Gisela E. Hagberg

Increased dopamine synthesis rate in medial prefrontal cortex and striatum in schizophrenia indicated by L-(β-11C) DOPA and PET

BACKGROUND The aim of the present study was to investigate dopamine synthesis in the brain of drug-free schizophrenic patients, not only in the striatum but also in extrastriatal areas like the prefrontal cortex, brain areas that for a long time has been in focus of interest in the pathophysiology of schizophrenia. METHODS PET was performed in 12 drug-free (10 drug-naive) psychotic schizophrenic patients and 10 healthy volunteers matched for age and gender using 11C-labelled L-DOPA as the tracer. The time-radioactivity curve from occipital cortex (located within Brodman area 17 and 18) was used as input function to calculate L-DOPA influx rate, Ki images, that were matched to a common brain atlas. A significant overall increase of the Ki values was found in the schizophrenic group as compared with healthy controls. RESULTS In particular, significantly higher Ki were found in the schizophrenic patients compared to the controls in the caudate nucleus, putamen and in parts of medial prefrontal cortex (Brod 24). The Ki value reflect an increased utilization of L-DOPA, presumably due to increased activity of the amino acid decarboxylate enzyme. CONCLUSIONS The results indicate that the synthesis of dopamine is elevated within the striatum and parts of medial prefrontal cortex in schizophrenia.

From magnetic resonance spectroscopy to classification of tumors. A review of pattern recognition methods

This article reviews the wealth of different pattern recognition methods that have been used for magnetic resonance spectroscopy (MRS) based tumor classification. The methods have in common that the entire MR spectra is used to develop linear and non‐linear classifiers. The following issues are adressed: (i) pre‐processing, such as normalization and digitization, (ii) extraction of relevant spectral features by multivariate methods, such as principal component analysis, linear discriminant analysis (LDA), and optimal discriminant vector, and (iii) classification by LDA, cluster analysis and artificial neural networks. Different approaches are compared and discussed in view of practical and theoretical considerations.

Functional changes in the activity of cerebellum and frontostriatal regions during externally and internally timed movement in Parkinson's disease.

We used fMRI to investigate the neurofunctional basis of externally and internally timed movements in Parkinsons disease (PD) patients. Ten PD patients whose medication had been withheld for at least 18h and 11 age- and sex-matched healthy controls were scanned while performing continuation paradigm with a visual metronome. Compared with the controls, PD patients displayed an intact capability to store and reproduce movement frequencies but with a significantly increased movement latencies. No differences in BOLD response were found in both groups when comparing the continuation with the preceding synchronization phase and viceversa, except for activity in visually related regions. Relative to healthy controls during the synchronization phase, PD patients exhibited an overall signal increase in the cerebellum and frontostriatal circuit (putamen, SMA and thalamus) activity together with specific brain areas (right inferior frontal gyrus and insula cortex) that are also implicated in primary timekeeper processes. By contrast, in the continuation phase the only neural network involved to a greater extent by the PD group was the cerebello-thalamic pathway. The lack of neurofunctional differences between the two timing phases suggests that rhythmic externally and internally guided movements engage similar neural networks in PD and matched healthy controls. Moreover, between-group comparison indicates that PD patients OFF medication may compensate for their basal ganglia-cortical loops dysfunction using different motor pathways involving cerebellum and basal ganglia relays during the two phases of rhythmic movement.

Volume and iron content in basal ganglia and thalamus

Magnetic resonance imaging (MRI) studies have highlighted the possibility to investigate brain iron content in vivo. In this study, we combined T2* relaxometry and automatic segmentation of basal ganglia based on T1‐weighted images in healthy subjects, with the aim of characterizing age related changes in volume and iron‐related relaxivity values (R2*) of these structures. Thirty healthy subjects underwent MR imaging at 3 Tesla. Mean R2* values and volumes were calculated for the selected subcortical structures (pallidum, putamen, thalamus and caudate nucleus). Our results showed a correlation between R2* values and iron concentration as calculated from published post‐mortem data. Furthermore, we observed a shrinkage/iron increase with a different pattern in the anatomical regions selected in this work, suggesting that the age‐related changes on these MR parameters are specific to the subcortical structure considered. In particular, the putamen demonstrated a decrease of volume and an increase of iron level, with the posterior region of this structure appearing more disposed to iron deposition. Our work suggests that combining volumetry and iron estimation in MRI permits to investigate in vivo neurophysiological and neuropathological changes of basal ganglia. Hum Brain Mapp 2009.

Brain Regions Involved in Fatigue Sensation: Reduced Acetylcarnitine Uptake into the Brain

Fatigue is an indispensable sense for ordering rest. However, the neuronal and molecular mechanisms of fatigue remain unclear. Chronic fatigue syndrome (CFS) with long-lasting fatigue sensation seems to be a good model for studying these mechanisms underlying fatigue sensation. Recently, we found that most patients with CFS showed a low level of serum acetylcarnitine, which well correlated with the rating score of fatigue, and that a considerable amount of acetyl moiety of serum acetylcarnitine is taken up into the brain. Here we show by metabolite analysis of the mouse brain that an acetyl moiety taken up into the brain through acetylcarnitine is mainly utilized for the biosynthesis of glutamate. When we studied the cerebral uptake of acetylcarnitine by using [2-(11)C]acetyl-L-carnitine in 8 patients with CFS and in 8 normal age- and sex-matched controls, a significant decrease was found in several regions of the brains of the patient group, namely, in the prefrontal (Brodmanns area 9/46d) and temporal (BA21 and 41) cortices, anterior cingulate (BA24 and 33), and cerebellum. These findings suggest that the levels of biosynthesis of neurotransmitters through acetylcarnitine might be reduced in some brain regions of chronic fatigue patients and that this abnormality might be one of the keys to unveiling the mechanisms of the chronic fatigue sensation.

Improved detection of event-related functional MRI signals using probability functions.

Selecting an optimal event distribution for experimental use in event-related fMRI studies can require the generation of large numbers of event sequences with characteristics hard to control. The use of known probability distributions offers the possibility to control event timing and constrain the search space for finding optimal event sequences. We investigated different probability distributions in terms of response estimation (estimation efficiency), detectability (detection power, parameter estimation efficiency, sensitivity to true positives), and false-positive activation. Numerous simulated event sequences were generated selecting interevent intervals (IEI) from the uniform, uniform permuted, Latin square, exponential, binomial, Poisson, chi(2), geometric, and bimodal probability distributions and fixed IEI. Event sequences from the bimodal distribution, like block designs, had the best performance for detection and the poorest for estimation, while high estimation and detectability occurred for the long-decay exponential distribution. The uniform distribution also yielded high estimation efficiency, but probability functions with a long tail toward higher IEI, such as the geometric and the chi(2) distributions, had superior detectability. The distributions with the best detection performance also had a relatively high incidence of false positives, in contrast to the ordered distributions (Latin square and uniform permuted). The predictions of improved sensitivities for distributions with long tails were confirmed with empirical data. Moreover, the Latin square design yielded detection of activated voxels similar to the chi(2) distribution. These results indicate that high detection and suitable behavioral designs have compatibility for application of functional MRI methods to experiments requiring complex designs.

The appreciation of wine by sommeliers: a functional magnetic resonance study of sensory integration

We set out to investigate how the expertise of a sommelier is embodied in neural circuitry by comparing brain activity elicited by wine tasting with that found in naive drinkers of wine. We used fMRI to study 7 sommeliers and 7 age- and sex-matched control subjects to test the hypothesis that any difference in brain activity would reflect a learned ability to integrate information from gustatory and olfactory senses with past experience. A group analysis showed activation of a cerebral network involving the left insula and adjoining orbito-frontal cortex in sommeliers. Both these areas have been implicated in gustatory/olfactory integration in primates. In addition, activation was found bilaterally in the dorsolateral prefrontal cortex, which is implicated in high-level cognitive processes such as working memory and selection of behavioral strategies. Naive individuals activated the primary gustatory cortex and brain areas, including the amygdala, implicated in emotional processing.

Voxel-based analysis of R2* maps in the healthy human brain

To develop a voxel‐based analysis of an R2* map of healthy human brain that is automatic, reproducible, and realizable in a single examination on a 3T MR imager. Such a tool could be useful to measure iron accumulation in neurodegenerative diseases.

Realistic simulations of neuronal activity: A contribution to the debate on direct detection of neuronal currents by MRI

Many efforts have been done in order to preview the properties of the magnetic resonance (MR) signals produced by the neuronal currents using simulations. In this paper, starting with a detailed calculation of the magnetic field produced by the neuronal currents propagating over single hippocampal CA1 pyramidal neurons placed inside a cubic MR voxel of length 1.2 mm, we proceeded on the estimation of the phase and magnitude MR signals. We then extended the results to layers of parallel and synchronous similar neurons and to ensembles of layers, considering different echo times, voxel volumes and neuronal densities. The descriptions of the neurons and of their electrical activity took into account the real neuronal morphologies and the physiology of the neuronal events. Our results concern: (a) the expected time course of the MR signals produced by the neuronal currents in the brain, based on physiological and anatomical properties; (b) the different contributions of post-synaptic potentials and of action potentials to the MR signals; (c) the estimation of the equivalent current dipole and the influence of its orientation with respect to the external magnetic field on the observable MR signal variations; (d) the size of the estimated neuronal current induced phase and magnitude MR signal changes with respect to the echo time, voxel-size and neuronal density. The inclusion of realistic neuronal properties into the simulation introduces new information that can be helpful for the design of MR sequences for the direct detection of neuronal current effects and the testing of bio-electromagnetic models.

Characterization of white matter fiber bundles with T2* relaxometry and diffusion tensor imaging

In this study, diffusion tensor imaging (DTI) and T  2* multiecho relaxometry were combined in 30 healthy subjects at 3T, with the aim of characterizing the spatial distribution of relaxation rates in white matter (WM). Region of interest (ROI) analysis was performed in 23 different fiber tracts automatically defined in standard space. Spearman rank analysis was performed on regional values of T  2* , fractional anisotropy (FA), and radial diffusivity (RD). A strong relationship was observed between the location and direction of fiber bundles and relaxation rates, and adjacent fiber bundles with similar orientation showed very different relaxation rates. Moreover, while relaxation rates varied largely between different fiber tracts, variation of the same parameter within the same anatomical fiber bundle across individuals was remarkably limited. The rich variability of relaxation rates in WM and their complex relationship with DTI data suggested that the two techniques might be sensitive to complementary characteristics of myelin structure. This has tremendous potential to allow for a more detailed understanding of brain development and pathology, in particular in the context of age‐related cognitive decline. Magn Reson Med, 2009.