Improving Cavalieri volume estimation based on non-equidistant planar sections: The trapezoidal estimator.

The Cavalieri estimator allows one to infer the volume of an object from area measurements in equidistant planar sections. It is known that applying this estimator in the non-equidistant case may inflate the coefficient of error considerably. We therefore consider a newly introduced variant, the trapezoidal estimator, and make it available to practitioners.

Evaluating the Feasibility of DNA Methylation Analyses Using Long-Term Archived Brain Formalin-Fixed Paraffin-Embedded Samples.

We here characterize the usability of archival formalin-fixed paraffin-embedded (FFPE) brain tissue as a resource for genetic and DNA methylation analyses with potential relevance for brain-manifested diseases. We analyzed FFPE samples from The Brain Collection, Aarhus University Hospital Risskov, Denmark (AUBC), constituting 9479 formalin-fixated brains making it one of the largest collections worldwide. DNA extracted from brain FFPE tissue blocks was interrogated for quality and usability in genetic and DNA methylation analyses by different molecular techniques.

Postmortem structural studies of the thalamus in schizophrenia.

In this review, we seek to answer the following question: Do findings in the current literature support the idea that thalamo-cortical dysfunction in schizophrenia is due to structural abnormalities in the thalamus? We base our review on the existing literature of design-unbiased stereological studies of the postmortem thalamus from subjects with schizophrenia. Thus, all reported results are based upon the use of unbiased principles of sampling to determine volume and/or total cell numbers of thalamus or its constituent nuclei. We found 28 such papers covering 26 studies.

Loss of Microtubule-Associated Protein 2 Immunoreactivity Linked to Dendritic Spine Loss in Schizophrenia.

Background: Microtubule-associated protein 2 (MAP2) is a neuronal protein that plays a role in maintaining dendritic structure through its interaction with microtubules. In schizophrenia (Sz), numerous studies have revealed that the typically robust immunoreactivity (IR) of MAP2 is significantly reduced across several cortical regions. The relationship between MAP2-IR reduction and lower dendritic spine density, which is frequently reported in Sz, has not been explored in previous studies, and MAP2-IR loss has not been investigated in the primary auditory cortex (Brodmann area 41), a site of conserved pathology in Sz.

Intracortical excitatory and thalamocortical boutons are intact in primary auditory cortex in schizophrenia.

Schizophrenia is associated with auditory processing impairments that could arise as a result of primary auditory cortex excitatory circuit pathology. We have previously reported a deficit in dendritic spine density in deep layer 3 of primary auditory cortex in subjects with schizophrenia. As boutons and spines can be structurally and functionally co-regulated, we asked whether the densities of intracortical excitatory or thalamocortical presynaptic boutons are also reduced.

Reduced glutamate decarboxylase 65 protein within primary auditory cortex inhibitory boutons in schizophrenia.

Background: Schizophrenia is associated with perceptual and physiological auditory processing impairments that may result from primary auditory cortex excitatory and inhibitory circuit pathology. High-frequency oscillations are important for auditory function and are often reported to be disrupted in schizophrenia. These oscillations may, in part, depend on upregulation of gamma-aminobutyric acid synthesis by glutamate decarboxylase 65 (GAD65) in response to high interneuron firing rates.

Design-based stereology: introduction to basic concepts and practical approaches for estimation of cell number.

In regulatory toxicology studies, qualitative histopathological evaluation is the reference standard for assessment of test article-related morphological changes. In certain cases, quantitative analysis may be required to detect more subtle morphological changes, such as small changes in cell number. When the detection of subtle test article-related morphological changes is critical to the decision-making process, sensitive quantitative methods are needed.

Stereological approaches to identifying neuropathology in psychosis.

The challenges involved in identifying the neuropathological substrates of the clinical syndrome recognized as schizophrenia are well known. Stereological sampling provides a means to obtain accurate and precise quantitative estimates of components of neural circuits and thus offers promise of an enhanced capacity to detect subtle alterations in brain structure associated with schizophrenia. In this review, we 1) consider the importance and rationale for robust quantitative measures of brain abnormalities in postmortem studies of schizophrenia; 2) provide a brief overview of stereological methods for obtaining such measures; 3) discuss the methodological details that should be reported to document the robustness of a stereological study; 4) given the constraints of postmortem human studies, suggest how to approach the limitations of less robust designs; and 5) present an overview of methodologically sound stereological estimates from postmortem studies of schizophrenia.

Pyramidal neuron number in layer 3 of primary auditory cortex of subjects with schizophrenia.

Individuals with schizophrenia demonstrate impairments of sensory processing within primary auditory cortex. We have previously identified lower densities of dendritic spines and axon boutons, and smaller mean pyramidal neuron somal volume, in layer 3 of the primary auditory cortex in subjects with schizophrenia, all of which might reflect fewer layer 3 pyramidal neurons in schizophrenia. To examine this hypothesis, we developed a robust stereological method based upon unbiased principles for estimation of total volume and pyramidal neuron numbers for each layer of a cortical area.

Volume and neuron number of the lateral geniculate nucleus in schizophrenia and mood disorders.

Subjects with schizophrenia show deficits in visual perception that suggest changes predominantly in the magnocellular pathway and/or the dorsal visual stream important for visiospatial perception. We previously found a substantial 25% reduction in neuron number of the primary visual cortex (Brodmann's area 17, BA17) in postmortem tissue from subjects with schizophrenia. Also, many studies have found reduced volume and neuron number of the pulvinar--the large thalamic association nucleus involved in higher-order visual processing.

Effect of chronic antipsychotic exposure on astrocyte and oligodendrocyte numbers in macaque monkeys.

Background: Both in vivo and postmortem studies suggest that oligodendrocyte and myelination alterations are present in individuals with schizophrenia. However, it is unclear whether prolonged treatment with antipsychotic medications contributes to these disturbances. We recently reported that chronic exposure of macaque monkeys to haloperidol or olanzapine was associated with a 10%-18% lower glial cell number in the parietal grey matter.

Primary visual cortex volume and total neuron number are reduced in schizophrenia.

A number of studies that assessed the visual system in subjects with schizophrenia found impairments in early visual processing. Furthermore, functional imaging studies suggested changes in primary visual cortex activity in subjects with schizophrenia. Interestingly, postmortem studies of subjects with schizophrenia reported an increased density of neurons in the primary visual cortex (Brodmann's area 17, BA17).

Effect of chronic exposure to antipsychotic medication on cell numbers in the parietal cortex of macaque monkeys.

Both in vivo and post-mortem investigations have demonstrated smaller volumes of the whole brain and of certain brain regions in individuals with schizophrenia. It is unclear to what degree such smaller volumes are due to the illness or to the effects of antipsychotic medication treatment. Indeed, we recently reported that chronic exposure of macaque monkeys to haloperidol or olanzapine, at doses producing plasma levels in the therapeutic range in schizophrenia subjects, was associated with significantly smaller total brain weight and volume, including an 11.

Mapping auditory core, lateral belt, and parabelt cortices in the human superior temporal gyrus.

The goal of the present study was to determine whether the architectonic criteria used to identify the core, lateral belt, and parabelt auditory cortices in macaque monkeys (Macaca fascicularis) could be used to identify homologous regions in humans (Homo sapiens). Current evidence indicates that auditory cortex in humans, as in monkeys, is located on the superior temporal gyrus (STG), and is functionally and structurally altered in illnesses such as schizophrenia and Alzheimer's disease. In this study, we used serial sets of adjacent sections processed for Nissl substance, acetylcholinesterase, and parvalbumin to identify the distinguishing cyto- and chemoarchitectonic features of the core, lateral belt, and parabelt in monkey.

The influence of chronic exposure to antipsychotic medications on brain size before and after tissue fixation: a comparison of haloperidol and olanzapine in macaque monkeys.

It is unclear to what degree antipsychotic therapy confounds longitudinal imaging studies and post-mortem studies of subjects with schizophrenia. To investigate this problem, we developed a non-human primate model of chronic antipsychotic exposure. Three groups of six macaque monkeys each were exposed to oral haloperidol, olanzapine or sham for a 17-27 month period.

Stereological analysis of the mediodorsal thalamic nucleus in schizophrenia: volume, neuron number, and cell types.

The mediodorsal thalamic nucleus (MD) is the principal relay nucleus for the prefrontal cortex, a brain region thought to be dysfunctional in schizophrenia. Several, but not all, postmortem studies of the MD in schizophrenia have reported decreased volume and total neuronal number. However, it is not clear whether the findings are specific for schizophrenia nor is it known which subtypes of thalamic neurons are affected.