Although substantial evidence has established that microglia and astrocytes play a key role in the establishment and maintenance of persistent pain in animal models, the role of glial cells in human ...pain disorders remains unknown. Here, using the novel technology of integrated positron emission tomography-magnetic resonance imaging and the recently developed radioligand (11)C-PBR28, we show increased brain levels of the translocator protein (TSPO), a marker of glial activation, in patients with chronic low back pain. As the Ala147Thr polymorphism in the TSPO gene affects binding affinity for (11)C-PBR28, nine patient-control pairs were identified from a larger sample of subjects screened and genotyped, and compared in a matched-pairs design, in which each patient was matched to a TSPO polymorphism-, age- and sex-matched control subject (seven Ala/Ala and two Ala/Thr, five males and four females in each group; median age difference: 1 year; age range: 29-63 for patients and 28-65 for controls). Standardized uptake values normalized to whole brain were significantly higher in patients than controls in multiple brain regions, including thalamus and the putative somatosensory representations of the lumbar spine and leg. The thalamic levels of TSPO were negatively correlated with clinical pain and circulating levels of the proinflammatory citokine interleukin-6, suggesting that TSPO expression exerts pain-protective/anti-inflammatory effects in humans, as predicted by animal studies. Given the putative role of activated glia in the establishment and or maintenance of persistent pain, the present findings offer clinical implications that may serve to guide future studies of the pathophysiology and management of a variety of persistent pain conditions.
We recently showed that constraining eye contact leads to exaggerated increase of amygdala activation in autism. Here, in a proof of concept pilot study, we demonstrate that administration of ...bumetanide (a NKCC1 chloride importer antagonist that restores GABAergic inhibition) normalizes the level of amygdala activation during constrained eye contact with dynamic emotional face stimuli in autism. In addition, eye-tracking data reveal that bumetanide administration increases the time spent in spontaneous eye gaze during in a free-viewing mode of the same face stimuli. In keeping with clinical trials, our data support the Excitatory/Inhibitory dysfunction hypothesis in autism, and indicate that bumetanide may improve specific aspects of social processing in autism. Future double-blind placebo controlled studies with larger cohorts of participants will help clarify the mechanisms of bumetanide action in autism.
The etiology of autism spectrum disorder (ASD) remains unknown, but gene-environment interactions, mediated through epigenetic mechanisms, are thought to be a key contributing factor. Prenatal ...environmental factors have been shown to be associated with both increased risk of ASD and altered histone deacetylases (HDACs) or acetylation levels. The relationship between epigenetic changes and gene expression in ASD suggests that alterations in histone acetylation, which lead to changes in gene transcription, may play a key role in ASD. Alterations in the acetylome have been demonstrated for several genes in ASD, including genes involved in synaptic function, neuronal excitability, and immune responses, which are mechanisms previously implicated in ASD. We review preclinical and clinical studies that investigated HDACs and autism-associated behaviors and discuss risk genes for ASD that code for proteins associated with HDACs. HDACs are also implicated in neurodevelopmental disorders with a known genetic etiology, such as 15q11-q13 duplication and Phelan-McDermid syndrome, which share clinical features and diagnostic comorbidities (e.g., epilepsy, anxiety, and intellectual disability) with ASD. Furthermore, we highlight factors that affect the behavioral phenotype of acetylome changes, including sensitive developmental periods and brain region specificity in the context of epigenetic programming.
Atypical face processing plays a key role in social interaction difficulties encountered by individuals with autism. In the current fMRI study, the Thatcher illusion was used to investigate several ...aspects of face processing in 20 young adults with high-functioning autism spectrum disorder (ASD) and 20 matched neurotypical controls. "Thatcherized" stimuli were modified at either the eyes or the mouth and participants discriminated between pairs of faces while cued to attend to either of these features in upright and inverted orientation. Behavioral data confirmed sensitivity to the illusion and intact configural processing in ASD. Directing attention towards the eyes vs. the mouth in upright faces in ASD led to (1) improved discrimination accuracy; (2) increased activation in areas involved in social and emotional processing; (3) increased activation in subcortical face-processing areas. Our findings show that when explicitly cued to attend to the eyes, activation of cortical areas involved in face processing, including its social and emotional aspects, can be enhanced in autism. This suggests that impairments in face processing in autism may be caused by a deficit in social attention, and that giving specific cues to attend to the eye-region when performing behavioral therapies aimed at improving social skills may result in a better outcome.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Individuals with Autism Spectrum Disorder (ASD) seem to have difficulties looking others in the eyes, but the substrate for this behavior is not well understood. The subcortical pathway, which ...consists of superior colliculus, pulvinar nucleus of the thalamus, and amygdala, enables rapid and automatic face processing. A specific component of this pathway - i.e., the amygdala - has been shown to be abnormally activated in paradigms where individuals had to specifically attend to the eye-region; however, a direct examination of the effect of manipulating the gaze to the eye-regions on all the components of the subcortical system altogether has never been performed. The subcortical system is particularly important as it shapes the functional specialization of the face-processing cortex during development. Using functional MRI, we investigated the effect of constraining gaze in the eye-region during dynamic emotional face perception in groups of participants with ASD and typical controls. We computed differences in activation in the subcortical face processing system (superior colliculus, pulvinar nucleus of the thalamus and amygdala) for the same stimuli seen freely or with the gaze constrained in the eye-region. Our results show that when constrained to look in the eyes, individuals with ASD show abnormally high activation in the subcortical system, which may be at the basis of their eye avoidance in daily life.
Objective
To characterize 11C‐PBR28 brain uptake using positron emission tomography (PET) in people with amyotrophic lateral sclerosis (ALS) and primary lateral sclerosis (PLS). We have previously ...shown increased 11C‐PBR28 uptake in the precentral gyrus in a small group of ALS patients. Herein, we confirm our initial finding, study the longitudinal changes, and characterize the gray versus white matter distribution of 11C‐PBR28 uptake in a larger cohort of patients with ALS and PLS.
Methods
Eighty‐five participants including 53 with ALS, 11 with PLS, and 21 healthy controls underwent integrated 11C‐PBR28 PET–magnetic resonance brain imaging. Patients were clinically assessed using the Upper Motor Neuron Burden (UMNB) and the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ALSFRS‐R). 11C‐PBR28 uptake was quantified as standardized uptake value ratio (SUVR) and compared between groups. Cortical thickness and fractional anisotropy were compared between groups and correlated with SUVR and the clinical data. 11C‐PBR28 uptake and ALSFRS‐R were compared longitudinally over 6 months in 10 ALS individuals.
Results
Whole brain voxelwise, surface‐based, and region of interest analyses revealed increased 11C‐PBR28 uptake in the precentral and paracentral gyri in ALS, and in the subcortical white matter for the same regions in PLS, compared to controls. The increase in 11C‐PBR28 uptake colocalized and correlated with cortical thinning, reduced fractional anisotropy, and increased mean diffusivity, and correlated with higher UMNB score. No significant changes were detected in 11C‐PBR28 uptake over 6 months despite clinical progression.
Interpretation
Glial activation measured by in vivo 11C‐PBR28 PET is increased in pathologically relevant regions in people with ALS and correlates with clinical measures. Ann Neurol 2018;83:1186–1197
Non-invasive positron emission tomography (PET) and single-photon emission computed tomography (SPECT) are techniques used to quantify molecular interactions, biological processes and protein ...concentration and distribution. In the central nervous system, these molecular imaging techniques can provide critical insights into neurotransmitter receptors and their occupancy by neurotransmitters or drugs. In recent years, there has been an increase in the number of studies that have investigated neurotransmitters in autism spectrum disorder (ASD), while earlier studies mostly focused on cerebral blood flow and glucose metabolism. The underlying and contributing mechanisms of ASD are largely undetermined and ASD diagnosis relies on the behavioral phenotype. Discovery of biochemical endophenotypes would represent a milestone in autism research that could potentially lead to ASD subtype stratification and the development of novel therapeutic drugs. This review characterizes the prior use of molecular imaging by PET and SPECT in ASD, addresses methodological challenges and highlights areas of future opportunity for contributions from molecular imaging to understand ASD pathophysiology.
Glucose is the principal source of energy for the brain and yet the dynamic response of glucose utilization to changes in brain activity is still not fully understood. Positron emission tomography ...(PET) allows quantitative measurement of glucose metabolism using 2-18F-fluorodeoxyglucose (FDG). However, FDG PET in its current form provides an integral (or average) of glucose consumption over tens of minutes and lacks the temporal information to capture physiological alterations associated with changes in brain activity induced by tasks or drug challenges. Traditionally, changes in glucose utilization are inferred by comparing two separate scans, which significantly limits the utility of the method. We report a novel method to track changes in FDG metabolism dynamically, with higher temporal resolution than exists to date and within a single session. Using a constant infusion of FDG, we demonstrate that our technique (termed fPET-FDG) can be used in an analysis pipeline similar to fMRI to define within-session differential metabolic responses. We use visual stimulation to demonstrate the feasibility of this method. This new method has a great potential to be used in research protocols and clinical settings since fPET-FDG imaging can be performed with most PET scanners and data acquisition and analysis are straightforward. fPET-FDG is a highly complementary technique to MRI and provides a rich new way to observe functional changes in brain metabolism.
•fPET-FDG is a method to dynamically measure FDG metabolism.•The new PET method uses constant infusion FDG.•Feasibility of the technique, termed fPET-FDG, was demonstrated with visual stimuli.•fPET-FDG can be used in an analysis pipeline similar to fMRI.•fPET-FDG can be performed with most PET scanners and is ideal for MR–PET.
OBJECTIVETo determine if migraine with aura is associated with neuroinflammation, which has been suggested by preclinical models of cortical spreading depression (CSD) as well as imaging of human ...pain conditions.
METHODSThirteen migraineurs with aura and 16 healthy controls received integrated PET/MRI brain scans with CPBR28, a radioligand that binds to the 18 kDa translocator protein, a marker of glial activation. Standardized uptake value ratio (SUVR) was compared between groups, and regressed against clinical variables, using region of interest and whole-brain voxelwise analyses.
RESULTSCompared to healthy controls, migraineurs demonstrated SUVR elevations in nociceptive processing areas (e.g., thalamus and primary/secondary somatosensory and insular cortices) as well as in areas previously shown to be involved in CSD generation (visual cortex). SUVR levels in frontoinsular cortex, primary/secondary somatosensory cortices, and basal ganglia were correlated with frequency of migraine attacks.
CONCLUSIONSThese findings demonstrate that migraine with aura is associated with neuroimmune activation/neuroinflammation, and support a possible link between CSD and glial activation, previously observed in animals.
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