000 â€‹Hz tones of varying intensity to evoke LDAEP. We then evaluated the relationship between LDAEP and 5-HT1A or 5-HTT binding in both the raphe (5-HT1A)/midbrain (5-HTT) areas and in the temporal cortex. We found that LDAEP was significantly correlated with 5-HT1A positively and with 5-HTT negatively in the temporal cortex (p â€‹< â€‹0.05), but not correlated with either in midbrain or raphe. In males only, exploratory analysis showed multiple regions in which LDAEP significantly correlated with 5-HT1A throughout the brain; we did not find this with 5-HTT. This multimodal study partially validates preclinical models of a serotonergic influence on LDAEP. Replication in larger samples is necessary to further clarify our understanding of the role of serotonin in perception of auditory tones.

Prediction of lithium treatment response in bipolar depression using 5-HTT and 5-HT1A PET.

BACKGROUND: Lithium, one of the few effective treatments for bipolar depression (BPD), has been hypothesized to work by enhancing serotonergic transmission. Despite preclinical evidence, it is unknown whether lithium acts via the serotonergic system. Here we examined the potential of serotonin transporter (5-HTT) or serotonin 1A receptor (5-HT1A) pre-treatment binding to predict lithium treatment response and remission. We hypothesized that lower pre-treatment 5-HTT and higher pre-treatment 5-HT1A binding would predict better clinical response. Additional analyses investigated group differences between BPD and healthy controls and the relationship between change in binding pre- to post-treatment and clinical response. Twenty-seven medication-free patients with BPD currently in a depressive episode received positron emission tomography (PET) scans using 5-HTT tracer [11C]DASB, a subset also received a PET scan using 5-HT1A tracer [11C]-CUMI-101 before and after 8 weeks of lithium monotherapy. Metabolite-corrected arterial input functions were used to estimate binding potential, proportional to receptor availability. Fourteen patients with BPD with both [11C]DASB and [11C]-CUMI-101 pre-treatment scans and 8 weeks of post-treatment clinical scores were included in the prediction analysis examining the potential of either pre-treatment 5-HTT or 5-HT1A or the combination of both to predict post-treatment clinical scores. RESULTS: We found lower pre-treatment 5-HTT binding (p = 0.003) and lower 5-HT1A binding (p = 0.035) were both significantly associated with improved clinical response. Pre-treatment 5-HTT predicted remission with 71% accuracy (77% specificity, 60% sensitivity), while 5-HT1A binding was able to predict remission with 85% accuracy (87% sensitivity, 80% specificity). The combined prediction analysis using both 5-HTT and 5-HT1A was able to predict remission with 84.6% accuracy (87.5% specificity, 60% sensitivity). Additional analyses BPD and controls pre- or post-treatment, and the change in binding were not significant and unrelated to treatment response (p > 0.05). CONCLUSIONS: Our findings suggest that while lithium may not act directly via 5-HTT or 5-HT1A to ameliorate depressive symptoms, pre-treatment binding may be a potential biomarker for successful treatment of BPD with lithium. CLINICAL TRIAL REGISTRATION: PET and MRI Brain Imaging of Bipolar Disorder Identifier: NCT01880957; URL: https://clinicaltrials.gov/ct2/show/NCT01880957.

In vivo PET Imaging of [11C]CIMBI-5, a 5-HT2AR Agonist Radiotracer in Nonhuman Primates.

PURPOSE: 5-HT2AR exists in high and low affinity states. Agonist PET tracers measure binding to the active high affinity site and thus provide a functionally relevant measure of the receptor. Limited in vivo data have been reported so far for a comparison of agonist versus antagonist tracers for 5-HT2AR used as a proof of principle for measurement of high and low affinity states of this receptor. We compared the in vivo binding of [11C]CIMBI-5, a 5-HT2AR agonist, and of the antagonist [11C]M100907, in monkeys and baboons. METHODS: [11C]CIMBI-5 and [11C]M100907 baseline PET scans were performed in anesthetized male baboons (n=2) and male vervet monkeys (n=2) with an ECAT EXACT HR+ and GE 64-slice PET/CT Discovery VCT scanners. Blocking studies were performed in vervet monkeys by pretreatment with MDL100907 (0.5 mg/kg, i.v.) 60 minutes prior to the scan. Regional distribution volumes and binding potentials were calculated for each ROI using the likelihood estimation in graphical analysis and Logan plot, with either plasma input function or reference region as input, and simplified reference tissue model approaches. RESULTS: PET imaging of [11C]CIMBI-5 in baboons and monkeys showed the highest binding in 5-HT2AR-rich cortical regions, while the lowest binding was observed in cerebellum, consistent with the expected distribution of 5-HT2AR. Very low free fractions and rapid metabolism were observed for [11C]CIMBI-5 in baboon plasma. Binding potential values for [11C]CIMBI-5 were 25-33% lower than those for [11C]MDL100907 in the considered brain regions. CONCLUSION: The lower binding potential of [11C]CIMBI-5 in comparison to [11C]MDL100907 is likely due to the preferential binding of the former to the high affinity site in vivo in contrast to the antagonist,  [11C]MDL100907, which binds to both high and low affinity sites.

Relations between cortical thickness, serotonin 1A receptor binding, and structural connectivity: A multimodal imaging study.

Serotonin 1A (5-HT1A ) receptors play a direct role in neuronal development, cell proliferation, and dendritic branching. We hypothesized that variability in 5-HT1A binding can affect cortical thickness, and may account for a subtype of major depressive disorder (MDD) in which both are altered. To evaluate this, we measured cortical thickness from structural magnetic resonance imaging (MRI) and 5-HT1A binding by positron emission tomography (PET) in an exploratory study. To examine a range of 5-HT1A binding and cortical thickness values, we recruited 25 healthy controls and 19 patients with MDD. We hypothesized increased 5-HT1A binding in the raphe nucleus (RN) would be negatively associated with cortical thickness due to reduced serotonergic transmission. Contrary to our hypothesis, raphe 5-HT1A binding was positively correlated with cortical thickness in right posterior cingulate cortex (PCC), a region implicated in the default mode network. Cortical thickness was also positively correlated with 5-HT1A in each cortical region. We further hypothesized that the strength of 5-HT1A -cortical thickness correlation depends on the number of axons between the raphe nucleus and each region. To explore this we related 5-HT1A -cortical thickness correlation coefficients to the number of tracts connecting that region and the raphe, as measured by diffusion tensor imaging (DTI) in an independent sample. The 5-HT1A -cortical thickness association correlated significantly with the number of tracts to each region, supporting our hypothesis. We posit a defect in the raphe may affect the PCC within the default mode network in MDD through serotonergic fibers, resulting in increased ruminative processing.

Development and evaluation of a multimodal marker of major depressive disorder.

This study aimed to identify biomarkers of major depressive disorder (MDD), by relating neuroimage-derived measures to binary (MDD/control), ordinal (severe MDD/mild MDD/control), or continuous (depression severity) outcomes. To address MDD heterogeneity, factors (severity of psychic depression, motivation, anxiety, psychosis, and sleep disturbance) were also used as outcomes. A multisite, multimodal imaging (diffusion MRI [dMRI] and structural MRI [sMRI]) cohort (52 controls and 147 MDD patients) and several modeling techniques-penalized logistic regression, random forest, and support vector machine (SVM)-were used. An additional cohort (25 controls and 83 MDD patients) was used for validation. The optimally performing classifier (SVM) had a 26.0% misclassification rate (binary), 52.2 ± 1.69% accuracy (ordinal) and r = .36 correlation coefficient (p < .001, continuous). Using SVM, R2 values for prediction of any MDD factors were <10%. Binary classification in the external data set resulted in 87.95% sensitivity and 32.00% specificity. Though observed classification rates are too low for clinical utility, four image-based features contributed to accuracy across all models and analyses-two dMRI-based measures (average fractional anisotropy in the right cuneus and left insula) and two sMRI-based measures (asymmetry in the volume of the pars triangularis and the cerebellum) and may serve as a priori regions for future analyses. The poor accuracy of classification and predictive results found here reflects current equivocal findings and sheds light on challenges of using these modalities for MDD biomarker identification. Further, this study suggests a paradigm (e.g., multiple classifier evaluation with external validation) for future studies to avoid nongeneralizable results.

Kappa opioid receptor binding in major depression: A pilot study.

Endogenous kappa opioids mediate pathological responses to stress in animal models. However, the relationship of the kappa opioid receptor (KOR) to life stress and to psychopathology in humans is not well described. This pilot study sought, for the first time, to quantify KOR in major depressive disorder (MDD) in vivo in humans using positron emission tomography (PET). KOR binding was quantified in vivo by PET imaging with the [11 C]GR103545 radiotracer in 13 healthy volunteers and 10 participants with current MDD. We examined the relationship between regional [11 C]GR103545 total volume of distribution (VT ) and diagnosis, childhood trauma, recent life stress, and, in a subsample, salivary cortisol levels during a modified Trier Social Stress Test (mTSST), amygdala, hippocampus, ventral striatum and raphe nuclei. Whole-brain voxel-wise analyses were also performed. [11 C]GR103545 VT did not differ significantly between MDD participants and healthy volunteers in the four a priori ROIs (p = 0.50). [11 C]GR103545 VT was unrelated to reported childhood adversity (p = 0.17) or recent life stress (p = 0.56). A trend-level inverse correlation was observed between [11 C]GR103545 VT and cortisol area-under-the curve with respect to ground during the mTSST (p = 0.081). No whole-brain voxel-wise contrasts were significant. Regional [11 C]GR103545 VT , a measure of in vivo KOR binding, does not differentiate MDD from healthy volunteers in this pilot sample. Future studies may examine KOR binding in subgroups of depressed individuals at increased risk for KOR abnormalities, including co-occurring mood and substance use disorders, as well as depression with psychotic features.

In vivo evaluation of [11C]TMI, a COX-2 selective PET tracer, in baboons.

Overexpression of Cyclooxygenase-2 (COX-2) enzyme is associated with the pathogenesis of inflammation, cancers, stroke, arthritis, and neurological disorders. Because of the involvement of COX-2 in these diseases, quantification of COX-2 expression using Positron Emission Tomography (PET) may be a biological marker for early diagnosis, monitoring of disease progression, and an indicator of effective treatment. At present there is no target-specific or validated PET tracer available for in vivo quantification of COX-2. The objective of this study is to evaluate [11C]TMI, a selective COX-2 inhibitor (Ki ≤ 1 nM) in nonhuman primates using PET imaging. PET imaging in baboons showed that [11C]TMI penetrates the blood brain barrier (BBB) and accumulates in brain in a somewhat heterogeneous pattern. Metabolite analyses indicated that [11C]TMI undergoes no significant metabolism of parent tracer in the plasma for baseline scans, however a relative faster metabolism was found for blocking scan. All the tested quantification approaches provide comparable tracer total distribution volume (VT) estimates in the range of 3.2-7 (mL/cm3). We observed about 25% lower VT values in blocking studies with meloxicam, a nonselective COX-2 inhibitor, compared to baseline [11C]TMI binding. Our findings indicate that [11C]TMI may be a suitable PET tracer for the quantification of COX-2 in vivo. Further experiments are needed to confirm the potential of this tracer in COX-2 overexpressing models for brain diseases.

Radiosynthesis and in vivo evaluation of [11C]MOV as a PET imaging agent for COX-2.

Radiosynthesis and in vivo evaluation of [11C]4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide (methoxy analogue of valdecoxib, [11C]MOV), a COX-2 inhibitor, was conducted in rat and baboon. Synthesis of the reference standard MOV (3), and its desmethyl precursor 2 for radiolabeling were performed using 1,2-diphenylethan-1-one as the starting material in five steps with 15% overall yield. Radiosynthesis of [11C]MOV was accomplished in 40 ±â€¯10% yield and >99% radiochemical purity by reacting the precursor 2 in dimethyl formamide (DMF) with [11C]CH3I followed by removal of the dimethoxytrityl (DMT) protective group using trifluroacetic acid. PET studies in anesthetized baboon showed very low uptake and homogeneous distribution of [11C]MOV in brain. The radioligand underwent rapid metabolism in baboon plasma. MicroPET studies in male Sprague Dawley rats revealed [11C]MOV binding in lower thorax. The tracer binding in rats was partially blocked in heart and duodenum by the administration of 1 mg/kg oral dose of COX-2 inhibitor valdecoxib.

Will imaging individual raphe nuclei in males with major depressive disorder enhance diagnostic sensitivity and specificity?

BACKGROUND: Positron emission tomography (PET) studies in major depressive disorder (MDD) have reported higher serotonin 1A (5-HT1A ) autoreceptor binding in the raphe. In males, the difference is so large that it can potentially be used as the first biological marker for MDD. However, the raphe includes several nuclei, which project to different regions of the brain and spinal cord and may be differentially involved in disease. We aimed to identify 5-HT1A differences in individual raphe nuclei using PET in order to determine whether use of subnuclei would provide greater sensitivity and specificity of diagnosing MDD. METHODS: We identified individual nuclei using a hybrid set-level technique on an average [11 C]-WAY100635 PET image derived from 52 healthy volunteers (HV). We delineated three nuclei: dorsal raphe nucleus (DRN), median raphe nucleus (MRN), and raphe magnus (RMg). An atlas image of these nuclei was created and nonlinearly warped to each subject (through an associated MRI) in a separate sample of 41 males (25 HV, 16 MDD) who underwent [11 C]-WAY100635 PET. RESULTS: 5-HT1A binding was elevated in DRN in MDD (P < .01), and was not different in the RMg and MRN between groups. Receiver operating characteristic (ROC) curves showed that combining DRN and MRN produces highest sensitivity (94%) and specificity (84%) to identify MDD. CONCLUSION: In agreement with postmortem studies, we found higher 5-HT1A autoreceptor binding in MDD selectively in the DRN. 5-HT1A autoreceptor binding in the combined DRN and MRN is a better biomarker for MDD than in the raphe as a whole.

In Vivo Brain Imaging, Biodistribution, and Radiation Dosimetry Estimation of [11C]Celecoxib, a COX-2 PET Ligand, in Nonhuman Primates.

COX-2 selective inhibitors (COXIBs) are non-steroidal anti-inflammatory drugs (NSAIDs), with fewer side effects compared with non-selective NSAIDs, and are used for the treatment of arthritis, headaches, and other inflammatory diseases of the brain and peripheral tissues. Radiolabeled COXIBs may permit positron emission tomography (PET) imaging of COX-2 localization and activity in diseases, enable monitoring of inflammatory processes, and determine target occupancy of COX-2 activity by NSAIDs, thus, accelerating the development of novel CIXIBs. We synthesized [11C]celecoxib, one of the COXIBs and a prescription drug, and here report its in vivo uptake in the brain, whole body biodistribution, and radiation dosimetry in baboons using PET. Brain imaging experiments were performed in one baboon and whole body PET scans were performed in triplicates in two male baboons using an ECAT ACCEL (Siemens Medical Solutions, Inc. Knoxville) under anesthetic conditions. PET studies in baboons show that [11C]celecoxib penetrates the blood brain barrier (BBB) and accumulates in the brain, followed by a washout of radioactivity. The liver has the highest residence time and the gallbladder is the critical organ for [11C]celecoxib. Organ Level Internal Dose Assessment (OLINDA) estimates indicate that the maximum permissible single study dosage of [11C]celecoxib in humans is 1110 MBq (30 mCi) for both males and females under the 21 CFR 361.1 dose limit for research subjects.

Positron emission tomography quantification of serotonin transporter binding in medication-free bipolar disorder.

OBJECTIVES: Bipolar disorder (BD) is associated with abnormalities in the serotonin transporter (5-HTT), but specific in vivo findings have been discrepant. Using positron emission tomography (PET) and [(11)C]DASB, we compared 5-HTT binding between unmedicated depressed BD subjects and healthy volunteers (HVs). EXPERIMENTAL DESIGN: 5-HTT binding in six brain regions was compared between 17 depressed, unmedicated BD subjects and 31 HVs, using the outcome measure of VT/fP (proportional to the total number of available transporters). Alternative outcome measures were examined as well. 47% of BD were BP I; and 65% reported a prior suicide attempt. PRINCIPAL OBSERVATIONS: 5-HTT binding (VT/fP ) did not differ between BD and HV groups considering six brain regions of interest simultaneously (P = 0.24). In contrast, alternative outcome measures (BPF*, BPP*, and BPND*) indicated lower binding in BD compared with HV across these six regions of interest (BPF*: P = 0.047; BPP*: P = 0.032; BPND*: P = 0.031). 5-HTT binding was unrelated to suicide attempt history, depression severity, bipolar subtype, or history of past substance use disorder. CONCLUSIONS: Choice of outcome measure strongly affects comparisons of serotonin transporter binding using PET with [(11)C]DASB. We do not find evidence of abnormal 5-HTT binding in bipolar depression using our primary outcome measure, VT /fP . However, we did observe lower 5-HTT binding in BD with alternative outcome measures that are frequently used with [(11)C]DASB. Relative merits and assumptions of different outcome measures are discussed. Evaluation in larger samples and during different mood states, including remission, is warranted.

A COMPREHENSIVE EXAMINATION OF WHITE MATTER TRACTS AND CONNECTOMETRY IN MAJOR DEPRESSIVE DISORDER.

BACKGROUND: Major depressive disorder (MDD) is a debilitating disorder characterized by widespread brain abnormalities. The literature is mixed as to whether or not white matter abnormalities are associated with MDD. This study sought to examine fractional anisotropy (FA) in white matter tracts in individuals with MDD using diffusion tensor imaging (DTI). METHODS: 139 participants with MDD and 39 healthy controls (HC) in a multisite study were included. DTI scans were acquired in 64 directions and FA was determined in the brain using four methods: region of interest (ROI), tract-based spatial statistics (TBSS), and diffusion tractography. Diffusion connectometry was used to identify white matter pathways associated with MDD. RESULTS: There were no significant differences when comparing FA in MDD and HC groups using any method. In the MDD group, there was a significant relationship between depression severity and FA in the right medial orbitofrontal cortex, and between age of onset of MDD and FA in the right caudal anterior cingulate cortex using the ROI method. There was a significant relationship between age of onset and connectivity in the thalamocortical radiation, inferior longitudinal fasciculus, and cerebellar tracts using diffusion connectometry. CONCLUSIONS: The lack of group differences in FA and connectometry analysis may result from the clinically heterogenous nature of MDD. However, the relationship between FA and depression severity may suggest a state biomarker of depression that should be investigated as a potential indicator of response. Age of onset may also be a significant clinical feature to pursue when studying white matter tracts.

Estimation of in vivo nonspecific binding in positron emission tomography studies without requiring a reference region.

Estimation of outcome measures in in vivo neuroreceptor mapping with positron emission tomography (PET) commonly depends on an assumption of uniform nondisplaceable binding throughout the brain. In many cases, this can be estimated based on data from a "reference region," an area of the brain devoid of the receptor of interest. However, often such a region does not exist, as there are some receptors everywhere throughout the brain. Erroneously designating a region as a "reference" can lead to biased estimation, and furthermore, if the level of specific binding in the purported reference region differs between comparison groups, the validity of resulting conclusions may be called into question. We present a method for estimation of all common PET outcome measures that can provide good estimates even when no reference region exists. Our aim is to use information from several regions simultaneously to estimate the information common to all regions. By not requiring specification (or validation) of a reference region, such an approach can provide an automated, objective approach for kinetic modeling of PET data. We illustrate the performance of these methods on simulated data, human [(11)C]WAY-100635 data, and [(11)C]CUMI-101 blocking data in baboons. We show close agreement between estimates obtained by using the proposed method (which does not require a reference region) and estimates based on either a reference region or a blocking study.

Test-retest reliability of freesurfer measurements within and between sites: Effects of visual approval process.

In the last decade, many studies have used automated processes to analyze magnetic resonance imaging (MRI) data such as cortical thickness, which is one indicator of neuronal health. Due to the convenience of image processing software (e.g., FreeSurfer), standard practice is to rely on automated results without performing visual inspection of intermediate processing. In this work, structural MRIs of 40 healthy controls who were scanned twice were used to determine the test-retest reliability of FreeSurfer-derived cortical measures in four groups of subjects-those 25 that passed visual inspection (approved), those 15 that failed visual inspection (disapproved), a combined group, and a subset of 10 subjects (Travel) whose test and retest scans occurred at different sites. Test-retest correlation (TRC), intraclass correlation coefficient (ICC), and percent difference (PD) were used to measure the reliability in the Destrieux and Desikan-Killiany (DK) atlases. In the approved subjects, reliability of cortical thickness/surface area/volume (DK atlas only) were: TRC (0.82/0.88/0.88), ICC (0.81/0.87/0.88), PD (0.86/1.19/1.39), which represent a significant improvement over these measures when disapproved subjects are included. Travel subjects' results show that cortical thickness reliability is more sensitive to site differences than the cortical surface area and volume. To determine the effect of visual inspection on sample size required for studies of MRI-derived cortical thickness, the number of subjects required to show group differences was calculated. Significant differences observed across imaging sites, between visually approved/disapproved subjects, and across regions with different sizes suggest that these measures should be used with caution.

Genetic variation in brain-derived neurotrophic factor val66met allele is associated with altered serotonin-1A receptor binding in human brain.

Brain Derived Neurotrophic Factor (BDNF) regulates brain synaptic plasticity. BDNF affects serotonin signaling, increases serotonin levels in brain tissue and prevents degeneration of serotonin neurons. These effects have hardly been studied in human brain. We examined the relationship of the functional val66met polymorphism of the BDNF gene to serotonin 1A (5-HT(1A)) receptor binding in vivo. 50 healthy volunteers (HV) and 50 acutely depressed, unmedicated patients with major depressive disorder (MDD) underwent PET scanning with the 5-HT(1A) receptor ligand, [(11)C]WAY-100635 and a metabolite corrected arterial input function. A linear mixed effects model compared 5-HT(1A) receptor binding potential (BP(F), proportional to the number of available receptors) in 13 brain regions of interest between met allele carriers (met/met and val/met) and noncarriers (val/val) using sex and C-1019G genotype of the 5-HT(1A) receptor promoter functional polymorphism as covariates. There was an interaction between diagnosis and allele (F=4.23, df=1, 94, p=0.042), such that met allele carriers had 17.4% lower BP(F) than non-met carriers in the HV group (t=2.6, df=96, p=0.010), but not in the MDD group (t=-0.4, df=96, p=0.58). These data are consistent with a model where the met allele of the val66met polymorphism causes less proliferation of serotonin synapses, and consequently fewer 5-HT(1A) receptors. In MDD, however, the effect of the val66met polymorphism is not detectable, possibly due to a ceiling effect of over-expression of 5-HT(1A) receptors in mood disorders.

Quantifying serotonin transporters by PET with [11C]-DASB before and after interferon-α treatment.

BACKGROUND: Interferon-α (IFN-α) therapy is frequently associated with disabling depression, fatigue, and related neuropsychiatric effects. Although depression in major depressive disorder is associated with low serotonin transporter binding, animal models suggest that IFN-associated mood effects are linked to increased presynaptic serotonin transporter binding. This study tested the hypotheses that IFN administration to human subjects increases presynaptic serotonin binding activity, and that this effect correlates with incident depression symptoms. METHODS: Positron emission tomography (PET) scans using [11C]-DASB were obtained for nine hepatitis C patients before and after IFN-α treatment for 8 weeks. Serotonin transporter binding was estimated using the likelihood estimation in graphical analysis (LEGA) model and measured as the volume of distribution (VT) divided by the free fraction of ligand (fP). Depression was measured with the Structured Clinical Interview for DSM-IV Diagnosis (SCID) and the Hamilton Rating Scale for Depression (HAM-D). RESULTS: Compared to pre-IFN treatment values, changes in serotonin transporter binding and depression symptoms were not significant. There was no correlation between changes in serotonin transporter binding and depression symptoms. LIMITATIONS: The study is limited by small sample size, minimal effect on observed mood symptoms within the sample, and brief duration of follow-up. CONCLUSION: These findings do not support the hypothesis of an IFN-induced change in serotonin transporter function as the cause of incident depressive symptoms in patients treated with IFN-α. Additional study of these possible relationships should be of longer duration and include more subjects with more pronounced changes in mood.

Cortical thickness differences between bipolar depression and major depressive disorder.

OBJECTIVES: Bipolar disorder (BD) is a psychiatric disorder with high morbidity and mortality that cannot be distinguished from major depressive disorder (MDD) until the first manic episode. A biomarker able to differentiate BD and MDD could help clinicians avoid risks of treating BD with antidepressants without mood stabilizers. METHODS: Cortical thickness differences were assessed using magnetic resonance imaging in BD depressed patients (n = 18), MDD depressed patients (n = 56), and healthy volunteers (HVs) (n = 54). A general linear model identified clusters of cortical thickness difference between diagnostic groups. RESULTS: Compared to the HV group, the BD group had decreased cortical thickness in six regions, after controlling for age and sex, located within the frontal and parietal lobes, and the posterior cingulate cortex. Mean cortical thickness changes in clusters ranged from 7.6 to 9.6% (cluster-wise p-values from 1.0 e-4 to 0.037). When compared to MDD, three clusters of lower cortical thickness in BD were identified that overlapped with clusters that differentiated the BD and HV groups. Mean cortical thickness changes in the clusters ranged from 7.5 to 8.2% (cluster-wise p-values from 1.0 e-4 to 0.023). The difference in cortical thickness was more pronounced when the subgroup of subjects with bipolar I disorder (BD-I) was compared to the MDD group. CONCLUSIONS: Cortical thickness patterns were distinct between BD and MDD. These results are a step toward developing an imaging test to differentiate the two disorders.