Entropy Drives Accelerated Ion Diffusion upon Carbon Dioxide Expansion of Electrolytes.

Carbon dioxide-expanded liquids, organic solvents with high concentrations of soluble carbon dioxide (CO2) at mild pressures, have gained attention as green catalytic media due to their improved properties over traditional solvents. More recently, carbon dioxide-expanded electrolytes (CXEs) have demonstrated improved reaction rates in the electrochemical reduction of CO2, by increasing the rate of delivery of CO2 to the electrode while maintaining facile charge transport. However, recent studies indicate that the limiting behavior of CXEs at higher CO2 pressures is a decline in solution conductivity due to reduced polarity, leading to poorer charge screening and greater ion pairing. In this article, we employ molecular dynamics simulations to investigate the energetic driving forces behind the diffusive properties of an acetonitrile and tetrapropylammonium hexafluorophosphate (TPrAPF6) CXE with increasing CO2 concentration. Our results indicate that entropy drives solvent and electrolyte diffusion with increasing CO2 pressure. The activation energy of ion diffusion increases with higher concentrations of CO2, indicating that increasing the temperature may improve solution conductivity in these systems. This trend in the activation energies is traced to stronger cation-anion Coulombic interactions due to weaker solvent screening at high CO2 concentrations, suggesting that the choice of ion may provide a route to diminish this effect.

PET Imaging of the Serotonin 1A Receptor in Major Depressive Disorder: Hierarchical Multivariate Analysis of [11C]WAY100635 Overcomes Outcome Measure Discrepancies.

The serotonin 1A receptor has been linked to both the pathophysiology of major depressive disorder (MDD) and the antidepressant action of serotonin reuptake inhibitors. Most PET studies of the serotonin 1A receptor in MDD used the receptor antagonist radioligand, [carbonyl-11C]WAY100635; however the interpretation of the combined results has been contentious owing to reports of higher or lower binding in MDD with different outcome measures. The reasons for these divergent results originate from several sources, including properties of the radiotracer itself, which complicate its quantification and interpretation; as well as from previously reported differences between MDD and healthy volunteers in both reference tissue binding and plasma free fraction, which are typically assumed not to differ. Recently, we have developed two novel hierarchical multivariate methods which we validated for the quantification and analysis of [11C]WAY100635, which show better accuracy and inferential efficiency compared to standard analysis approaches. Importantly, these new methods should theoretically be more resilient to many of the factors thought to have caused the discrepancies observed in previous studies. We sought to apply these methods in the largest [11C]WAY100635 sample to date, consisting of 160 individuals, including 103 MDD patients, of whom 50 were not-recently-medicated and 53 were antidepressant-exposed, as well as 57 healthy volunteers. While the outcome measure discrepancies were substantial using conventional univariate analysis, our multivariate analysis techniques instead yielded highly consistent results across PET outcome measures and across pharmacokinetic models, with all approaches showing higher serotonin 1A autoreceptor binding potential in the raphe nuclei of not-recently-medicated MDD patients relative to both healthy volunteers and antidepressant-exposed MDD patients. Moreover, with the additional precision of estimates afforded by this approach, we can show that while binding is also higher in projection areas in this group, these group differences are approximately half of those in the raphe nuclei, which are statistically distinguishable from one another. These results are consistent with the biological role of the serotonin 1A autoreceptor in the raphe nuclei in regulating serotonin neuron firing and release, and with preclinical and clinical evidence of deficient serotonin activity in MDD due to over expression of autoreceptors resulting from genetic and/or epigenetic effects. These results are also consistent with downregulation of autoreceptors as a mechanism of action of selective serotonin reuptake inhibitors. In summary, the results using multivariate analysis approaches therefore demonstrate both face and convergent validity, and may serve to provide a resolution and consensus interpretation for the disparate results of previous studies examining the serotonin 1A receptor in MDD.

Mechanistic Basis of Conductivity in Carbon Dioxide-Expanded Electrolytes: A Joint Experimental-Theoretical Study.

Electrolyte conductivity contributes to the efficiency of devices for electrochemical conversion of carbon dioxide (CO2) into useful chemicals, but the effect of the dissolution of CO2 gas on conductivity has received little attention. Here, we report a joint experimental-theoretical study of the properties of acetonitrile-based CO2-expanded electrolytes (CXEs) that contain high concentrations of CO2 (up to 12 M), achieved by CO2 pressurization. Cyclic voltammetry data and paired simulations show that high concentrations of dissolved CO2 do not impede the kinetics of outer-sphere electron transfer but decrease the solution conductivity at higher pressures. In contrast with conventional behaviors, Jones reactor-based measurements of conductivity show a nonmonotonic dependence on CO2 pressure: a plateau region of constant conductivity up to ca. 4 M CO2 and a region showing reduced conductivity at higher [CO2]. Molecular dynamics simulations reveal that while the intrinsic ionic strength decreases as [CO2] increases, there is a concomitant increase in ionic mobility upon CO2 addition that contributes to stable solution conductivities up to 4 M CO2. Taken together, these results shed light on the mechanisms underpinning electrolyte conductivity in the presence of CO2 and reveal that the dissolution of CO2, although nonpolar by nature, can be leveraged to improve mass transport rates, a result of fundamental and practical significance that could impact the design of next-generation systems for CO2 conversion. Additionally, these results show that conditions in which ample CO2 is available at the electrode surface are achievable without sacrificing the conductivity needed to reach high electrocatalytic currents.

Dynamic Human Brain Imaging with a Portable PET Camera: Comparison to a Standard Scanner.

Portable, cost-effective PET cameras can radically expand the applicability of PET. We present here a within-participant comparison of fully quantified [18F]FDG dynamic scans in healthy volunteers using the standard Biograph mCT scanner and portable CerePET scanner. Methods: Each of 20 healthy volunteers underwent dynamic [18F]FDG imaging with both scanners (1-154 d apart) and concurrent arterial blood sampling. Tracer SUV, net influx rate (Ki), and the corresponding cerebral metabolic rate of glucose (CMRglu) were quantified at regional and voxel levels. Results: At the regional level, CerePET outcome measure estimates within participants robustly correlated with Biograph mCT estimates in the neocortex, wherein the average Pearson correlation coefficients across participants ± SD were 0.83 ± 0.07 (SUV) and 0.85 ± 0.08 (Ki and CMRglu). There was also strong agreement between CerePET and Biograph mCT estimates, wherein the average regression slopes across participants were 0.84 ± 0.17 (SUV), 0.83 ± 0.17 (Ki), and 0.85 ± 0.18 (CMRglu). There was similar bias across participants but higher correlation and less variability in subcortical regions than in cortical regions. Pearson correlation coefficients for subcortical regions equaled 0.97 ± 0.02 (SUV) and 0.97 ± 0.03 (Ki and CMRglu), and average regression slopes equaled 0.79 ± 0.14 (SUV), 0.83 ± 0.11 (Ki), and 0.86 ± 0.11 (CMRglu). In voxelwise assessment, CerePET and Biograph mCT estimates across outcome measures were significantly different only in a cluster of left frontal white matter. Conclusion: Our results indicate robust correlation and agreement between semi- and fully quantitative brain glucose metabolism measurements from portable CerePET and standard Biograph mCT scanners. The results obtained with a portable PET scanner in this comparison in humans require follow-up but lend confidence to the feasibility of more flexible and portable brain imaging with PET.

In vivo serotonin transporter and 1A receptor binding potential and ecological momentary assessment (EMA) of stress in major depression and suicidal behavior.

We examined relationships between the serotonin system and stress in major depression and suicidal behavior. Twenty-five medication-free depressed participants (13 suicide attempters) underwent same-day [11C]DASB and [11C]CUMI-101 positron emission tomography (PET) imaging. Binding potential (BPND) to the serotonin transporter (5-HTT) and serotonin 1A (5-HT1A) receptor, respectively, was quantified using the NRU 5-HT atlas, reflecting distinct spatial distributions of multiple serotonin targets. Ecological momentary assessment (EMA) measured current stress over one week proximal to imaging. EMA stress did not differ between attempters and non-attempters. In all depressed participants, 5-HTT and 5-HT1A BPND were unrelated to EMA stress. There were region-specific effects of 5-HTT (p=0.002) and 5-HT1A BPND (p=0.03) in attempters vs. nonattempters. In attempters, region-specific associations between 5-HTT (p=0.03) and 5-HT1A (p=0.005) BPND and EMA stress emerged. While no post-hoc 5-HTT BPND correlations were significant, 5-HT1A BPND correlated positively with EMA stress in attempters in 9/10 regions (p-values<0.007), including the entire cortex except the largely occipital region 5. Brodmann-based regional analyses found diminished effects for 5-HTT and subcortically localized positive corrrelations between 5-HT1A and EMA stress, in attempters only. Given comparable depression severity and childhood and current stress between attempters and nonattempters, lower 5-HTT binding in attempters vs. nonattempters may suggest a biological risk marker. Localized lower 5-HTT and widespread higher 5-HT1A binding with stress among attempters specifically may suggest that a serotonergic phenotype might be a key determinant of risk or resiliency for suicidal behavior.

In vivo serotonin 1A receptor hippocampal binding potential in depression and reported childhood adversity.

BACKGROUND: Reported childhood adversity (CA) is associated with development of depression in adulthood and predicts a more severe course of illness. Although elevated serotonin 1A receptor (5-HT1AR) binding potential, especially in the raphe nuclei, has been shown to be a trait associated with major depression, we did not replicate this finding in an independent sample using the partial agonist positron emission tomography tracer [11C]CUMI-101. Evidence suggests that CA can induce long-lasting changes in expression of 5-HT1AR, and thus, a history of CA may explain the disparate findings. METHODS: Following up on our initial report, 28 unmedicated participants in a current depressive episode (bipolar n = 16, unipolar n = 12) and 19 non-depressed healthy volunteers (HVs) underwent [11C]CUMI-101 imaging to quantify 5-HT1AR binding potential. Participants in a depressive episode were stratified into mild/moderate and severe CA groups via the Childhood Trauma Questionnaire. We hypothesized higher hippocampal and raphe nuclei 5-HT1AR with severe CA compared with mild/moderate CA and HVs. RESULTS: There was a group-by-region effect (p = 0.011) when considering HV, depressive episode mild/moderate CA, and depressive episode severe CA groups, driven by significantly higher hippocampal 5-HT1AR binding potential in participants in a depressive episode with severe CA relative to HVs (p = 0.019). Contrary to our hypothesis, no significant binding potential differences were detected in the raphe nuclei (p-values > 0.05). CONCLUSIONS: With replication in larger samples, elevated hippocampal 5-HT1AR binding potential may serve as a promising biomarker through which to investigate the neurobiological link between CA and depression.

Ventral prefrontal serotonin 1A receptor binding: a neural marker of vulnerability for mood disorder and suicidal behavior?

Mood disorders and suicidal behavior have moderate heritability and are associated with altered corticolimbic serotonin 1A receptor (5-HT1A) brain binding. However, it is unclear whether this reflects genetic effects or epigenetic effects of childhood adversity, compensatory mechanisms, or illness stress-related changes. We sought to separate such effects on 5-HT1A binding by examining high familial risk individuals (HR) who have passed through the age of greatest risk for psychopathology onset with and without developing mood disorder or suicidal behavior. PET imaging quantified 5-HT1A binding potential BPND using [11C]CUMI-101 in healthy volunteers (HV, N = 23) and three groups with one or more relatives manifesting early-onset mood disorder and suicide attempt: 1. unaffected HR (N = 23); 2. HR with lifetime mood disorder and no suicide attempt (HR-MOOD, N = 26); and 3. HR-MOOD with previous suicide attempt (HR-MOOD + SA, N = 20). Findings were tested in an independent cohort not selected for family history (HV, MOOD, and MOOD + SA, total N = 185). We tested for regional BPND differences and whether brain-wide patterns distinguished between groups. Low ventral prefrontal 5-HT1A BPND was associated with lifetime mood disorder diagnosis and suicide attempt, but only in subjects with a family history of mood disorder and suicide attempt. Brain-wide 5-HT1A BPND patterns including low ventral prefrontal and mesiotemporal cortical binding distinguished HR-MOOD + SA from HV. A biological endophenotype associated with resilience was not observed. Low ventral prefrontal 5-HT1A BPND may reflect familial mood disorder and suicide-related pathology. Further studies are needed to determine if higher ventral prefrontal 5-HT1A BPND confers resilience, reducing risk of suicidal behavior in the context of familial risk, and thereby offer a potential prevention target.

Serotonin transporter binding in major depressive disorder: impact of serotonin system anatomy.

Serotonin transporter (5-HTT) binding deficits are reported in major depressive disorder (MDD). However, most studies have not considered serotonin system anatomy when parcellating brain regions of interest (ROIs). We now investigate 5-HTT binding in MDD in two novel ways: (1) use of a 5-HTT tract-based analysis examining binding along serotonergic axons; and (2) using the Copenhagen University Hospital Neurobiology Research Unit (NRU) 5-HT Atlas, based on brain-wide binding patterns of multiple serotonin receptor types. [11C]DASB 5-HTT PET scans were obtained in 60 unmedicated participants with MDD in a current depressive episode and 31 healthy volunteers (HVs). Binding potential (BPP) was quantified with empirical Bayesian estimation in graphical analysis (EBEGA). Within the [11C]DASB tract, the MDD group showed significantly lower BPP compared with HVs (p = 0.02). This BPP diagnosis difference also significantly varied by tract location (p = 0.02), with the strongest MDD binding deficit most proximal to brainstem raphe nuclei. NRU 5-HT Atlas ROIs showed a BPP diagnosis difference that varied by region (p < 0.001). BPP was lower in MDD in 3/10 regions (p-values < 0.05). Neither [11C]DASB tract or NRU 5-HT Atlas BPP correlated with depression severity, suicidal ideation, suicide attempt history, or antidepressant medication exposure. Future studies are needed to determine the causes of this deficit in 5-HTT binding being more pronounced in proximal axon segments and in only a subset of ROIs for the pathogenesis of MDD. Such regional specificity may have implications for targeting antidepressant treatment, and may extend to other serotonin-related disorders.

Source-to-Target Automatic Rotating Estimation (STARE) - A publicly-available, blood-free quantification approach for PET tracers with irreversible kinetics: Theoretical framework and validation for [18F]FDG.

INTRODUCTION: Full quantification of positron emission tomography (PET) data requires an input function. This generally means arterial blood sampling, which is invasive, labor-intensive and burdensome. There is no current, standardized method to fully quantify PET radiotracers with irreversible kinetics in the absence of blood data. Here, we present Source-to-Target Automatic Rotating Estimation (STARE), a novel, data-driven approach to quantify the net influx rate (Ki) of irreversible PET radiotracers, that requires only individual-level PET data and no blood data. We validate STARE with human [18F]FDG PET scans and assess its performance using simulations. METHODS: STARE builds upon a source-to-target tissue model, where the tracer time activity curves (TACs) in multiple "target" regions are expressed at once as a function of a "source" region, based on the two-tissue irreversible compartment model, and separates target region Ki from source Ki by fitting the source-to-target model across all target regions simultaneously. To ensure identifiability, data-driven, subject-specific anchoring is used in the STARE minimization, which takes advantage of the PET signal in a vasculature cluster in the field of view (FOV) that is automatically extracted and partial volume-corrected. To avoid the need for any a priori determination of a single source region, each of the considered regions acts in turn as the source, and a final Ki is estimated in each region by averaging the estimates obtained in each source rotation. RESULTS: In a large dataset of human [18F]FDG scans (N = 69), STARE Ki estimates were correlated with corresponding arterial blood-based Ki estimates (r = 0.80), with an overall regression slope of 0.88, and were precisely estimated, as assessed by comparing STARE Ki estimates across several runs of the algorithm (coefficient of variation across runs=6.74 ± 2.48%). In simulations, STARE Ki estimates were largely robust to factors that influence the individualized anchoring used within its algorithm. CONCLUSION: Through simulations and application to [18F]FDG PET data, feasibility is demonstrated for STARE blood-free, data-driven quantification of Ki. Future work will include applying STARE to PET data obtained with a portable PET camera and to other irreversible radiotracers.

Brain 5-HT1A Receptor PET Binding, Cortisol Responses to Stress, and the Familial Transmission of Suicidal Behavior.

BACKGROUND: The serotonin 1A (5-HT1A) receptor has been implicated in depression and suicidal behavior. Lower resting cortisol levels are associated with higher 5-HT1A receptor binding, and both differentiate suicide attempters with depression. However, it is not clear whether 5-HT1A receptor binding and cortisol responses to stress are related to familial risk and resilience for suicidal behavior. METHODS: [11C]CUMI-101 positron emission tomography imaging to quantify regional brain 5-HT1A receptor binding was conducted in individuals considered to be at high risk for mood disorder or suicidal behavior on the basis of having a first- or second-degree relative(s) with an early onset mood disorder and history of suicidal behavior. These high-risk individuals were subdivided into the following groups: high risk resilient having no mood disorder or suicidal behavior (n = 29); high risk with mood disorder and no suicidal behavior history (n = 31); and high risk with mood disorder and suicidal behavior (n = 25). Groups were compared with healthy volunteers without a family history of mood disorder or suicidal behavior (n = 34). Participants underwent the Trier Social Stress Task (TSST). All participants were free from psychotropic medications at the time of the TSST and PET scanning. RESULTS: We observed no group differences in 5-HT1A receptor binding considering all regions simultaneously, nor did we observe heterogeneity of the effect of group across regions. These results were similar across outcome measures (BPND for all participants and BPp in a subset of the sample) and definitions of regions of interest (ROIs; standard or serotonin system-specific ROIs). We also found no group differences on TSST outcomes. Within the high risk with mood disorder and suicidal behavior group, lower BPp binding (ß = -0.084, SE = 0.038, P = .048) and higher cortisol reactivity to stress (ß = 9.25, 95% CI [3.27,15.23], P = .004) were associated with higher lethality attempts. There were no significant relationships between 5-HT1A binding and cortisol outcomes. CONCLUSIONS: 5-HT1A receptor binding in ROIs was not linked to familial risk or resilience protecting against suicidal behavior or mood disorder although it may be related to lethality of suicide attempt. Future studies are needed to better understand the biological mechanisms implicated in familial risk for suicidal behavior and how hypothalamic-pituitary-adrenal axis function influences such risk.

Measuring brain glucose metabolism in order to predict response to antidepressant or placebo: A randomized clinical trial.

There is critical need for a clinically useful tool to predict antidepressant treatment outcome in major depressive disorder (MDD) to reduce suffering and mortality. This analysis sought to build upon previously reported antidepressant treatment efficacy prediction from 2-[18F]-fluorodeoxyglucose - Positron Emission Tomography (FDG-PET) using metabolic rate of glucose uptake (MRGlu) from dynamic FDG-PET imaging with the goal of translation to clinical utility. This investigation is a randomized, double-blind placebo-controlled trial. All participants were diagnosed with MDD and received an FDG-PET scan before randomization and after treatment. Hamilton Depression Rating Scale (HDRS-17) was completed in participants diagnosed with MDD before and after 8 weeks of escitalopram, or placebo. MRGlu (mg/(min*100 ml)) was estimated within the raphe nuclei, right insula, and left ventral Prefrontal Cortex in 63 individuals. Linear regression was used to examine the association between pretreatment MRGlu and percent decrease in HDRS-17. Additionally, the association between percent decrease in HDRS-17 and percent change in MRGlu between pretreatment scan and post-treatment scan was examined. Covariates were treatment type (SSRI/placebo), handedness, sex, and age. Depression severity decrease (n = 63) was not significantly associated with pretreatment MRGlu in the raphe nuclei (ß = -2.61e-03 [-0.26, 0.25], p = 0.98), right insula (ß = 0.05 [-0.23, 0.32], p = 0.72), or ventral prefrontal cortex (ß = 0.06 [-0.23, 0.34], p = 0.68) where ß is the standardized estimated coefficient, with a 95% confidence interval, or in whole brain voxelwise analysis (family-wise error correction, alpha = 0.05). MRGlu percent change was not significantly associated with depression severity decrease (n = 58) before multiple comparison correction in the RN (ß = 0.20 [-0.07, 0.47], p = 0.15), right insula (ß = 0.24 [-0.03, 0.51], p = 0.08), or vPFC (ß = 0.22 [-0.06, 0.50], p = 0.12). We propose that FDG-PET imaging does not indicate a clinically relevant biomarker of escitalopram or placebo treatment response in heterogeneous major depressive disorder cohorts. Future directions include focusing on potential biologically-based subtypes of major depressive disorder by implementing biomarker stratified designs.

Neuroinflammation in World Trade Center responders at midlife: A pilot study using [18F]-FEPPA PET imaging.

BACKGROUND: Neuroinflammation has long been theorized to arise from exposures to fine particulate matter and to be modulated when individuals experience chronic stress, both of which are also though to cause cognitive decline in part as a result of neuroinflammation. OBJECTIVES: Hypothesizing that neuroinflammation might be linked to experiences at the World Trade Center (WTC) events, this study explored associations between glial activation and neuropsychological measures including post-traumatic stress disorder (PTSD) symptom severity and WTC exposure duration. METHODS: Translocator protein 18-kDa (TSPO) is overexpressed by activated glial cells, predominantly microglia and astrocytes, making TSPO distribution a putative biomarker for neuroinflammation. Twenty WTC responders completed neuropsychological assessments and in vivo PET brain scan with [18F]-FEPPA. Generalized linear modeling was used to test associations between PTSD, and WTC exposure duratiioni as the predictor and both global and regional [18F]-FEPPA total distribution volumes as the outcomes. RESULT: Responders were 56.0 â€‹± â€‹4.7 years-old, and 75% were police officers on 9/11/2001, and all had at least a high school education. Higher PTSD symptom severity was associated with global and regional elevations in [18F]-FEPPA binding predominantly in the hippocampus (d â€‹= â€‹0.72, P â€‹= â€‹0.001) and frontal cortex (d â€‹= â€‹0.64, P â€‹= â€‹0.004). Longer exposure duration to WTC sites was associated with higher [18F]-FEPPA binding in the parietal cortex. CONCLUSION: Findings from this study of WTC responders at midlife suggest that glial activation is associated with PTSD symptoms, and WTC exposure duration. Future investigation is needed to understand the important role of neuroinflammation in highly exposed WTC responders.

Examination of structural brain changes in recent suicidal behavior.

We aimed to identify brain structural changes in cortical and subcortical regions linked to recent suicidal behavior. We performed secondary analyses of structural MRI data of two independent studies, namely the Establishing Moderators/Biosignatures of Antidepressant Response - Clinical Care (EMBARC) study and a Little Rock study on acute suicidal behavior. Study 1 (EMBARC, N = 187), compared individuals with remote suicide attempts (Remote-SA), individuals with lifetime suicide ideation but no attempts (Lifetime-SI only), and depressed individuals without lifetime suicide ideation or attempts (non-suicidal depressed). Study 2 (Little Rock data, N = 34) included patients recently hospitalized for suicide ideation or attempt constituted by: patients who recently attempted suicide (Recent-SA), individuals with remote suicide attempts (Remote-SA), and Lifetime-SI only. Study 3 combined the EMBARC and Little Rock datasets including Recent-SA, Remote-SA, Lifetime-SI only and non-suicidal depressed individuals. In Study 1 and Study 2, no significant differences were observed between groups. In Study 3, significantly lower middle temporal gyrus thickness, insular surface area, and thalamic volume and higher volume in the nucleus accumbens were observed in Recent-SA. This pattern of structural abnormalities may underlie pain and emotion dysregulation, which have been linked to the transition from suicidal thoughts to action.

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.

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.

Depression Severity Over 27 Months in Adolescent Girls Is Predicted by Stress-Linked Cortical Morphology.

BACKGROUND: Evidence supports the notion that early-life stress and trauma impact cortical development and increase vulnerability to depression. However, it remains unclear whether common stressful life events in community-dwelling adolescents have similar consequences for cortical development. METHODS: A total of 232 adolescent girls (mean age 15.29 ± 0.65 years) were assessed with the Stressful Life Events Schedule (a semistructured interview of stressors in the previous 9 months) and underwent a magnetic resonance imaging scan. FreeSurfer 5.3.0 was used to perform whole-brain surface-based morphometry. Dysphoria was assessed at the time of imaging and prospectively at three 9-month follow-up appointments using the Inventory of Depression and Anxiety Symptoms II. RESULTS: At least one stressful life event was reported in 90% of the adolescent participants during the 9 months preceding imaging. Greater burden of recent life stress was associated with less left precuneus and left postcentral cortical thickness and smaller left superior frontal and right inferior parietal volume (all p < .05 after multiple comparisons correction). Left precuneus thickness in the stress-associated cluster significantly predicted dysphoria for 27 months after imaging controlling for prior dysphoria (ß = -.11, p = .004). Left precuneus cortical thickness accounted for 17.0% of the association between stress and dysphoric mood for 27 months after imaging (ß = .04, p = .05). CONCLUSIONS: Consistent with evidence from imaging studies of trauma-exposed youths and preclinical stress models, a heavy burden of recent common life stress in community-dwelling adolescent girls was associated with altered frontal/parietal cortical morphology. Stress-linked precuneus cortical thickness represents a candidate prospective biomarker of adolescent depression.

Structural correlates of the orbitofrontal cortex and amygdala and personality in female adolescents.

The five-factor model consists of cognitive-affective-behavioral trait dimensions (neuroticism, extraversion, openness to experience, agreeableness, conscientiousness) that are central to models of psychopathology. In adults, individual differences in three of the Big Five traits, neuroticism, extraversion, and conscientiousness, have been linked to structural morphology and connectivity of the orbitofrontal cortex (OFC) and the amygdala, two brain regions critically involved in affective and regulatory processing. It is unclear whether these associations manifest in adolescence, a critical neurodevelopmental period during which many forms of psychiatric illness emerge. A total of 223 adolescent girls (ages 14-16 years) completed a multimodal neuroimaging study that utilized T1-weighted structural MRI (e.g., cortical thickness and volume) and tractography-based diffusion tensor imaging (64-direction). Cortical thickness and volume were extracted from the medial orbitofrontal cortex (mOFC) and amygdala and tractography-based fractional anisotropy was computed in the uncinate fasciculus (UF; the white matter tract connecting the OFC to the temporal lobe). We found that high neuroticism was associated with less mOFC volume (bilateral), and low conscientiousness was associated with higher white matter integrity in the UF, more amygdala volume, and less mOFC thickness (right hemisphere). Extraversion was not observed to share associations with OFC markers. These OFC-amygdala structural correlations to personality do not match those reported in adult samples. Multimodal neuroimaging techniques can help to clarify the underpinnings of personality development between adolescence and adulthood.

Brief Computer-Based Information Processing Measures are Linked to White Matter Integrity in Pediatric-Onset Multiple Sclerosis.

BACKGROUND AND PURPOSE: Pediatric-onset multiple sclerosis (POMS) is a demyelinating disorder with unique clinical challenges. A brief computer-administered cognitive screening battery measuring processing speed (Cogstate) and the Brief International Cognitive Assessment in MS (BICAMS) detect cognitive impairment in POMS. The neuroanatomic correlates of these deficits are incompletely understood. The purpose of this study is to define the neuroanatomic underpinnings of deficits identified with cognitive screening batteries in POMS. METHODS: Participants with POMS and age-matched healthy controls (HCs) were screened with Cogstate and BICAMS. Diffusion tensor imaging assessed region-wise and tractography-based fractional anisotropy (FA). RESULTS: The POMS (n = 15) and HC (n = 21) groups were matched on age (mean ages 17.9 ± 3.2 vs. 17.8 ± 3.3 years, respectively) and on an estimate of general intellectual functioning. The Cogstate composite revealed significant slowing in POMS relative to HCs (P = .004), but the BICAMS composite did not significantly distinguish the groups (P = .10). The Cogstate composite showed moderate-to-strong correlations with regional FA (r = -.67 to -.82) and significantly associated with uncinate fasciculus FA following multiple comparisons correction (P = .002) in POMS. However, the BICAMS composite measure showed only weak-to-moderate correlations with FA in POMS (r = -.19 to -.57), with none surviving multiple comparisons correction. CONCLUSIONS: Computer-administered measures of cognitive processing are particularly sensitive in POMS and are closely linked to white matter FA.

Quantification of Positron Emission Tomography Data Using Simultaneous Estimation of the Input Function: Validation with Venous Blood and Replication of Clinical Studies.

PURPOSE: To determine if one venous blood sample can substitute full arterial sampling in quantitative modeling for multiple positron emission tomography (PET) radiotracers using simultaneous estimation of the input function (SIME). PROCEDURES: Participants underwent PET imaging with [11C]ABP688, [11C]CUMI-101, and [11C]DASB. Full arterial sampling and additional venous blood draws were performed for quantification with the arterial input function (AIF) and SIME using one arterial or venous (vSIME) sample. RESULTS: Venous and arterial metabolite-corrected plasma activities were within 6 % of each other at varying time points. vSIME- and AIF-derived outcome measures were in good agreement, with optimal sampling times of 12 min ([11C]ABP688), 90 min ([11C]CUMI-101), and 100 min ([11C]DASB). Simulation-based power analyses revealed that SIME required fewer subjects than the AIF method to achieve statistical power, with significant reductions for [11C]CUMI-101 and [11C]DASB with vSIME. Replication of previous findings and test-retest analyses bolstered the simulation analyses. CONCLUSIONS: We demonstrate the feasibility of AIF recovery using SIME with one venous sample for [11C]ABP688, [11C]CUMI-101, and [11C]DASB. This method simplifies PET acquisition while allowing for fully quantitative modeling, although some variability and bias are present with respect to AIF-based quantification, which may depend on the accuracy of the single venous blood measurement.