Sophie E. Holmes

Pre- and Postsynaptic Serotonergic Differences in Males with Extreme Levels of Impulsive Aggression Without Callous Unemotional Traits: A Positron Emission Tomography Study Using 11C-DASB and 11C-MDL100907

BACKGROUNDnImpulsive aggression (IA) in adults is associated with brain serotonin (5-HT) system abnormalities and is more common following childhood adversity. Within aggressive behavior, IA and callous unemotional (CU) traits are core components of differentiable factors with opposing 5-HT abnormalities. We aimed to investigate 5-HT abnormalities in IA and potential correlations with severity of childhood adversity while controlling for confounding 5-HT effects of high CU traits and mental disorders.nnnMETHODSnHealthy male subjects (mean age 34 ± 9 years) without high CU traits were recruited with IA ratings in the high (n = 14) and low (n = 13) population extremes. Serotonin transporter (SERT) and 5-HT(2A) receptor availability was measured in multiple brain regions using positron emission tomography with (11)C-DASB and (11)C-MDL100907, respectively, and compared between high-IA and low-IA groups. Correlations were measured between SERT and 5-HT(2A) receptor availability, impulsivity and aggression, and childhood adversity.nnnRESULTSnCompared with the low-IA group, SERT were significantly higher in brainstem regions in the high-IA group (by 29.0% ± 11.4%) and modestly lower across cortical regions (by 11.1% ± 6.0%), whereas 5-HT(2A) receptors were also modestly lower (by 8.6% ± 4.0%). Across all subjects, brainstem SERT were significantly positively correlated with impulsivity, aggression, and childhood trauma ratings. Within the high-IA group, higher brainstem SERT was most strongly predicted by severity of childhood trauma (r = .76 in midbrain).nnnCONCLUSIONSnPre-and postsynaptic 5-HT differences are present in men with high levels of IA and are strongly suggestive of a persisting effect of childhood adversity on serotonergic neurodevelopment and emotional-behavioral control.

Elevated translocator protein in anterior cingulate in major depression and a role for inflammation in suicidal thinking: a positron emission tomography study

BACKGROUNDnMajor depressive disorder is associated with raised peripheral inflammatory markers. Mounting evidence also suggests that inflammation is involved in suicidal behavior. However, the involvement of inflammation in the brains of individuals with depression, and its association with suicidal ideation, needs further clarification. Translocator protein (TSPO), which is upregulated in activated glia (predominantly microglia), can be measured as an indication of neuroinflammation inxa0vivo using positron emission tomography and TSPO-specific radioligands.nnnMETHODSnWe used [11C](R)-PK11195 positron emission tomography to compare TSPO availability in the anterior cingulate cortex (ACC), prefrontal cortex, and insula between 14 medication-free patients in a major depressive episode of at least moderate severity and 13 matched healthy control subjects. In a post hoc analysis, we also compared TSPO availability between patients with and without suicidal thoughts.nnnRESULTSnMultivariate analysis of variance indicated significantly higher TSPO in patients compared with control subjects (pxa0= .005). The elevation was of large effect size and significant in the ACC (pxa0= .022, Cohens dxa0= 0.95), with smaller nonsignificant elevations in the prefrontal cortex (pxa0= .342, Cohens dxa0= 0.38) and insula (pxa0= .466, Cohens dxa0=xa00.29). TSPO was not elevated in patients without suicidal thinking but was significantly increased in those with suicidal thoughts compared with those without, most robustly in the ACC (pxa0= .008) and insula (pxa0= .023).nnnCONCLUSIONSnWe confirm evidence for increased TSPO availability, suggestive of predominantly microglial activation, in the ACC during a moderate to severe major depressive episode. Our findings provide further incentive for evaluating anti-inflammatory therapies in major depressive disorder.

Altered metabotropic glutamate receptor 5 markers in PTSD: In vivo and postmortem evidence

Significance Posttraumatic stress disorder (PTSD) is a highly prevalent and disabling disorder, but there are currently no targeted medications for its treatment. Glutamate dysfunction is thought to be involved in the pathophysiology of PTSD, and the metabotropic glutamate receptor 5 (mGluR5) may represent a treatment target. We show alterations in mGluR5 availability in vivo and mGluR5- and glucocorticoid-related gene expression in postmortem tissue in PTSD, providing insight into the molecular mechanisms underlying this disorder. Our findings could, therefore, help inform the development of critically needed targeted and effective treatments for those suffering from PTSD. Posttraumatic stress disorder (PTSD) is a prevalent and highly disabling disorder, but there is currently no targeted pharmacological treatment for it. Dysfunction of the glutamate system has been implicated in trauma and stress psychopathology, resulting in a growing interest in modulation of the glutamate system for the treatment of PTSD. Specifically, the metabotropic glutamate receptor 5 (mGluR5) represents a promising treatment target. We used [18F]FPEB, a radioligand that binds to the mGluR5, and positron emission tomography (PET) to quantify in vivo mGluR5 availability in human PTSD vs. healthy control (HCs) subjects. In an independent sample of human postmortem tissue, we investigated expression of proteins that have a functional relationship with mGluR5 and glucocorticoids in PTSD. We observed significantly higher cortical mGluR5 availability in PTSD in vivo and positive correlations between mGluR5 availability and avoidance symptoms. In the postmortem sample, we observed up-regulation of SHANK1, a protein that anchors mGluR5 to the cell surface, as well as decreased expression of FKBP5, implicating aberrant glucocorticoid functioning in PTSD. Results of this study provide insight into molecular mechanisms underlying PTSD and suggest that mGluR5 may be a promising target for mechanism-based treatments aimed at mitigating this disorder.

Metabotropic Glutamate Receptor 5 and Glutamate Involvement in Major Depressive Disorder: A Multimodal Imaging Study

BACKGROUNDnPreclinical and postmortem studies have implicated the metabotropic glutamate receptor 5 (mGluR5) in the pathophysiology of major depressive disorder (MDD). The goal of the present study was to determine the role of mGluR5 in a large group of individuals with MDD compared to healthy controls (HC) in vivo with [18F]FPEB and positron emission tomography (PET). Furthermore, we sought to determine the role glutamate plays on mGluR5 availability in MDD.nnnMETHODSnSixty-five participants (30 MDD and 35 HC) completed [18F]FPEB PET to estimate the primary outcome measure - mGluR5 volume of distribution (VT), and the secondary outcome measure - mGluR5 distribution volume ratio (DVR). A subgroup of 39 participants (16 MDD and 23 HC) completed proton magnetic resonance spectroscopy (1H MRS) to estimate anterior cingulate (ACC) glutamate, glutamine, and Glx (glutamate + glutamine) levels relative to creatine (Cr).nnnRESULTSnNo significant between-group differences were observed in mGluR5 VT or DVR. Compared to HC, individuals with MDD had higher ACC glutamate, glutamine, and Glx levels. Importantly, the ACC mGluR5 DVR negatively correlated with glutamate/Cr and Glx/Cr levels.nnnCONCLUSIONSnIn this novel in vivo examination, we show an inverse relationship between mGluR5 availability and glutamate levels. These data highlight the need to further investigate the role of glutamatergic system in depression.

Multimodal Investigation of Network Level Effects Using Intrinsic Functional Connectivity, Anatomical Covariance, and Structure-to-Function Correlations in Unmedicated Major Depressive Disorder

Converging evidence suggests that major depressive disorder (MDD) affects multiple large-scale brain networks. Analyses of the correlation or covariance of regional brain structure and function applied to structural and functional MRI data may provide insights into systems-level organization and structure-to-function correlations in the brain in MDD. This study applied tensor-based morphometry and intrinsic connectivity distribution to identify regions of altered volume and intrinsic functional connectivity in data from unmedicated individuals with MDD (n=17) and healthy comparison participants (HC, n=20). These regions were then used as seeds for exploratory anatomical covariance and connectivity analyses. Reduction in volume in the anterior cingulate cortex (ACC) and lower structural covariance between the ACC and the cerebellum were observed in the MDD group. Additionally, individuals with MDD had significantly lower whole-brain intrinsic functional connectivity in the medial prefrontal cortex (mPFC). This mPFC region showed altered connectivity to the ventral lateral PFC (vlPFC) and local circuitry in MDD. Global connectivity in the ACC was negatively correlated with reported depressive symptomatology. The mPFC–vlPFC connectivity was positively correlated with depressive symptoms. Finally, we observed increased structure-to-function correlation in the PFC/ACC in the MDD group. Although across all analysis methods and modalities alterations in the PFC/ACC were a common finding, each modality and method detected alterations in subregions belonging to distinct large-scale brain networks. These exploratory results support the hypothesis that MDD is a systems level disorder affecting multiple brain networks located in the PFC and provide new insights into the pathophysiology of this disorder.

Neurobiology of Chronic Stress-Related Psychiatric Disorders: Evidence from Molecular Imaging Studies:

Chronic stress accounts for billions of dollars of economic loss annually in the United States alone, and is recognized as a major source of disability and mortality worldwide. Robust evidence suggests that chronic stress plays a significant role in the onset of severe and impairing psychiatric conditions, including major depressive disorder, bipolar disorder, and posttraumatic stress disorder. Application of molecular imaging techniques such as positron emission tomography and single photon emission computed tomography in recent years has begun to provide insight into the molecular mechanisms by which chronic stress confers risk for these disorders. The present paper provides a comprehensive review and synthesis of all positron emission tomography and single photon emission computed tomography imaging publications focused on the examination of molecular targets in individuals with major depressive disorder, posttraumatic stress disorder, or bipolar disorder to date. Critical discussion of discrepant findings and broad strengths and weaknesses of the current body of literature is provided. Recommended future directions for the field of molecular imaging to further elucidate the neurobiological substrates of chronic stress-related disorders are also discussed. This article is part of the inaugural issue for the journal focused on various aspects of chronic stress.

β-Amyloid, APOE and BDNF Genotype, and Depressive and Anxiety Symptoms in Cognitively Normal Older Women and Men

OBJECTIVEnTo examine how β-amyloid (Aβ), APOE and BDNF genotypes, and cortisol relate to depressive and anxiety symptoms in cognitively normal older women and men.nnnMETHODSnCross-sectional data were analyzed from 423 older adults from the Australian Imaging Biomarkers and Lifestyle study. Analyses of covariance evaluated associations between Aβ, APOE and BDNF genotype, and cortisol in relation to severity of depressive and anxiety symptoms.nnnRESULTSnAmong Aβ+ older adults, APOE ε4 carriage was associated with greater severity of anxiety symptoms (du2009=u20090.55); and in the full sample, APOE ε4 carriage was linked to greater severity of depressive (du2009=u20090.26) and anxiety (du2009=u20090.21) symptoms. Among Aβ+ women, ε4 carriers reported greater anxiety symptoms than non-ε4 carriers (du2009=u20090.83), and female BDNF rs6265 Val66 Met allele carriers reported greater depressive symptoms (du2009=u20090.29).nnnCONCLUSIONnSex moderated the relationship between Aβ, APOE genotype, and BDNF genotype in predicting severity of anxiety and depressive symptoms in cognitively normal older adults.

Metabotropic Glutamatergic Receptor 5 and Stress Disorders: Knowledge Gained From Receptor Imaging Studies

The metabotropic glutamatergic receptor subtype 5 (mGluR5) may represent a promising therapeutic target for stress-related psychiatric disorders. Here, we describe mGluR5 findings in stress disorders, particularly major depressive disorder (MDD), highlighting insights from positron emission tomography studies. Positron emission tomography studies report either no differences or lower mGluR5 in MDD, potentially reflecting MDD heterogeneity. Unlike the rapidly acting glutamatergic agent ketamine, mGluR5-specific modulation has not yet shown antidepressant efficacy in MDD and bipolar disorder. Although we recently showed that ketamine may work, in part, through significant mGluR5 modulation, the specific role of mGluR5 downregulation in ketamines antidepressant response is unclear. In contrast to MDD, there has been much less investigation of mGluR5 in bipolar disorder, yet initial studies indicate that mGluR5-specific treatments may aid in both depressed and manic mood states. The direction of modulation needed may be state dependent, however, limiting clinical feasibility. There has been relatively little study of posttraumatic stress disorder or obsessive-compulsive disorder to date, although there is evidence for the upregulation of mGluR5 in these disorders. However, while antagonism of mGluR5 may reduce fear conditioning, it may also reduce fear extinction. Therefore, studies are needed to determine the role mGluR5 modulation might play in the treatment of these conditions. Further challenges in modulating this prevalent neurotransmitter system include potential induction of significant side effects. As such, more research is needed to identify level and type (positive/negative allosteric modulation or full antagonism) of mGluR5 modulation required to translate existing knowledge into improved therapies.

Trajectories of depressive and anxiety symptoms in older adults: a 6-year prospective cohort study

Depressive and anxiety symptoms are common in older adults, significantly affect quality of life, and are risk factors for Alzheimers disease. We sought to identify the determinants of predominant trajectories of depressive and anxiety symptoms in cognitively normal older adults.

Time-dependent neuronal changes associated with craving in opioid dependence: an fMRI study

Relapse after initially successful treatment is a significant problem facing the treatment of opioid dependence. Evidence suggests craving elicited by re‐exposure to drug cues may precipitate relapse. Attempts to identify neural biomarkers of cue‐elicited craving have yielded inconsistent findings. We aimed to apply a novel continuous functional magnetic resonance imaging technique to follow the minute‐to‐minute evolution of brain responses, which correlate with the waxing and waning of craving. Newly detoxified male opioid‐dependent patients and healthy control participants attended two separate, counterbalanced, functional magnetic resonance imaging scanning sessions during which they viewed a 10‐minute video (drug cue or neutral cue) followed by 5 minutes of fixation. Participants rated the intensity of their craving throughout each session. We hypothesized that subcortical/ventral prefrontal cortex (PFC) regions and dorsal PFC regions would show different associations with craving reflecting their putative roles in appetitive processing versus cognitive control. Compared with controls, drug cue (minus neutral cue) video recruited the left amygdala and was temporally correlated with craving. In contrast, dorsal anterior cingulate blood‐oxygen‐level‐dependent signal time course was higher than controls only during a period after cue exposure when craving levels were declining. Against expectations, neither the ventral striatum nor ventral PFC was significantly recruited by drug cue exposure. Findings suggest that the amygdala has a central role in craving, whereas the dorsal anterior cingulate may control craving in treatment‐seeking patients. Time course analysis yielded new insights into the neural substrates of craving that could objectively validate development of psychological and pharmacological approaches to sustained abstinence.