A stereological study of the mediodorsal thalamic nucleus in Down syndrome.

The total number of neurons and glial cells in the mediodorsal thalamic (MDT) nucleus of four aged females with Down syndrome (DS; mean age 69years) was estimated and compared to six age- and sex-matched controls. The MDT nucleus was delineated on coronal sections, and cell numbers (large and small neurons, oligodendrocytes, and astrocytes) were estimated using the optical fractionator technique. The DS brains had an average of 3.41×10(6) total neurons in the MDT nucleus in contrast to 5.97×10(6) in the controls, with no overlap (2p=0.004), affecting large (projecting) and small (local inhibitory) neurons nearly equally. In contrast, we observed no significant differences in either glial cell population. The cortical structures of the same four DS brains were previously estimated to be half the normal size of controls with a reduction in cell numbers whereas the basal ganglia were unaffected. As DS brains are affected by developmental delay, premature aging, and Alzheimer-like pathology, the finite cause of the reduced number of cells in MDT nucleus cannot be determined; however, these findings provide stereological evidence for a local reduction in neuron numbers in the MDT nucleus, which could affect the cognitive capacity of patients with DS.

Sensitivity of different MRI-techniques to assess gray matter atrophy patterns in Alzheimer's disease is region-specific.

The present study compares four different structural magnetic resonance imaging techniques used to measure gray matter (GM) atrophy in Alzheimer's disease (AD): manual and automated volumetry, cortical thickness (CT) and voxel-based morphometry (VBM). These techniques are used interchangeably in AD research and thus far it is unclear which technique is superior in detecting abnormalities early in the disease process. 18 healthy participants without any memory impairment, 18 patients with MCI, and 17 patients with mild AD were included and between-group differences were investigated in AD signature regions (areas in the prefrontal cortex (PFC), medial temporal lobe (MTL) and posterior parietal cortex (PPC)). Both manual volumetric measurements and VBM were able to detect GM atrophy in the early stages (differentiation controls and MCI), mainly in the MTL. In the early phase, automated volumetric measurements showed GM differences in the PPC but not in the MTL. In our sample, CT measurements were not sensitive for group differences in the early stages. PFC regions showed abnormalities in the later stages (controls vs AD) when manual volumetric measurements or VBM are employed. Manual volumetric measurements together with VBM are preferred techniques for assessing GM differences showing abnormalities in most of the investigated regions, with a predominance of the MTL in the early phase. Automated FreeSurfer volumetric measurements show similar performances in the early phase, displaying group differences in the PPC but not in MTL regions. Measurements of CT are less sensitive in the MCI stage and its sensitivity is restricted to the MTL and PPC regions in later stages of the disease (AD).

Age differences in speed of processing are partially mediated by differences in axonal integrity.

Advanced age is associated with declines in brain structure and in cognitive performance, but it is unclear which aspects of brain aging mediate cognitive declines. We inquired if individual differences in white matter integrity contribute to age differences in two cognitive domains with established vulnerability to aging: executive functioning and speed of processing. The participants were healthy volunteers aged 50-81, some of whom had elevated blood pressure, a known vascular risk factor. Using latent variable analyses, we examined whether age differences in regional white matter integrity mediated age-related differences in executive functions and speed of processing. Although diffusion-related latent variables showed stronger age differences than white matter volumes and white matter hyperintensity volumes, only one of them was significantly associated with cognitive performance. Smaller linear anisotropy partially mediated age-related reduction in speed of processing. The effect was significant in posterior (temporal-parietal-occipital) but not anterior (frontal) region, and appeared stronger for cognitive rather than reaction time measures of processing speed. The presence of hypertensive participants did not affect the results. We conclude that in healthy adults, deterioration of axonal integrity and ensuing breech of connectivity may underpin age-related slowing of information processing.

Atrophy in the parahippocampal gyrus as an early biomarker of Alzheimer's disease.

The main aim of the present study was to compare volume differences in the hippocampus and parahippocampal gyrus as biomarkers of Alzheimer's disease (AD). Based on the previous findings, we hypothesized that there would be significant volume differences between cases of healthy aging, amnestic mild cognitive impairment (aMCI), and mild AD. Furthermore, we hypothesized that there would be larger volume differences in the parahippocampal gyrus than in the hippocampus. In addition, we investigated differences between the anterior, middle, and posterior parts of both structures. We studied three groups of participants: 18 healthy participants without memory decline, 18 patients with aMCI, and 18 patients with mild AD. 3 T T1-weighted MRI scans were acquired and gray matter volumes of the anterior, middle, and posterior parts of both the hippocampus and parahippocampal gyrus were measured using a manual tracing approach. Volumes of both the hippocampus and parahippocampal gyrus were significantly different between the groups in the following order: healthy>aMCI>AD. Volume differences between the groups were relatively larger in the parahippocampal gyrus than in the hippocampus, in particular, when we compared healthy with aMCI. No substantial differences were found between the anterior, middle, and posterior parts of both structures. Our results suggest that parahippocampal volume discriminates better than hippocampal volume between cases of healthy aging, aMCI, and mild AD, in particular, in the early phase of the disease. The present results stress the importance of parahippocampal atrophy as an early biomarker of AD.

The posterior parahippocampal gyrus is preferentially affected in age-related memory decline.

Atrophy in the medial temporal lobe is generally considered to be highly associated with age-related memory decline. Volume loss in the hippocampus and entorhinal cortex has extensively been investigated, but the posterior parts of the parahippocampal gyrus have received little attention. The present MRI study investigated whether volume differences in medial temporal lobe areas are differentially related to age-related memory decline. Thirty-nine subjects from a longitudinal study on cognitive aging (the Maastricht Aging Study) have been examined: 20 participants (mean age=67 years, range 52-80) with memory decline over a period of 12 years were matched to 19 participants without memory decline. Manual tracing was performed on 3T MR images to measure the volumes of the anterior, middle and posterior parts of the hippocampus and parahippocampal gyrus. A robust group difference and a significant association with memory decline were observed only in the posterior part of the parahippocampal gyrus. Our results may suggest that the posterior parahippocampal gyrus plays a key role in age-related memory decline.

Multiple indicators of age-related differences in cerebral white matter and the modifying effects of hypertension.

We investigated differences associated with age and hypertension, a common risk factor for vascular disease, in three aspects of white matter integrity--gross regional volumes of the white matter, volume of the white matter hyperintensities (WMH) and diffusion properties. We acquired MRI scans on 93 adult volunteers (age 50-77 years; 36 with diagnosis of hypertension or elevated blood pressure), and obtained all measures in seven brain regions: frontal, temporal, parietal and occipital white matter, and the genu, body and splenium of the corpus callosum. The results demonstrated robust age-related differences in diffusion-based indices of cerebral white matter integrity and age-related increase in the WMH volume, but no age differences in the gross regional volumes of the white matter. Hypertension was associated with decline in fractional anisotropy, and exacerbated age differences in fractional anisotropy more than those in the volume of WMH. These findings indicate that of all examined measures, diffusion-based indices of white matter integrity may be the most sensitive indicators of global and regional declines and vascular damage in the aging brain.

Differential frontal-striatal and paralimbic activity during reversal learning in major depressive disorder and obsessive-compulsive disorder.

BACKGROUND: Several lines of research suggest a disturbance of reversal learning (reward and punishment processing, and affective switching) in patients with major depressive disorder (MDD). Obsessive-compulsive disorder (OCD) is also characterized by abnormal reversal learning, and is often co-morbid with MDD. However, neurobiological distinctions between the disorders are unclear. Functional neuroimaging (activation) studies comparing MDD and OCD directly are lacking. METHOD: Twenty non-medicated OCD-free patients with MDD, 20 non-medicated MDD-free patients with OCD, and 27 healthy controls performed a self-paced reversal learning task in an event-related design during functional magnetic resonance imaging (fMRI). RESULTS: Compared with healthy controls, both MDD and OCD patients displayed prolonged mean reaction times (RTs) but normal accuracy. In MDD subjects, mean RTs were correlated with disease severity. Imaging results showed MDD-specific hyperactivity in the anterior insula during punishment processing and in the putamen during reward processing. Moreover, blood oxygen level-dependent (BOLD) responses in the dorsolateral prefrontal cortex (DLPFC) and the anterior PFC during affective switching showed a linear decrease across controls, MDD and OCD. Finally, the OCD group showed blunted responsiveness of the orbitofrontal (OFC)-striatal loop during reward, and in the OFC and anterior insula during affective switching. CONCLUSIONS: This study shows frontal-striatal and (para)limbic functional abnormalities during reversal learning in MDD, in the context of generic psychomotor slowing. These data converge with currently influential models on the neuropathophysiology of MDD. Moreover, this study reports differential neural patterns in frontal-striatal and paralimbic structures on this task between MDD and OCD, confirming previous findings regarding the neural correlates of deficient reversal learning in OCD.

Prefrontal cortex atrophy predicts dementia over a six-year period.

The present study investigated prefrontal cortex (PFC) atrophy as a possible predictor of dementia. Eighty-eight older participants of the Maastricht Aging Study (MAAS) were administered for neuropsychological tests at baseline and after three years (t(3)). Magnetic resonance images were acquired at t(3) and nine years after baseline all participants were screened for dementia. Three groups were distinguished: (1) participants who did not develop dementia or cognitive decline, (2) participants who did not develop dementia but did show significant cognitive decline, and (3) participants who developed dementia. Gray matter volume of structures in the PFC and medial temporal lobe (MTL) was measured. Prefrontal volume was significantly smaller in group 3 than in the other two groups, and PFC volume was significantly better than MTL volume in distinguishing between groups 2 and 3. These findings suggest that PFC atrophy is highly associated with dementia and can be considered an important predictor of the disease. It may even be a better predictor than the MTL atrophy that has been found in earlier studies.

Contacts between medial and lateral perforant pathway fibers and parvalbumin expressing neurons in the subiculum of the rat.

The entorhinal cortex (EC) projects via the perforant pathway to all subfields in the hippocampal formation. One can distinguish medial and lateral components in the pathway, originating in corresponding medial and lateral subdivisions of EC. We analyzed the innervation by medial and lateral perforant pathway fibers of parvalbumin-expressing neurons in the subiculum. A neuroanatomical tracer (biotinylated dextran amine, BDA) was stereotaxically injected in the medial or lateral entorhinal cortex, thus selectively labeling either perforant pathway component. Transport was allowed for 1 week. Transported BDA was detected with streptavidin-Alexa Fluor 488. Parvalbumin neurons were visualized via immunofluorescence histochemistry, using the fluorochrome Alexa Fluor 594. Via a random systematic sampling scheme using a two-channel, sequential-mode confocal laser scanning procedure, we obtained image series at high magnification from the molecular layer of the subiculum. Labeled entorhinal fibers and parvalbumin-expressing structures were three dimensionally (3D) reconstructed using computer software. Further computer analysis revealed that approximately 16% of the 3D objects ('boutons') of BDA-labeled fibers was engaged in contacts with parvalbumin-immunostained dendrites in the subiculum. Both medial and lateral perforant pathway fibers and their boutons formed such appositions. Contacts are suggestive for synapses. We found no significant differences between the medial and lateral components in the relative numbers of contacts. Thus, the medial and lateral subdivisions of the entorhinal cortex similarly tune the firing of principal neurons in the subiculum by way of parvalbumin positive interneurons in their respective terminal zones.

Effects of psychotherapy on regional cerebral blood flow during trauma imagery in patients with post-traumatic stress disorder: a randomized clinical trial.

BACKGROUND: Functional brain-imaging studies in post-traumatic stress disorder (PTSD) have suggested functional alterations in temporal and prefrontal cortical regions. Effects of psychotherapy on these brain regions have not yet been examined. METHOD: Twenty civilian PTSD out-patients and 15 traumatized control subjects were assessed at baseline using psychometric ratings. Cerebral blood flow was measured using trauma script-driven imagery during 99mtechnetium hexamethyl-propylene-amine-oxime single-photon emission computed tomography scanning. All 20 out-patients were randomly assigned to treatment or wait-list conditions. Treatment was brief eclectic psychotherapy (BEP) in 16 weekly individual sessions. RESULTS: At baseline, greater activation was found in the right insula and right superior/middle frontal gyrus in the PTSD group than in the control group. PTSD patients treated with BEP significantly improved on all PTSD symptom clusters compared to those on the waiting list. After effective psychotherapy, lower activation was measured in the right middle frontal gyrus, compared to the PTSD patients on the waiting list. Treatment effects on PTSD symptoms correlated positively with activation in the left superior temporal gyrus, and superior/middle frontal gyrus. CONCLUSIONS: BEP induced clinical recovery in PTSD patients, and appeared to modulate the functioning of specific PTSD-related sites in the prefrontal cortical regions.

No postnatal doubling of number of neurons in human Broca's areas (Brodmann areas 44 and 45)? A stereological study.

In this study we explored whether a postnatal doubling of the total number of neurons occurs in the human Brodmann areas 44 and 45 (Broca's area). We describe the most recent error prediction formulae and their application for the modern stereological estimators for volume and number of neurons. We estimated the number of neurons in 3D optical disector probes systematically random sampled throughout the entire Brodmann areas (BA) 44 and 45 in developing and young adult cases. In the relatively small number of male and female cases studied no substantial postnatal increase in total number of neurons occurred in areas 44 and 45; the volume of these areas reached adult values around 7 years. In addition, we did find indications that a shift from a right-over-left to a left-over-right asymmetry may occur in the volume of BA 45 during postnatal development. No major asymmetry in total number of neurons in BA 44 and 45 was detected.

Consequences of large interindividual variability for human brain atlases: converging macroscopical imaging and microscopical neuroanatomy.

In human brain imaging studies, it is common practice to use the Talairach stereotaxic reference system for signifying the convergence of brain function and structure. In nearly all neuroimaging reports, the studied cortical areas are specified further with a Brodmann Area (BA) number. This specification is based upon macroscopic extrapolation from Brodmann's projection maps into the Talairach atlas rather than upon a real microscopic cytoarchitectonic study. In this review we argue that such a specification of Brodmann area(s) via the Talairach atlas is not appropriate. Cytoarchitectonic studies reviewed in this paper show large interindividual differences in 3-D location of primary sensory cortical areas (visual cortex) as well as heteromodal associational areas (prefrontal cortical areas), even after correction for differences in brain size and shape. Thus, the simple use of Brodmann cortical areas derived from the Talairach atlas can lead to erroneous results in the specification of pertinent BA. This in turn can further lead to wrong hypotheses on brain system(s) involved in normal functions or in specific brain disorders. In addition, we will briefly discuss the different 'Brodmann' nomenclatures which are in use for the cerebral cortex.

C-fos activation patterns in rat prefrontal cortex during acquisition of a cued classical conditioning task.

The prefrontal cortex (PFC) is known to be involved in associative learning; however, its specific role in acquisition of cued classical conditioning has not yet been determined. Furthermore, the role of regional differences within the PFC in the acquisition of cued conditioning is not well described. These issues were addressed by exposing rats to either one or four sessions of a cued classical conditioning task, and subsequently examining c-fos immunoreactivity in various areas of the PFC. Differences in patterns of c-fos immunopositive nuclei were found when comparing the PFC areas examined. No significant differences were found between rats presented with a temporally contingent conditioned stimulus (CS) light and food (paired groups) and those presented with the same stimuli temporally non-contingently (unpaired groups). In lateral and orbital PFC, both the paired and unpaired groups showed more c-fos immunopositive nuclei than control groups exposed only to the behavioral setup (context exposed groups), and all groups showed a drop in c-fos immunopositive nuclei from session 1 to session 4. In dorsal medial PFC, no differences were seen between the paired, unpaired and context exposed groups. These groups did, however, differ from naive animals, an effect that was not seen in the ventral medial PFC. The results of this study do not support a role for the PFC in the acquisition of a cued classical conditioning task. The differences seen between paired, unpaired and context exposed groups in orbital and lateral PFC could be due to contextual conditioning or reward-related effects.

The need for integrating neuronal morphology databases and computational environments in exploring neuronal structure and function.

Neurons connect to each other through a myriad of dendritic and axonal arborisations. Dendritic structures provide the substrate for integration of postsynaptic potentials and control of action potential generation. Axonal structures provide the substrate for action potential dissemination and signalling to target neurons. The morphological complexity of dendritic arborisations is assumed to play a critical role in the transformation of spatio-temporal patterns of postsynaptic potentials into time-structured series of action potentials. Although these transformations lie at the basis of information processing in the brain, it is still far from understood how their details are influenced by dendritic shape. To facilitate research in this area, it is necessary that data on both the morphology and electrical properties of neurons, as well as computational tools for analysis, become available in an integrated way. This requires a combined effort from the fields of informatics and neurosciences (together called neuroinformatics) in order to create data acquisition, databasing and computational tools. Focusing on neuronal morphology, this chapter will give a brief review of the current neuroinformatics developments in both reconstruction techniques, morphological quantification, modeling of morphological complexity, modeling of function and the need for databasing neuronal morphologies. Additionally, one of the dendritic modeling approaches is described in more detail in the Appendix.

The early differentiation of the neocortex: a hypothesis on neocortical evolution.

During development, a cerebral cortex appears in the wall of the telencephalic vesicle in reptiles and mammals. It arises from a cell-dense cortical plate, which develops within a primordial preplate. The neurons of the preplate are essential for cortical development; they regulate the neuronal migration of the cortical plate neurons and form the first axonal connections. In the reptilian cortex and in the hippocampus of the mammalian cerebral cortex, most ingrowing afferent axons run above the cortical plate, in the zone where the receptive tufts of apical dendrites of the cortical pyramidal neurons branch extensively. In the mammalian neocortex, however, axons enter mainly from below the cortical plate where they do not encounter the apical tufts of these pyramidal neurons. In this paper, we discuss the idea that this difference in cortical development has relieved a functional constraint in the expansion of the cortex during evolution. We hypothesize that the entrance of axons below the cell-dense cortical plate, together with the inside-out migration of cortical neurons, ensures that the neocortex remains an "open" system, able to differentiate into new (sub)layers and more cortical areas.

Thalamic volume predicts performance on tests of cognitive speed and decreases in healthy aging. A magnetic resonance imaging-based volumetric analysis.

Recent studies have indicated a role for the thalamus in attention, arousal and the capacity to perform tasks of speeded information processing. The present study evaluated the role of the thalamus in age-related cognitive decline by investigating the correlations between thalamic volume, cognition and age. This was done in 57 healthy subjects ranging from 21 to 82 years of age. All subjects underwent neurocognitive testing with information processing tests and structural magnetic resonance imaging. A significant decrease in volume of the thalamus with increasing age was found, relatively stronger than and independent of the decrease of total brain volume. The decrease of thalamic volume was apparent before the onset of loss of volume of the total brain. Over the age-span studied, the thalamic decrease in volume correlated with the diminished performance on tests of cognitive speed. Additionally, in young and middle-aged, but not in old subjects, the size of the thalamus predicted performance on tasks that require cognitive speed.

No deficit in total number of neurons in the prefrontal cortex in schizophrenics.

The prefrontal cortex (PFC), defined as the cortical region which has the major reciprocal connections with the mediodorsal thalamic nucleus (MD), has often been implicated in schizophrenia. Morphometric studies have shown altered neuronal density and structure in parts of the PFC in schizophrenic brains. In addition, the MD and nucleus accumbens have shown a significant deficit in total neuron number. The purpose of the present study was to estimate the total neuron number in the PFC in schizophrenics and controls. Using a stereological design, the PFC was studied in eight brains from schizophrenic patients and 10 age-matched control brains. The bilateral average total number of neurons in the PFC was estimated to be 2.76 x 10(9) (CV=S.D./mean=0.15) in the schizophrenic brains whereas that of controls was a non-significantly different value of 3.11 x 10(9) (CV=0.22; P=0.23). Furthermore, no significant differences were found between the two groups in neuronal density (P=0.10) or volume of the PFC (P=0.49). It is of course possible that a neuronal deficit, which cannot be revealed when estimating the total global number of neurons in the whole PFC, might exist in a subregion of the PFC. In conclusion, uniform loss of neuronal soma in the PFC does not appear to constitute the neural substrate of the pathological process in schizophrenia.