Mathias Schreckenberger

Correlation of positive symptoms exclusively to hyperperfusion or hypoperfusion of cerebral cortex in never-treated schizophrenics

BACKGROUNDnStudies of schizophrenia by single photon emission computed tomography (SPECT) and positron emission tomography (PET) have shown both regional cerebral hyperperfusion and hypoperfusion. The aim of this study was to examine the inter-relations between regional cerebral blood flow (rCBF), psychopathology, and effects of neuroleptic therapy.nnnMETHODSn24 never-treated patients with acute schizophrenia were examined with hexamethylpropyleneamine-oxime brain SPECT and assessed psychopathologically according to the positive and negative syndrome scale; they were studied again after neuroleptic treatment and psychopathological remission. rCBF values that deviated from those of 20 controls by more than 2 SD were regarded as abnormal.nnnFINDINGSnBoth hyperperfused and hypoperfused patterns were found among schizophrenia patients during acute illness. The seven positive symptoms on the symptom scale showed different correlations with rCBF: formal thought disorders and grandiosity correlated positively (and strongly) with bifrontal and bitemporal rCBF; delusions, hallucinations, and distrust correlated negatively (and strongly) with cingulate, left thalamic, left frontal, and left temporal rCBF. Stereotyped ideas as a negative symptom correlated negatively (and strongly) with left frontal, cingulate, left temporal, and left parietal rCBF. After neuroleptic treatment (and reduction of positive symptoms), only negative symptoms correlated exclusively with bifrontal, bitemporal, cingulate, basal ganglia, and thalamic hypoperfusion.nnnINTERPRETATIONnDifferent positive symptoms are accompanied by different rCBF values--some related to hyperperfusion, others to hypoperfusion. This finding may help to explain observed inconsistencies of perfusion patterns in drug-naïve schizophrenics.

Neurometabolic Effects of Psilocybin, 3,4-Methylenedioxyethylamphetamine (MDE) and d-Methamphetamine in Healthy Volunteers A Double-Blind, Placebo-Controlled PET Study with [18F]FDG

The neurometabolic effects of the hallucinogen psilocybin (PSI; 0.2 mg/kg), the entactogen 3,4-methylenedioxyethylamphetamine (MDE; 2 mg/kg) and the stimulant d-methamphetamine (METH; 0.2–0.4 mg/kg) and the drugs’ interactions with a prefrontal activation task were investigated in a double-blind, placebo-controlled human [F-18]fluorodeoxyglucoseFDG-positron emission tomographicPET study (each group: n = 8). Subjects underwent two scans (control: word repetition; activation: word association) within 2–4 weeks. Psilocybin increased rMRGlu in distinct right hemispheric frontotemporal cortical regions, particularly in the anterior cingulate and decreased rMRGlu in the thalamus. Both MDE and METH induced cortical hypometabolism and cerebellar hypermetabolism. In the MDE group, cortical hypometabolism was more pronounced in frontal regions, with the exception of the right anterior cingulate, which tended to be hyperactive. Cognitive activation-related increases in left frontocortical regions were attenuated under all three psychoactive substances, but less so under MDE. Taking into account performance data and subjective reports on task difficulty, these effects may result from different mechanisms across the three groups. Our PSI data are in line with studies on acute schizophrenic patients suggesting frontal overactivity at rest, but diminished capacity to activate prefrontal regions upon cognitive demand. The MDE data support the hypothesis that entactogens constitute a distinct psychoactive substance class, which takes an intermediate position between stimulants and hallucinogens.

Preoperative mapping of cortical language areas in adult brain tumour patients using PET and individual non-normalised SPM analyses

In patients scheduled for the resection of perisylvian brain tumours, knowledge of the cortical topography of language functions is crucial in order to avoid neurological deficits. We investigated the applicability of statistical parametric mapping (SPM) without stereotactic normalisation for individual preoperative language function brain mapping using positron emission tomography (PET). Seven right-handed adult patients with left-sided brain tumours (six frontal and one temporal) underwent 12 oxygen-15 labelled water PET scans during overt verb generation and rest. Individual activation maps were calculated for P<0.005 and P<0.001 without anatomical normalisation and overlaid onto the individuals magnetic resonance images for preoperative planning. Activations corresponding to Brocas and Wernickes areas were found in five and six cases, respectively, for P<0.005 and in three and six cases, respectively, for P<0.001. One patient with a glioma located in the classical Brocas area without aphasic symptoms presented an activation of the adjacent inferior frontal cortex and of a right-sided area homologous to Brocas area. Four additional patients with left frontal tumours also presented activations of the right-sided Brocas homologue; two of these showed aphasic symptoms and two only a weak or no activation of Brocas area. Other frequently observed activations included bilaterally the superior temporal gyri, prefrontal cortices, anterior insulae, motor areas and the cerebellum. The middle and inferior temporal gyri were activated predominantly on the left. An SPM group analysis (P<0.05, corrected) in patients with left frontal tumours confirmed the activation pattern shown by the individual analyses. We conclude that SPM analyses without stereotactic normalisation offer a promising alternative for analysing individual preoperative language function brain mapping studies. The observed right frontal activations agree with proposed reorganisation processes, but they may also reflect an unspecific recruitment of the right-sided Brocas homologue in the effort to perform the task.

Comparison of visual and ROI-based brain tumour grading using 18F-FDG PET: ROC analyses

Several studies have suggested that the use of simple visual interpretation criteria for the investigation of brain tumours by positron emission tomography with fluorine-18 fluorodeoxyglucose (FDG-PET) might be similarly or even more accurate than quantitative or semi-quantitative approaches. We investigated this hypothesis by comparing the accuracy of FDG-PET brain tumour grading using a proposed six-step visual grading scale (VGS; applied by three independent observers unaware of the clinical history and the results of histopathology) and three different region of interest (ROI) ratios (maximal tumour uptake compared with contralateral tissue [Tu/Tis], grey matter [Tu/GM] and white matter [Tu/WM]). The patient population comprised 47 patients suffering from 17 benign (7 gliomas of grade II, 10 non-gliomatous tumours) and 30 malignant (23 gliomas of grade III–IV, 7 non-gliomatous tumours) tumours. The VGS results were highly correlated with the different ROI ratios (R=0.91 for Tu/GM, R=0.82 for Tu/WM, and R=0.79 for Tu/Tis), and high inter-observer agreement was achieved (κ=0.63, 0.76 and 0.81 for the three observers). The mean ROI ratios and VGS readings of gliomatous and non-gliomatous lesions were not significantly different. For all measures, high-grade lesions showed significantly higher FDG uptake than low-grade lesions (P<0.005 to P<0.0001, depending on the measure used). Nominal logistic regressions and receiver operating characteristic (ROC) analyses were used to calculate cut-off values to differentiate low- from high-grade lesions. The predicted (by ROC) diagnostic sensitivity/specificity of the different tests (cut-off ratios shown in parentheses) were: Tu/GM: 0.87/0.85 (0.7), Tu/WM: 0.93/0.80 (1.3), Tu/Tis: 0.80/0.80 (0.8) and VGS: 0.84/0.95 (uptake < GM, but >> WM). The VGS yielded the highest Az (±SE) value (i.e. area under the ROC curve as a measure of predicted accuracy), 0.97±0.03, which showed a strong tendency towards being significantly greater than the Az of Tu/Tis (0.88±0.06; P=0.06). Tu/GM (0.92±0.04) and Tu/WM (0.91±0.05) reached intermediate Az values (not significantly different from any other value). We conclude that the VGS represents a measure at least as accurate as the Tu/GM and Tu/WM ratios. The Tu/Tis ratio is less valid owing to the high dependence on the location of the lesion. Depending on the investigators experience and the structure of the lesions, the easily used VGS might be the most favourable grading criterion.

Functional MRI and 18F FDG-Positron Emission Tomography for Presurgical Planning: Comparison with Electrical Cortical Stimulation

Summary.u2003Background: In patients with mass lesions near “eloquent” cortical areas different preoperative mapping techniques can be used. Two of the most widely used approaches include positron emission tomography (PET) and functional MRI (fMRI). We employed both methods in the same patients undergoing presurgical evaluation and compared the results to those obtained by direct electrical cortical stimulation (DECS).u2003Method: 22 patients with tumours of different aetiology near the central region were investigated. FMRI was performed using a T2*-weighted gradient-echo BOLD sequence at 1.5 T, PET was performed after injection of 122–301 MBq 18F-Fluorodeoxyglucose (18-FDG) under rest and activation conditions. DECS was performed in all patients with recordings of muscles primarily involved in the investigated tasks.u2003Findings: In 19 patients all three modalities could be compared, 1 patient demonstrated discordance between fMRI and PET with DECS speaking in favour of fMRI, 6 patients had neighbouring results of PET and fMRI (between 1–2 cm distance), 12 patients had overlapping results.u2003Interpretation: The high incidence of neighbouring results is presumably related to fMRI specific artefacts. Advantages of fMRI are: Higher spatial and temporal resolution, more and different functional runs, shorter examination time, wider availability, longitudinal examinations, non-invasiveness and cost-effectiveness, easy registration to anatomical images. Advantages of PET are: higher signal-to-noise ratio, lesser susceptibility to artefacts (motion, draining veins), evaluation of tumour metabolism. It is our opinion that the neurosurgeon has to decide on a case-by-case basis which study suits his specific needs in the presurgical evaluation of his patient.

Dual-head gamma camera 2-[fluorine-18]-fluoro-2-deoxy-d-glucose positron emission tomography in oncological patients: effects of non-uniform attenuation correction on lesion detection

Abstract. The purpose of this study was to evaluate a dual head coincidence gamma camera (DH-PET) equipped with single-photon transmission for 2-[fluorine-18]-fluoro-2-deoxy-d-glucose (FDG) imaging in oncological patients. Forty-five patients with known or suspected malignancies, scheduled for a positron emission tomography (PET) scan, were first studied with a dedicated ring PET and subsequently with DH-PET. All patients underwent measured attenuation correction using germanium-68 rod sources for ring PET and caesium-137 sources for DH-PET. Ring PET emission scan was started 64±17 min after intravenous administration of 235±42 MBq FDG. DH-PET emission followed 160±32 min after i.v. FDG. Attenuation-corrected and non-attenuation-corrected images were reconstructed for ring PET and DH-PET. The image sets were evaluated independently by three observers blinded to clinical data and to results of conventional imaging. Attenuation-corrected ring PET as the standard of reference depicted 118 lesions, non-attenuation-corrected ring PET 113 (96%) lesions, and attenuation-corrected DH-PET and non-attenuation-corrected DH-PET, 101 (86%) and 84 (71%) lesions, respectively (P<0.05). The lesion detection rate of attenuation-corrected and non-attenuation-corrected DH-PET was almost similar for lesions >20 mm, whereas attenuation correction increased the detection rate from 60% to 80% for lesions ≤20 mm (P<0.01). A patient-based analysis revealed concordant results relative to attenuation-corrected ring PET for non-attenuation-corrected ring PET, attenuation-corrected DH-PET and non-attenuation-corrected DH-PET in 42 (93%), 36 (80%) and 31 (69%) patients, respectively. Differences might have influenced patient management in two (4%), six (13%) and ten (22%) patients, respectively. In conclusion, measured attenuation correction markedly improves the lesion detection capability of DH-PET. With measured attenuation correction the diagnostic performance of DH-PET is closer to that of dedicated ring PET.

Does thyroid stunning exist? A model with benign thyroid disease

Abstract. With regard to the treatment of differentiated non-medullary thyroid carcinoma, there is controversy over whether radiation from a diagnostic radioiodine (131I) application really does have a suppressive effect on the uptake of subsequent therapeutic 131I (so-called thyroid stunning). However, inherent difficulties in exact remnant/metastatic tissue volumetry make it difficult to quantify how much diagnostic 131I is actually absorbed (absorbed energy dose) and hence to decide whether a threshold absorbed dose exists beyond which such stunning would occur. Since in benign thyroid disease the target volume can be readily quantified by ultrasonography, we sought to determine definitely whether stunning of thyroid cells occurs upon a second application of radioiodine 4 days following the first one. We therefore studied 171 consecutive patients with benign thyroid disease (diffuse goitre, Graves disease, toxic nodular goitre) who received two-step 131I therapy during a single in-patient stay. For application of both calculated 131I activities we performed kinetic dosimetry of 131I uptake, effective half-life and absorbed dose. At the second application, patients showed significant stunning (a 31.7% decrease in 131I uptake, from 34.7%±15.4% at first application to 23.7%±12.3% at second application, P<0.0005) without a significant difference in effective half-life (4.9±1.3 vs 5.0±1.7 days, P>0.2). ANOVA showed that the extent of stunning was influenced significantly only by the absorbed energy dose at first application (F=13.5, P<0.0005), while first-application 131I activity, target volume, gender and thyroid function had no influence (all F≤0.71, all P>0.4). There was no significant correlation between extent of thyroid stunning and first-application 131I activity (r=0.07, P>0.3), whereas there was a highly significant correlation between thyroid stunning and first absorbed energy dose (r=0.64, P<0.00005), the latter correlation fitting a logarithmic model best. Multivariate factor analysis also revealed first absorbed energy dose to be the only decisive stunning factor. In conclusion, our study confirms that stunning exists in benign thyroid conditions and that it is a purely radiobiological inhibitory phenomenon related to absorbed dose.

Localisation of motor areas in brain tumour patients: a comparison of preoperative [18F]FDG-PET and intraoperative cortical electrostimulation

Abstract. Assessment of the exact spatial relation between tumour and adjacent functionally relevant brain areas is a primary tool in the presurgical planning in brain tumour patients. The purpose of this study was to compare a preoperative fluorine-18 fluorodeoxyglucose positron emission tomography ([18F]FDG PET) activation protocol in patients with tumours near the central area with the results of intraoperative direct cortical electrostimulation, and to determine whether non-invasive preoperative PET imaging can provide results equivalent to those achieved with the invasive neurosurgical gold standard. In this prospective study, we examined 20 patients with various tumours of the central area, performing two PET scans (each 30xa0min after i.v. injection of 134–341xa0MBq [18F]FDG) in each patient: (1) a resting baseline scan and (2) an activation scan using a standardised motor task (finger tapping, foot stretching). Following PET/MRI realignment and normalisation to the whole brain counts, parametric images of the activation versus the rest study were calculated and pixels above categorical threshold values were projected to the individual MRI for bimodal assessment of morphology and function (PET/MRI overlay). Intraoperative direct cortical electrostimulation was performed using a Viking IV probe (5 pulses, each of 100xa0µs) and documented using a dedicated neuro navigation system. Results were compared with the preoperative PET findings. PET revealed significant activation of the contralateral primary motor cortex in 95% (19/20) of the brain tumour patients (hand activation 13/13, foot activation 6/7), showing a mean increase in normalised [18F]FDG uptake of 20.5%±5.2% (hand activation task) and 17.2%±2.5% (foot activation task). Additionally detected activation of the ipsilateral primary motor cortex was interpreted as a metabolic indication for interhemispheric compensational processes. Evaluation of the PET findings by cortical stimulation yielded a 94% sensitivity and a 95% specificity for identification of motor-associated brain areas. In conclusion, the findings indicate that a relatively simple and clinically available [18F]FDG PET activation protocol enables a sufficiently precise assessment of the local relation between the intracranial tumour and the adjacent motor cortex areas and may facilitate the presurgical planning of tumour resection.

”Ecstasy”-induced changes of cerebral glucose metabolism and their correlation to acute psychopathology

Abstract. The aim of this study was to determine the acute effects of the ”Ecstasy” analogue MDE (3,4-methylene dioxyethamphetamine) on cerebral glucose metabolism (rMRGlu) of healthy volunteers and to correlate neurometabolism with acute psychopathology. In a randomized double-blind trial, 15 healthy volunteers without a history of drug abuse were examined with fluorine-18-deoxyglucose (18FDG) positron emission tomography (PET) 110–120 min after oral administration of 2 mg/kg MDE (n=7) or placebo (n=8). Two minutes prior to radiotracer injection, constant cognitive stimulation was started and maintained for 32 min using a word repetition paradigm to ensure constant and comparable mental conditions during cerebral glucose uptake. Individual brain anatomy was represented using T1-weighted 3D flash magnetic resonance imaging (MRI), followed by manual regionalization into 108 regions of interest and PET/MRI overlay. After absolute quantification of rMRGlu and normalization to global metabolism, normalized rMRGlu under MDE was compared to placebo using the Mann-Whitney U-test. Acute psychopathology was assessed using the Positive and Negative Syndrome Scale (PANSS) and rMRGlu was correlated to PANSS scores according to Spearman. MDE subjects showed significantly decreased rMRGlu in the bilateral frontal cortex: left frontal posterior (–7.1%, P<0.05) and right prefrontal superior (–4.6%, P<0.05). On the other hand, rMRGlu was significantly increased in the bilateral cerebellum (right: +10.1%, P<0.05; left: +7.6%, P<0.05) and in the right putamen (+6.2%, P<0.05). There were positive correlations between rMRGlu in the middle right cingulate and grandiosity (r=0.87, P<0.05), both the right amygdala (r=0.90, P<0.01) and the left posterior cingulate (r=0.90, P<0.01) to difficulties in abstract thinking, and the right frontal inferior (r=0.85, P<0.05), right anterior cingulate (r=0.93, P<0.01), and left anterior cingulate (r=0.85, P<0.05) to attentional deficits. A negative correlation was found between the left frontal operculum (Broca’s area) and attentional deficits (r=–0.85, P<0.05). The present study revealed acute neurometabolic changes under the ”Ecstasy” analogue MDE, indicating a frontostriatocerebellar imbalance paralleling other psychotropic substances or various psychiatric disorders.

Cerebral interregional correlations of associative language processing: a positron emission tomography activation study using fluorine-18 fluorodeoxyglucose.

Abstract. Even though there have been numerous positron emission tomography (PET) activation studies on the perfusional and metabolic bases of language processing, little is known about the intracerebral functional network of language and cognitive processes. It was the aim of this study to investigate the cerebral interregional correlations during voluntary word association versus word repetition in healthy subjects to gain insight into the functional connectivity of associative speech processing. Due to individual variability in functional anatomy, the study protocol was designed as an averaged single-subject study. Eight healthy volunteers performed a verbal association task during fluorine-18 fluorodeoxyglucose (18F-FDG) PET scanning. Two different tasks were performed in randomized order: (a) word repetition (after auditory presentation of nouns) as a control condition, and (b) word association (after auditory presentation of nouns) as a specific semantic activation. The regional metabolic rate of glucose (rMRGlu) was calculated after brain regionalization [112 regions of interest on individual 3D flash magnetic resonance imaging (MRI)] and PET/MRI realignment. Statistical analysis was performed for comparison of association and repetition and for calculation of interregional correlation coefficients during both tasks. Compared with word repetition, word association was associated with significant increases in rMRGlu in the left prefrontal cortex, the left frontal operculum (Broca’s area) and the left insula, indicating involvement of these areas in associative language processing. Decreased rMRGlu was found in the left posterior cingulum during word association. During word repetition, highly significant negative correlations were found between the left prefrontal cortex, the contralateral cortex areas and the ipsilateral posterior cingulum. These negative correlations were almost completely eliminated during the association task, suggesting a functional decoupling of the strict intercorrelation pattern.