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In JoVE (1)
Other Publications (13)
Articles by Y. Iris Chen in JoVE
Bioluminescence Imaging of Heme Oxygenase-1 Upregulation in the Gua Sha Procedure
Kenneth K. Kwong1,2, Lenuta Kloetzer1,2,3,4, Kelvin K. Wong5,6, Jia-Qian Ren1,2, Braden Kuo1,2,3,4, Yan Jiang7, Y. Iris Chen1,2, Suk-Tak Chan1,2,8, Geoffrey S. Young9, Stephen T.C. Wong5,6
1Department of Radiology, Massachusetts General Hospital, Harvard Medical School, 2Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, 3Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, 4Department of Medicine, Massachusetts General Hospital, Harvard Medical School, 5Center for biotechnology and Informatics, The Methodist Hospital Research Institute, 6Department of Radiology, The Methodist Hospital, Weill Cornell Medical College, 7Bejing University of Chinese Medicine, 8Department of Health Technology and Informatics, The Hong Kong Polytechnic University, 9Department of Radiology, Brigham and Women's Hospital, Harvard Medical School
Gua Sha, traditional Chinese therapeutic skin scraping, causes subcutaneous microvascular blood extravasation. We report a protocol of bioluminescence imaging of HO-1-luciferase transgenic mice to demonstrate that Gua Sha upregulates heme oxygenase-1 (HO-1) in multiple organs.
Other articles by Y. Iris Chen on PubMed
Radiolabeling and Biodistribution of Methyl 2-(methoxycarbonyl)-2-(methylamino) Bicyclo[2.1.1] -hexane -5-carboxylate, a Potential Neuroprotective Drug
Life Sciences. Aug, 2003 | Pubmed ID: 12865097
Methyl 2-(methoxycarbonyl) -2-(methylamino) bicyclo[2.1.1] -hexane -5-carboxylate (MMMHC) is developed as a potential neuroprotective drug. It was labeled with C-11 from the desmethyl precursor methyl 2-(methoxycarbonyl)-2-amino bicyclo[2.1.1]-hexane-5-carboxylate with [11C]methyl triflate in acetone solution at 60 degrees C with labeling yield of 69% and with radiochemical purity of >99%. Positron Emission Tomography (PET) studies in a normal rat showed that Methyl 2-(methoxycarbonyl)-2-([11C]methylamino)bicyclo[2.1.1]-hexane-5-carboxylate ([11C] MMMHC) accumulated mainly in the cortical brain areas after iv administration. Frontal cortex/cerebellum ratios in a rat brain were 8.0/6.0, 6.8/4.2, 6.3/4.3, 5.5/4.2 and 5.2/4.5 percent of the injected dose in 100 ml at 2 min, 5 min, 10 min, 20 min and 40 min respectively after i.v. injection. During 20-40 min, 2.9+/-0.4% of the total activity stayed in the brain. These results showed that MMMHC could be labeled with C-11 with high yield, and it passed the brain-blood barrier and accumulated in several brain regions.
NeuroImage. Oct, 2003 | Pubmed ID: 14568476
Neurophysiological studies of the brain in normal and Parkinson's disease (PD) patients have indicated intricate connections for basal ganglia-induced control of signaling into the motor cortex. To investigate if similar mechanisms are controlling function in the primate brain (Macaca fascicularis) after MPTP-induced neurotoxicity, we conducted PET studies of cerebral blood flow, oxygen and glucose metabolism, dopamine transporter, and D2 receptor function. Our observations after MPTP-induced dopamine terminal degeneration of the caudate and putamen revealed increased blood flow (15%) in the globus pallidus (GP), while blood flow was moderately decreased (15-25%) in the caudate, putamen, and thalamus and 40 % in the primary motor cortex (PMC). Oxygen extraction fraction was moderately increased (10-20%) in other brain areas but the thalamus, where no change was observable. Oxygen metabolism was increased in the GP and SMA (supplementary motor area including premotor cortex, Fig. 3) by a range of 20-40% and decreased in the putamen and caudate and in the PMC. Glucose metabolism was decreased in the caudate, putamen, thalamus, and PMC (range 35-50%) and enhanced in the GP by 15%. No change was observed in the SMA. In the parkinsonian primate, [(11)C]CFT (2beta-carbomethoxy-3beta-(4-fluorophenyltropane) dopamine transporter binding was significantly decreased in the putamen and caudate (range 60-65%). [(11)C]Raclopride binding of dopamine D(2) receptors did not show any significant changes. These experimental results obtained in primate studies of striato-thalamo-cortico circuitry show a similar trend as hypothetized in Parkinson's disease-type degeneration.
3-Nitropropionic Acid-induced Neurotoxicity--assessed by Ultra High Resolution Positron Emission Tomography with Comparison to Magnetic Resonance Spectroscopy
Journal of Neurochemistry. Jun, 2004 | Pubmed ID: 15147513
To explore acute and long-term effects of 3-nitropropionic acid (3-NP)-induced neurotoxicity, longitudinal positron emission tomography (PET) studies of energy metabolism and magnetic resonance spectroscopic (MRS) studies of neurochemicals were conducted in a rat model. The first injection of 3-NP (20 mg/kg i.p.) was followed by MRS study of neurochemicals and PET study of glucose utilization using [(18)F]2-fluorodeoxy-D-glucose ((18)F-FDG). After that, 3-NP administration was done two times a day with a dose of 10 mg/kg i.p. until animals were symptomatic or for a maximum of 5 days combined with daily PET studies. Long-term effects were investigated 4 weeks and 4 months after cessation of 3-NP. These studies showed a significant inter-animal variation in response of 3-NP toxicity. Animals that developed large striatal lesions had decreased glucose utilization in the striatum and cortex 1 day after starting 3-NP injections. Similarly succinate and lactate/macromolecule levels were enhanced; these changes being, however, reversible. Progressive degeneration was observed by decreasing striatal glucose utilization and N-acetylaspartate (NAA) and increasing choline. These observations paralleled with weight loss and deficits in behavior. Animals that did not develop lesions showed reversible enhancement in cortical glucose utilization and no change in striatal glucose utilization or neurochemicals or locomotor activity.
Synapse (New York, N.Y.). Feb, 2005 | Pubmed ID: 15529335
Adenosine receptors in the basal ganglia are implicated in regulation of dopamine function and release. We investigated the interactions between dopamine receptors and adenosine receptors in the basal ganglia using pharmacologic MRI (phMRI) in rats. Stimulation of dopamine receptors was achieved using administration of 2 mg/kg of amphetamine. Then we investigated the antagonism of these changes using the selective A2a receptor antagonist 3,7-dimethyl-1-propargylaxanthine (DMPX). Amphetamine alone caused large increases (10-30%) in relative cerebral blood volume (rCBV) in caudate/putamen (CPu), nucleus accumbens (NAcc), thalamus, and frontal and cingulate cortices with changes that persisted for 70-80 min. DMPX alone (5 mg/kg) induced decreases in rCBV (approximately 8-10%) in NAcc, CPu, and olfactory tubercule, with smaller changes in thalamus (-6%) consistent with the regional distribution of A2a receptors. We examined the interactions between amphetamine and DMPX by assessing the effects of DMPX (5 mg/kg) administration 20 min after injection of 3 mg/kg amphetamine. These experiments showed that DMPX immediately decreased the rCBV increase induced by amphetamine in NAcc, CPu, and thalamus but not in cingulate or sensorimotor cortex. Companion microdialysis experiments showed that dopamine release in CPu was decreased in a similar manner. These experiments demonstrate the utility of phMRI for probing, in a noninvasive manner, the temporal and spatial dynamics of neurotransmitter interactions.
Brain Hemodynamic Changes Mediated by Dopamine Receptors: Role of the Cerebral Microvasculature in Dopamine-mediated Neurovascular Coupling
NeuroImage. Apr, 2006 | Pubmed ID: 16459104
The coupling between neurotransmitter-induced changes in neuronal activity and the resultant hemodynamic response is central to the interpretation of neuroimaging techniques. In the present study, MRI experiments showed that dopamine transporter blockers such as cocaine and dopamine releasers such as amphetamine and D1 receptor agonists induced large positive increases in relative cerebral blood volume (rCBV) that were not sensitive to nitric oxide synthase inhibition. However, D1/D5 receptor antagonism with SCH-23390 prevented or blocked the hemodynamic response without any concomitant effect on dopamine release. Dopamine D2/D3 receptor agonists, in contrast, induced negative changes in rCBV in brain regions corresponding largely to those endowed with these receptors. D1 and D5 receptor mRNAs were expressed in microvessels of responsive brain areas, while D2 and D3 receptors were not consistently associated with the microvascular bed. D3 receptors had an astroglial localization. Together, these experiments show that direct effects of dopamine upon the vasculature cannot be ignored in measuring the hemodynamic coupling associated with dopaminergic drugs. These results further suggest that this coupling is partially mediated through D1/D5 receptors on the microvasculature leading to increased rCBV and through astroglial D3 receptors leading to decreased rCBV. These data provide additional support for the role of local post-synaptic events in neurovascular coupling and emphasize that the interpretation of fMRI signals exclusively in terms of neuronal activity may be incomplete.
Synapse (New York, N.Y.). Aug, 2006 | Pubmed ID: 16715493
Nicotine is one of the most addictive substances known. To better understand the mechanisms of action, we mapped the regional brain response to nicotine administration using pharmacologic magnetic resonance imaging (phMRI) in rats. We measured the regional response of relative cerebral blood volume (rCBV) in rats to a challenge of 0.07 mg/kg (0.43 micromol/kg) of nicotine. The areas of the brain with significant and reproducible changes in the rCBV response were (in descending order of magnitude) infralimbic cortex, hippocampus (subiculum), agranular insular/pyriform cortex, visual cortex, interpeduncular area, nucleus accumbens, cingulate cortex, thalamus, and septum. This pattern of response is consistent with stimulation of both cholinergic and dopaminergic neuronal pathways and is consistent with the known behavioral properties of nicotine. The peak CBV response to nicotine occurred between 9 and 13 min depending upon brain region, and the average full width half-maximum of the rCBV response was 27 min. The high spatial and temporal resolution of the phMRI technique lends itself well to further, more detailed, studies of nicotine dynamics.
Inhibition of Stimulated Dopamine Release and Hemodynamic Response in the Brain Through Electrical Stimulation of Rat Forepaw
Neuroscience Letters. Feb, 2008 | Pubmed ID: 18178315
The subcortical response to peripheral somatosensory stimulation is not well studied. Prior literature suggests that somatosensory stimulation can affect dopaminergic tone. We studied the effects of electrical stimulation near the median nerve on the response to an amphetamine-induced increase in synaptic dopamine. We applied the electrical stimulation close to the median nerve 20 min after administration of 3mg/kg amphetamine. We used fMRI and microdialysis to measure markers of dopamine (DA) release, together with the release of associated neurotransmitters of striatal glutamate (Glu) and gamma-aminobutyric acid (GABA). Changes in cerebral blood volume (CBV), a marker used in fMRI, indicate that electrical stimulation significantly attenuated increased DA release (due to AMPH) in the striatum, thalamus, medial prefrontal and cingulate cortices. Microdialysis showed that electrical stimulation increased Glu and GABA release and attenuated the AMPH-enhanced DA release. The striatal DA dynamics correlated with the CBV response. These results demonstrate that electrical stimulation near the median nerve activates Glu/GABA release, which subsequently attenuate excess striatal DA release. These data provide evidence for physiologic modulation caused by electroacupuncture at points near the median nerve.
Electrical Stimulation Modulates the Amphetamine-induced Hemodynamic Changes: an FMRI Study to Compare the Effect of Stimulating Locations and Frequencies on Rats
Neuroscience Letters. Oct, 2008 | Pubmed ID: 18722508
Our previous fMRI and microdialysis measurements showed that electroacupuncture (EA) at LI4 was effective in alleviating excessive cerebral dopamine release induced by d-amphetamine (AMPH) in rats. We now compare the effect of EA in adjusting excess dopamine release at two stimulating frequencies (2 Hz versus 100 Hz at LI4) and at two acupoints (forepaw (LI4) versus hindpaw (ST36), at 2 Hz). fMRI measurements of relative cerebral blood volume (rCBV) were used to monitor the brain activity of "rest", followed by AMPH challenge, 10 min "rest", and then 20 min of EA. Results: EA at LI4 and ST36 significantly attenuated the AMPH-induced rCBV increases in the striatum, S1 cortex, and thalamus. Frequency: EA at 100 Hz induced greater attenuation of rCBV than EA at 2 Hz in the S1, insula, anterior cingulate cortices, dorsolateral striatum, and thalamus. Acupoints: EA at LI4 modulated a broader area in the medial anterior striatum while EA at ST36 modulated a more site-specific area in the dorsolateral striatum. In the thalamus, EA at LI4 showed greater attenuating effect than EA at ST36 did. However, in the insular cortex, EA at ST36 showed stronger attenuation. Conclusion: EA at both LI4 and ST36 was effective in restoring dopamine homeostasis from an excess state, with the most effective response at LI4 with 100 Hz, while the responses to 2Hz EA at LI4 and ST36 showed slightly different spatial distribution of MR signal. This therefore provided insight into the neurophysiological basis of electroacupuncture effects in cortical and subcortical circuits.
Synapse (New York, N.Y.). Sep, 2009 | Pubmed ID: 19484725
We studied the metabolic responses to different DA concentrations elicited by four doses of D-amphetamine (AMPH, 0, 0.25, 0.5, 1.0, or 3.0 mg/kg). We compared the degree of DA release (via microdialysis) with striatal cAMP activity and whole brain maps of cerebral blood volume (rCBV) changes (via pharmacological MRI, phMRI). Results: AMPH increased DA release in the caudate/putamen (CPu) and cAMP activity in the CPu, nucleus accumbens (NAc), and medial prefrontal cortex (mPFC) in a linear dose-dependent manner (P < 0.0001). The cAMP data suggest that, postsynaptically, signal transduction induced by D1 receptor is stronger than that of D2 receptor at the higher doses (1-3 mg/kg). phMRI showed that, while higher doses of AMPH (3 mg/kg (n = 7) and 1 mg/kg (n = 6)) induced significant rCBV increases in the CPu and NAc, the degree of rCBV increase was much smaller with AMPH of 0.5 mg/kg (n = 6). In contrast, AMPH of 0.25 mg/kg (n = 8) induced significant rCBV decreases in the anteromedial CPu and NAc. The sign switch of rCBV in response to AMPH from low to high doses likely reflects the switching in the balance of D2/D3 stimulation vs. D1/D5 stimulation. In conclusion, degree of postsynaptic signal transduction is linearly correlated to the extracellular DA concentration. However, the presynaptic binding may dominate the overall DA innervation at the lower range of DA concentration.
Developmental Neuroscience. Jul, 2010 | Pubmed ID: 20523024
Characterization of the ontogeny of the cerebral dopaminergic system is crucial for gaining a greater understanding of normal brain development and its alterations in response to drugs of abuse or conditions such as attention-deficit hyperactivity disorder. Pharmacological MRI (phMRI) was used to determine the response to dopamine transporter (DAT) blockers cocaine and methylphenidate (MPH), the dopamine releaser D-amphetamine (AMPH), the selective D1 agonist dihydrexidine, and the D2/D3 agonist quinpirole in young (<30 days old) and adult (>60 days old) rats. In adult rats, cocaine (0.5 mg/kg i.v.) or MPH (2 mg/kg) induced primarily positive cerebral blood volume (rCBV) changes in the dopaminergic circuitry, but negative rCBV changes in the young animals. Microdialysis measurements in the striatum showed that young rats have a smaller increase in extracellular dopamine in response to cocaine than adults. The young rats showed little rCBV response to the selective D1 agonist dihydrexidine in contrast to robust rCBV increases observed in the adults, whereas there was a similar negative rCBV response in the young and adult rats to the D2 agonist quinpirole. We also performed a meta-analysis of literature data on the development of D1 and D2 receptors and the DAT. These data suggest a predominance of D2-like over D1-like function between 20 and 30 days of age. These combined results suggested that the dopamine D1 receptor is functionally inhibited at young age.
Psychopharmacology. Sep, 2010 | Pubmed ID: 20628733
Dopamine D3 receptors (D3R) may be important therapeutic targets for both drug abuse and dyskinesias in Parkinson's disease; however, little is known about their functional circuitry.
Cocaine Self-administration Leads to Alterations in Temporal Responses to Cocaine Challenge in Limbic and Motor Circuitry
The European Journal of Neuroscience. Sep, 2011 | Pubmed ID: 21896062
Chronic use of cocaine is associated with lasting alterations in brain metabolism, circuitry, and receptor properties. We used neuroimaging with pharmacological magnetic resonance imaging to assess alterations in response to cocaine (0.5 mg/kg) in animals trained to self-administer cocaine on a fixed-ratio 5 schedule of reinforcement, as well as saline-yoked controls, after 28 days of cocaine abstinence. We fitted the cerebral blood volume (CBV) curves for full-width half-maximum (FWHM) as well as peak CBV response. There were significant increases in the FWHM of the response curves in the cocaine self-administering (SA) animals as compared with saline-yoked controls in the medial prefrontal cortex (mPFC) and the caudate/putamen (CPu), and increases in peak CBV in the M1 motor cortex, CPu, and pedunculopontine tegmental nucleus. Functional connectivity analysis showed increased correlations in the cocaine SA rats upon acute cocaine challenge, especially in the S1, mPFC, and thalamus. As D3 receptor expression is postulated to increase following chronic cocaine administration, we also examined the response to 0.2 mg/kg of the D3-preferring agonist 7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OHDPAT). Cocaine SA animals showed a decreased overall CBV response to this drug, except in the globus pallidus. The hypothalamus showed a negative CBV change in response to cocaine challenge, similar to that noted with the D3 agonist, and showed a smaller response in the cocaine SA animals than in the controls. Given the good coupling of cerebral hemodynamics with dopamine dynamics previously observed with pharmacological magnetic resonance imaging, these data suggest that increased persistence of dopamine in the prefrontal cortex may be responsible for some of the behavioral alterations observed subsequent to chronic cocaine use.
Synapse (New York, N.Y.). Apr, 2012 | Pubmed ID: 22170513
Deviation of dopamine homeostasis is known to be associated with disorders like drug addiction and Parkinson's disease. As dopamine function is tightly regulated within the basal ganglia circuitry, cortical perturbation would lead to modulation of dopaminergic activity in the striatum. We proposed and tested if somatosensory activity such as forepaw stimulation could modulate dopaminergic function. Specifically, we tested in rats if electrical forepaw stimulation (EFS) could attenuate dopamine release in the brain if dopamine is excessive, and boost dopamine release if dopamine is deficient. We had previously demonstrated that EFS effectively attenuated excessive DA concentration in the striatum. We now show in this manuscript with fMRI that EFS boosted DA release on two DA deficient conditions: (1) with quinpirole challenge, and (2) partial Parkinsonism model (PD). Quinpirole alone decreased dopamine release and thus the cerebral blood volume (CBV) that was restored by EFS. EFS also succeeded in increasing CBV in the basal-ganglia circuitry of the PD rats, but not in the controls. Context-dependent connectivity analysis showed increased connectivity during the basal state in the PD rats, compared with the controls. This "enhanced" yet abnormal connectivity of PD rats was reduced post-EFS. Our results suggest that EFS resets the deficient DA system by partially increasing DA release, in the meanwhile lessening the need for recruiting extra functional network in the basal ganglia circuitry. This study shows not only the capacity of peripheral stimulation to perturb neurotransmitter function, but also the potential of peripheral stimulation to restore neurotransmitter homeostasis. Synapse, 2012. © 2011 Wiley Periodicals, Inc.