PET Imaging of Fructose Metabolism in a Rodent Model of Neuroinflammation with 6-[18F]fluoro-6-deoxy-D-fructose.

Fluorine-18 labeled 6-fluoro-6-deoxy-D-fructose (6-[18F]FDF) targets the fructose-preferred facilitative hexose transporter GLUT5, which is expressed predominantly in brain microglia and activated in response to inflammatory stimuli. We hypothesize that 6-[18F]FDF will specifically image microglia following neuroinflammatory insult. 6-[18F]FDF and, for comparison, [18F]FDG were evaluated in unilateral intra-striatal lipopolysaccharide (LPS)-injected male and female rats (50 µg/animal) by longitudinal dynamic PET imaging in vivo. In LPS-injected rats, increased accumulation of 6-[18F]FDF was observed at 48 h post-LPS injection, with plateaued uptake (60-120 min) that was significantly higher in the ipsilateral vs. contralateral striatum (0.985 ± 0.047 and 0.819 ± 0.033 SUV, respectively; p = 0.002, n = 4M/3F). The ipsilateral-contralateral difference in striatal 6-[18F]FDF uptake expressed as binding potential (BPSRTM) peaked at 48 h (0.19 ± 0.11) and was significantly decreased at one and two weeks. In contrast, increased [18F]FDG uptake in the ipsilateral striatum was highest at one week post-LPS injection (BPSRTM = 0.25 ± 0.06, n = 4M). Iba-1 and GFAP immunohistochemistry confirmed LPS-induced activation of microglia and astrocytes, respectively, in ipsilateral striatum. This proof-of-concept study revealed an early response of 6-[18F]FDF to neuroinflammatory stimuli in rat brain. 6-[18F]FDF represents a potential PET radiotracer for imaging microglial GLUT5 density in brain with applications in neuroinflammatory and neurodegenerative diseases.

Relationship of neurite architecture to brain activity during task-based fMRI.

Functional MRI (fMRI) has been widely used to examine changes in neuronal activity during cognitive tasks. Commonly used measures of gray matter macrostructure (e.g., cortical thickness, surface area, volume) do not consistently appear to serve as structural correlates of brain function. In contrast, gray matter microstructure, measured using neurite orientation dispersion and density imaging (NODDI), enables the estimation of indices of neurite density (neurite density index; NDI) and organization (orientation dispersion index; ODI) in gray matter. Our study explored the relationship among neurite architecture, BOLD (blood-oxygen-level-dependent) fMRI, and cognition, using a large sample (n = 750) of young adults of the human connectome project (HCP) and two tasks that index more cortical (working memory) and more subcortical (emotion processing) targeting of brain functions. Using NODDI, fMRI, structural MRI and task performance data, hierarchical regression analyses revealed that higher working memory- and emotion processing-evoked BOLD activity was related to lower ODI in the right DLPFC, and lower ODI and NDI values in the right and left amygdala, respectively. Common measures of brain macrostructure (i.e., DLPFC thickness/surface area and amygdala volume) did not explain any additional variance (beyond neurite architecture) in BOLD activity. A moderating effect of neurite architecture on the relationship between emotion processing task-evoked BOLD response and performance was observed. Our findings provide evidence that neuro-/social-affective cognition-related BOLD activity is partially driven by the local neurite organization and density with direct impact on emotion processing. In vivo gray matter microstructure represents a new target of investigation providing strong potential for clinical translation.

Greater individual variability in functional brain activity during working memory performance in Schizophrenia Spectrum Disorders (SSD).

Heterogeneity has been a persistent challenge in understanding Schizophrenia Spectrum Disorders (SSD). Traditional case-control comparisons often show variable results, and may not map well onto individuals. To better understand heterogeneity and group differences in SSD compared to typically developing controls (TDC), we examined variability in functional brain activity during a working memory (WM) task with known deficits in SSD. Neuroimaging and behavioural data were extracted from two datasets collectively providing 34 TDC and 56 individuals with SSD (n = 90). Functional activity in response to an N-Back WM task (3-Back vs 1-Back) was examined between and within groups. Individual variability was calculated via the correlational distance of fMRI activity maps between participants; mean correlational distance from one participant to all others was defined as a 'variability score'. Greater individual variability in functional activity was found in SSD compared to TDC (p = 0.00090). At the group level, a case-control comparison suggested SSD had reduced activity in task positive and task negative networks. However, when SSD were divided into high and low variability subgroups, the low variability groups showed no differences relative to TDC while the high variability group showed little activity at the group level. Our results imply prior case-control differences may be driven by a subgroup of SSD who do not show specific impairments but instead show more 'idiosyncratic' activity patterns. In SSD but not TDC, variability was also related to cognitive performance and age. This novel approach focusing on individual variability has important implications for understanding the neurobiology of SSD.

Preclinical Evaluation of TSPO and MAO-B PET Radiotracers in an LPS Model of Neuroinflammation.

Discovery of novel PET radiotracers targeting neuroinflammation (microglia and astrocytes) is actively pursued. Employing a lipopolysaccharide (LPS) rat model, this longitudinal study evaluated the translocator protein 18-kDa radiotracer [18F]FEPPA (primarily microglia) and monoamine oxidase B radiotracers [11C]L-deprenyl and [11C]SL25.1188 (astrocytes preferred). Increased [18F]FEPPA binding peaked at 1 week in LPS-injected striatum whereas increased lazabemide-sensitive [11C]L-deprenyl binding developed later. No increase in radiotracer uptake was observed for [11C]SL25.1188. The unilateral intrastriatal LPS rat model may serve as a useful tool for benchmarking PET tracers targeted toward distinct phases of neuroinflammatory reactions involving both microglia and astrocytes.

Effects of Repetitive Transcranial Magnetic Stimulation on Working Memory Performance and Brain Structure in People With Schizophrenia Spectrum Disorders: A Double-Blind, Randomized, Sham-Controlled Trial.

BACKGROUND: There are currently no approved treatments for working memory deficits in schizophrenia spectrum disorders (SSDs). The objective of the present study was to assess whether repetitive transcranial magnetic stimulation (rTMS) to the bilateral dorsolateral prefrontal cortex (DLPFC) in people with SSDs 1) improves working memory deficits and 2) changes brain structure. METHODS: We conducted a double-blind, parallel, randomized, sham-controlled study at the Centre for Addiction and Mental Health in Toronto, Canada. We randomized 83 participants with SSDs to receive either active 20 Hz rTMS applied to the bilateral DLPFC or sham rTMS for 4 weeks. The participants also completed pre/posttreatment magnetic resonance imaging. Clinical and cognitive assessments were performed at baseline, treatment end, and 1 month later. The primary outcome was change in verbal n-back working memory performance accuracy (d-prime). The secondary outcome measures were change in DLPFC thickness and fractional anisotropy of white matter tracts connecting to the DLPFC. Prespecified exploratory outcome measures were changes in general cognition; positive, negative, and depressive symptoms. RESULTS: Compared with sham treatment, active rTMS did not lead to significant change in working memory performance; it was associated with an increase in right DLPFC thickness but not fractional anisotropy. Prespecified exploratory analysis showed a significant decrease in depressive symptoms in the active group; the decrease in depressive symptoms was correlated with an increase in right DLPFC thickness. CONCLUSIONS: Although rTMS applied to the bilateral DLPFC was not efficacious in treating working memory deficits in SSDs, it did increase right DLPFC thickness and decrease depressive symptoms. These findings deserve further study given the lack of efficacy of antidepressant medications in SSDs.

In Vivo Imaging of Gray Matter Microstructure in Major Psychiatric Disorders: Opportunities for Clinical Translation.

Postmortem studies reveal that individuals with major neuropsychiatric disorders such as schizophrenia and autism spectrum disorder have gray matter microstructural abnormalities. These include abnormalities in neuropil organization, expression of proteins supporting neuritic and synaptic integrity, and myelination. Genetic and postmortem studies suggest that these changes may be causally linked to the pathogenesis of these disorders. Advances in diffusion-weighted magnetic resonance image (dMRI) acquisition techniques and biophysical modeling allow for the quantification of gray matter microstructure in vivo. While several biophysical models for imaging microstructural properties are available, one in particular, neurite orientation dispersion and density imaging (NODDI), holds great promise for clinical applications. NODDI can be applied to both gray and white matter and requires only a single extra shell beyond a standard dMRI acquisition. Since its development only a few years ago, the NODDI algorithm has been used to characterize gray matter microstructure in schizophrenia, Alzheimer's disease, healthy aging, and development. These investigations have shown that microstructural findings in vivo, using NODDI, align with postmortem findings. Not only do NODDI and other advanced dMRI-based modeling methods provide a window into the brain previously only available postmortem, but they may be more sensitive to certain brain changes than conventional magnetic resonance imaging approaches. This opens up exciting new possibilities for clinicians to more rapidly detect disease signatures and allows earlier intervention in the course of the disease. Given that neurites and gray matter microstructure have the capacity to rapidly remodel, these novel dMRI-based methods represent an opportunity to noninvasively monitor neuroplastic changes posttherapy within much shorter time scales.

Stress-induced cortical dopamine response is altered in subjects at clinical high risk for psychosis using cannabis.

Stress and cannabis use are risk factors for the development of psychosis. We have previously shown that subjects at clinical high risk for psychosis (CHR) exhibit a higher striatal dopamine response to stress compared with healthy volunteers (HV), with chronic cannabis use blunting this response. However, it is unknown if this abnormal dopamine response extends to the prefrontal cortex (PFC). Here, we investigated dorsolateral PFC (dlPFC) and medial PFC (mPFC) dopamine release using [11 C]FLB457 positron emission tomography (PET) and a validated stress task. Thirty-three participants completed two PET scans (14 CHR without cannabis use, eight CHR regular cannabis users [CHR-CUs] and 11 HV) while performing a Sensory Motor Control Task (control scan) and the Montreal Imaging Stress Task (stress scan). Stress-induced dopamine release (ΔBPND ) was defined as percent change in D2/3 receptor binding potential between both scans using a novel correction for injected mass of [11 C]FLB457. ΔBPND was significantly different between groups in mPFC (F(2,30) = 5.40, .010), with CHR-CUs exhibiting lower ΔBPND compared with CHR (.008). Similarly, salivary cortisol response (ΔAUCI ) was significantly lower in CHR-CU compared with CHR (F(2,29) = 5.08, .013; post hoc .018) and positively associated with ΔBPND . Furthermore, CHR-CUs had higher attenuated psychotic symptoms than CHR following the stress task, which were negatively associated with ΔBPND . Length of cannabis use was negatively associated with ΔBPND in mPFC when controlling for current cannabis use. Given the global trend to legalize cannabis, this study is important as it highlights the effects of regular cannabis use on cortical dopamine function in high-risk youth.

Prefrontal cortical dopamine release in clinical high risk for psychosis during a cognitive task: a [11C]FLB457 positron emission tomography study.

Research suggests decreased cortical dopamine is a neural correlate of cognitive deficits in schizophrenia. Evidence of impaired cognitive task-induced cortical dopamine release was demonstrated in patients with psychosis. However, whether cortical dopamine release in response to a cognitive task in clinical high risk for psychosis (CHR) is also impaired, is currently unknown. We aimed to test dopamine release in the dorsolateral prefrontal cortex (DLPFC) and the anterior cingulate cortex (ACC) in antipsychotic-free CHR participants and healthy controls (HC) performing the Wisconsin Card Sorting Task (WCST). Two [11C]FLB457 PET scans were conducted for 13 CHR and 15 HC while performing the WCST and the sensorimotor control task (SMCT), respectively. A magnetic resonance image was acquired for anatomical delineation. Percentage change in binding potential (ΔBPND) in ACC and DLPFC in WCST were compared with the SMCT between CHR and HC. Mixed model analysis revealed no statistically significant differences in the cognitive task induced ΔBPND in any ROIs. There were no main effect of group (F(1, 26) = 0.348; p = 0.560) or ROI (F(1, 26) = 1.080; p = 0.308) and no significant Group x ROI interaction (F(1, 26) = 0.049; p = 0.826). Our findings suggest no statistically significant difference between CHR and HC in cognitive task-induced cortical dopamine release. This is the first in vivo study to illustrate that the cortical hypodopaminergic state observed in schizophrenia may not be present in its putative high-risk state.

Preliminary data indicating a connection between stress-induced prefrontal dopamine release and hippocampal TSPO expression in the psychosis spectrum.

Prolonged stress can cause neuronal loss in the hippocampus resulting in disinhibition of glutamatergic neurons proposed to enhance dopaminergic firing in subcortical regions including striatal areas. Supporting this, imaging studies show increased striatal dopamine release in response to psychosocial stress in healthy individuals with low childhood maternal care, individuals at clinical high risk for psychosis (CHR) and patients with schizophrenia. The prefrontal cortex (PFC) is connected to the hippocampus and a key region to control neurochemical responses to stressful stimuli. We recently reported a disrupted PFC dopamine-stress regulation in schizophrenia, which was intact in CHR. Given the available evidence on the link between psychosocial stress, PFC dopamine release and hippocampal immune activation in psychosis, we explored, for the first time in vivo, whether stress-induced PFC dopamine release is associated with hippocampal TSPO expression (a neuroimmune marker) in the psychosis spectrum. We used an overlapping sample of antipsychotic-naïve subjects with CHR (n = 6) and antipsychotic-free schizophrenia patients (n = 9) from our previously published studies, measuring PFC dopamine release induced by a psychosocial stress task with [11C]FLB457 positron emission tomography (PET) and TSPO expression with [18F]FEPPA PET. We observed that participants on the psychosis spectrum with lower stress-induced dopamine release in PFC had significantly higher TSPO expression in hippocampus (ß = -2.39, SE = 0.96, F(1,11) = 6.17, p = 0.030). Additionally, we report a positive association between stress-induced PFC dopamine release, controlled for hippocampal TSPO expression, and Global Assessment of Functioning. This is the first exploration of the relationship between PFC dopamine release and hippocampal TSPO expression in vivo in humans.

Cortical stress regulation is disrupted in schizophrenia but not in clinical high risk for psychosis.

While alterations in striatal dopamine in psychosis and stress have been well studied, the role of dopamine in prefrontal cortex is poorly understood. To date, no study has investigated the prefrontocortical dopamine response to stress in the psychosis spectrum, even though the dorsolateral and medial prefrontal cortices are key regions in cognitive and emotional regulation, respectively. The present study uses the high-affinity dopamine D2/3 receptor radiotracer 11C-FLB457 and PET together with a validated psychosocial stress challenge to investigate the dorsolateral and medial prefrontocortical dopamine response to stress in schizophrenia and clinical high risk for psychosis. Forty participants completed two 11C-FLB457 PET scans (14 antipsychotic-free schizophrenia, 14 clinical high risk for psychosis and 12 matched healthy volunteers), one while performing a Sensory Motor Control Task (control) and another while performing the Montreal Imaging Stress Task (stress). Binding potential (BPND) was estimated using Simplified Reference Tissue Model with cerebellar cortex as reference region. Dopamine release was defined as per cent change in BPND between control and stress scans (ΔBPND) using a novel correction for injected mass. Salivary cortisol response (ΔAUCI) was assessed throughout the tasks and its relationship with dopamine release examined. 11C-FLB457 binding at control conditions was significantly different between groups in medial [F(2,37) = 7.98, P = 0.0013] and dorsolateral [F(2,37) = 6.97, P = 0.0027] prefrontal cortex with schizophrenia patients having lower BPND than participants at clinical high risk for psychosis and healthy volunteers, but there was no difference in ΔBPND among groups [dorsolateral prefrontal cortex: F(2,37) = 1.07, P = 0.35; medial prefrontal cortex: F(2,37) = 0.54, P = 0.59]. We report a positive relationship between ΔAUCI and 11C-FLB457 ΔBPND in dorsolateral and medial prefrontal cortex in healthy volunteers (r = 0.72, P = 0.026; r = 0.76, P = 0.014, respectively) and in participants at clinical high risk for psychosis (r = 0.76, P = 0.0075; r = 0.72, P = 0.018, respectively), which was absent in schizophrenia (r = 0.46, P = 1.00; r = 0.19, P = 1.00, respectively). Furthermore, exploratory associations between ΔBPND or ΔAUCI and stress or anxiety measures observed in clinical high risk for psychosis were absent in schizophrenia. These findings provide first direct evidence of a disrupted prefrontocortical dopamine-stress regulation in schizophrenia.

Using molecular imaging to understand early schizophrenia-related psychosis neurochemistry: a review of human studies.

Schizophrenia is a chronic psychiatric disorder generally preceded by a so-called prodromal phase, which is characterized by attenuated psychotic symptoms. Advances in clinical research have enabled prospective identification of those individuals who are at clinical high risk (CHR) for psychosis, with the power to predict psychosis onset within the near future. Changes in several brain neurochemical systems and molecular mechanisms are implicated in the pathophysiology of schizophrenia and the psychosis spectrum, including the dopaminergic, γ-aminobutyric acid (GABA)-ergic, glutamatergic, endocannabinoid, and immunologic (i.e. glial activation) system and other promising future directions such as synaptic density, which are possible to quantify in vivo using positron emission tomography (PET). This paper aims to review in vivo PET studies in the mentioned systems in the early course of psychosis (i.e. CHR and first-episode psychosis (FEP)). The results of reviewed studies are promising; however, the current understanding of the underlying pathology of psychosis is still limited. Importantly, promising efforts involve the development of novel PET radiotracers targeting systems with growing interest in schizophrenia, like the nociceptive system and synaptic density.

Novel reinforcement learning paradigm based on response patterning under interval schedules of reinforcement.

There is a need to develop cognitive tasks that address valid neuropsychological constructs implicated in disease mechanisms and can be used in animals and humans to guide novel drug discovery. Present experiments aimed to characterize a novel reinforcement learning task based on a classical operant behavioral phenomenon observed in multiple species - differences in response patterning under variable (VI) vs fixed interval (FI) schedules of reinforcement. Wistar rats were trained to press a lever for food under VI30s and later weekly test sessions were introduced with reinforcement schedule switched to FI30s. During the FI30s test session, post-reinforcement pauses (PRPs) gradually grew towards the end of the session reaching 22-43% of the initial values. Animals could be retrained under VI30s conditions, and FI30s test sessions were repeated over a period of several months without appreciable signs of a practice effect. Administration of the non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist MK-801 ((5S,10R)-(+)-5-Methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate) prior to FI30s sessions prevented adjustment of PRPs associated with the change from VI to FI schedule. This effect was most pronounced at the highest tested dose of MK-801 and appeared to be independent of the effects of this dose on response rates. These results provide initial evidence for the possibility to use different response patterning under VI and FI schedules with equivalent reinforcement density for studying effects of drug treatment on reinforcement learning.