Exploring the influence of synaptic density and anxiety on pain perception: evidence from a [11C]UCB-J positron emission tomography imaging study.

Background: Structural and functional brain alterations may be associated with pain and anxiety. We hypothesized that synaptic density (measured in vivo with [11C]UCB-J and positron emission tomography quantification of synaptic vesicle glycoprotein 2A, SV2A) alterations may play a role in higher pain sensitivity and that this relationship may be mediated by anxiety symptoms.

Methods: Twenty-one mentally and medically healthy subjects (11 males, 10 females; age 45.

Evaluation of radio-thin-layer chromatography as an alternative to radio-HPLC for [F]SynVesT-1 metabolism analysis in rats.

Purpose: Alterations in synaptic vesicle glycoprotein 2A (SV2A) are linked to various neurodegenerative and neuropsychiatric disorders. Positron emission tomography (PET) imaging with radiotracers targeting SV2A, such as [F]SynVesT-1, has proven effective for monitoring these changes. However, SV2A PET quantification using kinetic modeling requires radiometabolite analysis, which presents challenges, particularly in preclinical longitudinal studies due to the relatively large sample volume required by the standard radio-high-performance liquid chromatography (radio-HPLC) method.

Metabotropic Glutamate Receptor 5 as a Potential Biomarker of the Intersection of Trauma and Cannabis Use.

Background: Metabotropic glutamate receptor 5 (mGlu5) dysregulation has been implicated in the pathophysiology of trauma-related psychopathology, and there are direct interactions between the endocannabinoid and glutamatergic systems. However, relationships between cannabis use (CU) and mGlu5 have not been directly investigated in trauma-related psychopathology.

Methods: Using positron emission tomography with [18F]FPEB, we examined relationships between CU status and mGlu5 availability in vivo in a cross-diagnostic sample of individuals with trauma-related psychopathology (n = 55).

Challenges and rewards of in vivo synaptic density imaging, and its application to the study of depression.

The development of novel radiotracers for Positron Emission Tomography (PET) imaging agents targeting the synaptic vesicle glycoprotein 2 A (SV2A), an integral glycoprotein present in the membrane of all synaptic vesicles throughout the central nervous system, provides a method for the in vivo quantification of synaptic density. This is of particular interest in neuropsychiatric disorders given that synaptic alterations appear to underlie disease progression and symptom severity. In this review, we briefly describe the development of these SV2A tracers and the evaluation of quantification methods.

Deficits in prefrontal metabotropic glutamate receptor 5 are associated with functional alterations during emotional processing in bipolar disorder.

Background: Elucidating biological mechanisms contributing to bipolar disorder (BD) is key to improved diagnosis and treatment development. With converging evidence implicating the metabotropic glutamate receptor 5 (mGlu5) in the pathology of BD, here, we therefore test the hypothesis that recently identified deficits in mGlu5 are associated with functional brain differences during emotion processing in BD.

Methods: Positron emission tomography (PET) with [F]FPEB was used to measure mGlu5 receptor availability and functional imaging (fMRI) was performed while participants completed an emotion processing task.

Preliminary Study of White Matter Abnormalities and Associations With the Metabotropic Glutamate Receptor 5 to Distinguish Bipolar and Major Depressive Disorders.

Background: Understanding distinct neurobiological mechanisms underlying bipolar disorder (BD) and major depressive disorder (MDD) is crucial for accurate diagnosis and the discovery of novel and more effective targeted treatments. Previous diffusion-weighted MRI studies have suggested some common frontotemporal corticolimbic system white matter (WM) abnormalities across the disorders. However, critical to the development of more precise diagnosis and treatment is identifying distinguishing abnormalities.

Examining mGlu5 Receptor Availability as a Predictor of Vulnerability to PTSD: An [F]FPEB and PET Study in Male and Female Rats.

Background: Females are twice as likely to experience post-traumatic stress disorder (PTSD) than males, yet specific factors contributing to this greater risk are not fully understood. Our clinical and recent preclinical findings suggest a role for the metabotropic glutamate receptor 5 (mGlu5) in PTSD and differential involvement between males and females.

Methods: Here, we further investigate whether mGlu5 receptor availability may contribute to individual and sex differences in PTSD susceptibility by quantifying receptor availability using the mGlu5 receptor-specific radiotracer, [F]FPEB, and positron emission tomography in male (n = 16) and female (n = 16) rats before and after traumatic footshock exposure (FE) and assessment of stress-enhanced fear learning (SEFL) susceptibility, as compared with no-shock controls (CON; n = 7 male; n = 8 female).

Evaluating infusion methods and simplified quantification of synaptic density with [C]UCB-J and [F]SynVesT-1 PET.

For some positron emission tomography studies, radiotracer is administered as bolus plus continuous infusion (B/I) to achieve a state of equilibrium. This approach can reduce scanning time and simplify data analysis; however, the method must be validated and optimized for each tracer. This study aimed to validate a B/I method for quantification of synaptic density using radiotracers which target the synaptic vesicle glycoprotein 2 A: [C]UCB-J and [F]SynVesT-1.

The metabotropic glutamate receptor 5 as a biomarker for psychiatric disorders.

The role of glutamate system in the etiology and pathophysiology of psychiatric disorders has gained considerable attention in the past two decades, including dysregulation of the metabotropic glutamatergic receptor subtype 5 (mGlu5). Thus, mGlu5 may represent a promising therapeutic target for psychiatric conditions, particularly stress-related disorders. Here, we describe mGlu5 findings in mood disorders, anxiety, and trauma disorders, as well as substance use (specifically nicotine, cannabis, and alcohol use).

Nicotine Use and Metabotropic Glutamate Receptor 5 in Individuals With Major Depressive and Posttraumatic Stress Disorders.

Metabotropic glutamate receptor 5 (mGluR5) dysregulation has been implicated in the pathophysiology of many psychiatric disorders, as well as nicotine use and dependence. We used positron emission tomography with [F]FPEB to measure mGluR5 availability in vivo in 6 groups: (1) nicotine users (NUs) without other psychiatric comorbidities (=23); (2) comparison controls (CCs) without nicotine use or psychiatric comorbidities (=38); (3) major depressive disorder subjects with concurrent nicotine use (MDD-NU; =19); (4) MDD subjects without concurrent nicotine use (MDD-CC; =20); (5) posttraumatic stress disorder subjects with concurrent nicotine use (PTSD-NU; =17); and (6) PTSD subjects without concurrent nicotine use (PTSD-CC; =16). The goal of the study was to test the hypothesis that mGluR5 availability in key corticolimbic regions of interest (ROIs) is different in NU with versus without comorbid psychiatric disorders (ROI: dorsolateral prefrontal cortex [dlPFC], orbitofrontal cortex [OFC], ventromedial prefrontal cortex [vmPFC], anterior cingulate cortex [ACC], amygdala, hippocampus).

Differences in Quantification of the Metabotropic Glutamate Receptor 5 Across Bipolar Disorder and Major Depressive Disorder.

Background: Understanding the neurobiology underlying bipolar disorder (BD) versus major depressive disorder (MDD) is crucial for accurate diagnosis and for driving the discovery of novel treatments. A promising target is the metabotropic glutamate receptor 5 (mGluR5), a modulator of glutamate transmission associated with synaptic plasticity. We measured mGluR5 availability in individuals with MDD and BD for the first time using positron emission tomography.

Examining sex differences in responses to footshock stress and the role of the metabotropic glutamate receptor 5: an [F]FPEB and positron emission tomography study in rats.

Clinical investigations suggest involvement of the metabotropic glutamate receptor 5 (mGluR5) in the pathophysiology of fear learning that underlies trauma-related disorders. Here, we utilized a 4-day fear learning paradigm combined with positron emission tomography (PET) to examine the relationship between mGluR5 availability and differences in the response of rats to repeated footshock exposure (FE). Specifically, on day 1, male (n = 16) and female (n = 12) rats received 15 footshocks and were compared with control rats who did not receive footshocks (n = 7 male; n = 4 female).

Lower synaptic density is associated with psychiatric and cognitive alterations in obesity.

Obesity is a serious medical condition that often co-occurs with stress-related psychiatric disorders. It is recognized that the brain plays a key role in the (patho)physiology of obesity and that there is a bidirectional relationship between obesity and psychopathology, yet molecular mechanisms altered in obesity have not been fully elucidated. Thus, we investigated relationships between obesity and synaptic density in vivo using the radioligand [C]UCB-J (which binds to synaptic glycoprotein SV2A) and positron emission tomography in individuals with obesity, and with or without stress-related psychiatric disorders.

Psychological Resilience to the Challenges of Physical Aging in Older U.S. Veterans: Results From the 2019-2020 National Health and Resilience in Veterans Study.

Objectives: To employ a novel analytic approach to quantify psychological resilience to physical health difficulties and identify factors associated with greater resilience in older U.S. veterans.

Polygenic risk for traumatic loss-related PTSD in US military veterans: Protective effect of secure attachment style.

Objectives: To examine whether attachment style moderates the relationship between polygenic risk scores (PRS) for posttraumatic stress disorder (PTSD) re-experiencing (PTSD) symptoms and the severity of and positive screen for traumatic loss-related PTSD.

Methods: Data were analysed from 631 US veterans who endorsed 'unexpected death of a loved one' as their 'worst' traumatic event. Multivariable models evaluated the association between PRS for PTSD attachment style, and their interaction in predicting severity and positive screen for PTSD.

Risk and resilience factors associated with traumatic loss-related PTSD in U.S. military veterans: Results from the National Health and Resilience in Veterans Study.

Purpose: Sudden death of a loved one is the most prevalent potentially traumatic event worldwide, yet little is known about risk and resilience factors associated with traumatic loss-related posttraumatic stress disorder (PTSD).

Methods: Data from a nationally representative sample of U.S.

Omega-3 fatty acid deficiency impairs frontostriatal recruitment following repeated amphetamine treatment in rats: A 7 Tesla phMRI study.

Although attention deficit hyperactivity disorder is associated with deficits in docosahexaenoic acid (DHA), an omega-3 fatty acid implicated in dopamine and glutamate synaptic plasticity, its role in neuroplastic brain changes that occur following repeated amphetamine (AMPH) treatment are not known. This study used pharmacological magnetic resonance imaging to investigate the impact of repeated AMPH exposure and alterations in brain DHA levels on AMPH-induced brain activation patterns. Male rats were fed a diet with no -3 fatty acids (Deficient, DEF,  = 20), a diet fortified with preformed DHA (fish oil, FO,  = 20), or a control diet fortified with alpha-linolenic acid ( = 20) from P21 to P90.

Deficits in Docosahexaenoic Acid Accrual during Adolescence Reduce Rat Forebrain White Matter Microstructural Integrity: An in vivo Diffusion Tensor Imaging Study.

Neuropsychiatric disorders that frequently initially emerge during adolescence are associated with deficits in the omega-3 (n-3) fatty acid docosahexaenoic acid (DHA), elevated proinflammatory signaling, and regional reductions in white matter integrity (WMI). This study determined the effects of altering brain DHA accrual during adolescence on WMI in the rat brain by diffusion tensor imaging (DTI), and investigated the potential mediating role of proinflammatory signaling. During periadolescent development, male rats were fed a diet deficient in n-3 fatty acids (DEF, n = 20), a fish oil-fortified diet containing preformed DHA (FO, n = 20), or a control diet (CON, n = 20).

Glutamate homeostasis in the adult rat prefrontal cortex is altered by cortical docosahexaenoic acid accrual during adolescence: An in vivoH MRS study.

Major psychiatric disorders are associated with dysregulated glutamate homeostasis and deficits in the omega-3 fatty acid docosahexaenoic acid (DHA). This study determined the effects of dietary-induced alterations in brain DHA accrual on cortical glutamate homeostasis in the adult rat brain. Adolescent rats were fed a control diet (n = 20), a n-3 fatty acid-deficient diet (DEF, n = 20), or a fish oil-fortified diet containing preformed DHA (FO, n = 20).

Role of polyunsaturated fatty acids in human brain structure and function across the lifespan: An update on neuroimaging findings.

There is a substantial body of evidence from animal studies implicating polyunsaturated fatty acids (PUFA) in neuroinflammatory, neurotrophic, and neuroprotective processes in brain. However, direct evidence for a role of PUFA in human brain structure and function has been lacking. Over the last decade there has been a notable increase in neuroimaging studies that have investigated the impact of PUFA intake and/or blood levels (i.