Deep brain stimulation of the nucleus basalis of Meynert in Alzheimer's dementia.

Cholinergic neurons of the medial forebrain are considered important contributors to brain plasticity and neuromodulation. A reduction of cholinergic innervation can lead to pathophysiological changes of neurotransmission and is observed in Alzheimer's disease. Here we report on six patients with mild to moderate Alzheimer's disease (AD) treated with bilateral low-frequency deep brain stimulation (DBS) of the nucleus basalis of Meynert (NBM). During a four-week double-blind sham-controlled phase and a subsequent 11-month follow-up open label period, clinical outcome was assessed by neuropsychological examination using the Alzheimer's Disease Assessment Scale-cognitive subscale as the primary outcome measure. Electroencephalography and [(18)F]-fluoro-desoxyglucose positron emission tomography were, besides others, secondary endpoints. On the basis of stable or improved primary outcome parameters twelve months after surgery, four of the six patients were considered responders. No severe or non-transitional side effects related to the stimulation were observed. Taking into account all limitations of a pilot study, we conclude that DBS of the NBM is both technically feasible and well tolerated.

Cytoarchitecture, probability maps and functions of the human frontal pole.

The frontal pole has more expanded than any other part in the human brain as compared to our ancestors. It plays an important role for specifically human behavior and cognitive abilities, e.g. action selection (Kovach et al., 2012). Evidence about divergent functions of its medial and lateral part has been provided, both in the healthy brain and in psychiatric disorders. The anatomical correlates of such functional segregation, however, are still unknown due to a lack of stereotaxic, microstructural maps obtained in a representative sample of brains. Here we show that the human frontopolar cortex consists of two cytoarchitectonically and functionally distinct areas: lateral frontopolar area 1 (Fp1) and medial frontopolar area 2 (Fp2). Based on observer-independent mapping in serial, cell-body stained sections of 10 brains, three-dimensional, probabilistic maps of areas Fp1 and Fp2 were created. They show, for each position of the reference space, the probability with which each area was found in a particular voxel. Applying these maps as seed regions for a meta-analysis revealed that Fp1 and Fp2 differentially contribute to functional networks: Fp1 was involved in cognition, working memory and perception, whereas Fp2 was part of brain networks underlying affective processing and social cognition. The present study thus disclosed cortical correlates of a functional segregation of the human frontopolar cortex. The probabilistic maps provide a sound anatomical basis for interpreting neuroimaging data in the living human brain, and open new perspectives for analyzing structure-function relationships in the prefrontal cortex. The new data will also serve as a starting point for further comparative studies between human and non-human primate brains. This allows finding similarities and differences in the organizational principles of the frontal lobe during evolution as neurobiological basis for our behavior and cognitive abilities.

Interoperable atlases of the human brain.

The last two decades have seen an unprecedented development of human brain mapping approaches at various spatial and temporal scales. Together, these have provided a large fundus of information on many different aspects of the human brain including micro- and macrostructural segregation, regional specialization of function, connectivity, and temporal dynamics. Atlases are central in order to integrate such diverse information in a topographically meaningful way. It is noteworthy, that the brain mapping field has been developed along several major lines such as structure vs. function, postmortem vs. in vivo, individual features of the brain vs. population-based aspects, or slow vs. fast dynamics. In order to understand human brain organization, however, it seems inevitable that these different lines are integrated and combined into a multimodal human brain model. To this aim, we held a workshop to determine the constraints of a multi-modal human brain model that are needed to enable (i) an integration of different spatial and temporal scales and data modalities into a common reference system, and (ii) efficient data exchange and analysis. As detailed in this report, to arrive at fully interoperable atlases of the human brain will still require much work at the frontiers of data acquisition, analysis, and representation. Among them, the latter may provide the most challenging task, in particular when it comes to representing features of vastly different scales of space, time and abstraction. The potential benefits of such endeavor, however, clearly outweigh the problems, as only such kind of multi-modal human brain atlas may provide a starting point from which the complex relationships between structure, function, and connectivity may be explored.

Primate prefrontal cortex evolution: human brains are the extreme of a lateralized ape trend.

The prefrontal cortex is commonly associated with cognitive capacities related to human uniqueness: purposeful actions towards higher-level goals, complex social information processing, introspection, and language. Comparative investigations of the prefrontal cortex may thus shed more light on the neural underpinnings of what makes us human. Using histological data from 19 anthropoid primate species (6 apes including humans and 13 monkeys), we investigate cross-species relative size changes along the anterior (prefrontal) and posterior (motor) axes of the cytoarchitectonically defined frontal lobe in both hemispheres. Results reveal different scaling coefficients in the left versus right prefrontal hemisphere, suggest that the primary factor underlying the evolution of primate brain architecture is left hemispheric prefrontal hyperscaling, and indicate that humans are the extreme of a left prefrontal ape specialization in relative white to grey matter volume. These results demonstrate a neural adaptive shift distinguishing the ape from the monkey radiation possibly related to a cognitive grade shift between (great) apes and other primates.

Genetics of primary cerebral gyrification: Heritability of length, depth and area of primary sulci in an extended pedigree of Papio baboons.

Genetic control over morphological variability of primary sulci and gyri is of great interest in the evolutionary, developmental and clinical neurosciences. Primary structures emerge early in development and their morphology is thought to be related to neuronal differentiation, development of functional connections and cortical lateralization. We measured the proportional contributions of genetics and environment to regional variability, testing two theories regarding regional modulation of genetic influences by ontogenic and phenotypic factors. Our measures were surface area, and average length and depth of eleven primary cortical sulci from high-resolution MR images in 180 pedigreed baboons. Average heritability values for sulcal area, depth and length (h(2)(Area)=.38+/-.22; h(2)(Depth)=.42+/-.23; h(2)(Length)=.34+/-.22) indicated that regional cortical anatomy is under genetic control. The regional pattern of genetic contributions was complex and, contrary to previously proposed theories, did not depend upon sulcal depth, or upon the sequence in which structures appear during development. Our results imply that heritability of sulcal phenotypes may be regionally modulated by arcuate U-fiber systems. However, further research is necessary to unravel the complexity of genetic contributions to cortical morphology.

Functional lateralization of face, hand, and trunk representation in anatomically defined human somatosensory areas.

We used functional magnetic resonance imaging (fMRI) and cytoarchitectonic probability maps to investigate the responsiveness of individual areas in the human primary and secondary somatosensory cortices to hand, face, or trunk stimulation of either body-side. A Bayesian modeling approach to quantify the probability of ipsilateral activations revealed that areas OP 1, OP 4, and OP 3 of the SII cortex as well as the trunk and face representations within all SI subareas (areas 3b, 1, and 2) show robust bilateral responses to unilateral stimulation. Such bilateral response properties are in good agreement with the transcallosal projections demonstrated for these areas in nonhuman primates and other mammals. In contrast, the SI hand region showed a different pattern. Whereas ipsilateral areas 3b and 1 were deactivated by tactile hand stimulation, particularly on the left, there was strong evidence for ipsilateral processing of information from the right hand in area 2. These results demonstrate not only the behavioral importance of the hand representation, but also suggest that area 2 may have particularly evolved to form the cortical substrate of these specialized demands, in line with recent studies on cortical evolution hypothesizing that area 2 has developed with increasing manual abilities in anthropoid primates featuring opposable thumbs.

Hierarchical processing of tactile shape in the human brain.

It is not known exactly which cortical areas compute somatosensory representations of shape. This was investigated using positron emission tomography and cytoarchitectonic mapping. Volunteers discriminated shapes by passive or active touch, brush velocity, edge length, curvature, and roughness. Discrimination of shape by active touch, as opposed to passive touch, activated the right anterior lobe of cerebellum only. Areas 3b and 1 were activated by all stimuli. Area 2 was activated with preference for surface curvature changes and shape stimuli. The anterior part of the supramarginal gyrus (ASM) and the cortex lining the intraparietal sulcus (IPA) were activated by active and passive shape discrimination, but not by other mechanical stimuli. We suggest, based on these findings, that somatosensory representations of shape are computed by areas 3b, 1, 2, IPA, and ASM in this hierarchical fashion.

Polymodal motion processing in posterior parietal and premotor cortex: a human fMRI study strongly implies equivalencies between humans and monkeys.

In monkeys, posterior parietal and premotor cortex play an important integrative role in polymodal motion processing. In contrast, our understanding of the convergence of senses in humans is only at its beginning. To test for equivalencies between macaque and human polymodal motion processing, we used functional MRI in normals while presenting moving visual, tactile, or auditory stimuli. Increased neural activity evoked by all three stimulus modalities was found in the depth of the intraparietal sulcus (IPS), ventral premotor, and lateral inferior postcentral cortex. The observed activations strongly suggest that polymodal motion processing in humans and monkeys is supported by equivalent areas. The activations in the depth of IPS imply that this area constitutes the human equivalent of macaque area VIP.

Detection of structural changes of the human brain in longitudinally acquired MR images by deformation field morphometry: methodological analysis, validation and application.

The progression of neurodegenerative diseases as well as healthy aging is accompanied by structural changes of the brain. These changes are often only subtle when considered over time intervals of several months. Therefore morphometrical techniques for their detection in longitudinally acquired MR images must be highly sensitive, and they require a careful validation. In the present study, a novel processing chain for a longitudinal analysis based on deformation field morphometry is described. Procedures for its quantitative validation are also reported: Deformation fields were computed for the simulation of non-linear, local structural changes of human brains. Applying these deformation fields to "original" MR images yielded deformed MR images. The volume changes defined by the deformation fields represented the standard, against which the results of the longitudinal analysis of each pair of original and deformed MR image were compared. The proposed processing chain enabled to localize and to quantify simulated local atrophies near the cortex as well as in deep brain structures. An exemplary analysis of serial MR images of a patient suffering from an atypical Parkinson syndrome (cortico-basal degeneration, CBD) and healthy control subjects is presented, showing a characteristic pattern of volume changes in the brain of the patient which is strikingly different from the controls' patterns of changes.

Stereotaxic probabilistic maps of the magnocellular cell groups in human basal forebrain.

The basal forebrain contains several interdigitating anatomical structures, including the diagonal band of Broca, the basal nucleus of Meynert, the ventral striatum, and also cell groups underneath the globus pallidus that bridge the centromedial amygdala to the bed nucleus of the stria terminalis. Among the cell populations, the magnocellular, cholinergic corticopetal projection neurons have received particular attention due to their loss in Alzheimer's disease. In MRI images, the precise delineation of these structures is difficult due to limited spatial resolution and contrast. Here, using microscopic delineations in ten human postmortem brains, we present stereotaxic probabilistic maps of the basal forebrain areas containing the magnocellular cell groups. Cytoarchitectonic mapping was performed in silver stained histological serial sections. The positions and the extent of the magnocellular cell groups within the septum (Ch1-2), the horizontal limb of the diagonal band (Ch3), and in the sublenticular part of the basal forebrain (Ch4) were traced in high-resolution digitized histological sections, 3D reconstructed, and warped to the reference space of the MNI single subject brain. The superposition of the cytoarchitectonic maps in the MNI brain shows the intersubject variability of the various Ch compartments and their stereotaxic position relative to other brain structures. Both the right and left Ch4 regions showed significantly smaller volumes when age was considered as a covariate. Probabilistic maps of compartments of the basal forebrain magnocellular system are now available as an open source reference for correlation with fMRI, PET, and structural MRI data of the living human brain.

Dopamine, Noradrenaline and Serotonin Receptor Densities in the Striatum of Hemiparkinsonian Rats following Botulinum Neurotoxin-A Injection.

Parkinson's disease (PD) is characterized by a degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) that causes a dopamine (DA) deficit in the caudate-putamen (CPu) accompanied by compensatory changes in other neurotransmitter systems. These changes result in severe motor and non-motor symptoms. To disclose the role of various receptor binding sites for DA, noradrenaline, and serotonin in the hemiparkinsonian (hemi-PD) rat model induced by unilateral 6-hydroxydopamine (6-OHDA) injection, the densities of D1, D2/D3, α1, α2, and 5HT2A receptors were longitudinally visualized and measured in the CPu of hemi-PD rats by quantitative in vitro receptor autoradiography. We found a moderate increase in D1 receptor density 3 weeks post lesion that decreased during longer survival times, a significant increase of D2/D3 receptor density, and 50% reduction in 5HT2A receptor density. α1 receptor density remained unaltered in hemi-PD and α2 receptors demonstrated a slight right-left difference increasing with post lesion survival. In a second step, the possible role of receptors on the known reduction of apomorphine-induced rotations in hemi-PD rats by intrastriatally injected Botulinum neurotoxin-A (BoNT-A) was analyzed by measuring the receptor densities after BoNT-A injection. The application of this neurotoxin reduced D2/D3 receptor density, whereas the other receptors mainly remained unaltered. Our results provide novel data for an understanding of the postlesional plasticity of dopaminergic, noradrenergic and serotonergic receptors in the hemi-PD rat model. The results further suggest a therapeutic effect of BoNT-A on the impaired motor behavior of hemi-PD rats by reducing the interhemispheric imbalance in D2/D3 receptor density.

Brain atlases--a new research tool.

Conventional brain atlases are collections of micrographs or schematic drawings of brain sections from one or a few brains in which anatomical structures are identified, for example, nuclei, cortical areas and fibre tracts. Conventional brain maps have now been replaced with modern computer-based brain atlases. The structures in computerized atlases are deformable so as to fit the sizes and shapes of individual brains, and transform three-dimensional reconstructions or images of brains into a standard brain format. In order to make generalizations about localization of function and structure at both the macroscopical and microscopical level computerized brain atlases are needed. Computerized brain atlases are also used to compensate for the shrinkage and distortions during sectioning and embedding of post-mortem brains, to study structural-functional relationships in the human brain at both the macroscopical and microscopical level, and variations in gross morphology and microstructure of the human brain, and for establishing a three-dimensional human-brain database for all of the above and also for topographically defined data from the literature.

A database generator for human brain imaging.

Sharing scientific data containing complex information requires new concepts and new technology. NEUROGENERATOR is a database generator for the neuroimaging community. A database generator is a database that generates new databases. The scientists submit raw PET and fMRI data to NEUROGENERATOR, which then processes the data in a uniform way to create databases of homogeneous data suitable for data sharing, met-analysis and modelling the human brain at the systems level. These databases are then distributed to the scientists.

Functions and structures of the motor cortices in humans.

Humans and non-human primates have several motor areas. Exactly how many is a matter of current debate. A proper parcellation of motor areas must be based on correlated structural and functional differences. Recent studies indicate that the primary motor cortex may be, in reality, two areas (4a and 4p). Similarly, there are undoubtedly two or more cingulate motor areas and perhaps two supplementary motor areas. The homologies between human and monkey brains are striking in some cases, making monkey models of human motor cortices attractive. The doctrine of a strict 'homuncular' somatotopical organization of motor areas will have to be abandoned. The engagement of motor areas in different types of voluntary seems merely a matter of degree of activation rather than exclusive specific contributions.

A comparison of three SPRITE techniques for the quantitative 3D imaging of the 23Na spin density on a 4T whole-body machine.

Sodium density maps acquired with three SPRITE-based methods have been compared in terms of the resulting quantitative information as well as image quality and acquisition times. Consideration of factors relevant for the clinical implementation of SPRITE shows that the Conical-SPRITE variant is preferred because of a 20-fold reduction in acquisition time, slightly improved image quality, and no loss of quantitative information. The acquisition of a 3D data set (32x32x16; FOV=256x256x160 mm) for the quantitative determination of sodium density is demonstrated. In vivo Conical-SPRITE 23Na images of the brain of a healthy volunteer were acquired in 30 min with a resolution of 7.5x7.5x7.5 mm and a signal-to-noise ratio of 23 in cerebrospinal fluid and 17 in brain tissue.

WITHDRAWN: Immunohistochemical localization of Ih channel HCN3 in the rat brain.

Ahead of Print article withdrawn by publisher

Illusory arm movements activate cortical motor areas: a positron emission tomography study.

Vibration at approximately 70 Hz on the biceps tendon elicits a vivid illusory arm extension. Nobody has examined which areas in the brain are activated when subjects perceive this kinesthetic illusion. The illusion was hypothesized to originate from activations of somatosensory areas normally engaged in kinesthesia. The locations of the microstructurally defined cytoarchitectonic areas of the primary motor (4a and 4p) and primary somatosensory cortex (3a, 3b, and 1) were obtained from population maps of these areas in standard anatomical format. The regional cerebral blood flow (rCBF) was measured with (15)O-butanol and positron emission tomography in nine subjects. The left biceps tendon was vibrated at 10 Hz (LOW), at 70 or 80 Hz (ILLUSION), or at 220 or 240 Hz (HIGH). A REST condition with eyes closed was included in addition. Only the 70 and 80 Hz vibrations elicited strong illusory arm extensions in all subjects without any electromyographic activity in the arm muscles. When the rCBF of the ILLUSION condition was contrasted to the LOW and HIGH conditions, we found two clusters of activations, one in the supplementary motor area (SMA) extending into the caudal cingulate motor area (CMAc) and the other in area 4a extending into the dorsal premotor cortex (PMd) and area 4p. When LOW, HIGH, and ILLUSION were contrasted to REST, giving the main effect of vibration, areas 4p, 3b, and 1, the frontal and parietal operculum, and the insular cortex were activated. Thus, with the exception of area 4p, the effects of vibration and illusion were associated with disparate cortical areas. This indicates that the SMA, CMAc, PMd, and area 4a were activated associated with the kinesthetic illusion. Thus, against our expectations, motor areas rather than somatosensory areas seem to convey the illusion of limb movement.

Object shape differences reflected by somatosensory cortical activation.

Humans can easily by touch discriminate fine details of the shapes of objects. The computation of representations and the representations of objects differing in shape are, when the differences are not founded in different sensory cues or the objects belong to different categories, assumed to take place in a series of cortical areas, which only show differences at the single-neuron level. How the somatosensory cortex computes shape is unknown, but theoretically it should depend heavily on the curvatures of the object surfaces. We measured regional cerebral blood flow (rCBF) of normal volunteers with positron emission tomography (PET) as an index of neuronal activation. One group discriminated a round set of ellipsoids having a narrow spectrum of curvatures and an oblong set of ellipsoids having a broad spectrum of curvatures. Another group discriminated curvatures. When the rCBF from the conditions round and oblong ellipsoid discrimination was contrasted, part of the cortex lining the postcentral sulcus had significantly higher rCBF when ellipsoids having a broader spectrum of curvatures were discriminated. This cortex was also activated by curvature discrimination. The activation is therefore regarded as crucial for the computation of curvature and in accordance with curvature being a major determinant of object form; this cortex is also crucially active in somatosensory shape perception. A comparison of the activation with cytoarchitectural maps, in the anatomical format of the standard brain for both PET and cytoarchitectural brain images, revealed that this part of the cortex lining the postcentral sulcus is situated caudally from cytoarchitectural area 1 and may involve presumptive area 2 on the posterior bank of the sulcus.

Somatotopy and attentional modulation of the human parietal and opercular regions.

The somatotopical organization of the postcentral gyrus is well known, but less is known about the somatotopical organization of area 2, the somatosensory association areas in the postparietal cortex, and the parietal operculum. The extent to which these areas are modulated by attention is also poorly understood. For these reasons, we measured the BOLD signal when rectangular parallelepipeds of varying shape were presented to the immobile right hand or right foot of 10 subjects either discriminating these or just being stimulated. Activation areas in each subject were mapped against cytoarchitectural probability maps of area 2, IP1, and IP2 along the intraparietal sulcus and the parietal opercular areas OP1-OP4. In area 2, the somatotopical representation of the hand and foot were distinctly separate, whereas there was considerable overlap in IP1 and no clear evidence of separate representations in OP1, OP4, and IP2. The overlap of hand and foot representations increased in the following order: area 3a, 3b, 1, 2, IP1, OP4, IP2, and OP1. There were significant foot representations but no hand representations in right (ipsilateral) areas 3a, 3b, and 1. Shape discrimination using the foot as opposed to stimulation enhanced the signal in OP4 bilaterally, whereas discrimination with the hand enhanced the signal bilaterally in area 2, IP1, and IP2. These results indicate that somatosensory areas in humans are arranged from strong somatotopy into no somatotopy in the following order: 3a, 3b, 1, 2, IP1, OP4, IP2, and OP1. Higher order areas such as IP1, IP2, and OP4 showed task-related attentional enhancement.

Layer-specific intracolumnar and transcolumnar functional connectivity of layer V pyramidal cells in rat barrel cortex.

Layer V pyramidal cells in rat barrel cortex are considered to play an important role in intracolumnar and transcolumnar signal processing. However, the precise circuitry mediating this processing is still incompletely understood. Here we obtained detailed maps of excitatory and inhibitory synaptic inputs onto the two major layer V pyramidal cell subtypes, intrinsically burst spiking (IB) and regular spiking (RS) cells, using a combination of caged glutamate photolysis, whole-cell patch-clamp recording, and three-dimensional reconstruction of biocytin-labeled cells. To excite presynaptic neurons with laminar specificity, the release of caged glutamate was calibrated and restricted to small areas of 50 x 50 microm in all cortical layers and in at least two neighboring barrel-related columns. IB cells received intracolumnar excitatory input from all layers, with the largest EPSP amplitudes originating from neurons in layers IV and VI. Prominent transcolumnar excitatory inputs were provided by presynaptic neurons also located in layers IV, V, and VI of neighboring columns. Inhibitory inputs were rare. In contrast, RS cells received distinct intracolumnar inhibitory inputs, especially from layers II/III and V. Intracolumnar excitatory inputs to RS cells were prominent from layers II-V, but relatively weak from layer VI. Conspicuous transcolumnar excitatory inputs could be evoked solely in layers IV and V. Our results show that layer V pyramidal cells are synaptically driven by presynaptic neurons located in every layer of the barrel cortex. RS cells seem to be preferentially involved in intracolumnar signal processing, whereas IB cells effectively integrate excitatory inputs across several columns.