No change in neuron numbers in the dentate nucleus of patients with schizophrenia estimated with a new stereological method – the smooth fractionator

The dentate nucleus is phylogenetically the most recent nucleus in the cerebellum. Owing to its connections to the thalamus and the prefrontal cortex it may be involved in the symptomathology in schizophrenia and other psychiatric illnesses. In this stereological study we implemented the smooth fractionator, which combines the unbiased principles of the optical fractionator with a new and more efficient sampling strategy to the dentate nucleus. The smooth fractionator represents the most efficient sampling strategy described so far in stereology, in terms of reducing the sampling variance and thus increasing the efficiency. It is the first application of the smooth fractionator to human brain tissue and presents estimations of total number of neurons in the dentate nuclei of eight patients with schizophrenia compared to eight control persons. The total number of neurons in the dentate nucleus was estimated to 3.36 × 106 in subjects with schizophrenia, which was not statistically significant different from 3.65 × 106 in control subjects (P = 0.63). The advantages and disadvantages of the smooth fractionator method are discussed and its precision in practical application is estimated.

[1]  H. Gundersen.  Stereology of arbitrary particles * , 1986, Journal of microscopy.

[2]  D. Pandya,et al.  Prefrontal cortex projections to the basilar pons in rhesus monkey: implications for the cerebellar contribution to higher function , 1995, Neuroscience Letters.

[3]  L M Cruz-Orive,et al.  Estimation of surface area from vertical sections , 1986, Journal of microscopy.

[4]  R. Passingham.  Changes in the size and organisation of the brain in man and his ancestors. , 1975, Brain, behavior and evolution.

[5]  H. Nasrallah,et al.  Perinatal brain injury and cerebellar vermal lobules I–X in schizophrenia , 1991, Biological Psychiatry.

[6]  H. J. G. GUNDERSEN,et al.  Some new, simple and efficient stereological methods and their use in pathological research and diagnosis , 1988, APMIS : acta pathologica, microbiologica, et immunologica Scandinavica.

[7]  Bente Pakkenberg,et al.  Stereological quantitation in cerebella from people with schizophrenia , 2003, British Journal of Psychiatry.

[8]  B. Bogerts,et al.  Increased number of nitric oxide synthase immunoreactive Purkinje cells and dentate nucleus neurons in schizophrenia , 2001, Journal of neurocytology.

[9]  A. L. Leiner,et al.  Cognitive and language functions of the human cerebellum , 1993, Trends in Neurosciences.

[10]  H. Gundersen,et al.  Unbiased stereological estimation of the total number of neurons in the subdivisions of the rat hippocampus using the optical fractionator , 1991, The Anatomical record.

[11]  N C Andreasen,et al.  Schizophrenia and cognitive dysmetria: a positron-emission tomography study of dysfunctional prefrontal-thalamic-cerebellar circuitry. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[12]  E. Bleuler,et al.  Dementia praecox oder Gruppe der Schizophrenien , 1911 .

[13]  T F Bendtsen,et al.  Stereological estimation of the total number of ECL cells and related parameters using the smooth, vertical fractionator in the rat oxyntic mucosa , 2002, Journal of microscopy.

[14]  J. Schmahmann.  An emerging concept. The cerebellar contribution to higher function. , 1991, Archives of neurology.

[15]  H. Braak,et al.  Morphological studies of local circuit neurons in the cerebellar dentate nucleus of man. , 1983, Human neurobiology.

[16]  H. Gundersen,et al.  The efficiency of systematic sampling in stereology — reconsidered , 1999, Journal of microscopy.

[17]  J. Kleinman,et al.  Cerebellar pathology in schizophrenia: a controlled postmortem study. , 1980, The American journal of psychiatry.

[18]  H J Gundersen,et al.  Pronounced loss of cell nuclei and anisotropic deformation of thick sections. , 1999, Journal of microscopy.

[19]  A. L. Leiner,et al.  Reappraising the cerebellum: what does the hindbrain contribute to the forebrain? , 1989, Behavioral neuroscience.

[20]  P. Strick,et al.  Activation of a cerebellar output nucleus during cognitive processing. , 1994, Science.

[21]  S. Paradiso,et al.  "Cognitive dysmetria" as an integrative theory of schizophrenia: a dysfunction in cortical-subcortical-cerebellar circuitry? , 1998, Schizophrenia bulletin.

[22]  Christopher S von Bartheld,et al.  Differential tissue shrinkage and compression in the z-axis: implications for optical disector counting in vibratome-, plastic- and cryosections , 2003, Journal of Neuroscience Methods.

[23]  R L Sidman,et al.  Histogenesis of cortical layers in human cerebellum, particularly the lamina dissecans , 1970, The Journal of comparative neurology.

[24]  Damentia Precox.  Damentia Præcox and Paraphrenia , 1920, The Indian Medical Gazette.

[25]  H J G Gundersen,et al.  The smooth fractionator , 2002, Journal of microscopy.

[26]  A. L. Leiner,et al.  The human cerebro-cerebellar system: its computing, cognitive, and language skills , 1991, Behavioural Brain Research.

[27]  M. Reyes,et al.  CEREBELLAR VERMIS IN SCHIZOPHRENIA , 1981, The Lancet.

[28]  B. Pakkenberg,et al.  Pronounced reduction of total neuron number in mediodorsal thalamic nucleus and nucleus accumbens in schizophrenics. , 1990, Archives of general psychiatry.

[29]  B. Pakkenberg,et al.  A quantitative study of the human cerebellum with unbiased stereological techniques , 1992, The Journal of comparative neurology.

[30]  T. Hyde,et al.  Neuropathology of the cerebellum in schizophrenia—An update: 1996 and future directions , 1997, Biological Psychiatry.

[31]  J R Nyengaard,et al.  Tissue shrinkage and unbiased stereological estimation of particle number and size * , 2001, Journal of microscopy.

[32]  D. Jeste,et al.  Cerebellar pathology in schizophrenia? a neuronometric study , 1986, Biological Psychiatry.

[33]  P. Strick,et al.  Anatomical evidence for cerebellar and basal ganglia involvement in higher cognitive function. , 1994, Science.