Henk W. Berendse

Chapter 5 The anatomical relationship of the prefrontal cortex with the striatopallidal system, the thalamus and the amygdala: evidence for a parallel organization

Recent findings in primates indicate that the connections of the frontal lobe, the basal ganglia, and the thalamus are organized in a number of parallel, functionally segregated circuits. In the present account, we have focused on the organization of the connections between the prefrontal cortex, the basal ganglia and the mediodorsal thalamic nucleus in the rat. It is concluded that in this species, in analogy with the situation in primates, a number of parallel basal ganglia-thalamocortical circuits exist. Furthermore, data are presented indicating that the projections from particular parts of the amygdala and from individual nuclei of the midline and intralaminar thalamic complex to the prefrontal cortex and the striatum are in register with the arrangements in the parallel circuits. These findings emphasize that the functions of the different subregions of the prefrontal cortex cannot be considered separately but must be viewed as components of the integrative functions of the circuits in which they are involved.

Restricted cortical termination fields of the midline and intralaminar thalamic nuclei in the rat

The projections from the midline and intralaminar thalamic nuclei to the cerebral cortex were studied in the rat by means of anterograde tracing with Phaseolus vulgaris-leucoagglutinin. The midline and intralaminar nuclear complex taken as a whole projects to widespread, predominantly frontal, cortical areas. Each of the constituent thalamic nuclei has a restricted cortical projection field that overlaps only slightly with the projection fields of adjacent midline and intralaminar nuclei. The projections of the intralaminar nuclei cover a larger cortical area than those of the midline nuclei. The laminar distributions of fibres from individual midline and intralaminar thalamic nuclei are different and include both deep and superficial cortical layers. The parataenial, paraventricular and intermediodorsal midline nuclei each project to circumscribed parts of the prefrontal cortex and the hippocampal and parahippocampal regions. In the prefrontal cortex, the projections are restricted to the medial orbital, infralimbic, ventral prelimbic and agranular insular fields, and the rostral part of the ventral anterior cingular cortex. In contrast to the other midline nuclei, the rhomboid nucleus projects to widespread cortical areas. The rostral intralaminar nuclei innervate dorsal parts of the prefrontal cortex, i.e. the dorsal parts of the prelimbic, anterior cingular and dorsal agranular insular cortical fields, the lateral and ventrolateral orbital areas, and the caudal part of the ventral anterior cingular cortex. Additional projections are aimed at the agranular fields of the motor cortex and the caudal part of the parietal cortex. The lateral part of the parafascicular nucleus sends fibres predominantly to the lateral agranular field of the motor cortex and the rostral part of the parietal cortex. The medial part of the parafascicular nucleus projects rather sparsely to the dorsal part of the prelimbic cortex, the anterior cingular cortex and the medial agranular field of the motor cortex. Individual midline and intralaminar thalamic nuclei are thus in a position to directly influence circumscribed areas of the cerebral cortex. In combination with previously reported data on the organization of the midline and intralaminar thalamostriatal projections and the prefrontal corticostriatal projections the present results suggest a high degree of differentiation in the convergence of thalamic and cortical afferent fibres in the striatum. Each of the recently described parallel basal ganglia-thalamocortical circuits can thus be expanded to include projections at both the cortical and striatal levels from a specific part of the midline and intralaminar nuclear complex. The distinctive laminar distributions of the fibres originating from the different nuclei emphasize the specificity of the midline and intralaminar thalamocortical projections.

Organization of the output of the ventral striatopallidal system in the rat: Ventral pallidal efferents

The efferent projections of the ventral pallidum in the rat were studied using anterograde tracing of Phaseolus vulgaris-leucoagglutinin and retrograde tracing of choleratoxin subunit B. The main aim of this study was to determine the degree of topographical organization in the outputs of the ventral pallidum. In the telencephalon, ventral pallidal fibers reach the prefrontal cortex, the ventral striatum, the lateral septum, the basolateral, lateral, and central amygdaloid nuclei, and the lateral entorhinal area. Diencephalic targets of ventral pallidal fibers are the lateral hypothalamus, the reticular nucleus of the thalamus, the mediodorsal thalamic nucleus, the dorsomedial part of the subthalamic nucleus, the medial part of the parafascicular nucleus and the lateral habenula. In the mesencephalon, ventral pallidal fibers terminate in the ventral tegmental area, the substantia nigra, the retrorubral area, the median raphe nucleus, the nucleus raphe magnus, the peribrachial area, the ventromedial part of the central gray substance and the locus coeruleus. The results of the experiments in which retrograde tracers were injected in different nuclei in the mesencephalon allow the distinction of two main areas in the ventral pallidum. Deposits of retrograde tracers in the substantia nigra, pars reticulata result in labeling of cells in the dorsolateral part of the ventral pallidum, located immediately ventral to the anterior limb of the anterior commissure. Retrograde tracer injections in other targets of the ventral mesencephalon, i.e. the dopaminergic cell groups A10, A9 or A8, or nuclei in the peribrachial area result in labeling of neurons in an extensive ventromedial and ventrolateral zone of the ventral pallidum. The medial part of this ventral pallidal zone projects to the ventral tegmental area, whereas ventral and lateral parts connect with more lateral and caudal mesencephalic targets. The projections from the ventral pallidum to the ventral striatum, the subthalamic nucleus and adjacent lateral hypothalamic area, and the mediodorsal thalamic nucleus are distinctly topographically organized. The ventral pallidostriatal projections preserve a medial-to-lateral, a dorsal-to-ventral and, to a lesser degree, a rostral-to-caudal topography. With respect to the subthalamic region, the dorsolateral part of the ventral pallidum projects to the dorsomedial part of the subthalamic nucleus, whereas the ventromedial and ventrolateral parts of the ventral pallidum are topographically connected with the area of the lateral hypothalamus medially adjacent to the subthalamic nucleus.(ABSTRACT TRUNCATED AT 400 WORDS)

The application of graph theoretical analysis to complex networks in the brain

Considering the brain as a complex network of interacting dynamical systems offers new insights into higher level brain processes such as memory, planning, and abstract reasoning as well as various types of brain pathophysiology. This viewpoint provides the opportunity to apply new insights in network sciences, such as the discovery of small world and scale free networks, to data on anatomical and functional connectivity in the brain. In this review we start with some background knowledge on the history and recent advances in network theories in general. We emphasize the correlation between the structural properties of networks and the dynamics of these networks. We subsequently demonstrate through evidence from computational studies, in vivo experiments, and functional MRI, EEG and MEG studies in humans, that both the functional and anatomical connectivity of the healthy brain have many features of a small world network, but only to a limited extent of a scale free network. The small world structure of neural networks is hypothesized to reflect an optimal configuration associated with rapid synchronization and information transfer, minimal wiring costs, resilience to certain types of damage, as well as a balance between local processing and global integration. Eventually, we review the current knowledge on the effects of focal and diffuse brain disease on neural network characteristics, and demonstrate increasing evidence that both cognitive and psychiatric disturbances, as well as risk of epileptic seizures, are correlated with (changes in) functional network architectural features.

Subclinical dopaminergic dysfunction in asymptomatic Parkinson's disease patients' relatives with a decreased sense of smell

By the time a clinical diagnosis of Parkinsons disease (PD) is made, a significant loss of dopaminergic neurons has already occurred. Identifying patients in the period between the presumed onset of dopaminergic cell loss and the appearance of clinical parkinsonism may be of major importance in the development of effective neuroprotective treatment strategies. In an effort to develop a feasible strategy to detect preclinical PD, a combination of olfactory processing tasks, including odor detection, odor identification, and odor discrimination was used to select groups of hyposmic and normosmic individuals from a total of 250 relatives (parents, siblings, or children) of subjects with PD. Single photon emission computed tomography (SPECT) with [123I]β‐CIT as a dopamine transporter ligand was used to assess nigrostriatal dopaminergic function in 25 hyposmic and 23 normosmic relatives of PD patients. An abnormal reduction in striatal dopamine transporter binding was found in 4 out of 25 hyposmic relatives of PD patients, 2 of whom subsequently developed clinical parkinsonism, and in none of the 23 normosmic relatives. These observations demonstrate that subclinical reductions in dopamine transporter binding can be detected in asymptomatic relatives of sporadic PD patients by means of [123I]β‐CIT and SPECT. The results further indicate that olfactory deficits may precede clinical motor signs in PD.

Magnetoencephalographic evaluation of resting-state functional connectivity in Alzheimer's disease

Statistical interdependencies between magnetoencephalographic signals recorded over different brain regions may reflect the functional connectivity of the resting-state networks. We investigated topographic characteristics of disturbed resting-state networks in Alzheimers disease patients in different frequency bands. Whole-head 151-channel MEG was recorded in 18 Alzheimer patients (mean age 72.1 years, SD 5.6; 11 males) and 18 healthy controls (mean age 69.1 years, SD 6.8; 7 males) during a no-task eyes-closed resting state. Pair-wise interdependencies of MEG signals were computed in six frequency bands (delta, theta, alpha1, alpha2, beta and gamma) with the synchronization likelihood (a nonlinear measure) and coherence and grouped into long distance (intra- and interhemispheric) and short distance interactions. In the alpha1 and beta band, Alzheimer patients showed a loss of long distance intrahemispheric interactions, with a focus on left fronto-temporal/parietal connections. Functional connectivity was increased in Alzheimer patients locally in the theta band (centro-parietal regions) and the beta and gamma band (occipito-parietal regions). In the Alzheimer group, positive correlations were found between alpha1, alpha2 and beta band synchronization likelihood and MMSE score. Resting-state functional connectivity in Alzheimers disease is characterized by specific changes of long and short distance interactions in the theta, alpha1, beta and gamma bands. These changes may reflect loss of anatomical connections and/or reduced central cholinergic activity and could underlie part of the cognitive impairment.

Loss of olfaction in de novo and treated Parkinson's disease: Possible implications for early diagnosis

Olfactory dysfunction is a common finding in patients with Parkinsons disease (PD). As most studies reported on odor identification in more advanced and treated PD, we administered an odor detection, discrimination, and identification test to a heterogeneous, partly de novo, group of patients. Forty‐one non‐demented PD patients, 24 of whom had untreated early PD, and 18 healthy controls, were examined. Odor identification and discrimination data were corrected for odor detection scores. PD patients scored significantly lower on all olfactory tests. Interestingly, the subgroup of de novo patients with early PD also showed significant olfactory disturbances compared with healthy subjects. Within the PD group, using multiple regression analysis, we found a significant, negative correlation between odor discrimination measures and disease severity.

Frequency-dependent functional connectivity within resting-state networks: An atlas-based MEG beamformer solution

The brain consists of functional units with more-or-less specific information processing capabilities, yet cognitive functions require the co-ordinated activity of these spatially separated units. Magnetoencephalography (MEG) has the temporal resolution to capture these frequency-dependent interactions, although, due to volume conduction and field spread, spurious estimates may be obtained when functional connectivity is estimated on the basis of the extra-cranial recordings directly. Connectivity estimates on the basis of reconstructed sources may similarly be affected by biases introduced by the source reconstruction approach. Here we propose an analysis framework to reliably determine functional connectivity that is based around two main ideas: (i) functional connectivity is computed for a set of atlas-based ROIs in anatomical space that covers almost the entire brain, aiding the interpretation of MEG functional connectivity/network studies, as well as the comparison with other modalities; (ii) volume conduction and similar bias effects are removed by using a functional connectivity estimator that is insensitive to these effects, namely the Phase Lag Index (PLI). Our analysis approach was applied to eyes-closed resting-state MEG data for thirteen healthy participants. We first demonstrate that functional connectivity estimates based on phase coherence, even at the source-level, are biased due to the effects of volume conduction and field spread. In contrast, functional connectivity estimates based on PLI are not affected by these biases. We then looked at mean PLI, or weighted degree, over areas and subjects and found significant mean connectivity in three (alpha, beta, gamma) of the five (including theta and delta) classical frequency bands tested. These frequency-band dependent patterns of resting-state functional connectivity were distinctive; with the alpha and beta band connectivity confined to posterior and sensorimotor areas respectively, and with a generally more dispersed pattern for the gamma band. Generally, these patterns corresponded closely to patterns of relative source power, suggesting that the most active brain regions are also the ones that are most-densely connected. Our results reveal for the first time, using an analysis framework that enables the reliable characterisation of resting-state dynamics in the human brain, how resting-state networks of functionally connected regions vary in a frequency-dependent manner across the cortex.

Generalized synchronization of MEG recordings in Alzheimer's Disease: evidence for involvement of the gamma band.

Summary The purpose of this study was to investigate interdependencies in whole-head magnetoencephalography (MEG) of Alzheimer patients and healthy control subjects. Magnetoencephalograms were recorded in 20 Alzheimer patients (11 men; mean age, 69.0 years [standard deviation, 8.2 years]); Mini-Mental State Examination score, 21.3 points; range, 15 to 27 points) and 20 healthy control subjects (9 men; mean age, 66.4 years [standard deviation, 9.0 years]) during a no-task eyes-closed condition with a 151 channel whole-head MEG system. Synchronization likelihood (a new measure for linear as well as nonlinear interdependencies between signals) and coherence were computed for each channel in different frequency bands (2 to 6, 6 to 10, 10 to 14, 14 to 18, 18 to 22, 22 to 40 Hz). Synchronization was lower in Alzheimer patients in the upper &agr; band (10 to 14 Hz), the upper &bgr; band (18 to 22 Hz), and the &ggr; band (22 to 40 Hz). In contrast, coherence did not show significant group differences at the p<0.05 level. The synchronization likelihood showed a spatial pattern (high synchronization central, parietal and right frontal; low synchronization, occipital and temporal). This study confirms a widespread loss of functional interactions in the &agr; and &bgr; bands, and provides the first evidence for loss of &ggr; band synchronization in Alzheimer’s disease. Synchronization likelihood may be more sensitive to detect such changes than the commonly used coherence analysis.

Genome-wide association study confirms extant PD risk loci among the Dutch.

In view of the population-specific heterogeneity in reported genetic risk factors for Parkinsons disease (PD), we conducted a genome-wide association study (GWAS) in a large sample of PD cases and controls from the Netherlands. After quality control (QC), a total of 514 799 SNPs genotyped in 772 PD cases and 2024 controls were included in our analyses. Direct replication of SNPs within SNCA and BST1 confirmed these two genes to be associated with PD in the Netherlands (SNCA, rs2736990: P=1.63 × 10−5, OR=1.325 and BST1, rs12502586: P=1.63 × 10−3, OR=1.337). Within SNCA, two independent signals in two different linkage disequilibrium (LD) blocks in the 3′ and 5′ ends of the gene were detected. Besides, post-hoc analysis confirmed GAK/DGKQ, HLA and MAPT as PD risk loci among the Dutch (GAK/DGKQ, rs2242235: P=1.22 × 10−4, OR=1.51; HLA, rs4248166: P=4.39 × 10−5, OR=1.36; and MAPT, rs3785880: P=1.9 × 10−3, OR=1.19).