Biomedical subjects

Jussi Hirvonen

Publications and source records attributed to Jussi Hirvonen.

8 recordsLinked to original sources

PubMed2006

Shape variability of the human striatum--Effects of age and gender.

Human striatum is involved in the regulation of movement, reinforcement, learning, reward, cognitive functioning, and addiction. Previous classical volumetric MRI studies have implicated age-, disease- and medication-related changes in striatal structures. Yet, no studies to date have addressed the effects of these factors on the shape variability and local structural alterations in the striatum. The local alterations may provide meaningful additional information in the context of functional neuroanatomy and brain connectivity. We developed image analysis methodology for the measurement of the volume and local shape variability of the human striatum. The method was applied in a group of 43 healthy controls to study the effects of age and gender on striatal shape variability. In the volume analysis, the volume of the striatum was normalized using the volume of the whole brain. In the local shape analysis, the deviations from a mean surface were studied for each surface point using high-dimensional mapping. Also, discriminant functions were constructed from a statistical shape model. The accuracy and reproducibility of the methods used were evaluated. The results confirmed that the volume of the striatum decreases as a function of age. However, the volume decrease was not uniform and age-related shape differences were observed in several subregions of the human striatum whereas no local gender differences were seen. Examination of the variability of striatal shape in the healthy population will pave the way for applying this method in clinical settings. This method will be particularly useful for investigating neuropsychiatric disorders that are associated with subtle morphological alterations of the brain, such as schizophrenia.

Adult↗

PubMed2006

Measurement of serotonin 5-HT1A receptor binding using positron emission tomography and [carbonyl-(11)C]WAY-100635-considerations on the validity of cerebellum as a reference region.

[Carbonyl-(11)C]WAY-100635 has been used extensively in positron emission tomography (PET) imaging of serotonin 1A receptors (5-HT1A) in vivo in the human brain. Specific binding to receptors is usually estimated using compartmental modeling with arterial plasma input function. The use of reference tissue input (cerebellum) enables quantification without the need of arterial blood sampling, but the accuracy of this method is highly dependent on the validity of the reference region in terms of both specific and nonspecific binding. In this paper, we report exceptionally high uptake of [carbonyl-(11)C]WAY-100635 in the gray matter of cerebellum in one healthy male subject, which was reproducible in repeated PET scanning and most likely represents specific binding to 5-HT1A receptors in cerebellar gray matter. Serotonin 1A receptors are transiently expressed in the human cerebellum during early childhood and usually level off until adolescence but may persist in some individuals. As a methodological implication, the results of this study with regard to test-retest characteristics of [carbonyl-(11)C]WAY-100635 measurements in healthy volunteers using both arterial plasma and reference tissue input functions support the use of cerebellar white matter as reference region, to avoid the potential bias originating from binding of [carbonyl-(11)C]WAY-100635 to 5-HT1A receptors in cerebellar gray matter.

Adult↗

PubMed2006

Brain dopamine d1 receptors in twins discordant for schizophrenia.

OBJECTIVE: It has been suggested that deficits in higher-order cognitive functions serve as intermediate phenotypic indicators of genetic vulnerability to schizophrenia. The dopamine hypothesis of schizophrenia postulates that insufficiency of dopamine transmission in the prefrontal cortex contributes to the cognitive deficits observed in patients with the disease, and there is robust empirical evidence for a central role of prefrontal cortex dopamine D(1) receptors in working memory functions. METHOD: The authors examined the genetic and nongenetic effects on D(1) receptor binding in schizophrenia by studying monozygotic and dizygotic twin pairs discordant for schizophrenia as well as healthy comparison twins using positron emission tomography (PET) and the D(1) receptor antagonist ligand [(11)C]SCH 23390. Performance on neuropsychological tests sensitive to frontal lobe functioning was evaluated. RESULTS: High D(1) receptor density in the medial prefrontal cortex, superior temporal gyrus, and heteromodal association cortex (angular gyrus) was associated with increasing genetic risk for schizophrenia (comparison twins < unaffected dizygotic co-twins < unaffected monozygotic co-twins). Medicated schizophrenia patients demonstrated a widespread reduction in D(1) receptor binding when compared with the unaffected co-twin, and higher doses of antipsychotics were associated with lower D(1) receptor binding in the frontotemporal regions. CONCLUSIONS: This study demonstrated an association between genetic risk for schizophrenia and alterations in cortical D(1) receptor binding, an observation that has implications for future studies of the molecular genetics of schizophrenia. In addition, the data indicate a widespread reduction of D(1) receptor binding in medicated schizophrenia patients, supporting a link between antipsychotic drug action and dopamine D(1) receptor down-regulation.

Benzazepines↗

PubMed2005

Striatal dopamine D1 and D2 receptor balance in twins at increased genetic risk for schizophrenia.

The dopamine hypothesis of schizophrenia postulates that a dysfunctional dopaminergic system is a major pathophysiological mechanism in the disease. Most studies have focused on striatal dopamine D2 receptors, but a disturbed link between dopamine D1 and D2 receptors has also been proposed. Schizophrenia is highly heritable, and recent evidence suggests that alterations in the dopaminergic system confer susceptibility for schizophrenia instead of being solely related to the to overt expression of the disease. To explore the impact of genetic vulnerability for schizophrenia on the balance of striatal dopamine D1 and D2 receptors, we studied monozygotic (MZ) and dizygotic (DZ) unaffected co-twins from twin pairs discordant for schizophrenia as well as healthy control twins using positron emission tomography (PET). Both [(11)C]SCH 23390 and [(11)C]raclopride were used to quantitate D1 and D2 receptor binding, respectively, in the same individuals during the same day. The association between D1 and D2 receptor binding was analyzed using conventional region of interests as well as voxel-wise D1/D2 ratio maps. All levels of analyses failed to show any differences in D1/D2 ratio between the unaffected MZ or DZ co-twins and control twins. We noted rostrocaudally declining and dorsoventrally increasing gradients in D1/D2 ratio in the striatum, with no differences between groups in these gradients. In this sample, we did not find evidence for an association between increased genetic risk for schizophrenia and altered D1/D2 receptor balance in the striatum.

Adult↗

PubMed2005

Cortical glutamate-dopamine interaction and ketamine-induced psychotic symptoms in man.

RATIONALE: The noncompetitive glutamate N-methyl-D: -aspartate receptor antagonist ketamine induces transient psychotic symptoms in man. Involvement of dopaminergic mechanisms in these effects has been suggested. OBJECTIVES: The purpose of this article is to study the effects of ketamine on extrastriatal dopamine receptor availability in healthy subjects and extracellular dopamine levels in rat cortex. MATERIALS AND METHODS: The effect of computer-driven subanesthetic ketamine infusion on cortical dopamine release was studied in healthy male subjects using a controlled study design. Dopamine D2/D3 receptor availability was quantified using positron emission tomography (PET) and [11C]FLB 457. A conventional region of interest-based analysis and voxel-based analysis was applied to the PET data. The ketamine-induced cortical dopamine release in rats was studied using in vivo microdialysis. RESULTS: Ketamine infusion reduced significantly the [11C]FLB 457 binding potential (BP) in the posterior cingulate/retrosplenial cortices, suggestive of increased dopamine release. This brain imaging finding was further supported by a microdialysis experiment in rats showing that ketamine increased the extracellular dopamine concentration by up to 200% in the retrosplenial cortex. Ketamine-induced psychotic symptoms were associated with changes in the [11C]FLB 457 BP in the dorsolateral prefrontal and anterior cingulate cortices. CONCLUSIONS: Our results suggest that cortical dopaminergic mechanisms have a role in the emergence of ketamine-induced psychosis-like symptoms in man. The glutamate-dopamine interaction in the posterior cingulate during ketamine infusion is well in line with the recent functional and structural imaging studies suggesting involvement of this cortical area in the development of schizophrenic psychosis.

Adult↗

PubMed2005

Increased caudate dopamine D2 receptor availability as a genetic marker for schizophrenia.

CONTEXT: Schizophrenia has a heritability of about 80%, but the detailed molecular genetic basis of the disorder has remained elusive. Relative hyperfunction of the subcortical dopamine system has been previously suggested to be one of the key pathophysiologic mechanisms in schizophrenic psychosis. OBJECTIVE: To examine the contributions of genetic vulnerability for schizophrenia to the dopamine system in the human brain. DESIGN: Population-based twin cohort study. SETTING: Finland. PARTICIPANTS: Six monozygotic and 5 dizygotic unaffected co-twins of patients with schizophrenia were ascertained, along with 4 monozygotic and 3 dizygotic healthy control twins with no family history of psychotic disorders. MAIN OUTCOME MEASURES: Striatal dopamine D(2) receptor availability estimated with positron emission tomographic imaging and carbon 11 ((11)C)-labeled raclopride, and performance on neuropsychological tests sensitive to frontal lobe functioning and to schizophrenia vulnerability. RESULTS: Unaffected monozygotic co-twins had increased caudate D(2) density compared with unaffected dizygotic co-twins and healthy control twins. Higher D(2) receptor binding in caudate was associated with a poor performance on cognitive tasks related to schizophrenia vulnerability in the whole sample. CONCLUSIONS: The caudate dopamine D(2) receptor up-regulation is related to genetic risk for schizophrenia. Higher dopamine D(2) receptor density in caudate is also associated with poorer performance on cognitive tasks involving corticostriatal pathways. This finding suggests that caudate dopamine dysregulation is also a trait phenomenon related to psychosis vulnerability. This pattern of results provides a theoretical rationale for early pharmacologic intervention approaches using dopamine D(2) receptor blocking drugs.

Carbon Radioisotopes↗

PubMed2004

Effects of fluoxetine on dopamine D2 receptors in the human brain: a positron emission tomography study with [11C]raclopride.

We have previously reported that repeated dosing with the selective serotonin reuptake inhibitor (SSRI) citalopram decreases striatal [11C]raclopride binding in healthy volunteers. As the SSRI-class antidepressant drugs are believed to have a similar mechanism of action, we wanted to explore whether the prototype SSRI drug, fluoxetine, shares the effects of citalopram on subcortical dopamine neurotransmission. Eight healthy male volunteers were studied using a randomized double-blind placebo-controlled study design. Striatal and thalamic D2-receptor binding was measured at baseline, after a single oral dose (20 mg) of fluoxetine, and after repeated dosing (2 wk, 20 mg/d). The D2-receptor binding potential (BP) was assessed using [11C]raclopride and 3D positron emission tomography. Repeated dosing of fluoxetine decreased BP in the right medial thalamus (p=0.022). Fluoxetine did not decrease striatal BP, but there was a trend (p=0.090) towards increased BP in the left putamen after repeated dosing. A single dose of fluoxetine did not affect BP in the thalamus or striatum. Fluoxetine appears to have a regionally selective effect on the dopaminergic neurotransmission in various areas of the brain. The current results after fluoxetine together with our previous data on citalopram suggest that the modulatory effects of these drugs on striatal dopaminergic neurotransmission are different upon repeated dosing and further substantiates pharmacological differences between SSRI-class drugs.

Adult↗

PubMed2002

Ketamine does not decrease striatal dopamine D2 receptor binding in man.

RATIONALE: A glutamate-dopamine interaction has been implicated in the psychosis-like effects of glutamate N-methyl- D-aspartate (NMDA) receptor antagonists, such as phencyclidine and ketamine. However, recent imaging studies addressing striatal glutamate-dopamine interaction directly in vivo in man have been controversial. OBJECTIVES: To examine whether the NMDA receptor antagonist ketamine in high subanesthetic concentrations decreases striatal [(11)C]raclopride binding potential in man. To further evaluate whether changes in striatal [(11)C]raclopride binding are associated with ketamine-induced behavioral effects. METHODS: The effect of computer-driven subanesthetic ketamine infusion on striatal dopamine release was studied in healthy male subjects using a controlled study design. Dopamine release was studied using positron emission tomography and the [(11)C]raclopride displacement paradigm. A conventional region of interest-based analysis and voxel-based analysis were applied to the positron emission tomography data. RESULTS: The average plasma ketamine concentration was 293+/-29 ng/ml. Ketamine did not alter striatal [(11)C]raclopride binding. Ketamine induced typical behavioral effects, such as hallucinations but there was no correlation between these effects and displacement of [(11)C]raclopride binding. CONCLUSIONS: This controlled study indicates that ketamine does not decrease striatal [(11)C]raclopride binding. Striatal dopamine release is of minor importance in the psychosis-like effects of ketamine.

Adult↗