6. Application for analysis of architectural changes of human cortex in schizophrenia
In our preliminary study conducted between 1992 and 1994, statistically significant differences were demonstrated between normal control group and schizophrenia patients group, even though group size was small (3 and 4 cases respectively). That could be explained by big volume of scanned tissue in each case, between 30 and 50 mm.sq.
Below is a brief report of major results.
Fig. 15. Profile comparison for CB- and PV-immunoreactive neuronal populations.
Fig. 16. P-values of the differences between normal control and schizophrenia patients can used to to determine depth zone of the cortical profile with statistically significant neuronal deficit.
Fig. 17. As above, the same approach was used to determine zones of abnormal density of specific immunoreactive neuronal sub-populations. Clearly, relative depth of these zones match first three zones in Fig. 16 above.
Even though presented results speak for themselves, applications for grant money to conduct this research on larger scale was denied by NIH and some other funding agencies four times in a row in 1992 and 1994.
To show more evidence of how it worked (or, rather, how it did not work), I would like to present a quote from page 3 of the “Summary Statement” regarding one of these grant applications dated March, 1992:
“Third, a further limitation comes from the relative nature of two of the morphometric variables selected, namely area or volume fraction and numerical density. Both of these variables are affected not only by the differences in t he immunostained neuronal size and number but also by any differential tissue volume changes whether antemortem or postmortem. Furthermore, the numerical density of immunostained neurons is affected not only by differences in number but also by immunostained area size and shape differences. Both of these limitations make the interpretation of any results in terms of actual neurons highly questionable.” (Chair of the review Committee – J.M.Musacchio, MD, SRA – R.E.Martenson, Ph.D.)
Why these people decided that actual neuronal number was even necessary to consider is still impossible to understand. I personally think that they had no idea what they were talking about. Obviously, 25 years ago automatic image processing was very poorly understood, and even today people have problems with understanding stereological data (see “GLI story”). The grant was given 315 priority score, with no chance to be funded. So, due to the lack of funding I had to stop my research in early 1995 and leave Mount Sinai to pursue similar opportunities in industrial areas.
As far as I know, the existence of PV-immunoreactve subpopulation deficit in schizophrenia was reported four years later by some group in Japan. However, systematic large-scale evaluation of cytoarchitectonic differences in human neocortex in schizophrenia using automatic image analysis technology was never implemented till present time.
It is useless to say, that the grant money was awarded to a guy who proposed to manually outline 100 neurons per sample, and to do basically the same research in a different brain region (thalamus). I followed his results, which were zero. Never mind: as you see, I continue this research now, on a smaller scale, of course. Better late than never…