Thomas Siessmeier

Region-specific encoding of sensory and affective components of pain in the human brain: A positron emission tomography correlation analysis.

Brain imaging with positron emission tomography has identified some of the principal cerebral structures of a central network activated by pain. To discover whether the different cortical and subcortical areas process different components of the multidimensional nature of pain, we performed a regression analysis between noxious heat‐related regional blood flow increases and experimental pain parameters reflecting detection of pain, encoding of pain intensity, as well as pain unpleasantness. The results of our activation study indicate that different functions in pain processing can be attributed to different brain regions; ie, the gating function reflected by the pain threshold appeared to be related to anterior cingulate cortex, the frontal inferior cortex, and the thalamus, the coding of pain intensity to the periventricular gray as well as to the posterior cingulate cortex, and the encoding of pain unpleasantness to the posterior sector of the anterior cingulate cortex. Ann Neurol 1999;45:40–47

The unpleasantness of tonic pain is encoded by the insular cortex

Objective: Muscle pain differs from skin pain with respect to quality, accuracy of localization, and unpleasantness. This study was conducted to identify the brain regions associated with the affective-motivational component of tonic skin and muscle pain. Methods: Forty healthy volunteers were investigated in three groups with different F-18 fluorodeoxyglucose PET activation scans. A verbal rating scale (VRS) was used to quantify pain intensity and unpleasantness. One group was investigated during painful infusion of an acidified phosphate buffer (pH 5.2) into either muscle or skin for 30 minutes. Muscle and skin infusions were adjusted to achieve pain intensity rating of VRS = 40. The second group received sham stimulation of muscle and skin by infusion of non-acidified phosphate buffer (pH 7.3 to 7.4, pain intensity = 0). The third group underwent only one PET scan without sensory stimulation. Results: Unpleasantness ratings were higher (VRS 38.3 vs 25.5) during IM compared to intracutaneous stimulation, despite the same pain intensity (VRS = 40). Sham stimulation revealed no pain or unpleasantness. Regional cerebral glucose metabolism during sham stimulation showed similar findings for intracutaneous and IM infusions with significant activations of the bilateral anterior cingulate, bilateral frontal (premotor) cortex, and the ipsilateral parietal operculum. The comparison of pain vs sham stimulation revealed activations of the bilateral insula for IM but not intracutaneous stimulation. The unpleasantness perception in skin and muscle stimulation was positively correlated to the bilateral insular metabolism. Conclusion: The data suggest that the insula represents one main structure where the unpleasantness of tonic pain perception is encoded.

High opiate receptor binding potential in the human lateral pain system.

To determine how opiate receptor distribution is co-localized with the distribution of nociceptive areas in the human brain, eleven male healthy volunteers underwent one PET scan with the subtype-nonselective opioidergic radioligand [(18)F]fluoroethyl-diprenorphine under resting conditions. The binding potential (BP), a parameter for the regional cerebral opioid receptor availability, was computed using the occipital cortex as reference region. The following regions of interest (ROIs) were defined on individual MR images: thalamus, sensory motor strip (SI/MI area), frontal operculum, parietal operculum, anterior insular cortex, posterior insular cortex, anterior cingulate cortex (ACC; peri- and subgenual part of classical ACC only), midcingulate cortex (MCC, posterior part of classical ACC), putamen, caudate nucleus and the amygdala. BP for [(18)F]fluoroethyl-diprenorphine was lowest in the sensory motor strip (0.30). Highest BP was found in thalamus (1.36), basal ganglia (putamen 1.22, caudate 1.16) and amygdala (1.21). In the cingulate cortex, ACC (1.11) had higher BP than MCC (0.86). In the operculo-insular region, we found high BPs in all ROIs: anterior insula (1.16), posterior insula (1.05), frontal operculum (0.99) and parietal operculum (0.77). Factor analysis of interindividual variability of opiate receptor BP revealed four factors (95% explained variance): (1) operculo-insular areas, ACC, MCC and putamen, (2) amygdala and thalamus, (3) caudate and thalamus, (4) SI/MI and MCC. Nociceptive areas of the lateral pain system (frontoparietal operculum and insula) have opiate receptor BPs significantly higher than SI/MI, comparable to anterior and midcingulate areas of the medial pain system. These findings suggest that the cortical anti-nociceptive effects of opiates are not only mediated by ACC and MCC, but also by the operculo-insular cortex, if it can be assumed that opioid binding mediates anti-nociception in those structures.

The thalamus as the generator and modulator of EEG alpha rhythm: a combined PET/EEG study with lorazepam challenge in humans.

BACKGROUNDnPurpose of this study was to investigate the functional relationship between electroencephalographic (EEG) alpha power and cerebral glucose metabolism before and after pharmacological alpha suppression by lorazepam.nnnMETHODSnTen healthy male volunteers were examined undergoing two F18-fluorodeoxyglucose (18-FDG) positron emission tomography (PET) scans with simultaneous EEG recording: 1x placebo, 1x lorazepam. EEG power spectra were computed by means of Fourier analysis. The PET data were analyzed using SPM99, and the correlations between metabolism and alpha power were calculated for both conditions.nnnRESULTSnThe comparison lorazepam versus placebo revealed reduced glucose metabolism of the bilateral thalamus and adjacent subthalamic areas, the occipital cortex and temporo-insular areas (P < 0.001). EEG alpha power was reduced in all derivations (P < 0.001). Under placebo, there was a positive correlation between alpha power and metabolism of the bilateral thalamus and the occipital and adjacent parietal cortex (P < 0.001). Under lorazepam, the thalamic and parietal correlations were maintained, whereas the occipital correlation was no longer detectable (P < 0.001). The correlation analysis of the difference lorazepam-placebo showed the alpha power exclusively correlated with the thalamic activity (P < 0.0001).nnnCONCLUSIONSnThese results support the hypothesis of a close functional relationship between thalamic activity and alpha rhythm in humans mediated by corticothalamic loops which are independent of sensory afferences. The study paradigm could be a promising approach for the investigation of cortico-thalamo-cortical feedback loops in neuropsychiatric diseases.

Elevated [18F]Fluorodopamine Turnover in Brain of Patients with Schizophrenia: An [18F]Fluorodopa/Positron Emission Tomography Study

Previous positron emission tomography (PET) studies with levodopa analogs have revealed a modestly increased capacity for dopamine synthesis in the striatum of patients with schizophrenia compared with healthy age-matched control subjects. We hypothesized that not just the synthesis but also the turnover of radiolabeled dopamine is elevated in patients. To test the hypothesis, we reanalyzed 2-h-long [18F]fluorodopa (FDOPA)/PET recordings from eight unmedicated patients with schizophrenia and 15 healthy age-matched control subjects, using new methods for the quantification of [18F]fluorodopamine steady-state kinetics. The fractional rate constant for the catabolism and elimination of [18F]fluorodopamine was elevated nearly twofold in striatum, the largest biochemical difference in brain of schizophrenics yet reported. The magnitude of the intrinsic blood–brain FDOPA clearance with correction for this loss of [18F]fluorodopamine metabolites was increased by 20% in caudate and putamen and by 50% in amygdala and midbrain of the patients. However, the magnitude of the steady-state storage of FDOPA and its decarboxylated metabolites (Vd) was reduced by one-third in the caudate nucleus and amygdala of the schizophrenic group. Thus, reduced steady-state storage of [18F]fluorodopamine occurs in the midst of accelerated synthesis in brain of untreated patients. Positive scores of the positive and negative syndrome scale correlated inversely with the magnitude of Vd in amygdala, suggesting an association between positive symptoms and impaired steady-state storage of FDOPA metabolites in that structure.

Dose-dependent regional cerebral blood flow changes during remifentanil infusion in humans: a positron emission tomography study.

Background The current study investigated dose-dependent effects of the &mgr;-selective agonist remifentanil on regional cerebral blood flow (rCBF) in volunteers using positron emission tomography (PET). Methods Ten right-handed male volunteers were included in a 15O-water PET study. Seven underwent three conditions: control (saline), low remifentanil (0.05 &mgr;g · kg−1 · min−1), and moderate remifentanil (0.15 &mgr;g · kg−1 · min−1). The remaining three participated in the low and moderate conditions. A semi-randomized study protocol was used with control and remifentanil conditions 3 or more months apart. The order of low and moderate conditions was randomized. Cardiovascular and respiratory parameters were monitored. Categoric comparisons between the control, low, and moderate conditions and a pixelwise correlation analysis across the three conditions were performed (P < 0.05, corrected for multiple comparisons) using statistical parametric mapping. Results Cardiorespiratory parameters were maintained constant over time. At the low remifentanil dose, significant increases in relative rCBF were noted in the lateral prefrontal cortices, inferior parietal cortices, and supplementary motor area. Relative rCBF decreases were observed in the basal mediofrontal cortex, cerebellum, superior temporal lobe, and midbrain gray matter. Moderate doses further increased rCBF in mediofrontal and anterior cingulate cortices, occipital lobe transition, and caudal periventricular grey. Significant decreases were detected in the inferior parietal lobes. These dose-dependent effects of remifentanil on rCBF were confirmed by a correlation analysis. Conclusion Remifentanil induced dose-dependent changes in relative rCBF in areas involved in pain processing. At moderate doses, rCBF responses were additionally detected in structures known to participate in modulation of vigilance and alertness. Insight into the mechanisms of opioid analgesia within the pain-processing neural network may lead to a better understanding of antinociception and opioid treatment.

The Striatal and Extrastriatal D2/D3 Receptor-Binding Profile of Clozapine in Patients with Schizophrenia

Positron emission tomography (PET) studies reveal that clozapine at clinically used doses occupies less than 60% of D2/D3 dopamine receptors in human striatum. Here, the occupancy of D2/D3 dopamine receptors by clozapine in patients with schizophrenia was determined to test the hypothesis that clozapine binds preferentially to extrastriatal dopamine receptors. A total of 15 clozapine-treated inpatients with schizophrenia underwent a [18F]fallypride PET scan. Receptor occupancy was calculated as percent reduction in binding potential relative to unblocked values measured in seven normal volunteers. Mean D2/D3 receptor occupancy was statistically significantly higher in cortical (inferior temporal cortex 55%) than in striatal regions (putamen 36%, caudate 43%, p<0.005). While the maximum attainable receptor occupancy Emax approached 100% both in the striatum and cortex, the plasma concentration at 50% of Emax (ED50) was much higher in the putamen (950u2009ng/ml) than in the inferior temporal cortex (333u2009ng/ml). Clozapine binds preferentially to cortical D2/D3 receptors over a wide range of plasma concentrations. This selectivity is lost at extremely high plasma levels. Occupancy of cortical receptors approaches 60% with plasma clozapine in the range 350–400u2009ng/ml, which corresponds to the threshold for antipsychotic efficacy of clozapine. Extrastriatal binding of clozapine may be more relevant to its antipsychotic actions than striatal. However, further studies with an intraindividual comparison of untreated vs treated state are desirable to confirm this finding.

Decreased Dopamine D2/D3‐Receptor Binding in Temporal Lobe Epilepsy: An [18F]Fallypride PET Study

Summary:u2002 Purpose: Although animal data are suggestive, evidence for an alteration of the extrastriatal dopaminergic system in human focal epilepsy is missing.

Modulation of [18F]fluorodopa (FDOPA) kinetics in the brain of healthy volunteers after acute haloperidol challenge

In animal studies, acute antipsychotic treatment was shown to enhance striatal DOPA-decarboxylase (DDC) activity. However, this phenomenon has not been demonstrated in humans by positron emission tomography (PET). Therefore, we investigated acute haloperidol effects on DDC activity in humans using [18F]fluorodopa (FDOPA) PET. Nine healthy volunteers were scanned with FDOPA in drug-free baseline conditions and after 3 days of haloperidol treatment (5 mg/day). A continuous performance test (CPT) was administered in both conditions. The net blood-brain clearance of FDOPA (K(in)app) in striatum, mesencephalon, and medial prefrontal cortex was calculated by volume-of-interest analysis. The macroparameter K(in)app is a composite of several kinetic terms defining the distribution volume of FDOPA in brain (V(e)D) and the relative activity of DOPA decarboxylase (k3D). Therefore, compartmental kinetic analysis was used to identify the physiological basis of the observed changes in K(in)app period. The magnitude of K(in)app was significantly increased in the putamen (18%) and mesencephalon (36%). Furthermore, V(e)D in the brain was increased by 15%. Increments of k3(D) in the basal ganglia did not attain statistical significance. The significant worsening of CPT results did not correlate with changes in FDOPA utilization. The present PET results indicate potentiation of FDOPA utilization in human basal ganglia by acute haloperidol treatment, apparently due to increased availability throughout the brain. The stimulation of DDC cannot be excluded due to insufficient statistical power in the estimation of k3(D) changes.

Acute alcohol effects on neuronal and attentional processing: striatal reward system and inhibitory sensory interactions under acute ethanol challenge.

The acute influence of ethanol on cerebral activity induces complex psycho-physiological effects that are considerably more pronounced during acute ethanol influx than during maximal blood alcohol concentration (elimination phase). Despite the psychiatric and forensic relevance of these different ethanol effects, the underlying neuronal mechanisms are still unclear. In total, 20 male healthy volunteers were investigated each with three different experimental conditions in a randomized order using an intravenous ethanol challenge (40 g bolus infusion): during influx phase, elimination phase, and under placebo condition. During and after the ethanol (or placebo) infusion, neuropsychological testing of divided attention for visual and auditory stimuli was performed with subsequent 18-FDG PET acquisition. The PET data were analysed using SPM99. Ethanol influx and elimination phase showed focal activations in the bilateral striatum and frontal cortex and deactivations in the occipital cortex. The comparison of influx phase vs elimination phase revealed activations in the anterior cingulate and right prefrontal cortex, relevant deactivations were found in the left superior temporal cortex including Wernickes area. Neuropsychological testing showed an attentional impairment under ethanol influx compared to ethanol elimination and placebo with an inverse correlation of the attentional performance for auditory stimuli to occipital activity and for visual stimuli to the left temporal (including auditory) cortex. Acute ethanol administration in healthy volunteers stimulates those striatal regions that are considered to have a particular relevance for alcohol craving (‘reward system’). Modality specific reciprocal inhibition of sensory cortex activity seems to be relevant for attentional performance during acute alcohol impact.