Christopher Coello

Thermal imaging is a non-invasive alternative to PET-CT for measurement of brown adipose tissue activity in humans

Obesity and its metabolic consequences are a major cause of morbidity and mortality. Brown adipose tissue (BAT) utilizes glucose and free fatty acids to produce heat, thereby increasing energy expenditure. Effective evaluation of human BAT stimulators is constrained by the current standard method of assessing BAT—PET/CT—as it requires exposure to high doses of ionizing radiation. Infrared thermography (IRT) is a potential noninvasive, safe alternative, although direct corroboration with PET/CT has not been established. Methods: IRT and 18F-FDG PET/CT data from 8 healthy men subjected to water-jacket cooling were directly compared. Thermal images were geometrically transformed to overlay PET/CT-derived maximum intensity projection (MIP) images from each subject, and the areas with the most intense temperature and glucose uptake within the supraclavicular regions were compared. Relationships between supraclavicular temperatures (TSCR) from IRT and the metabolic rate of glucose uptake (MR(gluc)) from PET/CT were determined. Results: Glucose uptake on MR(gluc)MIP was found to correlate positively with a change in TSCR relative to a reference region (r2 = 0.721; P = 0.008). Spatial overlap between areas of maximal MR(gluc)MIP and maximal TSCR was 29.5% ± 5.1%. Prolonged cooling, for 60 min, was associated with a further TSCR rise, compared with cooling for 10 min. Conclusion: The supraclavicular hotspot identified on IRT closely corresponded to the area of maximal uptake on PET/CT-derived MR(gluc)MIP images. Greater increases in relative TSCR were associated with raised glucose uptake. IRT should now be considered a suitable method for measuring BAT activation, especially in populations for whom PET/CT is not feasible, practical, or repeatable.

Loss of extra-striatal phosphodiesterase 10A expression in early premanifest Huntington's disease gene carriers

Huntingtons disease (HD) is a monogenic neurodegenerative disorder with an underlying pathology involving the toxic effect of mutant huntingtin protein primarily in striatal and cortical neurons. Phosphodiesterase 10A (PDE10A) regulates intracellular signalling cascades, thus having a key role in promoting neuronal survival. Using positron emission tomography (PET) with [(11)C]IMA107, we investigated the in vivo extra-striatal expression of PDE10A in 12 early premanifest HD gene carriers. Image processing and kinetic modelling was performed using MIAKAT™. Parametric images of [(11)C]IMA107 non-displaceable binding potential (BPND) were generated from the dynamic [(11)C]IMA107 scans using the simplified reference tissue model with the cerebellum as the reference tissue for nonspecific binding. We set a threshold criterion for meaningful quantification of [(11)C]IMA107 BPND at 0.30 in healthy control data; regions meeting this criterion were designated as regions of interest (ROIs). MRI-based volumetric analysis showed no atrophy in ROIs. We found significant differences in mean ROIs [(11)C]IMA107 BPND between HD gene carriers and healthy controls. HD gene carriers had significant loss of PDE10A within the insular cortex and occipital fusiform gyrus compared to healthy controls. Insula and occipital fusiform gyrus are important brain areas for the regulation of cognitive and limbic function that is impaired in HD. Our findings suggest that dysregulation of PDE10A-mediated intracellular signalling could be an early phenomenon in the course of HD with relevance also for extra-striatal brain areas.

Quantification of lung PET images: challenges and opportunities.

Millions of people are affected by respiratory diseases, leading to a significant health burden globally. Because of the current insufficient knowledge of the underlying mechanisms that lead to the development and progression of respiratory diseases, treatment options remain limited. To overcome this limitation and understand the associated molecular changes, noninvasive imaging techniques such as PET and SPECT have been explored for biomarker development, with 18F-FDG PET imaging being the most studied. The quantification of pulmonary molecular imaging data remains challenging because of variations in tissue, air, blood, and water fractions within the lungs. The proportions of these components further differ depending on the lung disease. Therefore, different quantification approaches have been proposed to address these variabilities. However, no standardized approach has been developed to date. This article reviews the data evaluating 18F-FDG PET quantification approaches in lung diseases, focusing on methods to account for variations in lung components and the interpretation of the derived parameters. The diseases reviewed include acute respiratory distress syndrome, chronic obstructive pulmonary disease, and interstitial lung diseases such as idiopathic pulmonary fibrosis. Based on review of prior literature, ongoing research, and discussions among the authors, suggested considerations are presented to assist with the interpretation of the derived parameters from these approaches and the design of future studies.

Loss of phosphodiesterase 4 in Parkinson disease Relevance to cognitive deficits

Objective: To assess in vivo the expression of phosphodiesterase 4 (PDE4) and its relevance to cognitive symptoms in patients with Parkinson disease (PD) using [11C]rolipram PET. Methods: We studied 12 levodopa-treated patients with PD with no concurrent diagnosis of mild cognitive impairment or dementia. Their data were compared with those from 12 healthy controls. All participants underwent neuropsychiatric and cognitive assessment using the Cambridge Neuropsychological Test Automated Battery. Parametric images of [11C]rolipram volume of distribution (VT) values were determined with the Logan plot. Results: Patients with PD performed worse than healthy controls in cognitive examinations assessing psychomotor speed, episodic memory, and spatial working memory and executive function. Patients with PD showed reductions in [11C]rolipram VT compared to healthy controls, in the caudate (28%), thalamus (23%), hypothalamus (32%), and cortex (16%). Within thalamic subregions, [11C]rolipram VT values in patients with PD were decreased by 12%–32%, with most marked decreases observed in prefrontal and temporal thalamic nuclei, whereas motor nuclei were less affected. Within the cortex, [11C]rolipram VT values in patients with PD were decreased by 11%–20%, with most marked decreases observed in posterior dorsolateral frontal cortex, medial frontal cortex, and supplementary motor area, whereas orbitofrontal cortex was less affected. Worse performance in spatial working memory correlated with lower [11C]rolipram VT values in posterior dorsolateral frontal cortex, medial frontal cortex, supplementary motor area, precentral gyrus, caudate, and prefrontal thalamic nuclei. Conclusions: Our findings demonstrate loss of PDE4 expression in the striato-thalamo-cortical circuit, which is associated with deficits of spatial working memory in patients with PD.

Single cocaine exposure does not alter striatal pre‐synaptic dopamine function in mice: an [18F]‐FDOPA PET study

Cocaine is a recreational drug of abuse that binds to the dopamine transporter, preventing reuptake of dopamine into pre‐synaptic terminals. The increased presence of synaptic dopamine results in stimulation of both pre‐ and post‐synaptic dopamine receptors, considered an important mechanism by which cocaine elicits its reinforcing properties. However, the effects of acute cocaine administration on pre‐synaptic dopamine function remain unclear. Non‐invasive imaging techniques such as positron emission tomography have revealed impaired pre‐synaptic dopamine function in chronic cocaine users. Similar impairments have been seen in animal studies, with microdialysis experiments indicating decreased basal dopamine release. Here we use micro positron emission tomography imaging techniques in mice to measure dopamine synthesis capacity and determine the effect of acute cocaine administration of pre‐synaptic dopamine function. We show that a dose of 20 mg/kg cocaine is sufficient to elicit hyperlocomotor activity, peaking 15–20 min post treatment (p < 0.001). However, dopamine synthesis capacity in the striatum was not significantly altered by acute cocaine treatment ( KiCer : 0.0097 per min vs. 0.0112 per min in vehicle controls, p > 0.05). Furthermore, expression levels of two key enzymes related to dopamine synthesis, tyrosine hydroxylase and aromatic l‐amino acid decarboxylase, within the striatum of scanned mice were not significantly affected by acute cocaine pre‐treatment (p > 0.05). Our findings suggest that while the regulation of dopamine synthesis and release in the striatum have been shown to change with chronic cocaine use, leading to a reduced basal tone, these adaptations to pre‐synaptic dopaminergic neurons are not initiated following a single exposure to the drug.

The role of dopamine in processing the meaningful information of observations, and implications for the aberrant salience hypothesis of schizophrenia

Abstract Background The aberrant salience hypothesis of schizophrenia proposes that symptoms such as paranoia arise when behavioural salience is attributed to neutral stimuli. Mesolimbic dopamine dysfunction is thought to be central to this mechanism; building on findings that activity in this pathway conveys a (signed) reward prediction error signal. Given that many psychotic symptoms are not explicitly related to reward learning, it is relevant that recent studies in rodents have demonstrated a role for midbrain dopamine neurons in value-neutral associative learning. Direct evidence for this role in humans, however, is lacking. In this study we asked whether the mesolimbic dopamine circuit is involved in encoding the value-neutral meaningful information of observations, using a model-based functional magnetic resonance imaging (fMRI) task and dopamine positron emission tomography (PET). We define ‘meaningful information’ as the degree to which an observation results in a belief-update to an agent’s internal model of the environment (Kullback-Leibler divergence from prior to posterior beliefs; ‘Bayesian surprise’). Methods Participants were tasked to infer the current (hidden) state of the environment, using partially-informative observations at each trial, and then report their belief at the end of each trial. Participant beliefs were modelled using a Hidden Markov Model of the task and iterative application of Bayes’ rule, allowing us to quantify the Bayesian surprise (meaningful information content) associated with a trial observation. Crucially, our task de-correlated Bayesian surprise from both the pure sensory unexpectedness of an observation (unexpected but meaningless information) and its signed reward prediction error. 39 healthy participants (22M, mean age 26y) performed 180 task trials within an fMRI scanner. 36 participants also had a [11C]-(+)-4-propyl-9-hydroxy-naphthoxazine (PHNO) PET scan to quantify dopamine-2/3 receptor (D2/3R) availability. 17 participants additionally had a second PET scan 3hrs post 0.5mg/kg oral dexamphetamine, to quantify striatal dopamine release capacity. Neuroimaging analyses were restricted to the bilateral substantia nigra/ventral tegmental area (SN/VTA) and ventral striatum (VS). Results Our computational model closely predicted participant behaviour (R2= .67), and there was a negative correlation between subclinical paranoia and the degree to which participant behaviour approximated normative Bayesian performance (rho = -.60, P<0.001). Neuronal activation encoding the meaningful information content of an observation (Bayesian surprise) was present in SN/VTA and VS (both P(peak)<0.05, SVC), whereas no such encoding was present for sensory unexpectedness or reward-prediction error. Crucially, activation encoding Bayesian surprise was inversely correlated with D2/3R availability in the SN/VTA (rho = -.43, P=0.009), consistent with a tonic inhibitory role for midbrain D2/3Rs. Moreover, activation encoding Bayesian surprise was inversely related to dopamine release capacity in the VS (rho = -.66, P=0.005), indicating that subjects with high dopamine release capacity showed blunted striatal activation in response to belief-changing information, as is also found in schizophrenia. Discussion We provide direct evidence in humans that a mesolimbic dopamine circuit is involved in encoding the meaningful information content of observations, distinct from its involvement in processing signed reward prediction error. These results implicate dopamine in a wider range of function than reward learning, including updating a predictive associative model of the world, and are therefore relevant for the aberrant salience hypothesis of schizophrenia.

Dopaminergic basis for signaling belief updates, but not surprise, and the link to paranoia

Significance To survive in changing environments animals must use sensory information to form accurate representations of the world. Surprising sensory information might signal that our current beliefs about the world are inaccurate, motivating a belief update. Here, we investigate the neuroanatomical and neurochemical mechanisms underlying the brain’s ability to update beliefs following informative sensory cues. Using multimodal brain imaging in healthy human participants, we demonstrate that dopamine is strongly related to neural signals encoding belief updates, and that belief updating itself is closely related to the expression of individual differences in paranoid ideation. Our results shed new light on the role of dopamine in making inferences and are relevant for understanding psychotic disorders such as schizophrenia, where dopamine function is disrupted. Distinguishing between meaningful and meaningless sensory information is fundamental to forming accurate representations of the world. Dopamine is thought to play a central role in processing the meaningful information content of observations, which motivates an agent to update their beliefs about the environment. However, direct evidence for dopamine’s role in human belief updating is lacking. We addressed this question in healthy volunteers who performed a model-based fMRI task designed to separate the neural processing of meaningful and meaningless sensory information. We modeled participant behavior using a normative Bayesian observer model and used the magnitude of the model-derived belief update following an observation to quantify its meaningful information content. We also acquired PET imaging measures of dopamine function in the same subjects. We show that the magnitude of belief updates about task structure (meaningful information), but not pure sensory surprise (meaningless information), are encoded in midbrain and ventral striatum activity. Using PET we show that the neural encoding of meaningful information is negatively related to dopamine-2/3 receptor availability in the midbrain and dexamphetamine-induced dopamine release capacity in the striatum. Trial-by-trial analysis of task performance indicated that subclinical paranoid ideation is negatively related to behavioral sensitivity to observations carrying meaningful information about the task structure. The findings provide direct evidence implicating dopamine in model-based belief updating in humans and have implications for understating the pathophysiology of psychotic disorders where dopamine function is disrupted.