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Movement Disorders : Official Journal... Dec 2019The objective of this study was to examine the effects of aerobic exercise on evoked dopamine release and activity of the ventral striatum using positron emission... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
The objective of this study was to examine the effects of aerobic exercise on evoked dopamine release and activity of the ventral striatum using positron emission tomography and functional magnetic resonance imaging in Parkinson's disease (PD).
METHODS
Thirty-five participants were randomly allocated to a 36-session aerobic exercise or control intervention. Each participant underwent an functional magnetic resonance imaging scan while playing a reward task before and after the intervention to determine the effect of exercise on the activity of the ventral striatum in anticipation of reward. A subset of participants (n = 25) completed [ C] raclopride positron emission tomography scans to determine the effect of aerobic exercise on repetitive transcranial magnetic stimulation-evoked release of endogenous dopamine in the dorsal striatum. All participants completed motor (MDS-UPDRS part III, finger tapping, Timed-up-and-go) and nonmotor assessments (Starkstein Apathy Scale, Beck Depression Inventory, reaction time, Positive and Negative Affect Schedule, Trail Making Test [A and B], and Montreal Cognitive Assessment) before and after the interventions.
RESULTS
The aerobic group exhibited increased activity in the ventral striatum during functional magnetic resonance imaging in anticipation of 75% probability of reward (P = 0.01). The aerobic group also demonstrated increased repetitive transcranial magnetic stimulation-evoked dopamine release in the caudate nucleus (P = 0.04) and increased baseline nondisplaceable binding potential in the posterior putamen of the less affected repetitive transcranial magnetic stimulation-stimulated hemisphere measured by position emission tomography (P = 0.03).
CONCLUSIONS
Aerobic exercise alters the responsivity of the ventral striatum, likely related to changes to the mesolimbic dopaminergic pathway, and increases evoked dopamine release in the caudate nucleus. This suggests that the therapeutic benefits of exercise are in part related to corticostriatal plasticity and enhanced dopamine release. © 2019 International Parkinson and Movement Disorder Society.
Topics: Aged; Aged, 80 and over; Caudate Nucleus; Dopamine; Exercise; Exercise Therapy; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Parkinson Disease; Positron-Emission Tomography; Prospective Studies; Tomography, X-Ray Computed; Transcranial Magnetic Stimulation; Ventral Striatum
PubMed: 31584222
DOI: 10.1002/mds.27865 -
International Review of Neurobiology 2019Even before the success of combined positron emission tomography and computed tomography (PET/CT), the neuroimaging community was conceiving the idea to integrate the... (Review)
Review
Even before the success of combined positron emission tomography and computed tomography (PET/CT), the neuroimaging community was conceiving the idea to integrate the positron emission tomography (PET), with very high molecular quantitative data but low spatial resolution, and magnetic resonance imaging (MRI), with high spatial resolution. Several technical limitations have delayed the use of a hybrid scanner in neuroimaging studies, including the full integration of the PET detector ring within the MRI system, the optimization of data acquisition, and the implementation of reliable methods for PET attenuation, motion correction, and joint image reconstruction. To be valid and useful in clinical and research settings, this instrument should be able to simultaneously acquire PET and MRI, and generate quantitative parametric PET images comparable to PET-CT. While post hoc co-registration of combined PET and MRI data acquired separately became the most reliable technique for the generation of "fused" PET-MRI images, only hybrid PET-MRI approach allows merging these measurements naturally and correlating them in a temporal manner. Furthermore, hybrid PET-MRI represents the most accurate tool to investigate in vivo the interplay between molecular and functional aspects of brain pathophysiology. Hybrid PET-MRI technology is still in the early stages in the movement disorders field, due to the limited availability of scanners with integrated optimized methodological models. This technology is ideally suited to investigate interactions between resting-state functional/arterial spin labeling MRI and [F]FDG PET glucose metabolism in the evaluation of the brain "hubs" particularly vulnerable to neurodegeneration, areas with a high degree of connectivity and associated with an efficient synaptic neurotransmission. In Parkinson's disease, hybrid PET-MRI is also the ideal instrument to deeper explore the relationship between resting-state functional MRI and dopamine release at [C]raclopride PET challenge, in the identification of early drug-naïve Parkinson's disease patients at higher risk of motor complications and in the evaluation of the efficacy of novel neuroprotective treatment able to restore at the same time the altered resting state and the release of dopamine. In this chapter, we discuss the key methodological aspects of hybrid PET-MRI; the evidence in movement disorders of the key resting-state functional and perfusion MRI; [F]FDG PET and [C]raclopride PET challenge studies; the potential advantages of using hybrid PET-MRI to investigate the pathophysiology of movement disorders and neurodegenerative diseases. Future directions of hybrid PET-MRI will be discussed alongside with up-to-date technological innovations on hybrid systems.
Topics: Humans; Magnetic Resonance Imaging; Movement Disorders; Multimodal Imaging; Neuroimaging; Positron-Emission Tomography
PubMed: 30638455
DOI: 10.1016/bs.irn.2018.10.003 -
Molecular Psychiatry Apr 2015Endogenous opioid and non-opioid mechanisms (for example, dopamine (DA), endocannabinoids (eCB)) have been implicated in the formation of placebo analgesic effects, with... (Review)
Review
Endogenous opioid and non-opioid mechanisms (for example, dopamine (DA), endocannabinoids (eCB)) have been implicated in the formation of placebo analgesic effects, with initial reports dating back three decades. Besides the perspective that placebo effects confound randomized clinical trials, the information so far acquired points to neurobiological systems that when activated by positive expectations and maintained through conditioning and reward learning are capable of inducing physiological changes that lead to the experience of analgesia and improvements in emotional state. Molecular neuroimaging techniques with positron emission tomography and the selective μ-opioid and D2/3 radiotracers [(11)C]carfentanil and [(11)C]raclopride have significantly contributed to our understanding of the neurobiological systems involved in the formation of placebo effects. This line of research has described neural and neurotransmitter networks implicated in placebo responses and provided the technical tools to examine inter-individual differences in the function of placebo-responsive mechanisms, and potential surrogates (biomarkers). As a consequence, the formation of biological placebo effects is now being linked to the concept of resiliency mechanisms, partially determined by genetic factors, and uncovered by the cognitive emotional integration of the expectations created by the therapeutic environment and its maintenance through learning mechanisms. Further work needs to extend this research into clinical conditions where the rates of placebo responses are high and its neurobiological mechanisms have been largely unexplored (for example, mood and anxiety disorders, persistent pain syndromes or even Parkinson disease and multiple sclerosis). The delineation of these processes within and across diseases would point to biological targets that have not been contemplated in traditional drug development.
Topics: Analgesics, Opioid; Brain; Humans; Neuroimaging; Neurotransmitter Agents; Personality; Placebo Effect
PubMed: 25510510
DOI: 10.1038/mp.2014.164 -
European Journal of Nuclear Medicine... Jun 2016To review the developments of recent decades and the current status of PET molecular imaging in Huntington's disease (HD). (Review)
Review
PURPOSE
To review the developments of recent decades and the current status of PET molecular imaging in Huntington's disease (HD).
METHODS
A systematic review of PET studies in HD was performed. The MEDLINE, Web of Science, Cochrane and Scopus databases were searched for articles in all languages published up to 19 August 2015 using the major medical subject heading "Huntington Disease" combined with text and key words "Huntington Disease", "Neuroimaging" and "PET". Only peer-reviewed, primary research studies in HD patients and premanifest HD carriers, and studies in which clinical features were described in association with PET neuroimaging results, were included in this review. Reviews, case reports and nonhuman studies were excluded.
RESULTS
A total of 54 PET studies were identified and analysed in this review. Brain metabolism ([(18)F]FDG and [(15)O]H2O), presynaptic ([(18)F]fluorodopa, [(11)C]β-CIT and [(11)C]DTBZ) and postsynaptic ([(11)C]SCH22390, [(11)C]FLB457 and [(11)C]raclopride) dopaminergic function, phosphodiesterases ([(18)F]JNJ42259152, [(18)F]MNI-659 and [(11)C]IMA107), and adenosine ([(18)F]CPFPX), cannabinoid ([(18)F]MK-9470), opioid ([(11)C]diprenorphine) and GABA ([(11)C]flumazenil) receptors were evaluated as potential biomarkers for monitoring disease progression and for assessing the development and efficacy of novel disease-modifying drugs in premanifest HD carriers and HD patients. PET studies evaluating brain restoration and neuroprotection were also identified and described in detail.
CONCLUSION
Brain metabolism, postsynaptic dopaminergic function and phosphodiesterase 10A levels were proven to be powerful in assessing disease progression. However, no single technique may be currently considered an optimal biomarker and an integrative multimodal imaging approach combining different techniques should be developed for monitoring potential neuroprotective and preventive treatment in HD.
Topics: Animals; Brain; Humans; Huntington Disease; Neuroprotective Agents; Positron-Emission Tomography
PubMed: 26899245
DOI: 10.1007/s00259-016-3324-6 -
NeuroImage Feb 2020
Topics: Brain; Carbon Radioisotopes; Humans; Raclopride; Reproducibility of Results
PubMed: 31715255
DOI: 10.1016/j.neuroimage.2019.116346 -
Neurology Sep 2022Cross-sectional studies suggest marked dopamine (DA) decline in aging, but longitudinal evidence is lacking. The aim of this study was to estimate within-person decline...
BACKGROUND AND OBJECTIVES
Cross-sectional studies suggest marked dopamine (DA) decline in aging, but longitudinal evidence is lacking. The aim of this study was to estimate within-person decline rates for DA D2-like receptors (DRD2) in aging and examine factors that may contribute to individual differences in DRD2 decline rates.
METHODS
We investigated 5-year within-person changes in DRD2 availability in a sample of older adults. At both occasions, PET with C-raclopride and MRI were used to measure DRD2 availability in conjunction with structural and vascular brain integrity.
RESULTS
Longitudinal analyses of the sample (baseline: n = 181, ages: 64-68 years, 100 men and 81 women; 5-year follow-up: n = 129, 69 men and 60 women) revealed aging-related striatal and extrastriatal DRD2 decline, along with marked individual differences in rates of change. Notably, the magnitude of striatal DRD2 decline was ∼50% of past cross-sectional estimates, suggesting that the DRD2 decline rate has been overestimated in past cross-sectional studies. Significant DRD2 reductions were also observed in select extrastriatal regions, including hippocampus, orbitofrontal cortex (OFC), and anterior cingulate cortex (ACC). Distinct profiles of correlated DRD2 changes were found across several associative regions (ACC, dorsal striatum, and hippocampus) and in the reward circuit (nucleus accumbens and OFC). DRD2 losses in associative regions were associated with white matter lesion progression, whereas DRD2 losses in limbic regions were related to reduced cortical perfusion.
DISCUSSION
These findings provide the first longitudinal evidence for individual and region-specific differences of DRD2 decline in older age and support the hypothesis that cerebrovascular factors are linked to age-related dopaminergic decline.
Topics: Aged; Aging; Cross-Sectional Studies; Dopamine; Female; Humans; Male; Middle Aged; Positron-Emission Tomography; Raclopride; Receptors, Dopamine D2; Receptors, Dopamine D3
PubMed: 35790424
DOI: 10.1212/WNL.0000000000200891 -
Affinity States of Striatal Dopamine D2 Receptors in Antipsychotic-Free Patients with Schizophrenia.The International Journal of... Nov 2017Dopamine D2 receptors are reported to have high-affinity (D2High) and low-affinity (D2Low) states. Although an increased proportion of D2High has been demonstrated in...
BACKGROUND
Dopamine D2 receptors are reported to have high-affinity (D2High) and low-affinity (D2Low) states. Although an increased proportion of D2High has been demonstrated in animal models of schizophrenia, few clinical studies have investigated this alteration of D2High in schizophrenia in vivo.
METHODS
Eleven patients with schizophrenia, including 10 antipsychotic-naive and 1 antipsychotic-free individuals, and 17 healthy controls were investigated. Psychopathology was assessed by Positive and Negative Syndrome Scale, and a 5-factor model was used. Two radioligands, [11C]raclopride and [11C]MNPA, were employed to quantify total dopamine D2 receptor and D2High, respectively, in the striatum by measuring their binding potentials. Binding potential values of [11C]raclopride and [11C]MNPA and the binding potential ratio of [11C]MNPA to [11C]raclopride in the striatal subregions were statistically compared between the 2 diagnostic groups using multivariate analysis of covariance controlling for age, gender, and smoking. Correlations between binding potential and Positive and Negative Syndrome Scale scores were also examined.
RESULTS
Multivariate analysis of covariance demonstrated a significant effect of diagnosis (schizophrenia and control) on the binding potential ratio (P=.018), although the effects of diagnosis on binding potential values obtained with either [11C]raclopride or [11C]MNPA were nonsignificant. Posthoc test showed that the binding potential ratio was significantly higher in the putamen of patients (P=.017). The Positive and Negative Syndrome Scale "depressed" factor in patients was positively correlated with binding potential values of both ligands in the caudate.
CONCLUSIONS
The present study indicates the possibilities of: (1) a higher proportion of D2High in the putamen despite unaltered amounts of total dopamine D2 receptors; and (2) associations between depressive symptoms and amounts of caudate dopamine D2 receptors in patients with schizophrenia.
Topics: Adult; Antipsychotic Agents; Apomorphine; Brain Mapping; Corpus Striatum; Female; Humans; Male; Positron-Emission Tomography; Raclopride; Radioligand Assay; Radiopharmaceuticals; Receptors, Dopamine D2; Schizophrenia; Statistics as Topic; Young Adult
PubMed: 29016872
DOI: 10.1093/ijnp/pyx063 -
European Psychiatry : the Journal of... Apr 2018We present the first results of the MINDVIEW project. An innovative imaging system for the human brain examination, allowing simultaneous acquisition of PET/MRI images,...
We present the first results of the MINDVIEW project. An innovative imaging system for the human brain examination, allowing simultaneous acquisition of PET/MRI images, has been designed and constructed. It consists of a high sensitivity and high resolution PET scanner integrated in a novel, head-dedicated, radio frequency coil for a 3T MRI scanner. Preliminary measurements from the PET scanner show sensitivity 3 times higher than state-of-the-art PET systems that will allow safe repeated studies on the same patient. The achieved spatial resolution, close to 1 mm, will enable differentiation of relevant brain structures for schizophrenia. A cost-effective and simple method of radiopharmaceutical production from C-carbon monoxide and a mini-clean room has been demonstrated. It has been shown that C-raclopride has higher binding potential in a new VAAT null mutant mouse model of schizophrenia compared to wild type control animals. A significant reduction in TSPO binding has been found in gray matter in a small sample of drug-naïve, first episode psychosis patients, suggesting a reduced number or an altered function of immune cells in brain at early stage schizophrenia.
Topics: Brain; Gray Matter; Humans; Magnetic Resonance Imaging; Multimodal Imaging; Positron-Emission Tomography; Psychotic Disorders; Schizophrenia
PubMed: 29398564
DOI: 10.1016/j.eurpsy.2018.01.002 -
Behavioural Pharmacology Apr 2018As important as perceiving pain is the ability to modulate this perception in some contextual salient situations. The periaqueductal gray (PAG) is perhaps the most...
As important as perceiving pain is the ability to modulate this perception in some contextual salient situations. The periaqueductal gray (PAG) is perhaps the most important site of endogenous pain modulation; however, little is known about dopaminergic mechanisms underlying PAG-mediated antinociception. In this study, we used a pharmacological approach to evaluate this subject. We found that µ-opioid receptor-induced antinociception (DAMGO, 0.3 μg) from PAG was blocked by the coadministration of either D1-like or D2-like dopaminergic antagonists (SCH23390, 2, 4, and 6 μg or raclopride, 2 and 4 μg, respectively) both in the tail-flick and in the mechanical paw-withdrawal test. A selective D2-like receptor agonist (piribedil, 6 and 12 μg into the PAG) induced antinociception in the mechanical paw-withdrawal test, but not in the tail-flick test. This effect was blocked by the coadministration of its selective antagonist (raclopride 4 μg), as well as by either a GABAA agonist (muscimol, 0.1 μg) or an opioid receptor antagonist (naloxone, 0.5 μg). A selective D1-like receptor agonist (SKF38393, 1, 5, and 10 μg into the PAG) induced a poor and transient antinociceptive effect, but when combined with piribedil, a potentiated antinociceptive effect emerged. None of these treatments affected locomotion in the open-field test. These findings suggest that µ-opioid antinociception from the PAG depends on dopamine acting on both D1-like and D2-like receptors. Selective activation of PAG D2-like receptors induces antinociception mediated by supraspinal mechanisms dependent on inhibition of GABAA and activation of opioid neurotransmission.
Topics: Analgesics; Analgesics, Opioid; Animals; Dopamine Agents; Dopaminergic Neurons; Male; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Periaqueductal Gray; Rats; Rats, Wistar; Receptors, Opioid; Receptors, Opioid, mu
PubMed: 29035918
DOI: 10.1097/FBP.0000000000000346 -
Experimental Neurology Aug 2021Parkinson's disease (PD) is characterized by Lewy body and neurite pathology associated with dopamine terminal dysfunction. Clinically, it is associated with motor...
BACKGROUND
Parkinson's disease (PD) is characterized by Lewy body and neurite pathology associated with dopamine terminal dysfunction. Clinically, it is associated with motor slowing, rigidity, and tremor. Postural instability and pain are also features. Physical exercise benefits PD patients - possibly by promoting neuroplasticity including synaptic regeneration.
OBJECTIVES
In a parkinsonian rat model, we test the hypotheses that exercise: (a) increases synaptic density and reduces neuroinflammation and (b) lowers the nociceptive threshold by increasing μ-opioid receptor expression.
METHODS
Brain autoradiography was performed on rats unilaterally injected with either 6-hydroxydopamine (6-OHDA) or saline and subjected to treadmill exercise over 5 weeks. [H]UCB-J was used to measure synaptic vesicle glycoprotein 2A (SV2A) density. Dopamine D2/3 receptor and μ-opioid receptor availability were assessed with [H]Raclopride and [H]DAMGO, respectively, while neuroinflammation was detected with the 18kDA translocator protein (TSPO) marker [H]PK11195. The nociceptive threshold was determined prior to and throughout the exercise protocol.
RESULTS
We confirmed a dopaminegic deficit with increased striatal [H]Raclopride D2/3 receptor availability and reduced nigral tyrosine hydroxylase immunoreactivity in the ipsilateral hemisphere of all 6-OHDA-injected rats. Sedentary rats lesioned with 6-OHDA showed significant reduction of ipsilateral striatal and substantia nigra [H]UCB-J binding while [H]PK11195 showed increased ipsilateral striatal neuroinflammation. Lesioned rats who exercised had higher levels of ipsilateral striatal [H]UCB-J binding and lower levels of neuroinflammation compared to sedentary lesioned rats. Striatal 6-OHDA injections reduced thalamic μ-opioid receptor availability but subsequent exercise restored binding. Exercise also raised thalamic and hippocampal SV2A synaptic density in 6-OHDA lesioned rats, accompanied by a rise in nociceptive threshold.
CONCLUSION
These data suggest that treadmill exercise protects nigral and striatal synaptic integrity in a rat lesion model of PD - possibly by promoting compensatory mechanisms. Exercise was also associated with reduced neuroinflammation post lesioning and altered opioid transmission resulting in an increased nociceptive threshold.
Topics: Animals; Brain; Exercise Test; Male; Oxidopamine; Parkinsonian Disorders; Physical Conditioning, Animal; Rats; Rats, Wistar; Synapses
PubMed: 33965411
DOI: 10.1016/j.expneurol.2021.113741