Dynamic metabolic changes after permanent cerebral ischemia in rats with/without post-stroke exercise: a positron emission tomography (PET) study

Abstract

Objectives:

Recent studies have suggested that rehabilitation therapy can accelerate functional recovery after a stroke. Although often overlooked, the cortical hemisphere contralateral to an infarction plays an important role. This study investigates alterations in metabolism of both the damaged (‘ipsilateral’) as well as the undamaged (‘contralateral’) hemisphere using ¹⁸F-fluorodeoxyglucose (FDG)-micro-positron emission tomography (PET) in a rat permanent stroke model (with or without post-injury exercise) in order to elucidate the relative importance of either hemisphere to the recovery process following stroke.

Methods:

Thirty-six adult, male Sprague-Dawley rats were divided into four groups before subsequent surgery: sham controls with or without exercise, and ischemic (‘stroke’) groups with or without exercise. Fluorodeoxyglucose micro-PET imaging was performed at 7, 14, and 21 days after the designated procedure according to group assignment. The imaging data was analyzed by ANOVA using SPMratIHEP software.

Results:

Both exercise and ischemia have measurable effects on the motor cortex as well as on the striatum, the effects of which notably include the contralateral hemisphere. To that end, regions of the contralateral motor cortex and striatum have been found to be in a hypermetabolic state following exercise. We further observed that exercise reversed the hypometabolism caused by ischemia back to control levels from day 7 through day 21 on the ipsilateral side. Its effect on the contralateral hemisphere, notably, bolsters an already vigorous response observed after ischemic insult. Thus, the beneficial effect of exercise, as inferred by an increase in metabolic activity, is evident in both hemispheres.

Discussion:

These findings suggest that the contralateral hemisphere can compensate for the damaged cortex by remodeling neuronal activity. Thus, clinical treatments specifically targeted to the ‘intact’ hemisphere following stroke may provide a complimentary strategy for promoting recovery of functional deficits and for improving quality of life in stroke patients.     

Patients with rest-tremor and scans with ipsilateral dopaminergic deficit

Dopamine transporter imaging is typically abnormal in Parkinson’s disease and shows reduced striatal uptake, which is typically greater contralateral to the clinically more affected side. However, tremor-dominant Parkinson’s disease patients may have significantly lower uptake in the striatum ipsilateral to the rest-tremor compared to akinetic-rigid PD patients, implying a possible role of an ipsilateral deficit in the generation of rest-tremor.We report here three patients with rest-tremor and the unexpected finding of an ipsilateral presynaptic dopaminergic deficit with normal uptake contralateral to the rest-tremor in dopamine transporter imaging. We divided them in two groups, with and without a corresponding structural lesion in brain imaging. These data may suggest a role of ipsilateral dopaminergic deficit in the generation of rest-tremor. An explanation of these findings could be damage of crossed dopaminergic fibres from the substantia nigra to thalamus, which can cause motor impairment ipsilateral to dopamine depletion experimentally. This is speculative but there is no doubt that these cases exist and we encourage others to report similar cases, as this may assist in the better understanding of the yet unknown pathophysiology of rest-tremor.     

Mapping the changed hubs and corresponding functional connectivity in idiopathic restless legs syndrome

ObjectiveThe hubs of the brain network play a key role in integrating and transferring information between different functional modules. However, whether the changed pattern in functional network hubs contributes to the onset of leg discomfort symptoms in restless legs syndrome (RLS) patients remains unclear. Using resting-state functional magnetic resonance imaging (rs-fMRI) and graph theory methods, we investigated whether alterations of hubs can be detected in RLS.MethodsFirst, we constructed the whole-brain voxelwise functional connectivity and calculated a functional connectivity strength (FCS) map in each of 16 drug-naive idiopathic RLS patients and 26 gender- and age-matched healthy control (HC) subjects. Next, a two-sample t test was applied to compare the FCS maps between HC and RLS patients, and to identify significant changes in FCS in RLS patients. To further elucidate the corresponding changes in the functional connectivity patterns of the aberrant hubs in RLS patients, whole-brain resting-state functional connectivity analyses for the hub areas were performed.ResultsThe hub analysis revealed decreased FCS in the cuneus, fusiform gyrus, paracentral lobe, and precuneus, and increased FCS in the superior frontal gyrus and thalamus in idiopathic drug-naive RLS patients. Subsequent functional connectivity analyses revealed decreased functional connectivity in sensorimotor and visual processing networks and increased functional connectivity in the affective cognitive network and cerebellar–thalamic circuit. Furthermore, the mean FCS value in the superior frontal gyrus was significantly correlated with Hamilton Anxiety Rating Scale scores in RLS patients, and the mean FCS value in the fusiform gyrus was significantly correlated with Hamilton Depression Rating Scale scores.ConclusionsThese findings may provide novel insight into the pathophysiology of RLS.     

Mechanisms of unilateral STN-DBS in patients with Parkinson’s disease

Bilateral symptoms and signs of Parkinson’s disease (PD) are often improved by unilateral subthalamic nucleus deep brain stimulation (STN-DBS). However, the mechanism for such bilateral effects is unknown. This study was intended to examine effects of unilateral STN-DBS using positron emission computed tomography (PET) and to elucidate mechanisms for bilateral improvement achieved by unilateral stimulation. We conducted ¹⁸F-fluorodeoxyglucose (¹⁸FDG) and ¹⁸F-fluorodopa (¹⁸F-DOPA ) PET scans in PD patients whose bilateral limb symptoms and axial symptoms were improved by unilateral DBS. Two scans were performed in each PET study: when DBS was on and off. We compared those images using statistic parametric mapping (SPM) 99. The significant clinical improvement obtained by unilateral DBS was shown as improvements in bilateral motor limb, axial, and gait subscores of the Unified PD Rating Scale (UPDRS). Moreover, ¹⁸FDG PET revealed significant metabolic increases in the ipsilateral ventrolateral thalamic areas and metabolic decrease at the contralateral globus pallidus interna (GPi). In contrast, ¹⁸F-DOPA PET showed no significant differences between DBS on and off. Ipsilateral thalamic activation might induce ipsilateral motor cortical activation, which explains the improvement of contralateral limb symptoms. Furthermore, deactivation of the contralateral GPi might disinhibit the thalamus and contralateral motor cortex, which explains reduction of ipsilateral limb symptoms. These results suggest the mechanisms for bilateral improvement achieved by unilateral DBS.     

Functional connectivity alternation of the thalamus in restless legs syndrome patients during the asymptomatic period: a resting-state connectivity study using functional magnetic resonance imaging

BackgroundRestless legs syndrome (RLS) is a primary sensory disorder with a secondary motor component (e.g., urge to move), and the thalamus is known to play a central role in RLS. The purpose of our study was to explore the intrinsic changes in the thalamocortical circuit in RLS patients using a resting-state functional magnetic resonance imaging (fMRI) paradigm.MethodsResting-state fMRIs were obtained in the morning from 25 idiopathic RLS patients who were not using RLS medications and 25 controls. Resting-state connectivity was analyzed by a seed-based method using Analysis of Functional NeuroImages (AFNI) software with the bilateral thalami (ventroposterolateral nucleus [VPLN]). The connectivity characteristics of RLS patients were compared to those of the controls.ResultsWe found that RLS patients showed reduced thalamic connectivity with the right parahippocampal gyrus, right precuneus, right precentral gyrus, and bilateral lingual gyri; however, the right superior temporal gyrus, bilateral middle temporal gyrus, and right medial frontal gyrus showed enhanced connectivity with the thalamus. RLS severity was negatively correlated with connectivity between the thalamus and right parahippocampal gyrus (r = −0.414; P = .040).ConclusionsOur results suggest that the characteristics of the connectivity changes may reflect the pathways involved in producing RLS symptoms and indicate that RLS patients may have deficits in controlling and managing sensory information, which supports the act of viewing RLS as a disorder disrupting somatosensory processing.     

Restless legs syndrome—new insights into clinical characteristics,pathophysiology, and treatment options

Abstract. We summarize recent advances in the clinical definition of restless legs syndrome (RLS), in understanding the basic mechanisms, and the successful treatments of RLS. New diagnostic instruments and severity scales have been developed for better phenotyping of the individual patient. Iron metabolism related components and the dopaminergic system have been extensively investigated in respect to the pathophysiology of RLS. The presence of mechanical hyperalgesia to pin-prick points towards an involvement of the nociceptive system. Genetic research has reported loci on chromosome 12q and 14q to play a role in the vulnerability to RLS. Placebo-controlled large-scale phase II and III treatment trials have shown that dopamine agonists are safe and efficacious agents for the treatment of this disorder.     

In vivo imaging of monoaminergic nerve terminals in normal and MPTP-lesioned primate brain using positron emission tomography (PET) and [11C]tetrabenazine

The first successful in vivo imaging of monoamine vesicular transporters in the living primate brain is described, using [¹¹C]tetrabenazine ([¹¹C]TBZ) and Positron Emission Tomography (PET). Radioligand uptake into brain is rapid, and at short time periods (10-30 minutes) the higher uptake and retention of the radiotracer in the more densely dopaminergic innervated striatum is clearly visualized. Specific binding in striatum can be entirely blocked with co-administration of a pharmacological dose (1 mg/kg i. v.) of tetrabenazine. In a unilaterally MPTP-lesioned monkey, specific binding of radioligand was absent in the striatum on the lesioned side, with no effect on radiotracer distribution in the cortex, cerebellum or contralateral striatum. PET imaging with [¹¹C]TBZ provides a new approach to the in vivo study of monoaminergic neurons and their loss in neurodegenerative diseases. © 1993 Wiley-Liss, Inc.     

Crossed cerebellocerebral diaschisis in patients with cerebellar stroke

Objectives– We performed single‐photon emission computed tomography (SPECT) to investigate crossed cerebellocerebral diaschisis (CCCD) in patients with cerebellar stroke. Material and methods– Fifteen patients with unilateral cerebellar stroke underwent SPECT of the brain with N‐isopropyl‐p‐[¹²³I] iodoamphetamine (¹²³I‐IMP). Regional cerebral blood flow (rCBF) was measured by the autoradiographic method. Regions of interest were defined in the cerebral cortex, striatum, thalamus and cerebellum to compare structures (contralateral to the cerebellar lesion) with counterparts ipsilateral to the stroke. Results– In the frontal and parietal cortices, especially the posterior superior frontal, anterior midfrontal, precentral, postcentral, and supramarginal areas, rCBF contralateral to the lesion was significantly lower than on the side of the lesion (showing CCCD). Conclusion – This CCCD phenomenon is important to be aware of in clinical reading of images.     

Restless legs syndrome,a predictor of subcortical stroke: a prospective study in 346 stroke patients

ObjectiveThe objective of this study was to assess the prevalence of restless legs syndrome (RLS) among patients with stroke and to examine the anatomical correlation between location of stroke and RLS symptoms.MethodsWe administered a pre-structured sleep questionnaire to consecutive stroke patients seen in our neurology services department over a 3-year period. Unconscious (Glasgow Coma Scale score <15) or aphasic, renally impaired, or neuropathic patients were excluded. Diagnosis of RLS was established according to the criteria of the International Restless Legs Syndrome Study Group (IRLSSG), and polysomnography was conducted.ResultsOf 346 stroke patients, 35 (10.11%) fulfilled IRLSSG diagnostic criteria for RLS, which had existed for an average (±standard deviation) of 60 ± 40 months before stroke. The mean age of onset was 52.94 (±10.32) years. Twenty-four patients (68%) had RLS symptoms contralateral to the hemisphere involved in the stroke (eight with unilateral and 16 with grossly asymmetrical RLS). Twenty-nine of 35 patients (82.86%) had imaging evidence of subcortical (16 with hemorrhagic and 13 with ischemic) stroke. Patients with pre-stroke RLS differed from those without it only by subcortical location of the stroke (82.9% vs 31.5% respectively, p < 0.001). The most significant differentiating factor between patients with subcortical stroke and those with cortical stroke was pre-stroke RLS (22.83% vs 2.74%, p < 0.001), the others being history of hypertension and hemorrhagic stroke type.ConclusionRLS, especially unilateral or asymmetrical, might frequently pre-exist in patients presenting with subcortical stroke. The common laterality may suggest an important predictive value for RLS, and may form an important point for future research.     

Brain imaging and networks in restless legs syndrome

Several studies provide information useful to our understanding of restless legs syndrome (RLS), using various imaging techniques to investigate different aspects putatively involved in the pathophysiology of RLS, although there are discrepancies between these findings.The majority of magnetic resonance imaging (MRI) studies using iron-sensitive sequences supports the presence of a diffuse, but regionally variable low brain-iron content, mainly at the level of the substantia nigra, but there is increasing evidence of reduced iron levels in the thalamus. Positron emission tomography (PET) and single positron emission computed tomography (SPECT) findings mainly support dysfunction of dopaminergic pathways involving not only the nigrostriatal but also mesolimbic pathways. None or variable brain structural or microstructural abnormalities have been reported in RLS patients; reports are slightly more consistent concerning levels of white matter. Most of the reported changes were in regions belonging to sensorimotor and limbic/nociceptive networks. Functional MRI studies have demonstrated activation or connectivity changes in the same networks. The thalamus, which includes different sensorimotor and limbic/nociceptive networks, appears to have lower iron content, metabolic abnormalities, dopaminergic dysfunction, and changes in activation and functional connectivity. Summarizing these findings, the primary change could be the reduction of brain iron content, which leads to dysfunction of mesolimbic and nigrostriatal dopaminergic pathways, and in turn to a dysregulation of limbic and sensorimotor networks. Future studies in RLS should evaluate the actual causal relationship among these findings, better investigate the role of neurotransmitters other than dopamine, focus on brain networks by connectivity analysis, and test the reversibility of the different imaging findings following therapy.     

Changes of cortical excitability after dopaminergic treatment in restless legs syndrome

ObjectiveDopaminergic pathways are most likely involved in the pathophysiology of restless legs syndrome (RLS). In previous investigations, an alteration of cortical excitability was suggested to be related to a dopaminergic dysfunction in RLS. The purpose of our study was to compare practice-dependent plasticity in RLS patients before and after a month of dopaminergic treatment.MethodsSingle-pulse transcranial magnetic stimulation (TMS) was used to define motor evoked potential (MEP) amplitude, motor threshold, and silent period (SP) as well. Subjects performed three exercise blocks (bimanual motor task). MEP amplitude, registered immediately after each exercise block and after a rest period, was compared to baseline. The time course of intra-cortical inhibition was tested using paired-pulse TMS at short inter-stimulus intervals. For the single-pulse TMS procedures, we enrolled 12 patients affected by primary RLS and 12 normal subjects. For the paired-pulse TMS procedures, only six patients underwent the examination. RLS patients underwent the examination in both pre- and post-dopaminergic treatment conditions.ResultsIn RLS patients MEP amplitude increased after the rest period only in the post-treatment condition, showing a delayed facilitation. After exercise, MEP amplitude increased, but not enough to be significant, showing a positive trend but not a clear-cut post-exercise facilitation. In the pre-treatment condition instead, MEP amplitude did not change either after rest period or after exercise.RLS patients showed a marked increase of the central motor inhibition, assessed by using paired-pulse TMS at short inter-stimulus intervals after pramipexole treatment. On the contrary, the duration of the SP did not change compared to the pre-treatment condition.ConclusionsIn RLS patients after dopaminergic treatment, the main finding was the changing of MEP amplitude after rest following a motor task. Since dopaminergic treatment can reverse delayed facilitation in RLS, we hypothesized that cortical plasticity related to dopaminergic systems may play a crucial role in RLS pathophysiology.     

Chorea-acanthocytosis in monozygotic twins: clinical findings and neuropathological changes as detected by diffusion tensor imaging,FDG-PET and <Superscript>123</Superscript>I-<Emphasis Type="Italic">β</Emphasis>-CIT-SPECT

Abstract We report on two 33 years old monozygotic twins with chorea-acanthocytosis (ChAc) misdiagnosed as schizophrenia and Tourette syndrome, respectively. Although the patients shared several clinical similarities, there were also some clear differences: twin 1 presented initially with an acute episode of a paranoid schizophrenia, while twin 2 suffered from generalized epileptic seizures. In both twins, MRI demonstrated caudate nucleus atrophy and an increased apparent diffusion coefficient (ADC) in the striatum bilaterally with right sided predominance. ¹⁸F-FDG PET showed bilaterally reduced glucose utilization in the striatum with clearly pronounced reduction on the right side compared to the left and in twin 1 compared to twin 2. Ratios of binding to striatal dopamine transporters (DAT) and serotonin transporters in the hypothalamus midbrain area as determined using ¹²³I-β-CIT-SPECT fell within the normal ranges. However, in twin 1 a significant difference in binding to presynaptic DAT with marked reduction on the right hemisphere was observed. Right hemispheric accentuated changes measured by MRI, FDG-PET, and ¹²³I-β-CITSPECT correspond to more severe hyperkinetic movements on the left part of the body in both twins. Different neuro-psychiatric features in this monocygotic twin pair suggest that not only genetic but also environmental factors contribute to the clinical symptomatology. Our findings suggest that the main neuropathological process in ChAc is located in the striatum, involving microstructural alterations, and disturbance of metabolism and dopaminergic neurotransmission.     

PET imaging of serotoninergic neurotransmission with [11C]DASB and [18F]altanserin after focal cerebral ischemia in rats

The use of selective serotonin reuptake inhibitors has shown functional improvement after stroke. Despite this, the role of serotoninergic neurotransmission after cerebral ischemia evolution and its involvement in functional recovery processes are still largely unknown. For this purpose, we performed in parallel in vivo magnetic resonance imaging and positron emission tomography (PET) with [¹¹C]DASB and [¹⁸F]altanserin at 1, 3, 7, 14, 21, and 28 days after middle cerebral artery occlusion (MCAO) in rats. In the ischemic territory, PET with [¹¹C]DASB and [¹⁸F]altanserin showed a dramatic decline in serotonin transporter (SERT) and 5-HT_2A binding potential in the cortex and striatum after cerebral ischemia. Interestingly, a slight increase in [¹¹C]DASB binding was observed from days 7 to 21 followed by the uppermost binding at day 28 in the ipsilateral midbrain. In contrast, no changes were observed in the contralateral hemisphere by using both radiotracers. Likewise, both functional and behavior testing showed major impaired outcome at day 1 after ischemia onset followed by a recovery of the sensorimotor function and dexterity from day 21 to day 28 after cerebral ischemia. Taken together, these results might evidence that SERT changes in the midbrain could have a key role in the functional recovery process after cerebral ischemia.     

Small-animal PET demonstrates brain metabolic change after using bevacizumab in a rat model of cerebral ischemic injury

To evaluate the effect of bevacizumab on cerebral ischemia, we used 2-deoxy-2-¹⁸F-fluoro-D-glucose (¹⁸F-FDG) small-animal positron emission tomography (PET) in the middle cerebral artery occlusion (MCAO) rat model. After baseline neurologic function tests and PET studies, MCAO Sprague-Dawley rats received bevacizumab or normal saline (controls). Weekly PET imaging and neurologic function tests showed that the ¹⁸F-FDG accumulation in the bevacizumab group was similar to that in the controls during the first 2 weeks, but lower than in controls at weeks 3 and 4. However, no difference was found in neurological scores between the groups. The number of von Willebrand factor-positive cells in the bevacizumab group was lower than that in controls. The expression of vascular endothelial growth factor was higher than in controls at week 4. These results suggested that bevacizumab does not influence functional recovery in this model of cerebral ischemia during a 4-week period, but inhibits vascular formation and metabolic recovery, which may be considered in cancer patients with a recent ischemic stroke.     

Early reperfusion improves the recovery of contralateral electrophysiological diaschisis following focal cerebral ischemia in rats

Abstract

Objectives: We evaluated electrophysiological benefits of reperfusion following ischemic stroke.

Methods: Rats received either transient proximal occlusion of the right middle cerebral artery for 30 (Group I, n=8) or 90 minutes (Group II, n=8) or permanent thermocoagulation of the distal right middle cerebral artery (Group III, n=6). Neurobehavioral outcome and somatosensory evoked potentials (SSEPs) were examined before and at 7 days after the onset of brain ischemia. Brain infarction was assessed after the rats were euthanized.

Results: Before ischemia, stable SSEPs were consistently recorded. At 7 days post-insult, Group III (permanent occlusion) had the greatest reduction in the SSEPs recorded ipsilaterally and contralaterally. Groups I and II (transient ischemic groups) also had depressant SSEPs recorded from the ipsilateral ischemic and the contralateral intact brain (electrophysiological diaschisis). However, prolonged ischemia resulted in greater brain infarction and increased neurological deficits in addition to greater reductions in the ipsilateral and the contralateral SSEPs.

Conclusion: Early reperfusion facilitates the electrophysiological recovery in both ipsilateral lesional and the contralateral intact brain, which may be closely relevant to post-injury brain rewiring. We also demonstrated that contralateral electrophysiological diaschisis could be greatly reversed by early reperfusion and is independent of the lesion size of striatum.     

Comparison of cerebral glucose metabolism between multiple system atrophy Parkinsonian type and Parkinson's disease

OBJECTIVE: To investigate the difference in the regional cerebral glucose metabolism between multiple system atrophy Parkinsonian type (MSA-P) and Parkinson's disease (PD). MATERIAL AND METHODS: Fifteen patients with MSA-P, 32 patients with PD and eight cases of healthy control underwent positron emission tomography (PET) with (18)F-fluorodeoxyglucose ((18)F-FDG) showing glucose metabolism. Glucose metabolism ratios of various cerebral regions were compared as an indicator of regional cerebral glucose metabolic patterns. RESULTS: The metabolism ratios of frontal lobe/occipital lobe, parietal lobe/occipital lobe, temporal lobe/occipital lobe and corpus striatum/occipital lobe in patients with MSA-P were lower than those in patients with PD and control, respectively (p<0.01). For patients with MSAP, the metabolism ratio in thalamus was higher than those in lenticular nucleus and anterior cortical brain, respectively (p<0.01) and the changes of metabolism ratio in cortex, corpus striatum and thalamus were symmetric. For patients with PD, the metabolism ratio in corpus striatum was higher than that in thalamus and two side of the basal ganglia show asymmetric change of metabolism (p<0.01). CONCLUSION: This study suggests that significant differences exist in the patterns of regional cerebral glucose metabolism between MSA-P and PD. (18)F-FDG PET might be a useful adjunctive method for differential diagnosis between MSA-P and PD.     

Differentiating radiation necrosis from tumor recurrence in high-grade gliomas: Assessing the efficacy of F-FDG PET,C-methionine PET and perfusion MRI

Purpose

The authors analyzed the characteristics of perfusion magnetic resonance imaging (MRI), ¹⁸F-fluorodeoxyglucose (FDG) positron emission tomography (PET) and ¹¹C-methionine (MET) PET to compare the efficacies of these modalities in making the distinction between radiation necrosis and tumor recurrence of high-grade glioma.

Patients and methods

Ten patients were evaluated with dynamic susceptibility contrast perfusion MRI, ¹¹C-MET PET and ¹⁸F-FDG PET to visualize gadolinium-enhanced lesions during the post-radiation follow-up period. In the perfusion MRI, four regions of interest (ROIs) were identified and average values were calculated. A reference ROI of the same size was defined in the contralateral white matter to obtain the relative cerebral blood volume (rCBV). After coregistering the PET images with the MRI, we measured the maximum uptake values of the lesion and of the contralateral cerebral white matter as reference area to calculate the L_max/R_max ratio.

Results

The rCBV was higher in the recurrence group than in the necrosis group (p = 0.010). There was no difference between groups in terms of the L_max/R_max ratio as derived from the ¹⁸F-FDG and ¹¹C-MET PET.

Conclusion

A quantitative rCBV as calculated from a perfusion MRI scan might be superior to the L_max/R_max ratio as derived from ¹⁸F-FDG and ¹¹C-MET PET in order to distinguish a recurrence of high-grade glioma from radiation necrosis.     

Characterization of dopaminergic dysfunction in familial progressive supranuclear palsy: an <Superscript>18</Superscript>F-dopa PET study

Summary. We analyzed ¹⁸F-dopa PET data from 11 members of kindreds with familial progressive supranuclear palsy (PSP) to characterize their cerebral dopaminergic dysfunction. Three clinically-affected PSP patients showed reduced ¹⁸F-dopa uptake in the striatum, orbitofrontal cortex and amygdala. One asymptomatic subject exhibited progressive putamen dopaminergic dysfunction. 60% of subjects with abnormal ¹⁸F-dopa scans developed PSP subsequently. This is the first in vivo documentation of cortical dopaminergic deficiency in PSP. Reduced striatal ¹⁸F-dopa uptake in susceptible relatives may predict later clinical disease.     

Are bilateral nigrostriatal dopaminergic pathways functionally linked in the rat brain? A microdialysis study in conscious rats

In the present study, we have infused 6 prototypical drugs known to affect nigrostriatal dopaminergic neurons (kainate, baclofen, muscimol (10 μmol/l), picrotoxin (50 μmol/l), tetrodotoxin (TTX) (5 μmol/l) and 1-methyl-4-phenylpyridinium ion (MPP⁺) (10 mmol/l) via a microdialysis probe unilaterally into the left substantia nigra. During the infusion of these compounds, the extracellular content of dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) was recorded simultaneously via microdialysis cannulas in both left and right striatum. Intranigral infusion of TTX, MPP⁺ and baclofen decreased dopamine release in the ipsilateral striatum, whereas muscimol, picrotoxin and kainate increased dopamine release. No changes were seen in the extracellular content of dopamine in the contralateral striatum. During all experiments, extracellular DOPAC increased in the ipsilateral striatum. No changes were seen in the extracellular content of DOPAC in the contralateral striatum. The present data provide no evidence that the bilateral nigrostriatal dopaminergic pathways are functionally linked in the rat brain.     

Impulse control disorders are associated with lower ventral striatum dopamine D3 receptor availability in Parkinson's disease: A [11C]-PHNO PET study

IntroductionReduced postsynaptic D3 dopaminergic receptor availability has been reported in the ventral striatum of pathological gamblers without Parkinson's disease (PD) and in patients with PD and impulse control disorders (ICD). However, a direct relationship between ventral striatum D3 dopaminergic receptors and the severity of ICD in PD patients has not yet been proven using a validated tool for ICD in PD, such as the Questionnaire for Impulsive-Compulsive Disorders in Parkinson's disease-Rating Scale (QUIP-RS). In this pilot study, we investigated the relationship between ventral striatum D3 dopamine receptor availability and severity of impulse control disorder (ICD) in Parkinson's disease (PD).MethodsTwelve patients were assessed with PET and the high affinity dopamine D3 receptor radioligand [¹¹C]-PHNO. Severity of ICD was assessed with the QUIP-RS.ResultsWe found that lower ventral striatum D3 receptor availability measured with [¹¹C]-PHNO PET was associated with greater severity of ICD, as measured by the QUIP-RS score (rho = −0.625, p = 0.03).ConclusionThese findings suggest that the occurrence and severity of ICD in Parkinson's disease may be linked to reductions in ventral striatum dopamine D3 receptor availability. Further studies in larger cohort of patients need to be performed in order to confirm our findings and clarify whether lower ventral striatum D3 receptor may reflect a pharmacological downregulation to higher dopamine release in ventral striatum of patients with ICD or a patients' predisposition to ICD.