Alfred Buck

Human hippocampus establishes associations in memory

Studies of amnesia have demonstrated that the hippocampus is necessary for long‐term memory, but its precise role in memory is unknown. We designed a positron emission tomography experiment with tailored encoding and retrieval tasks that permitted the isolation of different mnemonic functions theorized to be mediated by the hippocampus. These functions included encoding single items, establishing interitem associations, novelty detection, and retrieving recently formed associations. Of these, we found hippocampal and parahippocampal activation only during associative learning. Our results indicate that the hippocampal formation may be particularly involved in the establishment of associations among components of an episode in memory. Hippocampus 7:249–256, 1997. © 1997 Wiley‐Liss, Inc.

Glucocorticoid-induced impairment of declarative memory retrieval is associated with reduced blood flow in the medial temporal lobe

Previous work indicates that stress levels of circulating glucocorticoids can impair retrieval of declarative memory in human subjects. Several studies have reported that declarative memory retrieval relies on the medial temporal lobe. The present study used \mathrm{H}^{15}_{2}O‐positron emission tomography to investigate whether acutely elevated glucocorticoid levels affect regional cerebral blood flow in the medial temporal lobe, as well as in other brain regions, during declarative memory retrieval in healthy male human subjects. When measured over four different declarative memory retrieval tasks, a single, stress‐level dose of cortisone (25 mg) administered orally 1 h before retention testing, induced a large decrease in regional cerebral blood flow in the right posterior medial temporal lobe, the left visual cortex and the cerebellum. The decrease in the right posterior medial temporal lobe was maximal in the parahippocampal gyrus, a region associated with successful verbal memory retrieval. Cortisone administration also significantly impaired cued recall of word pairs learned 24 h earlier, while drug effects on performance in the other tasks (verbal recognition, semantic generation and categorization) were not significant. The present results provide further evidence that acutely elevated glucocorticoid levels can impair declarative memory retrieval processes and suggest that such impairments may be related to a disturbance of medial temporal lobe function.

Whole-body positron emission tomography using fluorodeoxyglucose for staging of lymphoma: effectiveness and comparison with computed tomography

Abstract. The purpose of this study was to evaluate whole-body positron emission tomography (WB-PET) as a staging modality in Hodgkin’s disease (HD) and non-Hodgkin lymphoma (NHL) and to compare it with computed tomography (CT) in a retrospective study. Seventy-one WB-PET studies using fluorodeoxyglucose (FDG) and 49 CT examinations were performed in 19 women and 31 men. Transaxial images were acquired and reformatted coronally and sagittally in PET. CT sections were obtained from the skull base to the pelvic floor. The written reports of the imaging data were compared with a reference standard constructed on the basis of all the data on the individual patients, including clinical follow-up of at least 6 months. The sensitivity and specificity of PET were, respectively, 86% and 96% for HD (n=53), and 89% and 100% for NHL (n=18). For CT sensitivity and specificity were 81% and 41% for HD (n=33) and 86% and 67% for NHL (n=16). Differences between PET and CT sensitivities were not significant, while in HD there was a significant difference in the specificity of PET and CT examinations, mainly because CT was unable to distinguish between active or recurrent disease and residual scar tissue after therapy. FDG tumour uptake was found in high- as well as low-grade NHL patients. In conclusion, PET appears to be highly sensitive and specific for staging of lymphoma. It is at least as sensitive as CT, and more specific, particularly in patients undergoing restaging, where a well-recognized diagnostic dilemma in CT is the presence of a post-therapeutic residual mass.

Electromagnetic fields, such as those from mobile phones, alter regional cerebral blood flow and sleep and waking EEG

Usage of mobile phones is rapidly increasing, but there is limited data on the possible effects of electromagnetic field (EMF) exposure on brain physiology. We investigated the effect of EMF vs. sham control exposure on waking regional cerebral blood flow (rCBF) and on waking and sleep electroencephalogram (EEG) in humans. In Experiment 1, positron emission tomography (PET) scans were taken after unilateral head exposure to 30‐min pulse‐modulated 900 MHz electromagnetic field (pm‐EMF). In Experiment 2, night‐time sleep was polysomnographically recorded after EMF exposure. Pulse‐modulated EMF exposure increased relative rCBF in the dorsolateral prefrontal cortex ipsilateral to exposure. Also, pm‐EMF exposure enhanced EEG power in the alpha frequency range prior to sleep onset and in the spindle frequency range during stage 2 sleep. Exposure to EMF without pulse modulation did not enhance power in the waking or sleep EEG. We previously observed EMF effects on the sleep EEG (A. A. Borbély, R. Huber, T. Graf, B. Fuchs, E. Gallmann and P. Achermann. Neurosci. Lett., 1999, 275: 207–210; R. Huber, T. Graf, K. A. Cote, L. Wittmann, E. Gallmann, D. Matter, J. Schuderer, N. Kuster, A. A. Borbély, and P. Achermann. Neuroreport, 2000, 11: 3321–3325), but the basis for these effects was unknown. The present results show for the first time that (1) pm‐EMF alters waking rCBF and (2) pulse modulation of EMF is necessary to induce waking and sleep EEG changes. Pulse‐modulated EMF exposure may provide a new, non‐invasive method for modifying brain function for experimental, diagnostic and therapeutic purposes.

In Vivo Evidence for Lactate as a Neuronal Energy Source

Cerebral energy metabolism is a highly compartmentalized and complex process in which transcellular trafficking of metabolites plays a pivotal role. Over the past decade, a role for lactate in fueling the energetic requirements of neurons has emerged. Furthermore, a neuroprotective effect of lactate during hypoglycemia or cerebral ischemia has been reported. The majority of the current evidence concerning lactate metabolism at the cellular level is based on in vitro data; only a few recent in vivo results have demonstrated that the brain preferentially utilizes lactate over glucose. Using voltage-sensitive dye (VSD) imaging, beta-probe measurements of radiotracer kinetics, and brain activation by sensory stimulation in the anesthetized rat, we investigated several aspects of cerebral lactate metabolism. The present study is the first in vivo demonstration of the maintenance of neuronal activity in the presence of lactate as the primary energy source. The loss of the voltage-sensitive dye signal found during severe insulin-induced hypoglycemia is completely prevented by lactate infusion. Thus, lactate has a direct neuroprotective effect. Furthermore, we demonstrate that the brain readily oxidizes lactate in an activity-dependent manner. The washout of 1-[11C]l-lactate, reflecting cerebral lactate oxidation, was observed to increase during brain activation from 0.077 ± 0.009 to 0.105 ± 0.007 min−1. Finally, our data confirm that the brain prefers lactate over glucose as an energy substrate when both substrates are available. Using [18F]fluorodeoxyglucose (FDG) to measure the local cerebral metabolic rate of glucose, we demonstrated a lactate concentration-dependent reduction of cerebral glucose utilization during experimentally increased plasma lactate levels.

Head and neck imaging with PET and PET/CT: artefacts from dental metallic implants

Abstract. Germanium-68 based attenuation correction (PETGe68) is performed in positron emission tomography (PET) imaging for quantitative measurements. With the recent introduction of combined in-line PET/CT scanners, CT data can be used for attenuation correction. Since dental implants can cause artefacts in CT images, CT-based attenuation correction (PETCT) may induce artefacts in PET images. The purpose of this study was to evaluate the influence of dental metallic artwork on the quality of PET images by comparing non-corrected images and images attenuation corrected by PETGe68 and PETCT. Imaging was performed on a novel in-line PET/CT system using a 40-mAs scan for PETCT in 41 consecutive patients with high suspicion of malignant or inflammatory disease. In 17 patients, additional PETGe68 images were acquired in the same imaging session. Visual analysis of fluorine-18 fluorodeoxyglucose (FDG) distribution in several regions of the head and neck was scored on a 4-point scale in comparison with normal grey matter of the brain in the corresponding PET images. In addition, artefacts adjacent to dental metallic artwork were evaluated. A significant difference in image quality scoring was found only for the lips and the tip of the nose, which appeared darker on non-corrected than on corrected PET images. In 33 patients, artefacts were seen on CT, and in 28 of these patients, artefacts were also seen on PET imaging. In eight patients without implants, artefacts were seen neither on CT nor on PET images. Direct comparison of PETGe68 and PETCT images showed a different appearance of artefacts in 3 of 17 patients. Malignant lesions were equally well visible using both transmission correction methods. Dental implants, non-removable bridgework etc. can cause artefacts in attenuation-corrected images using either a conventional 68Ge transmission source or the CT scan obtained with a combined PET/CT camera. We recommend that the non-attenuation-corrected PET images also be evaluated in patients undergoing PET of the head and neck.

Reduced Metabotropic Glutamate Receptor 5 Density in Major Depression Determined by [11C]ABP688 PET and Postmortem Study

OBJECTIVE Clinical and preclinical evidence suggests a hyperactive glutamatergic system in clinical depression. Recently, the metabotropic glutamate receptor 5 (mGluR5) has been proposed as an attractive target for novel therapeutic approaches to depression. The goal of this study was to compare mGluR5 binding (in a positron emission tomography [PET] study) and mGluR5 protein expression (in a postmortem study) between individuals with major depressive disorder and psychiatrically healthy comparison subjects. METHOD Images of mGluR5 receptor binding were acquired using PET with [(11)C]ABP688, which binds to an allosteric site with high specificity, in 11 unmedicated individuals with major depression and 11 matched healthy comparison subjects. The amount of mGluR5 protein was investigated using Western blot in postmortem brain samples of 15 depressed individuals and 15 matched comparison subjects. RESULTS The PET study revealed lower levels of regional mGluR5 binding in the prefrontal cortex, the cingulate cortex, the insula, the thalamus, and the hippocampus in the depression group relative to the comparison group. Severity of depression was negatively correlated with mGluR5 binding in the hippocampus. The postmortem study showed lower levels of mGluR5 protein expression in the prefrontal cortex (Brodmanns area 10) in the depression group relative to the comparison group, while prefrontal mGluR1 protein expression did not differ between groups. CONCLUSIONS The lower levels of mGluR5 binding observed in the depression group are consonant with the lower levels of protein expression in brain tissue in the postmortem depression group. Thus, both studies suggest that basal or compensatory changes in excitatory neurotransmission play roles in the pathophysiology of major depression.

Exposure to pulse‐modulated radio frequency electromagnetic fields affects regional cerebral blood flow

We investigated the effects of radio frequency electromagnetic fields (RF EMF) similar to those emitted by mobile phones on waking regional cerebral blood flow (rCBF) in 12 healthy young men. Two types of RF EMF exposure were applied: a ‘base‐station‐like’ and a ‘handset‐like’ signal. Positron emission tomography scans were taken after 30 min unilateral head exposure to pulse‐modulated 900 MHz RF EMF (10 g tissue‐averaged spatial peak‐specific absorption rate of 1 W/kg for both conditions) and sham control. We observed an increase in relative rCBF in the dorsolateral prefrontal cortex on the side of exposure. The effect depended on the spectral power in the amplitude modulation of the RF carrier such that only ‘handset‐like’ RF EMF exposure with its stronger low‐frequency components but not the ‘base‐station‐like’ RF EMF exposure affected rCBF. This finding supports our previous observation that pulse modulation of RF EMF is necessary to induce changes in the waking and sleep EEG, and substantiates the notion that pulse modulation is crucial for RF EMF‐induced alterations in brain physiology.

Performance of 18F-Fluoro-Ethyl-Tyrosine (18F-FET) PET for the Differential Diagnosis of Primary Brain Tumor: A Systematic Review and Metaanalysis

For the past decade, PET with 18F-fluoro-ethyl-tyrosine (18F-FET) has been used in the evaluation of patients with primary brain tumors (PBTs), but so far series have reported only a limited number of patients. The purpose of this systematic review and metaanalysis was to assess the diagnostic performance of 18F-FET PET in patients with suspicion of PBT. Methods: We examined studies published in the literature using MEDLINE and EMBASE databases. Inclusion criteria were use of 18F-FET PET for initial assessment of patients with a newly diagnosed brain lesion; patients who had no radiotherapy, surgery, or chemotherapy before 18F-FET PET; and use of histology as a gold standard. Metaanalysis was performed on a per-patient basis. We secondarily performed receiver-operating-characteristic analysis of pooled patients to determine tumor-to-background ratio (TBR) of 18F-FET uptake and best diagnostic value. Results: Thirteen studies totaling 462 patients were included. For the diagnosis of PBT, 18F-FET PET demonstrated a pooled sensitivity of 0.82 (95% confidence interval [CI], 0.74–0.88), specificity of 0.76 (95% CI, 0.44–0.92), area under the curve of 0.84 (95% CI, 0.80–0.87), positive likelihood ratio of 3.4 (95% CI, 1.2–9.5), and negative likelihood ratio of 0.24 (95% CI, 0.14–0.39). Receiver-operating-characteristic analysis indicated that a mean TBR threshold of at least 1.6 and a maximum TBR of at least 2.1 had the best diagnostic value for differentiating PBTs from nontumoral lesions. Conclusion: 18F-FET PET demonstrated excellent performance for diagnosing PBTs. Strict standardization of PET acquisition protocols and prospective, multicenter studies investigating the added value over current MRI are now needed to establish 18F-FET PET as a highly relevant tool for patient management.

3,4-Methylenedioxymethamphetamine (MDMA) Modulates Cortical and Limbic Brain Activity as Measured by [H215O]-PET in Healthy Humans

[H215O]-Positron Emission Tomography (PET) was used to examine regional cerebral blood flow (rCBF) after administration of a single oral dose of the serotonin realeaser and uptake inhibitor MDMA (1.7 mg/kg) or placebo to 16 MDMA-naïve subjects. Psychological changes were assessed by psychometric rating scales. MDMA produced distributed changes in regional blood flow including increases in ventromedial frontal and occipital cortex, inferior temporal lobe and cerebellum; and decreases in the motor and somatosensory cortex, temporal lobe including left amygdala, cingulate cortex, insula and thalamus. Concomitant with these changes, subjects experienced heightened mood, increased extroversion, slight derealization and mild perceptual alterations. MDMA also produced increases in blood pressure and several side effects such as jaw clenching, lack of appetite and difficulty concentrating. These results indicate that a distributed cluster of brain areas underlie the various effects of MDMA in humans.